Which Of The Following Compounds Does Not Undergo Friedel-crafts Reaction

Friedel-Crafts reactions, cornerstones in organic chemistry, offer a powerful method for attaching substituents to aromatic rings. However, the versatility of this reaction is limited by the structure and properties of the aromatic compound itself. Not all compounds are suitable candidates for Friedel-Crafts alkylation or acylation. Understanding the factors that inhibit these reactions is crucial for planning and executing successful syntheses. This article will delve into the reasons why certain compounds are unreactive towards Friedel-Crafts conditions, providing a comprehensive overview for students and chemists alike.

Introduction to Friedel-Crafts Reactions

Friedel-Crafts reactions, named after Charles Friedel and James Crafts, are a set of electrophilic aromatic substitution reactions used for the attachment of substituents to aromatic rings. There are two primary types:

• Friedel-Crafts Alkylation: Involves the substitution of a hydrogen atom on an aromatic ring with an alkyl group using an alkyl halide and a Lewis acid catalyst, such as aluminum chloride (AlCl3).
• Friedel-Crafts Acylation: Involves the substitution of a hydrogen atom on an aromatic ring with an acyl group (R-C=O) using an acyl halide or anhydride and a Lewis acid catalyst.

These reactions are invaluable for synthesizing a wide array of aromatic compounds, which serve as building blocks in pharmaceuticals, polymers, and various other industrial applications.

The Mechanism of Friedel-Crafts Reactions

To understand why certain compounds do not undergo Friedel-Crafts reactions, it's essential to review the underlying mechanisms:

1. Formation of the Electrophile: The Lewis acid catalyst (e.g., AlCl3) reacts with the alkyl or acyl halide to generate a strong electrophile. In alkylation, a carbocation is formed, while in acylation, an acylium ion is generated.
2. Electrophilic Attack: The electrophile attacks the π-electron system of the aromatic ring, forming a σ-complex (also known as an arenium ion or Wheland intermediate). This intermediate is resonance-stabilized but disrupts the aromaticity of the ring.
3. Proton Abstraction: A base (often a chloride ion from AlCl3) abstracts a proton from the carbon atom that bears the electrophile, regenerating the aromatic ring and forming the alkylated or acylated product.

Compounds That Do Not Undergo Friedel-Crafts Reactions

Several classes of compounds are either unreactive or give very poor yields in Friedel-Crafts reactions. These limitations arise from electronic, steric, or reactivity issues related to the aromatic ring or the reaction conditions. Here are the key categories:

1. Aromatic Rings with Strongly Deactivating Groups

   Aromatic rings substituted with strong electron-withdrawing groups (EWG) are generally unreactive towards Friedel-Crafts reactions. These groups significantly reduce the electron density of the aromatic ring, making it less nucleophilic and thus less susceptible to electrophilic attack.

   • Nitrobenzene: The nitro group (-NO2) is a powerful electron-withdrawing group. It deactivates the aromatic ring by withdrawing electron density through both inductive and resonance effects. This makes nitrobenzene and other nitroaromatics unsuitable substrates for Friedel-Crafts reactions.
   • Aromatic Compounds with Carbonyl Groups: Groups such as ketones (-C=O), carboxylic acids (-COOH), esters (-COOR), and amides (-CONR2) are also deactivating. The electronegativity of the oxygen atoms in these groups withdraws electron density from the ring, diminishing its reactivity towards electrophiles.
   • Cyano Group: The cyano group (-CN) is another strong deactivating group that renders the aromatic ring unreactive.

2. Aromatic Amines (Aniline and Derivatives)

   Aromatic amines, such as aniline (C6H5NH2), do not undergo Friedel-Crafts reactions due to a different set of issues. The nitrogen atom in aniline has a lone pair of electrons that can react with the Lewis acid catalyst.

