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Organic Chemistry
Table of Contents
Unit 23 Overview: Carbonyl Condensation Reactions
23.1 Carbonyl Condensations: The Aldol Reaction
23.2 Carbonyl Condensations versus Alpha Substitutions
23.3 Dehydration of Aldol Products: Synthesis of Enones
23.4 Using Aldol Reactions in Synthesis
23.5 Mixed Aldol Reactions
23.6 Intramolecular Aldol Reactions
23.7 The Claisen Condensation Reaction
23.8 Mixed Claisen Condensations
23.9 Intramolecular Claisen Condensations: The Dieckmann Cyclization
23.10 Conjugate Carbonyl Additions: The Michael Reaction
23.11 Carbonyl Condensations with Enamines: The Stork Enamine Reaction
23.12 The Robinson Annulation Reaction
23.13 Some Biological Carbonyl Condensation Reactions

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23.10 Conjugate Carbonyl Additions: The Michael Reaction

Citation:

The Michael reaction is a powerful tool for forming carbon-carbon bonds. It involves adding a nucleophilic donor to an α,β-unsaturated carbonyl compound, creating new stereocenters. Understanding the mechanism and reactivity factors is key to predicting products.

Factors like nucleophile strength, electrophile reactivity, and steric hindrance influence the reaction's outcome. Recognizing common Michael donors and acceptors helps in applying this reaction to synthesize complex organic molecules with specific stereochemistry.

Conjugate Carbonyl Additions: The Michael Reaction

Mechanism of Michael reaction

  • Conjugate addition reaction between nucleophilic donor (Michael donor) and α,β-unsaturated carbonyl compound (Michael acceptor)
    • Michael donor typically an enolate ion formed from ketone, ester, or 1,3-dicarbonyl compound in presence of base
    • Michael acceptor an α,β-unsaturated carbonyl compound (α,β-unsaturated ketone, aldehyde, ester, or amide)
  • Reaction mechanism involves following steps:
    1. Formation of enolate ion from Michael donor by deprotonation with base
    2. Nucleophilic addition of enolate ion to β-carbon of α,β-unsaturated carbonyl compound (Michael acceptor)
    3. Protonation of resulting enolate intermediate to form final Michael adduct
  • α,β-unsaturated carbonyl compound acts as electrophile due to electron-withdrawing effect of carbonyl group makes β-carbon more electrophilic and susceptible to nucleophilic attack

Michael acceptors and donors

  • Common Michael acceptors:
    • α,β-Unsaturated ketones, aldehydes, esters, and amides
    • Reactivity influenced by electron-withdrawing strength of carbonyl group and presence of additional electron-withdrawing groups
      • Stronger electron-withdrawing groups increase electrophilicity of β-carbon, making acceptor more reactive (nitro, cyano, sulfonyl)
  • Common Michael donors:
    • Enolate ions formed from ketones, esters, and 1,3-dicarbonyl compounds
    • Reactivity influenced by stability of enolate ion and acidity of α-hydrogen
      • More stable enolate ions and more acidic α-hydrogens lead to more reactive donors (malonates, β-ketoesters)
  • Factors affecting reactivity of Michael acceptors and donors:
    • Steric hindrance: Bulky substituents near reactive sites can decrease reactivity (tert-butyl, adamantyl)
    • Resonance stabilization: Extended conjugation can stabilize enolate ion or α,β-unsaturated system, affecting reactivity (phenyl, furan, thiophene)

Product prediction in Michael reactions

  • To predict products, consider following:
    1. Identify Michael donor and acceptor
    2. Determine site of nucleophilic attack on Michael acceptor (β-carbon)
    3. Consider stereochemistry of addition (syn or anti)
    4. Account for any subsequent protonation or other reactions
  • Examples of Michael reaction product predictions:
    • Reaction between ketone enolate and α,β-unsaturated ketone:
      • Enolate will add to β-carbon of α,β-unsaturated ketone, forming new carbon-carbon bond and new stereocenter (1,4-diketone product)
    • Reaction between 1,3-dicarbonyl compound and α,β-unsaturated ester:
      • Enolate formed from 1,3-dicarbonyl compound will add to β-carbon of α,β-unsaturated ester, forming new carbon-carbon bond and new stereocenter (β-ketoester product)
    • Intramolecular Michael reaction (Robinson annulation):
      • Enolate and α,β-unsaturated carbonyl compound within same molecule can undergo intramolecular Michael addition, forming cyclic product with new stereocenters (bicyclic enone product)

