We have used nitro groups very extensively so far because they are the best at stabilizing the anionic intermediate. Others that work include carbonyl, cyanide, and sulfur-based groups such as sulfoxides and sulfones. A direct comparison of the different groups Z that can assist the displacement of bromide (by the secondary amine piperidine in this example) is shown in the margin.

All the compounds react more slowly than the nitro compound. The sulfone reacts 18 times slower, the nitrile 32 times slower, and the ketone 80 times slower. Nitro is the best activating group, but the others will all perform well, especially when com bined with a fluoride rather than a bromide as the leaving group. Here are two reactions that work well in a preparative sense with other anion-stabilizing groups. Note that the trifluoro methyl group works by using only its powerful inductive effect.

●To summarize

 An anion-stabilizing (electron-withdrawing) group ortho or para to a potential leaving group can be used to facilitate nucleophilic aromatic substitution.

Conjugate and nucleophilic aromatic substitution reactions in action: the synthesis of an antibiotic We want to convince you that this chemistry is useful and also that it works in more complicated molecules so we are going to describe in part the preparation of the antibiotic ofloxacin. The sequence starts with an aromatic compound having four fluorine atoms. Three are replaced sequentially by nucleophiles and the last is present in the antibiotic itself. The fi rst reaction is a conjugate substitution of the ethoxy group marked in orange. An amino alcohol is used as the nucleophile and it is the more nucleophilic amino group (rather than the hydroxyl group) that adds to the alkene.

Now for the first nucleophilic aromatic substitution. The amino group attacks in the position ortho to the carbonyl group so that an enolate intermediate can be formed. The first fluoride is expelled in the elimination step.

Only two fluorines are left, and one of these is now displaced by an external nucleophile—an amine. The site of attack of the amine is determined by the need to stabilize the charge in the intermediate, which is an enolate.

All that is left is to hydrolyse the ester to the free acid with aqueous base. Every single reaction in this quite complicated sequence is one that you have met earlier in the book, and it illustrates the power of simple organic mechanisms to allow chemists to make important life-saving compounds.

Nucleophilic substitution on aromatic rings is possible by alternative mechanisms as well. We will now turn to these.

مواضيع ذات صلة

How to reduce carboxylic acids to alcohols

How to reduce amides to amines

The benzyne mechanism

Other nucleophiles

The SN1 mechanism for nucleophilic aromatic substitution: diazonium compounds

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