# Electrophilic Aromatic Substitutions

### Introduction to Electrophilic Aromatic Substitution

Electrophilic aromatic substitutions are the most common type of reaction for benzene and can be used to add a variety of functional groups to a benzene ring.
An electrophilic aromatic substitution (EAS) is a type of reaction involving the formation of a powerful electrophile that will react with benzene to temporarily destroy aromaticity and form a stabilized sigma complex that will then undergo an E1-like elimination to re-form the benzene ring. E1 eliminations are eliminations that occur on a carbocation intermediate. They are the most common type of reaction of benzene (C6H6). This reaction forms an intermediate called the arenium ion, or sigma complex, which is a benzene ring that has lost a double bond and formed a carbocation with three equivalent resonance contributors.

#### Generic Arenium Ion

Halogenation of benzene is a common example of an EAS reaction. For halogenation reactions, a dihalide and a Lewis acid catalyst are used. For example, to add a bromine atom (bromination) to benzene in an EAS reaction, bromine and iron tribromide (Br2/FeBr3) is the reagent combination used, with the FeBr3 catalyzing the reaction. For chlorination, the addition of chlorine, chlorine and iron trichloride (Cl2/FeCl3) is the reagent combination used, with the FeCl3 catalyzing the reaction. Iodination, the addition of iodine, is a more difficult EAS reaction. So instead of a Lewis acid catalyst (FeBr3 or FeCl3), a Brønsted acid catalyst, nitric acid (HNO3), is used along with iodine (I2). For bromination and chlorination, many different Lewis acid catalysts can be used, but FeBr3 and FeCl3 are most commonly used.

#### Halogenation of Benzene

The EAS reaction can also be used in sulfonation and nitration. Sulfonation is the addition of a sulfonic acid (${-}{\rm{SO}_3H}$) functional group to the benzene ring. This is accomplished through an EAS reaction in the presence of fuming sulfuric acid (H2SO4) and sulfur trioxide (SO3). The sulfur in the sulfur trioxide is electrophilic because it is bonded to three electronegative atoms (oxygen atoms).

#### Sulfonation of Benzene

As its name suggests, nitration is the addition of a nitro group (${-}{\rm{NO}}_2$) to the benzene ring. This is accomplished through an EAS reaction in the presence of sulfuric acid (H2SO4) and nitric acid (HNO3). The sulfuric acid reacts with the nitric acid to produce the nitronium ion (NO2), which is electrophilic.

#### Nitration of Benzene

Alkyl and acyl groups can be substituted on a benzene ring in place of a hydrogen using Friedel-Crafts reactions, which are also EAS reactions. Friedel-Crafts alkylation is a reaction that adds an alkyl group to the benzene ring using an alkyl halide or an alkene. The alkyl halide is used with a Lewis acid catalyst, and the alkene is used with a Brønsted acid catalyst. Friedel-Crafts reactions have three main limitations. Friedel-Crafts alkylations can undergo rearrangements and polyalkylations. Friedel-Crafts alkylation using alkyl halides of two carbons or more will rearrange to a branched alkyl group if possible. Friedel-Crafts reactions (alkylation and acylation) will not take place if there is an electron withdrawing group (EWG) or amine (${-}{\rm{NH}_2}$) on the benzene ring. Electron withdrawing groups are substituents that deactivate the benzene ring by removing electron density from the ring. The electron pair on an amine is a Lewis base that reacts with the Lewis acid catalyst to form an insoluble complex that prevents the Friedel-Crafts reaction from occurring. One method to accomplish a Friedel-Crafts alkylation is to add an alkyl halide (RX) with a Lewis acid catalyst (AlX3 or FeX3). The halogen atom on the alkyl halide attacks the aluminum or iron atom to form a complex that is either attacked directly (if the alkyl halide is primary) or breaks apart into a carbocation (if the alkyl halide is secondary or tertiary) that is then attacked by the $\pi$ bond of the benzene ring.

#### Alkylation of Benzene via Friedel-Crafts Reaction Using an Alkyl Halide

Another method to accomplish a Friedel-Crafts alkylation is to add an alkene (${\rm {R}_2C}{=}{\rm{CR}}_2$) with a Brønsted acid catalyst (HX or H2SO4, H2O). The $\pi$ bond of the alkene attacks the hydrogen of the acid catalyst to form a carbocation that is then attacked by the $\pi$ bond of the benzene ring.

