Aryl halides Arynic substitution

These reactions follow first-order kinetics and proceed with racemisalion if the reaction site is an optically active centre. For alkyl halides nucleophilic substitution proceeds easily primary halides favour Sn2 mechanisms and tertiary halides favour S 1 mechanisms. Aryl halides undergo nucleophilic substitution with difficulty and sometimes involve aryne intermediates. 

Elimination-addition mechanism (Section 23.8) Two-stage mechanism for nucleophilic aromatic substitution. In the first stage, an aryl halide undergoes elimination to form an aryne intermediate. In the second stage, nucleophilic addition to the aryne yields the product of the reaction. 

Aromatic substitution, a quantitative treatment of directive effects in, 1, 35 Aromatic substitution reactions, hydrogen isotope effects in, 2, 163 Aromatic systems, planar and non-planar, 1, 203 Aryl halides and related compounds, photochemistry of, 20, 191 Arynes, mechanisms of formation and reactions at high temperatures, 6, I A-Se2 reactions, developments in the study of, 6,63... 

A variety of substituted aromatic compounds have been prepared through addition of anionic nucleophiles to arynes generated from readily accessible precursors.1 Most of the laboratory preparations start with aryl halides. The coupling yields are usually good to modest (equations 13-15) but can be poor (equation 16).83 Sometimes, a dramatic improvement in reaction efficiency can be achieved by the change of the base/solvent pair or other reaction conditions. For instance, in arylation of phenoxides and benzenethiolates, a switch over to DMSO as the solvent boosted the yield considerably (equation 17).86 Another example, illustrative of this point, is the reaction of N-methylpyrrolidone with aryl halides where an acceptable yield could not be obtained under a variety of conditions except with LICA in THF (equation 18).71... 

Just as in aryl halides, the halogen can be replaced by hydrogen and by a metal, or be involved in transition metal-catalyzed processes (covered in Section 3.2.3.11.2). Three of the mechanisms of such nucleophilic substitutions are familiar from benzene chemistry via arynes, SrnI processes, and Pd(0)-catalyzed sequences. However, of the two further mechanisms of nucleophilic replacement, the ANRORC (Addition of Micleophile, Ring Opening, Ring Closure) is unique to heterocycles, and Sae reactions occur only with strongly activated benzenoid systems. 

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

Some typical reactions of stannylanionoids which result in the formation of a C-Sn bond are shown in Table 4-1. Primary and secondary alkyl halides react mainly by substitution, but tertiary alkyl halides give mainly elimination. Aryl halides can also give arynes through elimination reactions. 

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. 

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