Benzyne carbanion intermediates

The Dow Process utilizes an elimination/addition reaction to convert chlorobenzene to phenol. The proposed mechanism for this reaction is shown in Figure 8-3. The high-temperature reaction begins with chlorobenzene and aqueous sodium hydroxide. Note that this mechanism starts with the hydroxide attacking as a base, beginning dehydrohalogenation to form benzyne. The second hydroxide ion attacks as a nucleophile to form a carbanion intermediate, which behaves as a base in the last step to yield the final product. 

The preceding explanation would seem to explain most of the data in Table 8.21, but there is one apparent discrepancy. We might have expected the methoxy substituent to be electron-donating, but it gives the same product orientation as does trifluoromethyl. This intuitive expectation of the substituent effect of methoxy is based primarily on its influence on electrophilic aromatic substitution (SeAr) and on nucleophilic aromatic substitution (SwAr) reactions, both of which involve attachment of a species to an aromatic ring to form a cr complex. In contrast, the carbanionic intermediates presumed to be formed in the benzyne reaction have the nonbonded pair of electrons in... 

Nucleophilic addition of amide ion to a carbon of the benzyne triple bond gives a carbanion intermediate. Addition to either carbon of the triple bond is possible. 

It has been found that aryl groups can also be introduced into the a-position of sulphoxides. Corey and Chaykovsky have demonstrated that chlorobenzene reacts at room temperature with an excess of sodium methylsulphinyl carbanion to give methyl benzyl sulphoxide in 41% yield. The authors believe that a benzyne intermediate may be involved in the reaction400,401 (equation 174). 

A route based on a benzyne intermediate can afford the isoindole ring via a category lb process. iV-Cyanomethyl-Af-methyl-0-chlorobenzylamine cyclizes to 1-methylisoindole under the influence of potassium amide in liquid ammonia (equation 36) (77T581). The cyano group plays two important roles. First, it provides stabilization of the carbanion... 

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. 

The carbanion can expel bromide ion to become a neutral species. As bromide leaves with its bonding electrons, an empty sp2 orbital remains. This orbital overlaps with the filled orbital adjacent to it, giving additional bonding between these two carbon atoms. The two sp2 orbitals are directed 60° away from each other, so their overlap is not very effective. This reactive intermediate is called a benzyne because it can be symbolized by drawing a triple bond between these two carbon atoms. Triple bonds are usually linear, however, so this is a very reactive, highly strained triple bond. 

Step 2 The carbanion expels the leaving group to give a benzyne intermediate. 

Chapter 2 includes complete discussion on reaction intermediates including carboca-tions, carbanions, free radicals, carbenes, nitrines and benzynes. The structure, methods of generation and important reactions of all the intermediates are discussed in this chapter. The author has emphasized on their applications in the asymmetric synthesis. 

The Kametani group has made considerable use of the intramolecular trapping of benzynes by pendant carbanion centers. The nitrile (133) is a key and versatile intermediate in many of the K etani studies, including the preparation of optically pure estradiol. The ester of the benzocyclobutenecarboxylic acid (134) was prepared by a similar benzyne cyclization. The acid (134) was converted via oxidative decarboxylation and HCl hydrolysis to the very labile tra/t5-2-arylbenzocyclobutenol (135), which was used in the preparation of p ophyllotoxin. ... 

Nor shall we discuss reactions of highly reactive intermediates such as carbocations, carbanions, ketenes (such as 14), or benzynes that are always prepared in the presence of the molecule with which they are to react. This 2 + 2 ketene cycloaddition 15 actually involves three steps but the ketene is very reactive and cyclopentadiene must be present when it is formed if a good yield of the important adduct 16 is to be had. 

When an unactivated aryl halide (333) is treated with a very strong base, an elimination reaction is possible that generates an intermediate called a benzyne (336). Benzyne is electron deficient and will be attacked by nucleophiles in a reaction that opens the Jt bond not part of the aromatic cloud, and produces a new carbanion (337). Protonation completes the sequence to give the aromatic substitution product 338. 

In solution, benzyne and its derivatives are strained, short-lived intermediates which react with a broad array of nucleophiles, including carbanions, amines, alcohols and their salts, water, and even ethers. They also undergo pericyclic reactions such as Diels-Alder cycloadditions, 1,3-dipolar cycloadditions or ene reactions. The instability of benzyne and its derivatives is due to the strain caused by the deformation of the linear geometry of the formal sp-hybridized carbons of the triple bond to the angles close to 120° imposed by the ring geometry [2,3]. 

Two different benzyne intermediates can be formed by reaction of meta-substituted halobenzenes, but we expect a lower activation energy (and therefore faster reaction and thus more product) for the pathway involving benzyne formation via the more stable carbanion. Therefore, if R is electron-donating, the proton para to R will be removed faster by amide ion, as shown in Figure 8.63. If R is electron-withdrawing, then the carbanion with the... 

Removal of the proton at C-2, giving a carbanion species in which the lithium is stabilised by chelation to the adjacent nitrogen and chlorine atoms, is followed by P- elimination of chloride. This gives the benzyne intermediate directly. 

Eliminations to create alkenes can occur from neutral structures, or they can involve car-benium ions, carbanions, or radical intermediates. We look at all these possibilities below within the context of aliphatic systems. Although eliminations can occur on alkenes to make alkynes and on arenes (see the benzyne reaction. Section 10.20), we concentrate our discussion on aliphatics, because this is the most common type of system to undergo elimination. Before looking at the details, let s review the E2 and El mechanisms and electron pushing, and define the terms "1,2-elimination", "1,4-elimination", and "p-elimination". 

Many other species are stabilized in 18-electron organometallic complexes car-benes and carbynes, enyls and polyenyls (XL ligands), o-xylylene (o-quinodime-thane), trimethylenemethane, benzyne, norbornadiene-7-one, cyclohexyne, 1,2-di-hydropyridines (intermediates in biological processes), thermodynamically unfavorable organic tautomers such as vinyl alcohols [less stable by 14 kcafrmol (58.5 kJ mol ) than their aldehyde tautomers], aromatic anions resulting from deprotonation in juxta-cyclic position such as tautomers of phenolates and benzylic carbanions. All these species have a specific reactivity that can lead to synthetic applications in the same way as cyclobutadiene above. 

---