#### Alkylation of Benzene via Friedel-Crafts Reaction Using an Alkene

A similar set of reagents to the ones used for alkylation can be used to have a Friedel-Crafts acylation. But instead of an alkyl halide (RX) with a Lewis acid catalyst (AlX3 or FeX3), an acyl chloride (RCOCl) with a Lewis acid catalyst (AlX3 or FeX3) is used. An acyl chloride is a carbonyl compound with a halogen attached to the carbon of the carbon-oxygen double bond. A lone pair of electrons on the oxygen attacks the metal of the Lewis acid catalyst to form a complex that breaks apart into a carbocation. A $\pi$ bond of benzene attacks the carbocation, forming an arenium ion that then re-forms the benzene ring. A Friedel-Crafts acylation is a reaction that adds an acyl group to the benzene ring. An acylation followed by a Clemmensen reduction can yield alkyl groups of any length without branching or rearrangements. A Clemmensen reduction is a reaction that removes the oxygen of a carbonyl in an aldehyde or ketone. Friedel-Crafts acylation reactions are only limited by electron withdrawing groups (EWG) or amine (${-}{\rm{NH}_2}$) groups on the benzene ring.

### Properties of Electrophilic Aromatic Substitutions

Substituent groups direct where the electrophilic attacks will occur; electron donating groups (EDG) direct the attack to the ortho or para position, and electron withdrawing groups (EWG) direct the attack to the meta position. EDG are activating groups, and EWG are deactivating groups.

Substituent groups already on the benzene will direct where the electrophilic attack occurs. These groups are called directing groups, and if the groups are electron withdrawing groups (EWG) except for the halides, the attack occurs at the meta positions. If the groups are electron donating group (EDG) or halides, the attack occurs at the ortho or para position. These directing groups are also classified as activating groups or deactivating groups.

Electrophilic aromatic substitution (EAS) reactions replace one of the hydrogen atoms on an aromatic ring with a substituent group. A substituent group is any atom or group that replaces one of the hydrogens found on a benzene ring.

An activating group is a group on a benzene ring that can make the ring more active than benzene alone. Conversely, a deactivating group is a group on a benzene ring that can make the ring less active than the benzene alone. In general, groups that are electron donating groups (EDG) are activators, and electron withdrawing groups (EWG) are deactivators. Groups such as the hydroxyl group have electron withdrawing effects because of the electronegative oxygen atom, but the electron withdrawing effect is small compared to their electron donating resonance structures.

### Substituent Groups and Their Effects on EAS Reactions

Substituent Group Electron Donating Group (EDG) or Electron Withdrawing Group (EWG) Activating or Deactivating Director
Alkoxide EDG Activating Ortho, para
Amine EDG Activating Ortho, para
Hydroxyl EDG Activating Ortho, para
Amide EDG Activating Ortho, para
Alkoxy EDG Activating Ortho, para
Ester EDG Activating Ortho, para
Alkyl EDG Activating Ortho, para
Halide (halogen) EWG Deactivating Ortho, para
Carbonyl EWG Deactivating Meta
Sulfonyl EWG Deactivating Meta
Cyano EWG Deactivating Meta
Nitro EWG Deactivating Meta
Haloalkyl EWG Deactivating Meta
Ammonium EWG Deactivating Meta

EDG activate the benzene ring and are all ortho, para directors. EWG deactivate the benzene ring and are all meta directors except the halogens, which are ortho, para directors.

A directing group is a substituent on a benzene ring that directs where substitutions will occur. Electron donating groups (EDG) and the halogens are ortho and para directors, and electron withdrawing groups (EWG) are meta directors. The directing effects of these groups are dictated by the formation of a stabilized resonance form.

#### Directions of Attack Comparison

When multiple substituents are attached to a benzene ring, the stronger ortho-para substituent will dictate the orientation of the EAS reaction. When two substituents are separated by one carbon atom, substitution will never occur between those two groups unless there is no alternative. All other factors being equal, substitution will occur away from sterically hindered carbons. Using the various EAS reactions and directing effects, disubstituted and polysubstituted benzene can be synthesized with regiochemical control.