Factors Influencing Michael Reaction

  • Nucleophile strength: Stronger nucleophiles (e.g., more stable enolates) generally lead to faster reactions and higher yields
  • Electrophile reactivity: More electrophilic Michael acceptors increase reaction rate and yield
  • Resonance effects: Extended conjugation in either donor or acceptor can affect reactivity and product distribution
  • Stereochemistry considerations: The approach of the nucleophile to the electrophile can be influenced by existing stereocenters or chiral catalysts
  • Enolate stability: More stable enolates are generally better Michael donors due to their increased nucleophilicity
  • Steric hindrance: Bulky groups near the reaction centers can slow down the reaction or affect the stereochemical outcome

Key Terms to Review (36)

Anti stereochemistry: Anti stereochemistry describes the spatial arrangement in a chemical reaction where two substituents are positioned on opposite sides of a double bond or ring structure after the reaction. It is particularly relevant in the halogenation of alkenes, resulting in products where the added atoms are located across from each other.
Nitrogen rule: The Nitrogen Rule in organic chemistry is a guideline stating that organic compounds with an odd number of nitrogen atoms will have an odd molecular mass. This rule is useful for determining the possible presence of nitrogen in a compound based on its molecular ion peak in mass spectrometry.
Robinson annulation reaction: The Robinson annulation reaction is a chemical process that combines an aldol condensation with a Michael addition to construct ring systems, particularly useful in synthesizing cyclohexenones. It's a pivotal method in organic chemistry for building complex molecular structures from simpler compounds.
Conjugate addition: Conjugate addition is a type of nucleophilic addition reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated aldehyde or ketone. This process expands the molecule by forming a new carbon-carbon bond, effectively incorporating the nucleophile into the molecule.
Enolate ion: An enolate ion is a negatively charged intermediate formed from the deprotonation of an alpha carbon adjacent to a carbonyl group in aldehydes and ketones. It plays a crucial role in various organic reactions, including nucleophilic addition and substitution reactions.
Michael reaction: The Michael reaction is a nucleophilic addition of a carbanion to an α,β-unsaturated carbonyl compound. It results in the formation of a carbon-carbon bond, expanding the carbon skeleton of organic molecules.
Stereochemistry: Stereochemistry is the study of the three-dimensional arrangement of atoms in molecules and how this arrangement affects the chemical and physical properties of the substance. It examines the spatial orientation of atoms and their relationship to one another, which is crucial in understanding many organic chemistry concepts.
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.
Tert-Butyl: The tert-butyl group is a branched alkyl substituent with the chemical formula (CH3)3C-. It is a tertiary alkyl group, meaning the carbon atom to which the three methyl groups are attached is also bonded to another carbon atom. This structural feature gives the tert-butyl group unique properties that are relevant in the context of organic chemistry topics such as alkyl groups, the stability of alkenes, reactions of ethers, and conjugate carbonyl additions.
Steric Hindrance: Steric hindrance, also known as steric strain or steric effect, refers to the repulsive forces that arise between atoms or groups of atoms in a molecule due to their physical size and spatial arrangement. This phenomenon can significantly impact the stability, reactivity, and conformations of organic compounds.
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.
Syn Addition: Syn addition is a type of organic reaction where two substituents are added to the same side of a carbon-carbon double bond, resulting in the formation of a new stereocenter with a specific stereochemical configuration. This term is particularly relevant in the context of various organic chemistry topics, including electrophilic addition reactions of alkenes, hydration of alkenes, reduction of alkenes, and oxidation of alkenes.
Anti Addition: Anti addition refers to the stereochemical outcome of an electrophilic addition reaction, where the incoming electrophilic species adds to the opposite face of the alkene or alkyne relative to the existing substituents. This results in the formation of the anti-addition product, where the new substituents are arranged in an anti-configuration.
