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Organic Chemistry
Table of Contents
Unit 16 Overview: Benzene: Electrophilic Aromatic Substitution
16.1 Electrophilic Aromatic Substitution Reactions: Bromination
16.2 Other Aromatic Substitutions
16.3 Alkylation and Acylation of Aromatic Rings: The Friedel–Crafts Reaction
16.4 Substituent Effects in Electrophilic Substitutions
16.5 Trisubstituted Benzenes: Additivity of Effects
16.6 Nucleophilic Aromatic Substitution
16.7 Benzyne
16.8 Oxidation of Aromatic Compounds
16.9 Reduction of Aromatic Compounds
16.10 Synthesis of Polysubstituted Benzenes

Polysubstituted benzenes are key players in organic synthesis. They're made through electrophilic aromatic substitution, where hydrogen atoms on benzene rings are swapped out for other groups. Planning these reactions involves working backwards from the end product, considering how existing groups affect new additions.

Directing effects of substituents are crucial in benzene synthesis. Activating groups make the ring more reactive and guide new groups to specific spots. Deactivating groups do the opposite. Understanding these effects helps chemists plan smart synthetic routes and avoid unwanted products.

Synthesis of Polysubstituted Benzenes

Synthetic routes for polysubstituted benzenes

  • Electrophilic aromatic substitution (EAS) reactions replace hydrogen atoms on benzene rings with electrophiles (halogenation, nitration, sulfonation, Friedel-Crafts alkylation/acylation)
  • Plan synthetic routes by determining desired final product and working backwards to starting material
  • Consider directing effects of existing substituents on benzene ring when choosing reagents and reaction conditions for each step
  • Examples of EAS reactions in synthesis:
    • Chlorination using $\ce{Cl2}$ with $\ce{FeCl3}$ catalyst
    • Nitration using $\ce{HNO3}$ and $\ce{H2SO4}$
    • Sulfonation using $\ce{H2SO4}$ or $\ce{SO3}$
    • Friedel-Crafts alkylation using $\ce{RCl}$ with $\ce{AlCl3}$ catalyst
    • Friedel-Crafts acylation using $\ce{RCOCl}$ with $\ce{AlCl3}$ catalyst

Directing effects in benzene synthesis

  • Activating groups $\ce{(-OH, -OR, -NH2, -NHR, -NR2)}$ increase reactivity of benzene ring towards EAS reactions and direct incoming electrophiles to ortho and para positions
  • Deactivating groups $\ce{(-NO2, -CN, -SO3H, -COOH, -COR, -COOR, -CHO)}$ decrease reactivity of benzene ring towards EAS reactions and direct incoming electrophiles to meta position
    • Exception: Halogens $\ce{(-F, -Cl, -Br, -I)}$ are ortho/para directors despite being deactivating
  • Bulky substituents can hinder approach of incoming electrophiles to ortho positions due to steric effects, leading to preference for para substitution
  • Plan synthetic routes by considering directing effects of substituents:
    • Introduce activating groups early to facilitate subsequent EAS reactions
    • Install deactivating groups later to avoid complications
  • Substituent effects influence the overall reactivity and regioselectivity of the benzene ring

Analysis of aromatic synthesis schemes

  • Identify incompatible reagents that may react with existing substituents and lead to undesired products
    • Using $\ce{Br2}$ in presence of phenol can result in bromination of $\ce{-OH}$ group
  • Recognize incorrect reaction order that can lead to formation of undesired isomers or prevent desired transformation
    • Attempting nitration before sulfonation may yield mixture of ortho and para nitro compounds
  • Consider overlooked directing effects of substituents that can lead to formation of undesired isomers
    • Friedel-Crafts alkylation on nitrobenzene will result in meta isomer, not desired para isomer
  • Assess steric hindrance from bulky substituents that can prevent desired reaction or lead to unexpected products
    • Installing large substituent at ortho position of heavily substituted benzene ring may be unsuccessful
  • Anticipate purification difficulties from synthetic routes that form byproducts challenging to separate from desired product
    • Friedel-Crafts alkylation can result in polyalkylation, difficult to separate from monoalkylated product

Aromaticity and Reactivity

  • Benzene's unique stability is due to its aromaticity, resulting from the delocalization of electrons in its resonance structures
  • The aromatic character of benzene influences its reactivity in substitution reactions
  • Nucleophilic aromatic substitution can occur in highly electron-deficient aromatic systems, complementing electrophilic aromatic substitution in synthesis strategies

Key Terms to Review (32)

