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Synthesis Strategies

Polysubstituted benzenes and other aromatic systems have to be prepared by carefully planned sequences of SEAr reactions.

YouTube video: synthetic strategies for polysubstituted benzenes▶ Watch the video on YouTube

One has to bear in mind the activating or deactivating and directing properties of the groups being introduced.

Unlike an arithmetic operation, in a synthetic sequence, the order in which the synthesis steps are planned DOES ALTER the product.

Trick 1

Some functional groups can be transformed into others, so that their activating and directing properties can be changed.

Conversion of the NO₂ group, deactivating and meta-directing, into NH₂, activating and ortho-para-directing, with Zn(Hg)/HCl, H₂/Ni or Fe/HCl, and the reverse oxidation with CF₃CO₃H

Conversion of an NO2 group, a strong deactivator and meta director, into an NH2 group, an activator and ortho-para director.

And vice versa.

But beware of acidic media, which transform NH2 into NH3+! All your plans would go down the drain.

Clemmensen reduction with Zn(Hg)/HCl: the ketone, a meta director, becomes an alkyl group, an ortho-para director

Conversion of a ketone group, a deactivator and meta director, into an alkyl group, an activator and ortho-para director.

Trick 2

Reversible sulfonation allows the temporary blocking of the para position.

Blocking the para position: direct methylation of chlorobenzene gives only 30% of the ortho isomer; sulfonating first, methylating and removing the SO₃H gives 80%

By "protecting" the para position, ortho-disubstituted compounds can be prepared more efficiently.

Trick 3

Transformation of an NH2 group into a diazonium salt.

Reactivity of diazonium salts: aniline with NaNO₂/HCl gives the salt, which is replaced by OH, I, Cl, Br, CN, F or H, or couples with another arene to give an azo compound

Diazonium groups can be replaced by a great number of other functional groups.