The Friedel-Crafts (FC) reaction is a foundational method in organic chemistry used to attach carbon chains to aromatic rings via electrophilic aromatic substitution. This process is categorized into two main types: alkylation, which adds an alkyl group, and acylation, which introduces an acyl group. In both cases, the aromatic ring acts as an electron source, attacking a highly reactive, positively charged electrophile.
The reaction requires a strong Lewis acid catalyst, commonly anhydrous aluminum chloride (\(\text{AlCl}_3\)), to generate the electrophile from an alkyl or acyl halide. The Lewis acid coordinates with the halogen, weakening the carbon-halogen bond and facilitating the formation of a carbocation or a resonance-stabilized acylium ion. While widely used, the success of this methodology is highly sensitive to the electronic nature of the reactants and specific structural limitations.
Aromatic Rings with Deactivating Groups
The efficiency of the Friedel-Crafts reaction depends on the electron density of the aromatic ring, as the initial step involves an attack by the ring’s pi electrons. If the ring contains a strong electron-withdrawing group (EWG), the reaction rate drops to near zero. Strong EWGs, such as the nitro (\(\text{NO}_2\)), cyano (\(\text{CN}\)), or sulfonic acid (\(\text{SO}_3\text{H}\)) groups, pull electron density away from the ring through inductive and resonance effects.
This reduction in electron density makes the aromatic ring significantly less nucleophilic, meaning it is no longer attracted to the electrophile. The presence of a strong EWG also destabilizes the cationic intermediate (the arenium ion) required by the mechanism, making its formation energetically unfavorable.
The Friedel-Crafts reaction generally fails on any aromatic ring less reactive than a monohalobenzene. For instance, nitrobenzene, a strongly deactivated ring, cannot undergo either Friedel-Crafts alkylation or acylation. The reaction is only practical on benzene or rings containing weak deactivating groups (like halogens) or activating groups.
Complexation with Basic Substituents
A distinct mode of failure occurs when the aromatic ring contains a strongly basic functional group, leading to catalyst poisoning. Groups with readily available lone pairs of electrons, such as the amino (\(\text{NH}_2\)) or hydroxyl (\(\text{OH}\)) groups, fall into this category. The Lewis acid catalyst, like \(\text{AlCl}_3\), preferentially reacts with these basic groups instead of the alkyl or acyl halide.
This acid-base reaction forms a stable, unreactive complex, consuming the Lewis acid and rendering it incapable of generating the required electrophile. For example, when aniline is subjected to Friedel-Crafts conditions, the amino group coordinates with the \(\text{AlCl}_3\) to form a salt-like adduct, sequestering the Lewis acid.
The complexation further exacerbates the problem by transforming the activating amino group into a powerful deactivating group. The positive charge generated on the nitrogen atom (\(\text{N}^+\text{H}_2\text{AlCl}_3^-\)) acts as an extreme electron-withdrawing group. This double failure—catalyst consumption and extreme ring deactivation—makes Friedel-Crafts reactions impossible on substrates like aniline and many phenols.
Constraints on Halide Reactants
The nature of the halide reactant imposes strict limitations on the Friedel-Crafts process. The halide must be capable of generating a stable, highly reactive electrophile in the presence of the Lewis acid catalyst. This requirement excludes the use of vinyl halides (\(\text{C=C-X}\)) and aryl halides (\(\text{Ar-X}\)) from the alkylation reaction.
In these halides, the halogen is directly bonded to an \(\text{sp}^2\)-hybridized carbon atom, resulting in a stronger carbon-halogen bond that is difficult to cleave. This prevents the formation of the necessary carbocation. The resulting vinyl or phenyl carbocations are highly unstable because the positive charge would reside on an \(\text{sp}^2\) orbital, which is energetically unfavorable.
Consequently, the Lewis acid cannot generate the electrophile required for the electrophilic aromatic substitution. The reaction only proceeds effectively when the halogen is attached to an \(\text{sp}^3\)-hybridized carbon, as in standard alkyl halides. This structural requirement dictates which starting materials can be used.
Rearrangement and Over-Alkylation
The Friedel-Crafts alkylation variant is subject to two major practical limitations: carbocation rearrangement and over-alkylation, which compromise product purity and yield. Carbocation rearrangement is unique to alkylation, where the intermediate carbocation shifts to a more stable structure before attacking the aromatic ring. For instance, an unstable primary carbocation often undergoes a 1,2-hydride or 1,2-methyl shift to form a more stable secondary or tertiary carbocation.
If \(n\)-propyl chloride is used to introduce a linear propyl group, the initial primary carbocation quickly rearranges to the more stable secondary isopropyl carbocation. The resulting product is isopropylbenzene (cumene) instead of the desired \(n\)-propylbenzene. This rearrangement issue is bypassed in Friedel-Crafts acylation because the resonance-stabilized acylium ion electrophile does not rearrange.
The second issue, polyalkylation, occurs because an alkyl group is an electron-donating substituent that activates the aromatic ring toward further electrophilic attack. Once the first alkyl group is added, the product is more reactive than the starting material. This leads to the rapid addition of multiple alkyl groups (polysubstitution). In contrast, the acyl group added during acylation is deactivating, ensuring the reaction typically stops after a single substitution.