Aryne intermediates, nucleophilic substitution

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. 

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 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... 

With 3-halopyridines, the nucleophilic substitution takes place by an aryne mechanism. For instance, reaction of 3-chloropyridine with KNH2 in liquid NH3 yields a mixture of 3- and 4-aminopyridine, which is indicative of a 3,4-dehydropyridine ( hetaryne ) as an intermediate (for comparison, cf. p 279). 

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. 

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

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. 

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. 

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. 

The aryne 533 was also considered and rejected as an intermediate in the nucleophilic substitution of 5-halothiazoles (538) based on the following evidence only normal substitution to 539 is obtained, inconsistent with the expected formation of 535 from the aryne 533 as described above no exchange of the 4-proton is observed the reactivity of the 4-phenyl derivative 540, which cannot form the aryne 533, is similar to that of 538 and finally no aryne... 

Different carbon- or heteroatom-centered nucleophilic positions a-bonded to a suitable electrophilic functionality can undergo facile cleavage by adding to arynes and by further intramolecular nucleophilic substitution in the initially formed aryl anion or zwitterion intermediate. The overall process results in the insertion of an aryne into a nucleophilic-electrophilic o-bond. 

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