16.3 Alkylation and Acylation of Aromatic Rings: The Friedel–Crafts Reaction
3 min read•may 7, 2024
Friedel-Crafts reactions are key players in organic synthesis, allowing us to add alkyl or acyl groups to aromatic rings. These reactions use catalysts to create electrophiles that attack the ring, forming new carbon-carbon bonds.
Understanding the mechanisms and factors affecting Friedel-Crafts reactions is crucial. From to potential rearrangements, these reactions offer both challenges and opportunities for creating diverse aromatic compounds in the lab and in nature.
Friedel-Crafts Alkylation
Mechanism of Friedel-Crafts alkylation
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- reaction introduces an alkyl group onto an aromatic ring
- Involves an (R-X) and an with a catalyst ()
- Lewis acid () reacts with (R-X) forming a () and
- Electrophilic carbocation attacks the aromatic ring forming a resonance-stabilized intermediate
- Proton loss from arenium ion restores yielding the alkylated aromatic product
- Lewis acid catalyst generates the electrophilic carbocation species by reacting with the alkyl halide
- Catalyst serves as an electron pair acceptor stabilizing the arenium ion intermediate
- Rearrangement of carbocations can lead to a mixture of products (isomers)
- Multiple alkylations can occur resulting in polyalkylated products ()
- Intramolecular alkylation can form cyclic products ()
- Deactivated aromatic rings with electron-withdrawing groups () are less reactive towards alkylation
- Regioselectivity of the reaction is influenced by the substituents on the aromatic ring
Comparison of Friedel-Crafts Alkylation and Acylation
Alkylation vs acylation in Friedel-Crafts
- Both are reactions requiring a Lewis acid catalyst ()
- Both involve the formation of a resonance-stabilized arenium ion intermediate
- Alkylation uses an alkyl halide (R-X) as the electrophile while acylation uses an (RCO-X)
- Alkylation forms a new C-C single bond while acylation forms a new C-C(O) bond (ketone)
- Acylation is more selective and does not typically result in multiple substitutions or rearrangements
- yields an alkylated aromatic compound ()
- yields an aromatic ketone ()
Biological Aromatic Alkylations
Biological aromatic alkylations
- Occur without the need for metal catalysts like
- Enzymes catalyze these reactions by:
- Activating the electrophile through the formation of reactive intermediates
- Stabilizing the transition state and arenium ion intermediate
- Providing a specific orientation for the substrates to facilitate the reaction
- Biosynthesis of () involves an aromatic alkylation step
- Catalyzed by the enzyme
- Alkylation of with (isoprenoid) forms
- Enzyme active site facilitates the reaction by:
- Binding and orienting the substrates for optimal reaction
- Activating the isoprenoid electrophile through the formation of a carbocation intermediate
- Stabilizing the arenium ion intermediate formed during the alkylation step
Factors Affecting Friedel-Crafts Reactions
Key considerations in Friedel-Crafts reactions
- Aromaticity of the substrate is crucial for the reaction to proceed
- of the arenium ion intermediate affects reaction rate and product distribution
- can occur, leading to unexpected products
- The nature of the electrophile (alkyl or acyl) influences reaction outcome and selectivity
Key Terms to Review (34)
1,4-dihydroxy-2-naphthoate: 1,4-dihydroxy-2-naphthoate is a chemical compound that consists of a naphthalene ring structure with two hydroxyl groups attached at the 1 and 4 positions, and a carboxylate group at the 2 position. This compound is relevant in the context of the Friedel-Crafts reaction, which is a type of electrophilic aromatic substitution.
1,4-dihydroxy-2-naphthoate prenyltransferase: 1,4-dihydroxy-2-naphthoate prenyltransferase is an enzyme that catalyzes the prenylation of 1,4-dihydroxy-2-naphthoate, an important step in the biosynthesis of secondary metabolites in certain organisms. This enzyme is particularly relevant in the context of the Friedel-Crafts reaction, which is a type of electrophilic aromatic substitution that can be used to alkylate or acylate aromatic rings.
2-phytyl-1,4-naphthoquinone: 2-phytyl-1,4-naphthoquinone is a naturally occurring organic compound that is a derivative of 1,4-naphthoquinone, with a phytyl group (a long hydrocarbon chain) attached at the 2-position. It is an important component in the structure of vitamin K1, also known as phylloquinone, which is essential for blood clotting and other physiological processes.
Acetophenone: Acetophenone is an aromatic ketone compound with the chemical formula C6H5COCH3. It is a colorless liquid with a characteristic floral odor and is widely used in the production of various organic compounds and as a fragrance in personal care products.
