Benzynes towards nucleophiles

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. 

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. 

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. 

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... 

Formation and reactivity of o-benzynes o-benzynes serve as illustrative stereoelectronic models due to two features a) structural rigidity that restricts orbital interactions exclusively to syn-periplanar geometries and b) distortion of the in-plane x-system. These features are translated in the interplay of two related stabilizing effects controlling the structure of substituted benzynes and their reactivity towards nucleophiles 1) interaction of o-acceptors with bent bonds and 2) interaction of o-acceptors with anionic centers. 

Despite their high electrophilicity, arynes are discriminatory toward nucleophiles (33). An interesting reaction involving an additive rearrangement of benzyne with alkylidenetriphenylphosphoranes (34) is depicted as the following. 

Because of the overlap of the sp orbitals in the second 7t bond of benzyne, the bond is very reactive toward nucleophiles. Attack of a nucleophile such as amide ion can occur at either carbon atom of the triple bond. Subsequent protonation of both of the two possible anions yields the product mixture. These two steps constitute the addition portion of the mechanism. 

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 ... 

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). ... 

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... 

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. 

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,... 

This subject has been thoroughly reviewedand only the main features will be briefly summarized here in order to set the following sections in context. Nucleophiles generally exhibit a smaller range of reactivities toward arynes than toward other substrates. This is because of the extreme reactivity and electrophilicity of arynes. Even so, selectivities are evident with benzyne in liquid ammonia, for example, the nucleophilicity order is PhS > PhO" > RO" and with benzyne in alcohol the order is F > Br > CF EtOH. In water at 318 °C the relative reactivities toward 4-methylbenzyne are PhS (46), F (6.2), piperidine (3.0), Br (1.7), PhNH2 (1.3), PhO (1.0), CF (1.0), NH3 (0.5), F (0.2)229 this compressed... 

Phenyl aryl sulfides are prepared in excellent yield from benzyne and ethyl aryl sulfides by a similar mechanism (10 examples, 87-97% yields). Even o-bis(phenylthio)benzene could be obtained (90%) from the corresponding bis(ethylthio)benzene and excess benzyne. When Ar in these reactions was a 9-anthryl group similar reactions occurred except for 9- -butylthioanthracene 583, which gave Diels-Alder adducts 584 and 585 instead. Apparently, steric hindrance at the sulfur is sufficient to negate its effectiveness as a nucleophile, even toward the highly reactive and sterically unencumbered benzyne. 

An intermediate known as benzyne, which has a triple bond, accounts for the equivalence of two carbon atoms toward the nucleophile. This intermediate was proposed on the basis of isotopic labeling studies using chlorobenzene labeled with C at C-1. Reaction with amide ion gives a mixture of two differently labeled anihnes in equal amounts. The following equation shows location of the C with an asterisk. 

---