We now need to introduce you to one last mechanism for aromatic nucleophilic substitution and you may well feel that this is the weirdest mechanism you have yet seen with the most unlikely intermediate ever! For our part, we hope to convince you that this mechanism is not only possible but also useful. Earlier in this chapter we said that the displacement by nucleophiles of bromide from bromobenzene does not occur. In fact, substitution reactions of bromobenzene can occur but only under the most vigorous conditions, such as when bromobenzene and NaOH are melted together (fused) at very high temperature. A similar reaction with the very powerful reagent NaNH₂ (which supplies NH₂ − ion) also happens, at a rather lower temperature.

These reactions were known for a long time before anyone saw what was happening. They do not happen by an SN2 mechanism, as we explained earlier, and they can’t happen by the addition–elimination mechanism because there is nothing to stabilize the negative charge in the intermediate. The first clue to the true mechanism is that all the nucleophiles that react in this way are very basic. They start the reaction off by removing a proton ortho to the leaving group.

The carbanion is in an sp² orbital in the plane of the ring. Indeed, this intermediate is very similar to the aryl cation intermediate in the SN1 mechanism from diazonium salts. That had no electrons in the sp2 orbital; the carbanion has two. Why should this proton be removed rather than any other? The bromine atom is electronegative and the C–Br bond is in the plane of the sp2 orbital and removes electrons from it. The stabilization is nonetheless weak and only exceptionally strong bases will do this reaction. The next step is the loss of bromide ion in an elimination reaction. This is the step that is difficult to believe as the intermediate we are proposing looks impossible. The orbitals are bad for the elimination too—it is a syn- rather than an anti-periplanar elimination. But it happens.

The intermediate is called benzyne as it is an alkyne with a triple bond in a benzene ring. But what does this triple bond mean? It certainly isn’t a normal alkyne as these are linear. In fact one π bond is normal—it is just part of the aromatic system. One π bond—the new one—is abnormal and is formed by overlap of two sp2 orbitals outside the ring. This external π bond is very weak and benzyne is a very unstable intermediate. Indeed, when the structure was proposed few chemists believed it and some pretty solid evidence was needed before they did. We shall come to that shortly, but let us first finish the mechanism. Unlike normal alkynes, benzyne is electrophilic as the weak third bond can be attacked by nucleophiles.

The whole mechanism from bromobenzene to aniline involves an elimination to give benzyne followed by an addition of the nucleophile to the triple bond of benzyne. In many ways, this mechanism is the reverse of the normal addition–elimination mechanism for nucleophilic aromatic substitution and it is sometimes called the elimination–addition mechanism. Any nucleophile basic enough to remove the ortho proton can carry out this reaction. Known examples include oxyanions, amide anions (R2N−), and carbanions. The rather basic alkoxide t-butoxide will do the reaction on bromobenzene if the potassium salt is used in the dipolar aprotic solvent DMSO to maximize reactivity.

One rather special feature of the benzyne mechanism allows us to be certain that this proposed mechanism is correct, and this is the fact that the triple bond could in principle be attacked by nucleophiles at either end. This is of no consequence with bromobenzene as the products would be the same, but we can make the ends of the triple bond different and then we see something interesting. ortho-Chloro aryl ethers are easy to prepare by chlorination of the ether. When these compounds are treated with NaNH₂ in liquid ammonia, a single amine is formed in good yield.

The new amino group finds itself in the meta position even though the chlorine was at the ortho position. It would be very difficult to explain this other than by the benzyne mechanism. Using the same elimination–addition sequence, this must be the mechanism:

That shows how the meta product might be formed, but why should it be formed? Attack could also occur at the ortho position, so why is there no ortho product? There are two reasons: electronic and steric. Electronically, the anion next to the electronegative oxygen atom is preferred because oxygen is inductively electron-withdrawing. The same factor facilitates deprotonation next to Cl in the formation of the benzyne. Sterically, it is better for the amide anion to attack away from the OMe group rather than come in alongside it. Nucleophilic attack on a benzyne has to occur in the plane of the benzene ring because that is where the orbitals are. This reaction is therefore very sensitive to steric hindrance as the nucleophile must attack in the plane of the substituent as well.

This is a useful way to make amino ethers with a meta relationship as both groups are ortho, para-directing and so the meta compounds cannot be made by electrophilic substitution. para-Disubstituted halides can again give only one benzyne and most of them give mixtures of products. A simple alkyl substituent is too far from the triple bond to have much steric effect.

If the substituent is an electron-repelling anion, then the meta product is formed exclusively because this puts the product anion as far as possible from the anion already there. This again is useful as it creates a meta relationship between two ortho, para-directing groups.

مواضيع ذات صلة

How to reduce carboxylic acids to alcohols

How to reduce amides to amines

Other nucleophiles

The SN1 mechanism for nucleophilic aromatic substitution: diazonium compounds

The activating anion-stabilizing substituent

The leaving group and the mechanism

The intermediate in the addition–elimination mechanism

The addition–elimination mechanism

Nucleophilic aromatic substitution

Nucleophilic epoxidation

Conjugate substitution reactions

Unsaturated nitriles and nitro compounds