Acyl Halide: An acyl halide is a functional group consisting of a carbonyl carbon bonded to a halogen atom, typically chlorine, bromine, or iodine. These compounds are highly reactive and are commonly used as intermediates in organic synthesis, particularly in reactions involving the acylation of aromatic rings.
Acylated: Acylation is the process in which an acyl group is introduced to a molecule, often seen in the context of attaching to an aromatic ring via electrophilic aromatic substitution reactions. In organic chemistry, this typically involves the use of an acyl chloride and an aluminum chloride catalyst in what is known as the Friedel–Crafts acylation reaction.
Acylium ion: An acylium ion is a positively charged ion with the general formula RCO+, where R is an alkyl or aryl group, and it forms during the Friedel–Crafts acylation reaction when an acyl chloride reacts with a Lewis acid catalyst. It acts as an electrophile in electrophilic aromatic substitution reactions, attacking the aromatic ring to form a new carbon-carbon bond.
AlCl3-assisted: In the context of organic chemistry, particularly in the Friedel–Crafts reaction, AlCl3-assisted refers to the role of aluminum chloride (AlCl3) as a catalyst that facilitates the alkylation or acylation of aromatic rings. This process enhances the reactivity of an aromatic compound, allowing it to form new bonds with alkyl or acyl groups.
Alkyl halide: An alkyl halide is an organic compound in which one or more hydrogen atoms in an alkane (saturated hydrocarbon) have been replaced by a halogen atom (fluorine, chlorine, bromine, or iodine). This substitution results in a molecule with distinct chemical and physical properties compared to its alkane precursor.
Alkyl Halide: An alkyl halide is a type of organic compound that consists of an alkyl group (a hydrocarbon chain) bonded to a halogen atom (fluorine, chlorine, bromine, or iodine). These compounds are important intermediates in many organic reactions, including polar reactions, elimination reactions, and substitution reactions.
Aluminum Chloride: Aluminum chloride (AlCl3) is a Lewis acid compound that is widely used in organic chemistry, particularly in the Friedel-Crafts alkylation and acylation reactions, as well as in the synthesis of polysubstituted benzenes.
Arenium Ion: The arenium ion, also known as the arene cation, is a positively charged intermediate species that arises during electrophilic aromatic substitution reactions. It is a key concept in understanding the mechanisms of various aromatic substitution reactions, including bromination, other aromatic substitutions, and the Friedel-Crafts reactions.
Aromatic Compound: Aromatic compounds are a class of cyclic organic molecules that exhibit unusual stability and reactivity due to the presence of a delocalized system of pi electrons within a planar ring structure. These compounds are characterized by their ability to undergo electrophilic aromatic substitution reactions, which is a key feature in the context of the Friedel-Crafts reaction.
Aromaticity: Aromaticity is a fundamental concept in organic chemistry that describes the unique stability and reactivity of certain cyclic compounds with delocalized pi electron systems. This term is central to understanding the structure, stability, and reactivity of a wide range of organic compounds, including benzene and other aromatic heterocycles.
Carbocation: A carbocation is a positively charged carbon atom that is part of an organic molecule. These reactive intermediates play a crucial role in various organic reactions, including electrophilic additions, nucleophilic substitutions, and elimination reactions.
Carbocation Rearrangement: Carbocation rearrangement is a process in organic chemistry where a carbocation, a positively charged carbon atom, undergoes a structural change to form a more stable carbocation. This rearrangement is particularly relevant in the context of understanding carbocation stability and the Friedel-Crafts reaction.
Electrophile: An electrophile is a species that is attracted to electron-rich regions and seeks to form new bonds by accepting electron density. Electrophiles play a crucial role in many organic reactions, including polar reactions, electrophilic aromatic substitution, and nucleophilic acyl substitution, among others.
Electrophilic aromatic substitution: Electrophilic aromatic substitution is a chemical reaction in which an atom, typically hydrogen, attached to an aromatic system, such as benzene, is replaced by an electrophile. This process preserves the aromaticity of the compound while introducing a functional group.
Electrophilic Aromatic Substitution: Electrophilic aromatic substitution is a fundamental organic reaction in which an electrophile (a species that is attracted to electrons) replaces a hydrogen atom on an aromatic ring, resulting in the formation of a new carbon-electrophile bond. This reaction is crucial in understanding the behavior and reactivity of aromatic compounds, which are prevalent in many organic molecules and have widespread applications.
