Nucleophilic reactions aryne intermediates

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. 

Aryl halides in which electron-withdrawing groups activate the halogen atom to nucleophilic displacement react directly with ammonia to produce amines. Non-activated aryl halides yield amines on reaction with sodamide through the intermediacy of an aryne intermediate (see Chapter 9). 

The aryne intermediate is usually written with a triple bond and a delocalized aromatic system, as shown in 3-44. The anion in the side chain reacts as a nucleophile with the electrophilic aryne. The resulting anion, 3-45, can remove a proton from ammonia to give 3-46. Because the product has been reached, we usually stop writing the reaction mechanism at this point. However, in the reaction mixture, amide will remove a proton from the carbon a to the cyano group of 3-46. Only during workup will the anion be protonated to give back 3-46. 

Aryl triflates 35, generated from the corresponding phenols, react with lithium diisopropylamide (EDA) in diisopropylamine (DIA) to give 36 in good yield. The reaction was demonstrated (via substitution pattern in the products) to proceed via an aryne intermediate. The choice of LDA as the base is critical BuLi, NaNH2, sodium acetylide and 2-lithiofuran all failed to generate an aryne from 35 (R = p- h). Application of the method to other nucleophiles than DIA, or to cycloadditions, has not yet been demonstrated. 

Although there are some mechanistic uncertainties, there is evidence that the reaction occurs via two successively formed arynes produced after metal-halogen exchange at both iodines. If arynes were formed independently at each halogen pair, one would expect a mixture of m- and p-terphenyls as products. It is thought that the regioselectivity in the nucleophilic additions to aryne intermediates 638 and 639 is a consequence of the need to keep the two carbanionic sites on the benzene ring remote (i.e. para) to each other. 

The main reactions currently used belong either to nucleophilic or to electrophilic substitutions, the latter, especially iododemetallation, being widely used. Some reactions have lost the interest of radiochemists, such as electrophilic addition, S l, S L or passage through an aryne intermediate. 

Since the aryllithiums are highly polar and very strong bases, several side-reactions are possible. Certain aryl halides can undergo the elimination of HX to generate the aryne intermediates that may produce an isomeric biaryl via nucleophilic addition to the adjacent carbon atom, Scheme 4. 

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 second example of a cine-substitution of a thiophene involves the reaction of arylthiolates with 3,4-dinitrothiophene (331) or 3-nitro-4-phenylsul-fonylthiophene (332) to give the 2,4-substituted products 333. Both an elimination-addition mechanism via the aryne (334) or an abnormal addition-elimination (AEa) mechanism (Section II.2.A.e) via the Meisenheimer complex (335) have been considered for these reactions. The former is unlikely for several reasons including the lack of precedence for aryne formation from aryl nitro compounds (Section II. 1) under these reaction conditions and the fact that addition of the nucleophile ArS" to the aryne (334) would have to proceed via the 3-thienyl anion (336) rather than via a more stable 2-thienyl anion such as 320 as would be expected. Contrariwise, cine-substitution by the AEa mechanism is favored by the ability of the complex (335) to stabilize the negative charge by delocalization to both the NO2 group and the a position of the thiophene ring." As in the pyrrole series (Section III.2.B) the actual mechanism appears to be more complex, however, involving several addition and elimination steps via 337, which was recently isolated from the reaction (X = NO2) and shown to go to the product 333 under the reaction conditions. It therefore appears that neither of the cine-substitutions of thiophene described in this Section proceeds via an aryne intermediate. 

Reaction of chlorotriaryl derivatives with potassium diisopropylamide have been reported to give alkyl-shifted phenazine derivatives by either intramolecular nucleophilic attack on an aryne intermediate leading to a zwitterionic intermediate and alkyl transfer via a 5-endo-tet process or via a Smiles rearrangement (Scheme 193). ... 

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