   • Lewis Acid-Base Complex Formation: The lone pair on the nitrogen atom of aniline reacts with the Lewis acid (e.g., AlCl3) to form a stable complex. This complex effectively ties up the catalyst, preventing it from activating the alkyl or acyl halide.
   • Formation of a Meta-Directing Ammonium Ion: The protonation of the amine group by the Lewis acid results in an ammonium ion (-NH3+), which is a strong meta-directing group. Even if the reaction were to proceed, the product distribution would be unfavorable for most synthetic purposes.

3. Aromatic Rings with Strongly Activating Groups (Phenols and Derivatives)

   While it might seem counterintuitive, aromatic rings with very strong activating groups like phenols (-OH) and their derivatives also present challenges in Friedel-Crafts reactions.

   • Over-Activation and Polymerization: Strongly activating groups greatly enhance the nucleophilicity of the aromatic ring, leading to uncontrolled polyalkylation or polyacylation. The reaction becomes difficult to control, often resulting in a mixture of products, including polymers and other undesirable byproducts.
   • Reaction with Lewis Acid: Similar to amines, the oxygen atom in phenols can coordinate with the Lewis acid catalyst, forming a complex that reduces the catalyst's effectiveness.

4. Haloarenes (Fluorobenzene)

   While chlorine, bromine, and iodine are ortho- and para- directing and weakly deactivating, fluorobenzene presents a unique case. Fluorine is the most electronegative element, and its strong electron-withdrawing inductive effect deactivates the ring significantly.

   • Strong -I Effect: The strong inductive withdrawal of electron density by fluorine makes the aromatic ring less reactive towards electrophilic attack. This deactivation can be sufficient to prevent Friedel-Crafts reactions from occurring, especially under milder conditions.

5. Compounds That Promote Rearrangements

   Some alkyl halides are prone to carbocation rearrangements under Friedel-Crafts conditions. This can lead to a mixture of products, making the reaction synthetically useless.

   • Secondary and Tertiary Alkyl Halides: When using secondary or tertiary alkyl halides, the initially formed carbocation can rearrange to a more stable carbocation through hydride or alkyl shifts. For example, n-propyl chloride can rearrange to isopropyl chloride, leading to the formation of isopropylbenzene instead of n-propylbenzene.

6. Vinyl and Aryl Halides

   Vinyl halides (e.g., chloroethene) and aryl halides (e.g., chlorobenzene) do not readily undergo Friedel-Crafts alkylation.

   • Stability of Vinyl and Aryl Cations: The formation of vinyl or aryl cations is highly unfavorable due to their high energy. These cations are not stabilized by resonance and are therefore not formed under normal Friedel-Crafts conditions.

Specific Examples and Explanations

To further illustrate these points, let's examine some specific examples:

1. Nitrobenzene:

   • Reason: The nitro group (-NO2) is a strong electron-withdrawing group due to the resonance and inductive effects. The nitrogen atom carries a formal positive charge, pulling electron density away from the aromatic ring.
   • Explanation: This electron withdrawal drastically reduces the nucleophilicity of the aromatic ring, making it less reactive towards electrophilic attack. The electrophile finds it difficult to attack the electron-deficient ring, preventing the Friedel-Crafts reaction from occurring.

2. Aniline:

   • Reason: The lone pair of electrons on the nitrogen atom in aniline reacts with the Lewis acid catalyst (e.g., AlCl3), forming a complex.
   • Explanation: This complexation ties up the Lewis acid, preventing it from activating the alkyl or acyl halide. Furthermore, the protonation of aniline forms the anilinium ion (-NH3+), which is a strong meta-directing group, making the reaction unfavorable.

3. Phenol:

   • Reason: Phenol is highly activated due to the electron-donating effect of the hydroxyl group (-OH).
   • Explanation: While this activation might seem beneficial, it leads to over-activation of the ring, resulting in polyalkylation or polyacylation. Additionally, the oxygen atom in phenol can coordinate with the Lewis acid, reducing the catalyst's effectiveness and leading to complex product mixtures.