Ethylbenzene: Ethylbenzene is an aromatic hydrocarbon compound with the chemical formula C6H5CH2CH3. It is a colorless, flammable liquid with a distinctive petrol-like odor. Ethylbenzene is an important industrial chemical with applications in the production of other organic compounds and the synthesis of various materials.
Friedel-Crafts Acylation: Friedel-Crafts acylation is a type of electrophilic aromatic substitution reaction in organic chemistry where an acyl group is introduced onto an aromatic ring in the presence of a Lewis acid catalyst. This reaction is used to synthesize aromatic ketones and is an important tool in the construction of more complex organic molecules.
Friedel-Crafts Alkylation: Friedel-Crafts alkylation is an electrophilic aromatic substitution reaction that allows for the alkylation of aromatic rings. It involves the use of a Lewis acid catalyst, typically aluminum chloride (AlCl3), to facilitate the addition of an alkyl group to the aromatic ring, resulting in the formation of a new carbon-carbon bond.
Friedel–Crafts reaction: The Friedel–Crafts reaction is a method used in organic chemistry to attach alkyl or acyl groups to an aromatic ring, utilizing a Lewis acid catalyst. This process transforms benzene and its derivatives by alkylation (adding alkyl groups) or acylation (adding acyl groups), enhancing the molecule's complexity and functional utility.
Geranylgeranyl Diphosphate: Geranylgeranyl diphosphate is a key intermediate in the biosynthesis of various terpenoid compounds, including carotenoids, chlorophyll, and certain plant hormones. It also plays a role in the Friedel-Crafts alkylation and acylation reactions of aromatic rings.
Indanes: Indanes are a class of organic compounds that consist of a benzene ring fused to a cyclopentane ring. They are structurally related to indenes, with the key difference being the presence of a saturated cyclopentane ring instead of an unsaturated cyclopentene ring. Indanes are commonly encountered in the context of Friedel-Crafts alkylation and acylation reactions.
Lewis acid: A Lewis acid is a chemical species that accepts an electron pair from another molecule during the formation of a covalent bond. Unlike the traditional concept of acids and bases, which focuses on proton donors and acceptors, the Lewis definition emphasizes the role of electron pair donors and acceptors.
Lewis Acid: A Lewis acid is an electron pair acceptor that can form a coordinate covalent bond with a Lewis base, which is an electron pair donor. Lewis acids play a crucial role in various organic chemistry reactions, including electrophilic aromatic substitution, the Friedel-Crafts reaction, and cyanohydrin formation.
Nitrobenzene: Nitrobenzene is an aromatic organic compound with the chemical formula C6H5NO2. It is a pale yellow oily liquid with a distinctive almond-like odor. Nitrobenzene is an important industrial chemical and an intermediate in the production of various pharmaceuticals, dyes, and other organic compounds.
Phylloquinone: Phylloquinone, also known as vitamin K1, is a fat-soluble vitamin that plays a crucial role in blood clotting and bone health. It is primarily involved in the Friedel-Crafts alkylation and acylation reactions, which are important organic chemistry reactions used in the synthesis of various compounds.
Polyalkylation: Polyalkylation is a type of electrophilic aromatic substitution reaction where multiple alkyl groups are introduced onto an aromatic ring. It is a key aspect of the Friedel-Crafts alkylation reaction, which is used to synthesize a wide range of alkylated aromatic compounds.
Regioselectivity: Regioselectivity refers to the preference of a chemical reaction to occur at a specific site or region of a molecule, leading to the formation of one regioisomeric product over another. This concept is particularly important in the context of electrophilic addition reactions of alkenes, electrophilic aromatic substitution, and other organic transformations.
Resonance Stabilization: Resonance stabilization is a phenomenon where the delocalization of electrons in a molecule or ion leads to a more stable configuration compared to a single Lewis structure. This concept is crucial in understanding the behavior and properties of various organic compounds, including their acidity, basicity, reactivity, and stability.
Vitamin K1: Vitamin K1, also known as phylloquinone, is an essential nutrient that plays a crucial role in blood clotting and bone health. It is the primary form of vitamin K found in the diet and is primarily derived from green leafy vegetables and certain plant-based oils.
Xylenes: Xylenes are a group of aromatic hydrocarbon compounds with the chemical formula C8H10. They are isomeric compounds, meaning they have the same molecular formula but different arrangements of atoms. Xylenes are particularly relevant in the context of alkylation and acylation of aromatic rings through the Friedel-Crafts reaction.