Benzyne substituted, reactions

Bromobenzyl 2-fluorophenyl thioether, derived from 2-fluorothiophenol and 2-bromobenzyl bromide, is a source of a benzyne through reaction with /-butyllithium. Simultaneously, the bromobenzyl moiety generates the tethered aryllithium 405 and an intramolecular anionic cyclisation is promoted. The sequence is completed by the addition of an electrophilic species leading to 1-substituted b/Z-dibenzol //]thiopyrans (Scheme 121) <2002CEJ2034>. 

Benzyne produced from the zwitterion can also be captured by dienes in a Diels—Alder reaction (see Chapter 35). But this merely shows that benzyne can exist for a short time. It does not at all prove that benzyne is an intermediate in aromatic substitution reactions. Fortunately, there is very convincing evidence for this as well. 

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. 

An unusual reaction occurs with aromatic halides and very strong bases the substitution reaction can go via elimination to the highly reactive benzyne followed by addition, path E2 then AdN2. 

As exemplified by equation (2), the Perkin condensation of o-hydroxybenzaldehydes is an important method for the synthesis of substituted coumarins. An interesting variation on this procedure has been reported recently. Heating a mixture of o-fluorobenzaldehyde, 2-thiopheneacetic acid, acetic anhydride and triethylamine affords directly the coumarin (20 equation 13) instead of the expected cinnamic acid (21). The reaction proceeds similarly with several arylacetic acids. The reaction presumably proceeds through the cinnamic acids (21). The observed product can conceivably arise by direct nucleophilic displacement involving the carboxylate or by an elimination/addition (benzyne) mechanism. The authors note that when 2-fluorobenzaldehyde is replaced by its 2-bromo analog in this reaction, the substituted cinnamic acid (22) is the major product and the corresponding coumarin (20) is obtained only in low yield. It is suggested that since it is known that fluoride is displaced more rapidly in nucleophilic aromatic substitution reactions, while bromo aromatic compounds form benzynes more rapidly, this result is consistent with a nucleophilic displacement mechanism. 

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. 

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. 

In the presence of a strong base, an aryl halide undergoes a nucleophilic substitution reaction via a benzyne intermediate. After a hydrogen halide is eliminated, the nucleophile can attack either of the carbons of the distorted triple bond in benzyne. Direct substitution is substitution at the carbon that was attached to the leaving group cine substitution is substitution at the adjacent carbon. 

Aromatic substitution reactions that proceed by the elimination-addition mechanism are not widely used synthetically, as a very strong base (pIsTb — 35) is required to generate the aryne intermediate by /3-elimination of HX. In addition, there is regiochemical ambiguity for unsymmetrical aryl halides. Even benzyne itself is much more readily prepared by several other methods. 

The intermediacy of benzyne in the elimination-addition mechanism for aryl halides accounts for the regioselectivity observed in the substitution reactions of labeled chlorobenzene and 6>-bromotoluene because both can give only a single aryne intermediate. Attack at either of the aryne carbons gives rise to the products. 

Arynes are structures having an additional bond in an aromatic ring. The classic aryne is benzyne (51)/ which is thought to be an intermediate in some substitution reactions (Chapter 8). Pyridyne (52) has also been de-tected. ... 

Wu, Sha, and coworkers found that aziridines react with benzyne to give novel spiroindoles (Scheme 9, equation 1) [34], The products are [4+2] dimers of l-benzyl-2-methyl-eneindolin-3-one. Similar compounds were obtained using Af-substituted aziridines and substituted benzynes. This reaction did not occur with KF or TBAF instead, a-fluoro-p-amino acid derivatives were the products. When water was present, the intermediate aziridinium ion-aryl... 

Benzyne is highly electrophilic, and is readily attacked by nucleophiles, in this case dimethylcuprate. The resulting anion is trapped by allyl bromide (as an electrophile) in a nucleophilic substitution reaction. 

In addition to the SNAr mechanism, several other mechanisms are known for nucleophilic aromatic substitutions. For example, an SnI mechanism is relevant for nucleophilic substitution reactions which encounter aromatic diazonium salts. Radical-nucleophilic aromatic substitutions (SrnI) are known in reactions where no electron-withdrawing group is available, whereas a mechanism via a benzyne intermediate is of relevance for substitutions employing NHJ as a nucleophile. 

Another substitution reaction that occurs on aromatic rings in the presence of nucleophiles involves the intermediacy of benzyne. Benzyne is benzene minus two adjacent hydrogens, producing a formal triple bond (C6H4). The structure of benzyne has been examined both experimentally and theoretically, and the alkyne representation is most widely accepted, although the cummulene and biradical structures are significant resonance contributors. 

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. 

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). 

We have already briefly considered substitution reactions involving benzyne intermediates in Chapter 10, when we focused on the eUmination process. To have a substitution reaction, overall we need to have elimination, followed by addition (Figure 13.22). We should note that because the rate-hmiting step of the process is elimination, it s crucial that we use a very strong base, such as sodamide, Na+[NH2] . 

The neat resin preparation for PPS is quite compHcated, despite the fact that the overall polymerization reaction appears to be simple. Several commercial PPS polymerization processes that feature some steps in common have been described (1,2). At least three different mechanisms have been pubUshed in an attempt to describe the basic reaction of a sodium sulfide equivalent and -dichlorobenzene these are S Ar (13,16,19), radical cation (20,21), and Buimett s (22) Sj l radical anion (23—25) mechanisms. The benzyne mechanism was ruled out (16) based on the observation that the para-substitution pattern of the monomer, -dichlorobenzene, is retained in the repeating unit of the polymer. Demonstration that the step-growth polymerization of sodium sulfide and /)-dichlorohenzene proceeds via the S Ar mechanism is fairly recent (1991) (26). Eurther complexity in the polymerization is the incorporation of comonomers that alter the polymer stmcture, thereby modifying the properties of the polymer. Additionally, post-polymerization treatments can be utilized, which modify the properties of the polymer. Preparation of the neat resin is an area of significant latitude and extreme importance for the end user. 

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