4. Fluorobenzene:

   • Reason: Fluorine is the most electronegative element, and it strongly withdraws electron density through inductive effects.
   • Explanation: This strong inductive withdrawal deactivates the aromatic ring, making it less susceptible to electrophilic attack. Although fluorine is ortho- and para- directing, its deactivating effect outweighs its directing influence in Friedel-Crafts reactions.

Alternative Strategies for Introducing Substituents

When a direct Friedel-Crafts reaction is not feasible due to the reasons discussed above, alternative synthetic strategies can be employed to introduce the desired substituents onto the aromatic ring. Some of these strategies include:

1. Electrophilic Aromatic Substitution with Modification:

   • Protecting Groups: For compounds with activating groups (e.g., phenols), protecting groups can be used to temporarily block the activating group, allowing the Friedel-Crafts reaction to proceed in a controlled manner. After the desired substitution, the protecting group can be removed to regenerate the original functional group.
   • Indirect Introduction: Instead of directly attaching the desired substituent, a precursor can be attached via Friedel-Crafts, followed by chemical transformation. For example, if you need an amino group on the ring but can't directly use aniline in Friedel-Crafts, you could add a nitro group, then reduce it to an amine.

2. Nucleophilic Aromatic Substitution (SNAr):

   • Activated Haloarenes: For aromatic rings activated by electron-withdrawing groups, nucleophilic aromatic substitution (SNAr) can be used to introduce substituents. This reaction involves the displacement of a leaving group (usually a halide) by a nucleophile.

3. Transition Metal-Catalyzed Cross-Coupling Reactions:

   • Suzuki, Heck, and Negishi Couplings: These reactions utilize transition metal catalysts (e.g., palladium) to couple aryl halides or triflates with various nucleophiles. These methods are highly versatile and can be used to introduce a wide range of substituents onto aromatic rings.

4. Sandmeyer Reaction:

   • Diazonium Salts: This reaction involves the conversion of an aromatic amine to a diazonium salt, which can then be reacted with various reagents to introduce substituents such as halides, cyano groups, or hydroxyl groups.

Experimental Considerations and Troubleshooting

Even when dealing with compounds that are generally considered suitable for Friedel-Crafts reactions, several experimental factors can affect the outcome. Here are some troubleshooting tips:

1. Catalyst Quality:

   • Fresh Catalyst: Ensure that the Lewis acid catalyst (e.g., AlCl3) is fresh and has not been exposed to moisture. AlCl3 is highly hygroscopic and can be deactivated by water.
   • Catalyst Loading: Use an appropriate amount of catalyst. Too little catalyst may result in a slow or incomplete reaction, while too much can lead to side reactions.

2. Solvent Selection:

   • Inert Solvent: Use an inert solvent such as dichloromethane (CH2Cl2), carbon disulfide (CS2), or nitrobenzene. The solvent should not react with the catalyst or the reactants.

3. Reaction Temperature:

   • Controlled Temperature: Control the reaction temperature carefully. Low temperatures may slow down the reaction, while high temperatures can lead to side reactions or decomposition.

4. Moisture Control:

   • Anhydrous Conditions: Ensure that all glassware and reagents are dry to prevent deactivation of the catalyst. Use a drying tube or perform the reaction under an inert atmosphere.

5. Substrate Purity:

   • Pure Reactants: Use pure starting materials to avoid side reactions and improve yields.

Conclusion

Friedel-Crafts reactions are powerful tools in organic synthesis, but their application is limited by the electronic and structural properties of the aromatic compounds involved. Compounds with strongly deactivating groups, aromatic amines, and certain phenols do not undergo Friedel-Crafts reactions due to reduced nucleophilicity, catalyst complexation, or over-activation. Understanding these limitations is essential for planning synthetic strategies and selecting appropriate reaction conditions. When direct Friedel-Crafts reactions are not feasible, alternative methods such as electrophilic aromatic substitution with modification, nucleophilic aromatic substitution, transition metal-catalyzed cross-coupling reactions, and Sandmeyer reactions can be employed to achieve the desired transformations. By carefully considering these factors, chemists can effectively navigate the challenges of aromatic substitution and synthesize a wide range of complex molecules.