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Organic Chemistry
Table of Contents
Unit 22 Overview: Carbonyl Alpha–Substitution Reactions
22.1 Keto–Enol Tautomerism
22.2 Reactivity of Enols: α-Substitution Reactions
22.3 Alpha Halogenation of Aldehydes and Ketones
22.4 Alpha Bromination of Carboxylic Acids
22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation
22.6 Reactivity of Enolate Ions
22.7 Alkylation of Enolate Ions

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22.2 Reactivity of Enols: α-Substitution Reactions

Citation:

Enols pack a punch in organic reactions, acting as powerful nucleophiles thanks to their electron-rich double bond and hydroxyl group. They're more reactive than regular alkenes, eagerly attacking electrophiles to form new bonds at the α-carbon position.

When enols meet electrophiles, it's a dance of electrons. The α-carbon launches an attack, forming a cation intermediate that's stabilized by resonance. This can lead to different outcomes, from simple substitutions to more complex transformations like halogenation or aldol reactions.

Enol Reactivity and α-Substitution Reactions

Nucleophilic behavior of enols

  • Enols act as nucleophiles due to the electron-rich carbon-carbon double bond and the presence of a hydroxyl group
    • Electron density from the double bond makes the α-carbon nucleophilic and reactive towards electrophiles (alkyl halides, aldehydes)
    • Hydroxyl group enhances nucleophilicity of the α-carbon through resonance stabilization distributes negative charge
  • Enols are more nucleophilic and reactive towards electrophiles compared to alkenes
    • Resonance stabilization of the intermediate cation formed during the reaction with electrophiles lowers activation energy
    • Hydroxyl group stabilizes the positive charge on the intermediate cation facilitating the reaction progress
  • Enols exist in equilibrium with their keto form through keto-enol tautomerism

Mechanism of enol-electrophile reactions

  • Nucleophilic attack of the enol's α-carbon on the electrophile initiates the reaction
    • Electrons from the carbon-carbon double bond attack the electrophilic center forming a new covalent bond
  • Formation of an intermediate cation results from the electrophilic attack
    • Positive charge is stabilized by resonance delocalization between the α-carbon and the oxygen atom of the hydroxyl group
  • Intermediate cation undergoes subsequent steps based on the reaction conditions and the nature of the electrophile
    1. Deprotonation by a base removes the proton from the hydroxyl group yielding a neutral α-substituted carbonyl compound
    2. Nucleophilic attack on the electrophilic α-carbon by a nucleophile generates an α-substituted product incorporating the nucleophile
  • In some reactions, an enolate intermediate may form, which is more reactive than the enol

Enols vs alkenes in electrophilic reactions

  • Regioselectivity differs between alkene and enol reactions with electrophiles
    • Alkenes follow Markovnikov's rule forming the more stable carbocation intermediate leading to the major product (propene, HCl)
    • Enols are directed by the hydroxyl group position guiding the electrophile to the α-carbon
  • Product formation varies for alkenes and enols reacting with electrophiles
    • Alkenes undergo addition of the electrophile across the double bond resulting in a saturated product (bromoethane from ethene and Br2)
    • Enols experience substitution of the α-hydrogen with the electrophile forming an α-substituted carbonyl compound (α-bromoketone from ketone enol and Br2)
  • Stereochemistry of the products can differ between alkene and enol electrophilic reactions
    • Alkenes may produce stereoisomers depending on the structure of the reactants (cis/trans 2-butene, HCl)
    • Enols generally proceed with retention of stereochemistry at the α-carbon due to the planar intermediate (chiral ketone enols)

Common α-Substitution Reactions

  • α-Halogenation reactions introduce a halogen atom at the α-position of a carbonyl compound
  • Aldol reactions involve the condensation of two carbonyl compounds, forming a β-hydroxy carbonyl product
  • The formation of kinetic vs. thermodynamic enolate can influence the outcome of α-substitution reactions

Key Terms to Review (23)

