The synthesis of aromatic compounds is very important because organic compounds with benzene rings are common. Compounds with aromatic rings are highly stable and usually do not react chemically.

In some cases, however, it is possible to replace substituents on the aromatic rings. This is called nucleophilic aromatic substitution. If a leaving group is present in the benzene ring, it can be replaced by another substituent by reacting with a nucleophilic reagent.

The best nucleophilic aromatic substitution is the Sandmeyer reaction. Any substituent can be synthesized via a diazonium salt. Other nucleophilic aromatic substitution reactions include synthetic reactions using halogens and benzynes.

What are the reaction mechanisms of nucleophilic aromatic substitution reactions? And what kind of substituents can be added? We will discuss these questions.

Nucleophilic Aromatic Substitution Reactions in which the Substituents of the Benzene Ring are Replaced

In most compounds with an aromatic ring, substituents are attached to it. Some of these substituents may undergo a substitution reaction in the presence of a nucleophilic reagent.

In a nucleophilic substitution reaction, a leaving group must be present. The nucleophilic reagent (Nu) attacks the molecule and replaces it with a leaving group (L). Nucleophilic substitution reactions occur on the benzene ring by the following reaction mechanism.

As in general nucleophilic substitution reactions for alkanes, the substituents are replaced on the same carbon atom. Therefore, the reaction mechanism is simple.

Substitution Reactions to Halogens Occur on Aromatic Rings

One of the simplest nucleophilic aromatic substitution is the substitution of a halogen. In nucleophilic substitution reactions for alkyl chains, the halogen becomes a leaving group. Similarly, halogens on the benzene ring are also leaving groups and are subject to attack by nucleophilic reagents.

For example, by reacting with an aromatic ring containing a halogen under basic conditions, the halogen is replaced by -OH. As a result, phenol can be synthesized.

In this way, the halogens can be replaced with other substituents.

Of course, if you change the reaction conditions, you can get different compounds. For example, if you react with ammonia instead of reacting with water, you get aniline instead of phenol. It is possible to synthesize amines.

Note that the leaving groups of halogens are easy to be released in the following order.

  • F (fluorine) > Cl (chlorine) > Br (bromine) > I (iodine)

Regarding the leaving ability of halogens, the reactivity is opposite to the SN1 and SN2 reactions to alkyl chains. In the nucleophilic substitution reaction of alkyl chains, the more easily the leaving group becomes an ion, the easier it is to react. Therefore, iodine, which has a weak carbon-halogen bond, has the highest reactivity.

On the other hand, for halogens on the benzene ring, attack and addition by nucleophiles is the rate-limiting step. As a result, fluorine atoms are the best leaving groups, since atoms with fewer steric hindrances are more likely to leave.

Halogens Are Replaced by the Presence of Electron Withdrawing Groups or Pyridines

Note that aromatic rings are stable, and the synthesis does not proceed under normal conditions. However, in the presence of electron-withdrawing groups, halogen substitution reactions can exceptionally take place. The following are known to be electron-withdrawing groups.

  • Nitro group (-NO2)
  • Cyano group (-CN)
  • Carbonyl group (-CO)
  • Sulfur group (-SO3H)

Why does the presence of these substituents activate the benzene ring and facilitate nucleophilic substitution reactions? This is because the presence of electron-withdrawing groups allows us to write the following resonance structure.

The ortho and para positions of the electron-withdrawing group are found to have a positive charge. This makes it easier for nucleophiles with a negative charge to attack them, and halogen substitution is more likely to occur.

An exception to this is the presence of an electron-withdrawing group in the benzene ring, which leads to a nucleophilic aromatic substitution of the halogen. For reference, this reaction mechanism is also called SNAr.

-The Reaction Also Occurs with Heterocyclic Compounds such as Pyridine

It is not only electron-withdrawing groups that aromatic rings are positively charged due to their resonance structure. The same is true for heterocyclic compounds.

A pyridine with a nitrogen atom in the benzene ring has a lower electron density on the benzene ring, as does an electron-withdrawing group. This is because we can write the following resonance structure.

