The benzyne mechanism

There is one last mechanism for aromatic nucleophilic substitution and you may well feel that this is the weirdest mechanism you have ever seen with the most unlikely intermediate ever For our part, we hope to convince you that this mechanism is not only possible but useful. 

At the start of the section on Nucleophilic aromatic substitution we said that the displacement of bromide from bromobenzene with hydroxide ion does not occur . That statement is not quite correct. Substitution by hydroxide on bromobenzene can occur but only under the most vigorous conditions—such as when bromobenzene and NaOH are melted together (fused) at very high temperature. A similar reaction with the very powerful reagent NaNH2 (which supplies NH2 ion) also happens, at rather lower temperature. 

These reactions were known for a long time before anyone saw what was happening. They do not happen by an 3 2 mechanism, as we explained at the start of the section, and they can t happen by the addition-elimination mechanism because there is nowhere to put the negative charge in the intermediate. The first clue to the true mechanism is that all the nucleophiles that react in this way 

The carbanion is in an sp orbital in the plane of the ring. Indeed, this intermediate is very similar to the aryl cation intermediate in the Sjsjl mechanism from diazonium salts. That had no electrons in the sp orbital the carbanion has two. 

Why should this proton be removed rather than any other The bromine atom is electronegative and the C-Br bond is in the plane of the sp orbital and removes electrons from it. The stabilization is nonetheless weak and only strong bases will do this reaction. 

As often in aromatic chemistry, it s the versatility of the nitro group that makes this sequence work—easy introduction by electrophilic substitution, easy reduction, and easy nucleophilic substitution of its diazonium derivative. 

The carbanion is in an sp orbital in the plane of the ring. Indeed, this intermediate is very similar to the aryl cation intermediate in the SnI mechanism from diazonium salts. That had no electrons in the sp orbitai the carbanion has two. Why should this proton be removed rather than any other The bromine atom is electronegative and the C—Br bond is in the plane of the sp2 orbital and removes electrons from it. The stabilization is nonetheless weak and only exceptionally strong bases will do this reaction. 

The next step is the ioss of bromide ion in an eiimination reaction. This is the step that is difficult to believe as the intermediate we are proposing iooks impossible. The orbitals are bad for the elimination too—it is a syn- rather than an ci f/-peripianar eiimination. But it happens. 

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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. 

Species such as 5 and 6 are called benzynes (sometimes dehydrobenzenes), or more generally, arynes, and the mechanism is known as the benzyne mechanism. Benzynes are very reactive. Neither benzyne nor any other aryne has yet been isolated under ordinary conditions, but benzyne has been isolated in an argon matrix at 8 where its IR spectrum could be observed. In addition, benzynes can be trapped for example, they undergo the Diels-Alder reaction (see 15-58). It should be noted that the extra pair of electrons does not affect the aromaticity. The... 

To explain the iodo result, it has been proposed that besides the benzyne mechanism, this free radical mechanism is also operating here ... 

Unactivated aryl halides can be converted to amines by the use of NaNH2, NaNHR, or NaNR2. With these reagents, the benzyne mechanism generally operates, so cine substitution is often found. Ring closure has been effected by this type of reaction,for example. 

Problem 11.28 How do the following observations support the benzyne mechanism (a) Compounds lacking ortho H s, such as 2,6-dimethylchlorobenzene, do not react, (t) 2,6-Dideuterobromobenzene reacts more slowly than bromobenzene. (c) o-Bromoanisole, o-CHjOC H Br, reacts with NaNH /NH, to form m-CHjOC H.NHj. 

Unactivated aryl iodides undergo the conversion Arl — ArCHj when treated with tris(diethylamino)sulfonium difluorotrimethylsilicate and a palladium catalyst.131 A number of methods, all catalyzed by palladium complexes, have been used to prepare unsymmetrical biaryls (see also 3-16). In these methods, aryl bromides or iodides are coupled with aryl Grignard reagents,152 with arylboronic acids ArB(OH)2,153 with aryltin compounds Ar-SnR3,154 and with arylmercury compounds.155 Unsymmetrical binaphthyls were synthesized by photochemically stimulated reaction of naphthyl iodides with naphthoxide ions in an SrnI reaction.156 Grignard reagents also couple with aryl halides without a palladium catalyst, by the benzyne mechanism.157 OS VI, 916 65, 108 66, 67. 

However, arylation with such systems will occur with strong bases by the benzyne mechanism (Sections 14-6C and 23-8). 