Aldol reaction: The Aldol reaction is a chemical reaction in organic chemistry where two aldehydes or ketones, or one of each, react together in the presence of a base to form a β-hydroxyaldehyde or β-hydroxyketone. It is a fundamental process for forming carbon-carbon bonds and is widely used in the synthesis of complex molecules.
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.
Stereoisomer: Stereoisomers are molecules that have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in space. This variation can significantly affect the physical and chemical properties of the compounds.
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.
Enolate: An enolate is a negatively charged oxygen-containing species that arises from the removal of a proton from the α-carbon of a carbonyl compound. Enolates are important reactive intermediates in various organic reactions, including aldol condensations, Claisen condensations, and α-substitution reactions.
Aldehyde: An aldehyde is a class of organic compounds containing a carbonyl group (C=O) where the carbon atom is bonded to one hydrogen atom and one alkyl or aryl group. Aldehydes are important functional groups in organic chemistry and are involved in various reactions and synthesis pathways.
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.
Nucleophile: A nucleophile is a species that donates a pair of electrons to form a covalent bond with another atom or molecule. Nucleophiles are central to understanding many organic reactions, including polar reactions, electrophilic addition reactions, and nucleophilic substitution reactions.
Markovnikov's Rule: Markovnikov's rule is a principle in organic chemistry that describes the orientation of addition reactions involving unsaturated compounds, such as alkenes. It states that in the addition of a hydrogen halide (HX) to an alkene, the hydrogen atom of the HX bond attaches to the carbon atom of the alkene that can best stabilize the resulting carbocation intermediate.
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.
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.
Keto-Enol Tautomerism: Keto-enol tautomerism is the reversible chemical equilibrium between a keto (carbonyl) form and an enol form of a compound. This process is particularly relevant in the context of carbonyl chemistry, as it affects the reactivity and properties of these compounds.
Stereoisomer: Stereoisomers are molecules that have the same molecular formula and connectivity, but differ in the spatial arrangement of their atoms. This term is particularly relevant in the context of organic chemistry, as it helps explain the diverse structures and properties of various compounds.
Deprotonation: Deprotonation is the process of removing a proton (H+) from a molecule or ion, resulting in the formation of a negatively charged species. This chemical reaction is central to various organic chemistry topics, as it allows for the generation of reactive intermediates and the manipulation of molecular structures.
Enol: An enol is an organic compound that contains a carbon-carbon double bond where one of the carbon atoms is also bonded to a hydroxyl (OH) group. Enols are important intermediates in various organic reactions, including the hydration of alkynes, alpha-substitution reactions of carbonyl compounds, and carbonyl condensation reactions.
α-carbon: The α-carbon is the carbon atom that is directly bonded to a carbonyl group (C=O) in organic compounds. It is a crucial structural feature that plays a significant role in various reactions and transformations involving carbonyl-containing molecules.
α-Halogenation: α-Halogenation is a chemical reaction where a halogen atom (such as chlorine, bromine, or iodine) is introduced onto the α-carbon, which is the carbon atom adjacent to a carbonyl group (a carbon-oxygen double bond). This reaction is particularly relevant in the context of carboxylic acid reactions, the reactivity of enols, and the reactivity of enolate ions.
Aldol Reaction: The aldol reaction is a type of carbonyl condensation reaction that involves the nucleophilic addition of an enolate ion to a carbonyl compound, followed by an elimination step to form an α,β-unsaturated carbonyl compound.
α-Substituted Carbonyl Compound: An α-substituted carbonyl compound is a type of organic compound where a substituent group is attached to the carbon atom adjacent to the carbonyl group (the α-carbon). These compounds exhibit unique reactivity patterns that are central to the topics of enol reactivity and enolate ion chemistry.
Kinetic vs. Thermodynamic Enolate: The kinetic enolate and thermodynamic enolate are two different types of enolates that can be formed in organic chemistry reactions. These enolates differ in their stability and reactivity, which is crucial in understanding the outcomes of α-substitution reactions involving enols.
Intermediate Cation: An intermediate cation is a positively charged species that forms during the course of a reaction, serving as a key step in the mechanism of certain organic chemistry reactions. It plays a crucial role in understanding the reactivity of enols and their substitution reactions.
α-Substitution: α-Substitution is a type of nucleophilic addition-elimination reaction that occurs at the α-carbon of an enol or enolate, where the α-carbon is the carbon atom adjacent to the carbonyl group. This reaction involves the replacement of a hydrogen atom on the α-carbon with a new substituent, typically introduced by a nucleophile.
α-bromoketone: An α-bromoketone is an organic compound containing a bromine atom attached to the carbon atom adjacent to a carbonyl (ketone) group. These compounds are important intermediates in organic synthesis and exhibit unique reactivity due to the presence of the bromine substituent at the α-carbon position.