Therefore, nucleophilic aromatic substitution reactions occur not only with electron-withdrawing groups, but also with heterocyclic compounds such as pyridines.

Sandmeyer Reaction with Diazonium Salts Is the Most Common

What are the most common nucleophilic aromatic substitution? The most commonly used nucleophilic aromatic substitution is the Sandmeyer reaction.

In the halogen substitution reaction just described, the reaction cannot proceed unless an electron-withdrawing group is present at the benzene ring. On the other hand, in the case of the Sandmeyer reaction in which diazonium salts are formed, nucleophilic aromatic substitution can occur regardless of the substituents present in the aromatic ring.

When sodium nitrite (NaNO2) is added to an aniline under acidic conditions, the diazonium salt is formed. Under acidic conditions, sodium nitrite becomes a nitrosonium ion, as shown below.

Subsequently, aniline reacts with nitrosonium ions to form a diazonium compound. The reaction mechanism is as follows.

Diazonium salts are known for their strength as leaving groups. Therefore, when a nucleophile is added to a diazonium compound, a nucleophilic aromatic substitution reaction can occur.

For example, phenol can be synthesized by reacting a diazonium compound with water.

In diazonium salts, the phenyl cation is formed as an intermediate. The phenyl cation is extremely unstable and is attacked by nucleophiles. As a result, substitution reactions occur.

Any Substituents Can Be Put in via Diazonium Compounds

Why is the Sandmeyer reaction the most important nucleophilic aromatic substitution? It is because many substituents can be put in via diazonium compounds.

We have just described an example of synthesizing phenol by reacting it with water. By changing the reagent to be reacted, different substituents can be added as follows.

ReagentsSubstituents generated
CuClCl (chloro group)
CuBrBr (bromo group)
KII (iodine)
H2OOH (phenol)
CuCNCN (cyano group)
BF4F (fluorine)

Of course, there are many other types of nucleophiles. For example, alcohols and thiols act as nucleophiles and cause nucleophilic aromatic substitution reactions. In any case, any molecule that has even a small amount of nucleophilic properties, including water, causes nucleophilic aromatic substitution with diazonium compounds.

The reason why the Sandmeyer reaction with diazonium compounds is the most important nucleophilic aromatic substitution is because it can synthesize any substituent.

Nucleophilic Aromatic Substitution Reaction via Benzyne

When studying nucleophilic aromatic substitution reactions, the reaction mechanism of benzyne is often used as an example. New substituents are generated by a different reaction mechanism than the Sandmeyer reaction.

Compounds with a triple bond on the benzene ring are called benzynes. Nucleophilic aromatic substitution reactions with benzynes are possible in the case of fluorine and chlorine atoms on the benzene ring, such as fluorobenzene and chlorobenzene.

When a strong base is added to fluorobenzene or chlorobenzene, the hydrogen (proton) is withdrawn and benzyne is formed. If a nucleophilic agent such as ammonia is present in the solution, the nucleophilic agent attacks the benzyne to form a substituent.

Strictly speaking, the synthetic reaction of benzyne is different from the nucleophilic aromatic substitution. The first reaction is an elimination reaction. As the elimination reaction takes place, benzyne is formed. Subsequently, aniline is synthesized by the addition of ammonia.

But as a whole, a substitution reaction is occurring. This is why we learn about synthetic reactions with benzyne in nucleophilic aromatic substitution.

Learn About the Properties of Substitution Reactions on Aromatic Rings

The benzene ring is a highly stable substance and therefore does not normally cause a reaction. However, under certain conditions, substitution reactions can occur with aromatic rings.

There are only three important nucleophilic aromatic substitution reactions. They are as follows.

  • Halogen substitution reactions
  • Sandmeyer reaction
  • Reaction via benzyne

The most important of these is the Sandmeyer reaction. It is one of the most frequent synthetic reactions, so most of laboratories that perform organic synthesis use diazonium salts. Therefore, it is particularly important to understand the reaction mechanism of the Sandmeyer reaction.

The nucleophilic aromatic substitution is useful when you want to add a new substituent to the benzene ring. It is important to understand the mechanism of the reaction and to proceed with the synthetic reaction.