A variation on the aryne mechanism for nucleophilic aromatic substitution (discussed above, Scheme 2.8) is the SrnI mechanism (see also Chapter 10). Product analysis, with or without radical initiation or radical inhibition, played a crucial role in establishing a radical anion mechanism [21]. The four isomeric bromo- and chloro-trimethylbenzenes (23-X and 25-X, Scheme 2.9) reacted with potassium amide in liquid ammonia, as expected for the benzyne mechanism, giving the same product ratio of 25-NH2/23-NH2 = 1.46. As the benzyne intermediate (24) is unsymmetrical, a 1 1 product ratio is not observed. 

Aromatic compounds are dechlorinated by the general mechanism shown in Sch. 1. Electron transfer to a ir-antibonding orbital forms an aromatic radical anion, which then ejects Cl" to give an aromatic radical. This radical picks up a second electron to give a very basic cx-anion, which abstracts a proton either from NH3 or from a more acidic source like water, when water is present. If water is not present, then an NH2 anion can be formed. The presence of ME can lead to the formation of aminated products via the benzyne mechanism. Aminated products were formed in dry NH3 but not when water was present [24], A further reduction via radical anion formation and proton abstraction can give dihydroaromatics or tetrahydroaromatics, or dimerization may occur. In soils, both water and... 

When electron-withdrawing groups were attached to the aryl halide as in /7-chloro, p-bromo and /7-iodobenzonitriles and 4-bromobenzophenone, most of the reaction with 143 follows the benzyne mechanism, yielding anilines. When the aryl halides were added to a... 

The photostimulated reaction of l-bromo-2,4,6-trimethylbenzene (a substrate with no o-hydrogen atoms in order to avoid the benzyne mechanism) with NH2 ions gave 1-amino-2,4,6-trimethylbenzene (70%) and the reduction product 1,3,5-trimethylbenzene (6%). This reaction did not occur in the dark221. By competition experiments of NH2 ions with Ph2P" ions toward 2,4,6-trimethylphenyl radicals, it was found that Ph2P ions are 6.4 times more reactive than NH2 ions221, whereas NH2 ions are twice more reactive than acetone enolate ions toward the same radical in liquid ammonia222. 

When the photostimulated reaction of equation 188 was carried out in the presence of NH2 ions in liquid ammonia, besides oxindoles 315, products derived from the benzyne mechanism were formed338. However, when the substrate has no o-hydrogens, such as 316 good yields of oxindoles were obtained (equation 189). 

Mechanism of nucleophilic aromatic substitution by elimination addition (the benzyne mechanism). 

After a new (and unusual) mechanism, such as the benzyne mechanism for nucleophilic aromatic substitution, is proposed, experiments are usually designed to test that mechanism. A classic experiment supporting the benzyne mechanism used a radioactive carbon label. Examination of the mechanism shown in Figure 17.6 shows that the carbon bonded to the leaving chlorine and the carbon ortho to it become equivalent in the benzyne intermediate. Consider what would happen if the carbon bonded to the chlorine were a radioactive isotope of carbon (l4C) rather than the normal isotope of carbon (I2C). If we follow the position of the radioactive carbon label through the mechanism of Figure 17.6, we find that the label should be equally distributed between the carbon attached to the amino group in the product and the carbon ortho to it. 

When the experiment was conducted in the laboratory, this is exactly the result that was observed. Although it does not prove the benzyne mechanism, this experiment provides strong evidence supporting it. 

Elimination-Addition (The Benzyne Mechanism) Section 17.12 Figure 17.6... 

These two products can be explained by an elimination-addition mechanism, called the benzyne mechanism because of the unusual intermediate. Sodium amide (or sodium hydroxide in the Dow process) reacts as a base, abstracting a proton. The product is a carbanion with a negative charge and a nonbonding pair of electrons localized in the sp2 orbital that once formed the C—H bond. 

In summary, the benzyne mechanism operates when the halobenzene is unactivated toward nucleophilic aromatic substitution, and forcing conditions are used with a strong base. A two-step elimination forms a reactive benzyne intermediate. Nucleophilic attack, followed by protonation, gives the substituted product. 

The benzyne mechanism (elimination-addition) is likely when the ring has no strong electron-withdrawing groups. It usually requires a powerful base or high temperatures. 

With strong electron-withdrawing groups ortho or para, the addition-elimination mechanism is more likely. Without these activating groups, stronger conditions are required, and the benzyne mechanism is likely. 

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