Benzynes towards

In one of the first contributions to the field, Friedman reported on the ability of silver to influence the reactivity of benzyne toward benzene (Scheme 2.1). In the absence of silver, benzyne 2, generated in situ from 1, reacted with benzene in a [4+2] manner to afford adduct 3 in addition to small amounts of dimerization product 4.6 However, in the presence of substochiometric amounts of silver ions, the course of the reaction was altered, leading to formation of biphenyl 5 and benzocycloctatriene 6. A contingent of other metal ions including T1+, Cu +, Cu2 +, Hg22 +, and Hg2 + were unable to influence product formation in a similar manner. 

It had been reported that, for example, 5.7.9(ll)-cholestatrienyl acetate shows a greater reactivity towards dienophiles than the corresponding 5,7-dienes 153>. We therefore investigated reactions with tetra-fluoro- and tetrachloro-benzyne 152>. The two isomeric adducts (115) and (116) were obtained in only modest yields with tetrafluorobenzyne, while with tetrachlorobenzyne no adducts or ene products were isolated. 

The triple bond in the benzyne intermediate is very reactive toward a wide range of nucleophiles. The reaction of acetaldehyde with methanol to produce a hemiacetal is also a base-catalyzed reaction. In this reaction, the methoxide ion, CH30, is the base ... 

Dehydrophenol 20i is a tautomeric form of carbene la, and a [1,3]-H migration should in principal interconvert these species. However, under the conditions of matrix isolation the benzynes 201—1 are thermally and photochemically stable towards rearrangement to the corresponding carbenes. UV irradiation of 20i results in a ring-opening and formation of so far unidentified acetylenic products. 

Coordination to strongly orf/zo-directing groups is responsible for the regiochemistry of some other reactions which do not involve ortholithiation. For example, while the electron-withdrawing nature of the oxazoline would be expected to direct the addition of the organolithium nucleophile to benzyne 11 towards the meta position, the major product that arises is the result of addition at the ortho position to give 12 (Scheme 1). ... 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

Aromatic compounds can also behave as dienes.858 Benzene is very unreactive toward dienophiles very few dienophiles (one of them is benzyne) have been reported to give Diels-Alder adducts with it.859 Naphthalene and phenanthrene are also quite resistant, though naphthalene has given Diels-Alder addition at high pressures.860 However, anthracene and other compounds with at least three linear benzene rings give Diels-Alder reactions readily. The interesting compound triptycene can be prepared by a Diels-Alder reaction between benzyne and anthracene 861... 

However, this achievement was then marred by an unfortunate error. The calcium salt of 4-fluorobenzoic acid was heated in admixture with calcium hydroxide, and fluorobenzene was claimed to be formed by decarboxylation. Later, it was shown16 that the product, a solid, was phenol. It had been analyzed only for carbon and hydrogen content an early warning to all workers in fluorine chemistry of the need for quantitative assays for fluorine in their products. Being more activated than fluorobenzene towards nucleophilic attack, the fluorobenzoate anion itself probably lost fluorine before decarboxylation occurred. A benzyne-type process seems to be a less likely reaction pathway. 

The above series perhaps do not exactly reflect the order of inherent nucleophilicities towards arynes, because factors like the size of the attacking reagent, its state of association and the nature of the counterion can play an important role. For instance, diethylamine is 18 times more reactive towards benzyne than the bulkier diisopropylamine.68 Nevertheless, aryne preference for soft nucleophiles is clear in a... 

The benzyne functions as a dienophile towards reactive diene systems. The reactivity of the 9,10-positions in anthracene is well known (Diels-Alder reaction, Section 7.6), and addition of benzyne to 9-bromoanthracene yields the interesting cage-ring alkyl halide 9-bromotriptycene (9-bromo-9,10-o-benzenoanthracene). The reaction is incomplete and some unreacted 9-bromoanthracene remains in the crude reaction products, but may be removed by virtue of its ready conversion into a maleic anhydride adduct in a further Diels-Alder-type reaction. 

Benzyne generated from 2-iodophenyl 4-chlorobenzenesulfonate by treatment with tropropyl magnesium chloride at low temperature adds to the magnesium thiolate derived from thiosalicylic acid 530 to form thioxanthone. The carboxyl function behaves as an electrophile towards the intermediate aryl magnesium species and an intramolecular cyclization ensues (Scheme 212) <2005AGE4258>. 

In the course of discovery research, reexamination of the benzyne chemistry led to an easily and safely operated benzyne reaction (Scheme 4).38 Solvent was found to affect the rate of halogen-metal exchange processes and the basicity of RLi reagents toward cyclopentadiene, a compound with a low pKa ( 14). Noncoordinating solvents... 

The photostimulated reaction of l-bromo-2,4,6-trimethylbenzene (a substrate with no o-hydrogen atoms in order to avoid the benzyne mechanism) with NH2 ions gave 1-amino-2,4,6-trimethylbenzene (70%) and the reduction product 1,3,5-trimethylbenzene (6%). This reaction did not occur in the dark221. By competition experiments of NH2 ions with Ph2P" ions toward 2,4,6-trimethylphenyl radicals, it was found that Ph2P ions are 6.4 times more reactive than NH2 ions221, whereas NH2 ions are twice more reactive than acetone enolate ions toward the same radical in liquid ammonia222. 

