Arynes

Finally, reference must be made to benzyne and other arynes. Something of their history may be gleaned from the autobiography of R. Huisgen, whose research on 

The most recent review is by Kauffmann and Wirthwein in 1971 but intentionally slights five-membered hetarynes with one heteroatom in favor of their six-membered homologs. With the exception of Hoffmann s classic monograph on arynes in 1967, reviews devoted to general aryne chemistry tend to neglect hetarynes. Considering the recent activity in this field it seems appropriate to review five-membered hetarynes at this time both as a summary of past research and as a stimulus to future research in this area. An attempt has been made to cover all pertinent literature and unpublished observations available to the author as of December 1981.  

The function of structural formulas and nomenclature is to unambiguously specify and characterize a molecular species without implying more than is justified by experimental fact about the structure and properties of the species. This task is particularly difficult for reactive intermediates and hence necessitates this preliminary discussion. 

Although not formally arynes those species whose reactive orbitals are on nonadjacent atoms are usually considered in the same category of reactive intermediates. For such species as 2 or 3, a diradical notation, 2a or 3a, will be used rather than the bonded structures, 2b or 3b, since the latter have been shown to be distinguishably different entities. 

Generic nomenclature for arynes simply replaces the final ene of the parent aromatic hydrocarbon with the suffix yne, i.e., benzene becomes ben-zyne, naphthalene becomes naphthalyne, etc. The ambiguity which arises with the possibility of isomeric intermediates can be clarified either with the usual prefixes or preferably by numbers. Hence 1 is called benzyne, or Ao-benzyne, or 1,2-benzyne, while 2 becomes meta- or 1,3-benzyne and 3 para- or 1,4-benzyne. 

The unwarranted structural implication associated with the suffix yne is eliminated by the dehydro system of nomenclature in which 1 becomes 1,2-dehydrobenzene, 2, 1,3-dehydrobenzene, and 3, 1,4-dehydrobenzene. This seems to be the most popular nomenclature because of its lack of ambiguity and connotation as well as its use in the definitive monograph in the field. 

The most common aryne is based on benzene itself, although all aromatic and heteroaromatic systems can potentially give similar species. The need to postulate a 

Reactive Intermediates in Or mic ChemistrY Structure, Mechanism, and Reactions, First Edition. 

Hoffman, Dehydrobeozene and Cydoalkynes, Academic Press, New York (1967) 

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Nucleophilic substitution of benzene itself is not possible but the halogeno derivatives undergo nucleophilic displacement or elimination reactions (see arynes). Substituents located in the 1,2 positions are called ortho- 1,3 meta- and 1,4 para-. 

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. 

Once the intermediacy of an aryne intermediate was established the reason for the observed regioselectivity of substitution mo m and p chlorotoluene became evident Only a single aryne intermediate may be formed from o chlorotoluene but this aryne yields a mixture containing comparable amounts of o and m methylanilme... 

Similarly p chlorotoluene gives a single aryne and this aryne gives a mixture of m and p methylanilme... 

Two isomeric arynes give the three isomeric substitution products formed from m chloro toluene... 

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... 

Aryne (Section 23 8) A species that contains a triple bond within an aromatic nng (see benzyne)... 

An unusual case of addition of a carbanion to an unconjugated carbon-carbon double bond is shown in Scheme 47a. The subsequent transfer of the amide group is also noteworthy (80CC1042). The intramolecular addition of a carbanion to an aryne is a more widely established process. Such reactions have been applied to the synthesis of indoles (Scheme 47b) (75CC745> and oxindoles (Scheme 47c) (63JOC1,80JA3646). 

N-Arylation of azoles is achieved either by using arynes, activated halobenzenes (e.g. dinitro) or under Ullmann conditions. Thus benzyne reacts with imidazoles to give N-arylimidazoles (70AHC(12)103), and these compounds have also been prepared under modified Ullmann conditions. 

The first benzazetidine (243) was isolated from the photolysis of 3-phenyldihydroben-zotriazine (242) (66JA1580). Another route to benzazetidines involving formation of the N to aryl-C bond utilizes intramolecular nucleophilic substitution via aryne (287). It is not general, however, and is only satisfactory when R and/or are alkoxy groups. The reaction also fails for iV-alkylamines (78LA608). 

Benzo[b]furan-4(5H)-one, 6,7-dihydro-synthesis, 4, 710 Benzofuranones H NMR, 4, 579 Benzo[b]furanones from 3-hydroxyflavanone, 3, 729 Benzo[b]furan-2(3H)-ones — see 2-Coumaranones Benzo[b]furan-3(2H)-ones IR spectra, 4, 590 reactions, 4, 650 Benzo[ c]furan-1 (3 W) -ones carbanions, 4, 579 H NMR, 4, 579 reactions with arynes, 1, 415 structure, 4, 552... 

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. 

The heterocyclic aryne (trithiadiazepyne) 12.18, generated by treatment of the monobromo derivative of 12.16 with a strong base, can be trapped as a Diels-Alder adduct with furan (Scheme 12.3). ... 

Prior to 1960 little work had been done on reactions of heterocyclic compounds involving hetarynes, i.e. intermediates with a triple bond in the nucleus containing the hetero atom. Since then interest in hetarynes has grown and investigations in this area are developing rapidly using information available from carbocyclic aryne chemistry. Therefore, a short survey of the chemistry of arynes is presented before summarizing typical problems encountered in hetaryne chemistry. 

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. 

It has been established that arynes are formed in the following classes of reaction ... 

There is sound evidence for the existence of aryne intermediates as indicated by the following experiments, which also illustrate their reactivity. 

Both 1- (5) and 2-fluoronaphthalene (9) yield with phenyl-lithium the same (Mymmetrical aryne (6) after subsequent carbona-tion, mixtures containing l-phenylnaphthalene-2-carboxylic acid (7) and 2-phenylnaphthalene-l-carboxylic acid (8) in the ratio 1 1.7 were... 

At the same time proof accumulated that arynes can be considered as real intermediates and not, e.g., as resonance structures in the activation complex of the transition state ... 

Although neither benzyne nor any other aryne has been isolated, it appears from the foregoing that we are justifled in considering these intermediates to be short-lived substances, the properties of which can be described by the series of resonance structures 17 and 21-23. 

For discussions concerning their structure and further information on the generation and reactivity of arynes the reader is referred to a series of published reviews. ... 

Hetarynes can be expected to differ from carbocyclic arynes in several respects, i.e. ... 

Heterocyclic compounds may show a higher tendency than carbocycles to react with nucleophiles according to the addition-elimination mechanism than via arynes. 

This review covers the hterature up to the beginning of 1963. Papers published before the era of aryne chemistry that merely give incidental information on reactions which might proceed via hetarynes are not included. 

The amination of 2-chloropyridine-A-oxide (53) with potassium amide in liquid ammonia yielded a mixture of 2-(55) and 3-amino-pyridine-A-oxide (56) in 5-10% total yield.This rearrangement might be explained by an aryne mechanism involving 2,3-pyridyne-A-oxide (54). Since the structure of 56, with its quaternary nitrogen atom, is more analogous to that of 3-methoxybenzyne (39) than to that of 2,3-pyridyne (26), an orientation effect directing the amide ion to C-3 can be expected here. 

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