Nucleophilic substitution, aromatic aryne intermediates

A computer-assisted mechanistic evaluation that includes nucleophilic aromatic substitution via aryne intermediates has been developed . 

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. 

Arynes are intermediates in certain reactions of aromatic compounds, especially in some nucleophilic substitution reactions. They are generated by abstraction of atoms or atomic groups from adjacent positions in the nucleus and react as strong electrophiles and as dienophiles in fast addition reactions. An example of a reaction occurring via an aryne is the amination of o-chlorotoluene (1) with potassium amide in liquid ammonia. According to the mechanism given, the intermediate 3-methylbenzyne (2) is first formed and subsequent addition of ammonia to the triple bond yields o-amino-toluene (3) and m-aminotoluene (4). It was found that partial rearrangement of the ortho to the meta isomer actually occurs. 

The intermediate with a triple bond is called benzyne. For substituted aromatic compounds, this type of intermediate is called an aryne. In benzyne, the ends of the triple bond are equivalent, and either can react with a nucleophile. 

The second synthesis of cephalotaxine was reported by Semmelhack and co-workers (24), also in 1972. Their convergent strategy involved the alkylation of spirocycle 49, prepared in several steps from p)nTolidone 45, with p-nitrobenzenesulfonate ester 50, prepared from piperonal in 45-55% overall yield as shown in Scheme 2. The resulting key intermediate, 51a (X = Cl), was converted to ( )-cephalotaxinone (22), initially through an aryne intermediate. Route I, Scheme 3, in 15% yield. Cephalotaxinone was then converted to ( )-cephalotaxine (1) upon reduction with diisobutyl-aluminum hydride. The Semmelhack group expended considerable effort studying the conditions of the nucleophilic aromatic substitution (i.e., 51a-c... 

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... 

In addition to nucleophilic substitution of aromatics by the addition-elimination mechanism, nucleophilic substitution is also possible through the effect of a strong base (BI via an elimination-addition mechanism. Arynes occur as intermediates in such a process. 

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... 

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. 

The first characteristic reaction of arynes to be discovered was the addition of polar species, especially nucleophiles, to the triple bond. Since arynes are bidentate intermediates, such additions could lead to two different products in the event of unsymmetrical substitution in the aryne ring. If, as is often the case for such polar additions, the aryne was generated by elimination of HX from a monosubstituted aromatic compound 126, then the product 127 with the entering group in the position previously occupied by the substituent is called the product of normal or ipso-substitution while the rearranged product 128 is referred to as that of cine-substitution. Should the aryne be generated from the isomeric precursor 129 then the designation of which is the normal... 

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