Attack at the heteroatoms was observed in the reactions of (1) and (2) with dimethyl acetylenedicarboxylate and with benzyne (78JCS(P1)1006). Compound (2) behaves as a heterodiene toward the acetylene ester, producing the quinoxaline (25) and selenium. The diester (25) was obtained only in trace amounts from (1). These reactions, and the failure of (1) and (2) to react with maleic anhydride, contrast with the behavior of naphtho[2,3-c] [l,2,5]thiadiazole which reacts with maleic anhydride across the center ring (64TL3815). 

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. 

In spite of their high total energy, arynes in general are selective towards different nucleophiles thus benzyne selectively captures the anion of acetonitrile in the presence of an excess of the dimethylamide ion used to generate both it and the benzyne. Nucleophilicity towards benzyne, determined by competition experiments, is in the order RLi RS- > R2N RO and I- > Br > Cl, which is an order of softness. The low energy of the LUMO of benzyne, coupled with its being uncharged, makes it a soft electrophile. 

We take up the aryl halides in a separate chapter because they differ so much from the alkyl halides in their preparation and properties. Aryl halides as a class are comparatively unreactive toward the nucleophilic substitution reactions so characteristic of the alkyl halides. The presence of certain other groups on the aromatic ring, however, greatly increases the reactivity of aryl halides in the absence of such groups, reaction can still be brought about by very basic reagents or high temperatures. We shall find that nucleophilic aromatic substitution can follow two very different paths the bimolecular displacement mechanism for activated aryl halides and the elimination-addition mechanismy which involves the remarkable intermediate called benzyne. 

We have seen that electron-withdrawing groups activate aryl halides toward nucleophilic substitution. In the absence of such activation, substitution can be made to take place, by use of very strong bases, for example. But when this is done, substitution does not take place by the mechanism we have just discussed (the so-called bimolecular mechanism), but by an entirely different mechanism the benzyne (or elimination-addition) mechanism. Let us f rst see what this mechanism is, and then examine some of the evidence for it. 

Each ring contains 6 rr electrons. 20. (a) Via an aryne (b) direct displacement accompanies elimination-addition. Fluoride least reactive toward benzyne formation (p. 838), most reactive toward direct displacement (Sec. 25.12). Piperidine shifts equilibrium (1) toward left, tends to inhibit benzyne formation. 21. UU is aromatic, with 14 n electrons. Methyl protons are insii/e aromatic ring see Fig. 13.4, p. 419. 

The electrophilicity of benzyne (90) is 1.95 eV, a value that falls within the range of strong electrophiles in the w scale.102 This value, which is larger than that evaluated for acetylene (32), to = 0.54 eV, allows to explain the reactivity of the benzyne derivatives towards nucleophilic additions. The electrophilicity of the fused four-membered... 

In spite of their very high total energy, arynes in general are quite selective towards different nucleophiles thus benzyne (112) easily captures the anion (113) of acetonitrile,... 

In the past decade, reports on the interactions between main group elements, including phosphorus derivatives, and zirconium species such as [Cp2ZrHCl]n [7], Cp2ZrMe2 [8],[Cp2Zr] [9,10], or others [11,12] have appeared in the literature. The present review is focused on the use of /]2-benzyne-zirconocene and the parent rf-phosphabenzyne-zirconocene in phosphorus chemistry. The versatile behavior of these complexes towards unsaturated phosphorus reagents and the versatile behavior of the resulting products will be more precisely reported. 

We speculated that the electron-withdrawing nature of the pyridine ring was responsible for the lack of reactivity of 23 toward benzyne. In troubleshooting the benzyne addition we examined the use of a methoxy group to offset the electron-withdrawing properties of the pyridine. Compounds 24-28 (Fig. 8) were prepared in the order indicated. As each was... 

Benzoselenadiazole (128) behaves as a heterodiene toward dimethyl acetylenedicarboxylate, with which it gives the quinoxaline 124 and selenium. But 128 reacts differently with benzyne (generated from 4 or from 9) to give the 1,2-benzisoselenazole derivative 132 (88%) and a small amount of a cis,trans stereoisomer of 132.82 The analogous adduct 131 is obtained in lower yield from benzyne and 2,1,3-benzothiadiazole (127). The structure of these benzyne adducts is strikingly reminiscent of 135, which is obtained from a photochemical addition of dimethyl acetylenedicarboxylate to 126 via a nitrile oxide intermediate.84 However, for reasons given elsewhere,82 a nitrile selenide is unlikely to be an intermediate in the formation of 132, which is better explained by the mechanism outlined in Scheme 16. As in the case of thiophen (Section V,B), this is a 1,3-cycloaddition (in one or two steps) of benzyne to the heterocycle, enabled by the use of d orbitals on the sulfur or selenium atom. 

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