Ortho (o): In organic chemistry, specifically within the context of benzene and aromaticity, "ortho" (abbreviated as "o") indicates that two substituents on a benzene ring are adjacent to each other, meaning they are positioned on carbon atoms that are next to one another. This term is part of the nomenclature used in naming aromatic compounds where the spatial arrangement of atoms is crucial for identifying chemical structures.
Nucleophilic aromatic substitution reactions: Nucleophilic aromatic substitution reactions are a class of chemical reactions where an electron-rich nucleophile selectively replaces a leaving group (usually a halogen) on an aromatic ring. This reaction differs from the more common electrophilic aromatic substitution by involving a nucleophile attacking an aromatic system that typically contains an electron-withdrawing group to facilitate the substitution.
Deactivating groups: In the context of electrophilic aromatic substitution reactions, deactivating groups are substituents attached to a benzene ring that decrease the reactivity of the ring towards an electrophile. They accomplish this by either withdrawing electron density from the ring or by being meta-directing in orientation.
Para (p): In the context of organic chemistry, specifically when discussing benzene and aromaticity, "para" refers to the positioning of substituents on a benzene ring where they are located opposite each other, with two carbon atoms between them. This is one of the configurations used in naming aromatic compounds based on their structure.
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.
Carboxyl group: A carboxyl group is a functional group consisting of a carbon atom double-bonded to an oxygen atom and single-bonded to a hydroxyl group (-COOH). It is characteristic of carboxylic acids, giving these compounds their acidic properties.
Resonance: Resonance is a fundamental concept in organic chemistry that describes the ability of certain molecules to exist in multiple equivalent structures or resonance forms. This phenomenon arises from the delocalization of electrons within the molecule, leading to the stabilization of the overall structure and the distribution of electron density across multiple atoms.
Benzene: Benzene is a planar, aromatic hydrocarbon compound with the chemical formula C6H6. It is a key building block in organic chemistry and has a unique resonance structure that contributes to its stability and reactivity.
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.
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.
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.
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.
Halogenation: Halogenation is the process of introducing a halogen atom (fluorine, chlorine, bromine, or iodine) into an organic compound, typically through a substitution or addition reaction. This term is closely tied to various topics in organic chemistry, including functional groups, alkane properties, reaction mechanisms, and the reactivity of different classes of organic compounds.
Substituent Effects: Substituent effects refer to the influence that specific functional groups or atoms have on the chemical and physical properties of a molecule. These effects can significantly impact the reactivity, stability, and behavior of organic compounds in various contexts, including conformational analysis, electrophilic and nucleophilic substitutions, and acidity determination.
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.
Halogens: Halogens are a group of five highly reactive nonmetal elements in the periodic table, including fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and astatine (At). They are known for their strong oxidizing properties and ability to form a wide range of compounds with other elements.
Steric Effects: Steric effects refer to the influence of the spatial arrangement and size of atoms or functional groups on the chemical and physical properties of a molecule. These spatial factors can impact reactivity, stability, and spectroscopic characteristics of chemical compounds.
Deactivating Groups: Deactivating groups are substituents on an aromatic ring that decrease the reactivity of the ring towards electrophilic aromatic substitution reactions. These groups make the aromatic ring less susceptible to further substitution by electrophiles.
Sulfonation: Sulfonation is a chemical reaction in which a sulfonic acid group (-SO3H) is introduced into an organic compound, typically an aromatic compound. This process is widely used in the synthesis of various sulfonated compounds, which have diverse applications in the chemical industry.
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.
Nitration: Nitration is a chemical reaction in which a nitro group (-NO2) is introduced into an organic compound, typically an aromatic ring structure. This process is widely used in the synthesis of various pharmaceuticals, explosives, and other important chemical products.
Nucleophilic Aromatic Substitution: Nucleophilic aromatic substitution is a reaction in organic chemistry where a nucleophile replaces a leaving group on an aromatic ring, typically a halogen or nitro group. This process is crucial in understanding the reactivity and synthesis of various aromatic compounds, including heterocyclic systems and polysubstituted benzenes.
Activating Groups: Activating groups are substituents on an aromatic ring that increase the reactivity of the ring towards electrophilic aromatic substitution reactions. These groups facilitate the addition of electrophiles to the aromatic system by stabilizing the intermediate carbocation formed during the reaction.
Nitro Group: The nitro group (−NO2) is a functional group consisting of a nitrogen atom double-bonded to two oxygen atoms. It is an important substituent in organic chemistry, known for its ability to influence the reactivity and properties of aromatic compounds.
Ferric Chloride: Ferric chloride, also known as iron(III) chloride, is an inorganic compound with the chemical formula FeCl3. It is a common reagent used in various organic chemistry reactions, particularly in the context of the synthesis of polysubstituted benzenes.
Chlorination: Chlorination is a chemical process that involves the introduction of chlorine atoms into organic compounds, particularly aromatic compounds like benzene. This process is widely used in various chemical reactions and transformations, including the synthesis of polysubstituted benzenes and the reactions of phenols.
Meta: The term 'meta' is a prefix that denotes something of a higher or more comprehensive nature, often referring to an abstract or self-referential concept. In the context of organic chemistry, the term 'meta' is particularly relevant in the synthesis of polysubstituted benzenes and the understanding of substituent effects on acidity.
Sulfonyl Group: The sulfonyl group (−SO2−) is a functional group consisting of a sulfur atom double-bonded to two oxygen atoms. It is an important moiety in organic chemistry, particularly in the context of the synthesis of polysubstituted benzenes.
Ortho: Ortho refers to the positioning of substituents on a benzene ring, specifically when they are located adjacent to each other, or in the 1,2-position. This term is particularly relevant in the context of the synthesis of polysubstituted benzenes and the effects of substituents on the acidity of aromatic compounds.
Para: The term 'para' refers to a specific spatial arrangement of substituents on an aromatic ring. It describes a 1,4-disubstituted benzene, where two substituents are positioned directly across from each other on the ring.
Carboxyl Group: The carboxyl group is a functional group consisting of a carbon atom double-bonded to an oxygen atom and single-bonded to a hydroxyl group (-COOH). It is a key structural feature in various organic compounds, including carboxylic acids, amino acids, and proteins, and plays a crucial role in their chemical reactivity and properties.
Carbonyl group: A carbonyl group is a functional group characterized by a carbon atom double-bonded to an oxygen atom, represented as C=O. This group is pivotal in organic chemistry as it forms the backbone of various important classes of compounds, influencing their chemical properties and reactivity.