Substitution, nucleophilic benzyne mechanism

Problem 11.29 How is it that the nucleophilic substitution of nitrochlorobenzenes is by addition and elimination, whereas a benzyne mechanism is found with chlorobenzene M... 

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. 

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. 

Mechanism 17-8 Nucleophilic Aromatic Substitution (Benzyne Mechanism) 789... 

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. 

As exemplified by equation (2), the Perkin condensation of o-hydroxybenzaldehydes is an important method for the synthesis of substituted coumarins. An interesting variation on this procedure has been reported recently. Heating a mixture of o-fluorobenzaldehyde, 2-thiopheneacetic acid, acetic anhydride and triethylamine affords directly the coumarin (20 equation 13) instead of the expected cinnamic acid (21). The reaction proceeds similarly with several arylacetic acids. The reaction presumably proceeds through the cinnamic acids (21). The observed product can conceivably arise by direct nucleophilic displacement involving the carboxylate or by an elimination/addition (benzyne) mechanism. The authors note that when 2-fluorobenzaldehyde is replaced by its 2-bromo analog in this reaction, the substituted cinnamic acid (22) is the major product and the corresponding coumarin (20) is obtained only in low yield. It is suggested that since it is known that fluoride is displaced more rapidly in nucleophilic aromatic substitution reactions, while bromo aromatic compounds form benzynes more rapidly, this result is consistent with a nucleophilic displacement mechanism. 

The presence of strong electron-withdrawing groups such as NO2 ortho or para to a potential leaving group favors nucleophilic aromatic substitution by the addition-elimination mechanism. Without such groups in these positions, the benzyne mechanism is favored. 

The benzyne mechanism can be denoted as an Sn(EA) (substitution nucleophilic elimination addition) reaction (reference 7). 

Just as the benzyne mechanism was proposed in order to explain apparent anomalies in reactions considered initially to be SNAr reactions, another mechanism for nucleophilic aromatic substitution was developed because of results of studies under conditions in which the benzyne mechanism was expected. Kim and Burmett investigated the reaction of halogen-substituted isomers of pseudocumene (1,2,4-trimethylbenzene, 94) with KNH2 in liquid NH3. ° As shown in Figure 8.68, ehmination of HX from both the 5-halo-pseudocumenes (95a,b,c) and the 6-halopseudociunenes (96a,b,c) should produce the same aryne intermediate, 97. Therefore, the distribution of... 

The S,jAr reaction is circumscribed by the major mechanisms of nucleophilic aromatic substitution the most common S, Ar addition-ehmination (Chapter 6), the oxidative nucleophilic aromatic substitution of hydrogen (ONSH Chapter 11), the benzyne mechanism (Chapter 12), and the radical-nucleophilic aromatic substitution Sj j l (Chapter 10). The chiral inductor can be bonded (Section 8.2) or nonbonded to the reactants (Section 8.3) (Scheme 8.1). 

The Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution Benzyne... 

THE ELIMINATION-ADDITION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION BENZYNE... 

Nucleophilic aromatic substitution can also occur by an elimination-addition mechanism This pathway is followed when the nucleophile is an exceptionally strong base such as amide ion m the form of sodium amide (NaNH2) or potassium amide (KNH2) Benzyne and related arynes are intermediates m nucleophilic aromatic substitutions that pro ceed by the elimination-addition mechanism... 

Although nucleophilic aromatic substitution by the elimination-addition mechanism is most commonly seen with very strong amide bases, it also occurs with bases such as hydroxide ion at high temperatures. A " C-labeling study revealed that hydrolysis of chlorobenzene proceeds by way of a benzyne intennediate. 

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