Making the aromatic ring available for attack by nucleophiles

Most preparations of aromatic compounds we have seen (such as electrophilic aromatic substitution, as well as the Suzuki reaction covered in the previous section) involve the aromatic ring as nucleophile, reacting with an electrophilic reagent.  Nucleophilic aromatic substitution (in 17.1.) involves nucleophilic reagents, but it is limited to rings with strong electron-withdrawing groups ortho or para to a leaving group.  The most versatile way to make aromatic rings available for nucleophilic attack is to prepare arenediazonium salts, containing the ArN₂⁺ ion.  The diagram below shows the variety of reactions possible with arenediazonium salts.

Arenediazonium salts are easily prepared from arylamines (anilines) using a process called diazotization.  The process involves dissolving the amine in a suitable acid, cooling in an ice bath to 0-5 ^oC, then adding sodium nitrite (NaNO₂) solution.  The acid reacts with the NaNO₂ to form nitrous acid (HNO₂), which then reacts with the arylamine to form the arenediazonium salt. The most common salt to use for these reactions is the chloride (made using HCl as the acid), which are fairly soluble but decompose rapidly at room temperature.  However, in some reactions (such as phenol formation) the chloride ion may interfere and substitute a Cl, so in those cases the sulfate (made using H₂SO₄) is used.  Diazonium sulfates are a little more stable than chlorides, but they are also generally less soluble and thus more awkward to use.  Diazonium tetrafluoroborates are made from chlorides by adding HBF₄; they are usually completely insoluble, which allows them to be filtered off, then dried for decomposition without water present to introduce a fluorine onto the ring.  This method for introducing fluorine onto an aromatic ring is called the Balz-Schiemann reaction.

Arenediazonium salts are useful intermediates, and they easily lose nitrogen react with a variety of nucleophiles, as shown in the diagram above.  Since nitrogen is very stable, and is lost as a gas, this provides a powerful driving force for these reactions to occur.  In the case of water or iodide ion, the nucleophile reacts without need for any catalysis.  However, many reactions of diazonium salts are catalyzed by copper(I), in which case the reaction is referred to as a Sandmeyer reaction.

One reaction that retains the two nitrogens involves coupling to another (electron-rich) aromatic ring, as shown on the left part of the reaction scheme.  This is very important in the artificial dye industry, which was mainly established using the production of these “azo dyes” after the discovery of Perkin’s mauve in 1856.

Use in synthesis

Diazonium salt chemistry, being based on nucleophilic reagents used with an electrophilic aromatic ring, is complementary to electrophilic aromatic substitution (EAS, which uses electrophilic reagents).  Diazonium salts are easily prepared from aromatics via a three step synthesis:

If other substituents are needed, these can be introduced during the synthesis.  If a meta substituent is needed, the substituent is introduced at or before the nitro stage; for ortho/para substituents, this can be done at the NH₂ stage.  The amino group in an arylamine (aniline) is a very powerful activator, so many EAS reactions of arylamines rapidly introduce 2 or 3 substituents unless the NH₂ group’s reactivity is moderated by formation of an amide – recall this method for protection of amines via acetylation, from chapter 16.  In some cases, the new substituent may also be reduced during the reduction of the nitro group, as in this synthesis of meta-propylbenzenediazonium chloride from benzene:

For the synthesis of the para isomer, the arylamine is acetylated before the Friedel-Crafts reaction, then deacetylated by heating with excess aq. HCl right before diazotization.

This para isomer synthesis shows the use of the acetyl group to control the reactivity of the amino group.  (An alternative synthesis could avoid this by introducing the propyl group first, before nitration.)  Although these syntheses appear to be long, they involve synthetic steps that are reliable and reproducible, and they follow a standard pattern.  Also, the fact that different substituents can be introduced at selected positions along the way makes this approach a very valuable synthetic sequence.