In this article, you will learn about the basics of electrophilic aromatic substitution, important mechanisms, and regioselectivity.
Topics Covered in Other Articles
- Diels-Alder Reaction
- Aldol Condensation
- Keto-Enol Tautomerization
- Wittig Reaction
- What is a Leaving Group?
What is an Electrophilic Aromatic Substitution?
Despite the remarkable stability of aromatic compounds, like benzene, organic chemists have found ways of chemically altering their structure. In synthesis, these alterations typically happen through substitution reactions, where a new chemical group replaces a hydrogen on the aromatic ring. Importantly, these reactions maintain the cyclic movement of electrons in aromatic compounds, keeping their chemical stability.
In electrophilic aromatic substitution (EAS), an electrophilic group adds to the aromatic ring, such as a hydrocarbon, nitrate, or sulfate. EAS has a counterpart involving nucleophiles, appropriately called nucleophilic aromatic substitution (NAS). EAS and NAS follow similar mechanisms, but there exist unique quirks in the EAS reaction not shared in NAS.
Electrophilic Aromatic Substitution Mechanism
The first step in electrophilic substitution reactions involves a pair of pi electrons from the aromatic ring attacking an electrophile. This temporarily breaks the aromaticity of the ring and places a positive charge on the carbon attached to the electrophile. Then, a generic base deprotonates the positive carbon, which frees an electron pair. Finally, this electron pair forms a pi bond within the carbon cyclic structure, which becomes aromatic again.
Importantly, the compound’s aromaticity must cease during EAS temporarily but returns to form the final product. Any chemical alteration to an aromatic structure must often involve aromaticity returning when the reaction completes. This is due to the remarkable stability of aromatic compounds. For a reaction to completely transform an aromatic structure into a non-aromatic one, such a reaction would likely be thermodynamically unfavorable without drastic environmental conditions or remarkably effective catalysts.
Electrophilic Aromatic Substitution Examples
To place a hydrocarbon onto an aromatic ring, a particular EAS reaction called Friedel-Crafts Alkylation must take place. This reaction involves two important reactants, an alkyl halide and a Lewis acid, commonly AlCl3. The Lewis acid first removes the halogen, leaving a carbocation. The carbocation then serves as the electrophile in EAS.
Chemists use the term “Friedel-Crafts Acylation” to describe a similar reaction involving an acid halide instead of an alkyl halide.
To halogenate an aromatic ring, you also need a Lewis acid, typically FeCl3 or FeBr3, as well as a diatomic halogen. The Lewis acid binds to the halogen, which makes it more electrophilic. Then, the electrophilic halogen may perform EAS with an aromatic substance. Due to the intricacy of the halogen-Lewis acid intermediate, a complicated series of rearrangements must occur during the EAS.
To place a nitro group onto an aromatic ring, a special compound called a nitronium ion which acts as an electrophile in electrophilic aromatic substitution. To generate a nitronium ion, nitric acid must be protonated by some other acid, which destabilizes its structure, resulting in the release of a hydroxy group. Typically, sulfuric acid serves as the secondary acid because its conjugate base, dihydrogen sulfate, isn’t very nucleophilic, and thus wouldn’t compete with the nitronium to react with the aromatic ring.
Following a similar reaction, sulfonation involves reacting sulfuric acid with itself to generate electrophilic hydrogen sulfur trioxide. This electrophilic species can then perform EAS, which results in a negatively charged oxygen after deprotonating the aromatic ring. Since unreacted sulfuric acid exists in the reaction mixture, this oxygen becomes protonated.
Sometimes, rather than replacing a hydrogen on the aromatic ring, an attacking electrophile instead replaces another substituent. Chemists call this “ipso-substitution” or “ipso-attack”. For instance, when performing nitration on salicylic acid, the incoming nitronium ion reacts with the carbon that has the carboxylic acid. This releases the carboxyl group from the ring as carbon dioxide.
Electrophilic Aromatic Substitution Regioselectivity
Interestingly, if an aromatic compound already has substituents and then performs EAS, the electrophile may be more likely to react with certain sites on the ring than others. This tendency of certain regions of a molecule being more likely to react than others is called regioselectivity.
The electron affinity of the substituents has the most influence over regioselectivity in aromatic electrophilic substitution. Specifically, in monosubstituted benzene, electron-withdrawing groups are called meta directors. This means that electrophiles have higher reactivity with carbons two spots away from the substituent. Conversely, electron-donating groups are called para/ortho directors. This means that electrophiles have higher reactivity with carbons adjacent (ortho) or opposite (para) the substituent. These relationships between substituents and regioselectivity inform synthesis reaction pathways involving aromatic substances.
The reason why certain groups make certain carbons more reactive to electrophiles comes from resonance. Let’s take a closer look.
As mentioned before, electron-withdrawing groups, such as carbonyls, halides, and nitro groups, direct electrophiles to bond with meta carbons. This comes from partial positive charges placed on the carbons ortho and para to the withdrawing group, coming from the molecule’s resonance forms. As a result, the non-meta carbons electrostatically repulse electrophiles, making meta carbons relatively more reactive in EAS. However, chemists use the term “deactivating group” to describe these meta directors, because benzene with an electron-withdrawing group has significantly less overall reactivity than unsubstituted benzene, due to decreasing electron density on the ring structure.
Electron donating groups, such as hydrocarbons, alcohols, acetates, and aminos, direct electrophiles to bond to ortho and para carbons. This comes from partial negative charges placed on the carbons ortho and para to the donating group, coming from the molecule’s resonance forms. As a result, ortho and para groups electrostatically attract electrophiles. Additionally, chemists call donating groups “activating groups” because they add electron density to the aromatic ring, making it more reactive than unsubstituted benzene toward electrophiles.
Given an electron donating group, an electrophile may preferentially react with the para carbon over the ortho carbons or vice versa. This level of regioselectivity depends on the sterics of the donating group. If the group is large and bulky, electrophiles preferentially react with the para carbon because the bulk of the donating group sterically hinders an incoming molecule from interacting with the adjacent ortho carbons.
Conversely, if the group is small with little steric effect, electrophiles are more likely to perform a substitution on the ortho carbons because benzenes have two ortho carbons and only one para carbon. Specifically, the electrophile would have an equal likelihood of reacting with the two ortho carbons and one para carbon, so the product mix would involve 67% ortho product and 33% para product.