Halides, aryl reaction with strong bases

Arynes are generated from aryl halides by reaction with strong bases. The final outcome of the reaction is substitution of the halide. 

The reaction of strong bases with aryl halides results in the generation of an aryne through loss of HX, Arynes can also be formed by reaction of aryl halides with lithium and organolithium compounds. 

The reactions of unactivated aryl halides with strong bases or at high temperatures, which proceed via benzyne, are finding increasing synthetic importance. The Dow process, which has been used for many years in the manufacture of phenol (Sec. 24.4), turns out to be what Bunnett (p. 478) calls benzyne chemistry on the tonnage scale ... 

One piece of evidence for this mechanism is that the reaction of strong bases with o- and m-substituted aryl halides gives a mixture of products resulting from substitution both at the C bearing the leaving group and at its next-door neighbor. Neither the addition-elimination mechanism nor the SrnI mechanism can account for this observation. 

The reaction of strong bases with aryl halides results in the gen- ... 

Although steric hindrance of aryl halides is not a major factor for the formation of substituted biaryls, low yields resulted when ortfto-disnbstituted arylboronic acids were used. For example, the reaction with mesitylboronic acid proceeds slowly because of steric hindrance during the transmetallation to Pd(II) halide. The addition of strong bases, for example, aqueous NaOH or Ba(OH>2, both in benzene and DME exerts a remarkable effect on the acceleration of the coupling rate (Scheme 6). ... 

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 henzyne. 

Benzyne is formed as a reactive intermediate in the reaction of aryl halides with very strong bases such as potassium amide... 

Alkyltriphenylphosphonium halides are only weakly acidic, and a strong base must be used for deprotonation. Possibilities include organolithium reagents, the anion of dimethyl sulfoxide, and amide ion or substituted amide anions, such as LDA or NaHMDS. The ylides are not normally isolated, so the reaction is carried out either with the carbonyl compound present or with it added immediately after ylide formation. Ylides with nonpolar substituents, e.g., R = H, alkyl, aryl, are quite reactive toward both ketones and aldehydes. Ylides having an a-EWG substituent, such as alkoxycarbonyl or acyl, are less reactive and are called stabilized ylides. 

Very strong bases such as NaNH2 convert unactivated aryl halides into benzyne intermediates which react rapidly with nucleophiles to form the products of an apparently simple nucleophilic substitution. It is now clear that hetarynes are frequent intermediates in reactions of not too highly activated heteroaromatic halides. 

The reactivities of aryl halides, such as the halobenzenes, are exceedingly low toward nucleophilic reagents that normally effect displacements with alkyl halides and activated aryl halides. Substitutions do occur under forcing conditions of either high temperatures or very strong bases. For example, chlorobenzene reacts with sodium hydroxide solution at temperatures around 340° and this reaction was once an important commercial process for the production of benzenol (phenol) ... 

Mechanistic features of SNAr displacement reactions involving amino nucleophiles have been the object of many investigations, a major point of interest being the occurrence of base-catalyzed paths. Strongly activated aryl halides react readily with ammonia and with primary and secondary amines to give the corresponding arylamines. Thus, for example, 2,4-dinitrofluorobenzene is used to tag the amino end of a peptide or protein chain. 

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. 

Aryl chlorides are more reluctant to participate in amination than most other aryl halides/pseudohalides. To tackle this problem, Caddick et al. examined the effect of palladium-N-heterocyclic carbenes as catalysts in rapid microwave-promoted reactions [87]. Para-tolyl and -anisyl chloride were reacted with aromatic and aliphatic amines in mostly good yields within 6 minutes of heating at 160 °C. Reactions using anisyl, tolyl or phenyl chlorides and aliphatic amines have also been reported by Maes et al. using a phosphine ligand and a strong base, which creates the desired products after 10 minutes of heating at 110-200 °C [88]. 

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