Radical-nucleophilic aromatic substitution halides

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 However, this synthetic method is outdated and the transfer of amides from tin to palladium will not be discussed.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. 

This equation also describes the overall reaction of either an 5 2 or a nucleophilic aromatic substitution process. In some cases, the only way to distinguish an reaction from these processes is that an is inhibited by radical inhibitors. Another distinguishing feature is that the order of the relative leaving group abilities of halides are opposite that found for nucleophilic aromatic substitution by the addition-elimination mechanism (see Chapter 3). 

One way of carrying out nucleophilic aromatic substitution reactions under mild conditions is the Ar RNl process, which is initiated by (usually, but not necessarily, photoinduced) electron transfer to an aryl halide, e.g., from an enolate Cleavage of the resulting aryl radical anion with loss of a halide anion gives an aryl radical that combines with the enolate, thus forming the desired aryl-carbon bond. 

The mechanism of the reactions of aryl halides cannot occur by the common S 2 patii for the oxidative addition of methyl halides, and most aryl halides lack substituents that would make them sufficiently electrophilic to react by nucleophilic aromatic substitution pathways. As presented in the section on radical pathways for oxidative addition, aryl halides react with metal complexes that readUy imdergo one-electron oxidation by radical mechanisms. However, metal complexes that do not readily undergo one-electron processes tend to react by two-electron mechanisms. Thus, aryl halides typically react with tP" palladium(O) complexes by concerted pathways through three-centered transition states. No strong data for a radical pathway has been gained during the many studies on the oxidative addition of aryl halides to Pd(0). In contrast, evidence that oxidative addition of aryl halides to P, iridium, Vaska-t)q)e complexes occurs by a radical pathway has been published. ... 

Primer and Rosenthal (25) have demonstrated that the reaction of O2 with nitro substituted aromatic halides occurs via an electron transfer from O2 to the substituted benzene to yield the anion radical which is subsequently scavenged by molecular oxygen (equation 26). They were able to distinguish this reaction pathway from direct addition of O2 to the aromatic ring as in normal nucleophilic aromatic substitution by utilizing... 

The best nucleophiles for the SrnI mechanism can make a relatively stable radical in the initiation part, either by resonance (enolates) or by placing the radical on a heavy element (second-row or heavier nucleophiles). The best electrophiles for the SrnI mechanism are able to delocalize the odd electron in the radical anion (aromatic leaving groups, carbonyl compounds), can make a stable radical (3° alkyl halides), and have a weak R-X (Br, I) bond. Tosylates and other pseudohalides are very poor SrnI electrophiles. If light is required for substitution to occur, the mechanism is almost certainly SrnI. 

The addition of the nucleophile to the aryl radical is the reverse of the cleavage of substituted aromatic anion radicals that we have discussed in Section 2 in terms of an intramolecular concerted electron-transfer-bondbreaking process and illustrated with the example of aryl halides. The present reaction may thus be viewed conversely as an intramolecular concerted electron-transfer-bond-forming process. The driving force of the reaction can be divided into three terms as in (131). The first of these, the... 

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