Nitro: The nitro group (NO2) is a functional group composed of a nitrogen atom double-bonded to two oxygen atoms. It is a key structural feature in organic chemistry, with significant implications in various reactions and properties of compounds.
Michael Reaction: The Michael reaction is a type of conjugate addition reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated carbonyl compound, forming a new carbon-carbon bond. This reaction is named after the German chemist Arthur Michael, who first reported it in 1887.
Conjugate Addition: Conjugate addition is a type of nucleophilic addition reaction where a nucleophile adds to the β-carbon of an α,β-unsaturated carbonyl compound, rather than the carbonyl carbon. This results in the formation of a new carbon-carbon bond and the addition of the nucleophile to the conjugated system.
β-carbon: The β-carbon is the carbon atom that is positioned two atoms away from a functional group or other point of interest in an organic molecule. It plays a crucial role in the reactivity and behavior of certain organic reactions, particularly in the context of conjugate nucleophilic additions and the Michael reaction.
Enolate Ion: An enolate ion is a type of conjugate base formed when the alpha hydrogen of a carbonyl compound is removed, resulting in a negatively charged oxygen atom adjacent to a carbon-carbon double bond. This reactive intermediate is a key player in various organic reactions, including conjugate nucleophilic additions, reactions of carboxylic acids, and carbonyl condensation reactions.
Robinson Annulation: The Robinson annulation is a powerful synthetic method used to construct cyclic compounds, particularly cyclohexenones, from acyclic precursors. It involves a conjugate addition-aldol reaction sequence that allows for the efficient construction of complex molecular scaffolds.
β-ketoester: A β-ketoester is a type of organic compound that contains both a ketone group and an ester group, with the ketone group located at the β-carbon position relative to the ester group. This structural feature allows β-ketoesters to participate in a variety of important organic reactions, including the Claisen condensation, Dieckmann cyclization, and Michael addition.
Michael Adduct: A Michael adduct is the product of a Michael addition reaction, which is a type of conjugate addition involving the nucleophilic addition of a carbon nucleophile to an α,β-unsaturated carbonyl compound. The resulting Michael adduct contains a new carbon-carbon bond and a β-substituted carbonyl compound.
Malonate: Malonate is a dicarboxylic acid with the chemical formula CH2(COOH)2. It is an important organic compound that plays a key role in the context of conjugate carbonyl additions, specifically the Michael reaction.
Adamantyl: The adamantyl group is a cyclic hydrocarbon consisting of a cage-like structure with four six-membered rings fused together. It is known for its rigid, three-dimensional geometry and chemical stability, which make it a unique structural motif in organic chemistry.
Michael Donor: A Michael donor is a nucleophilic species that participates in the Michael reaction, a conjugate addition to an α,β-unsaturated carbonyl compound. These donors contribute the nucleophilic component that adds to the β-carbon of the unsaturated system, forming a new carbon-carbon bond.
α,β-unsaturated ketone: An α,β-unsaturated ketone is a type of carbonyl compound that features a carbon-carbon double bond conjugated to a carbonyl group. This structural arrangement creates a system of delocalized π electrons, leading to unique reactivity and properties compared to non-conjugated ketones.
α,β-unsaturated carbonyl compound: An α,β-unsaturated carbonyl compound is an organic molecule that contains a carbonyl group (a carbon-oxygen double bond) conjugated with a carbon-carbon double bond. This structural feature creates a system of alternating single and double bonds, known as a conjugated system, which has important implications for the compound's reactivity and stability.
1,3-Dicarbonyl Compound: A 1,3-dicarbonyl compound is an organic molecule that contains two carbonyl groups (C=O) separated by a single carbon atom. These types of compounds are important intermediates in various organic reactions, including the Michael reaction, which is a key topic in the context of 23.10 Conjugate Carbonyl Additions.
Sulfonyl: The sulfonyl group (SO2) is a functional group consisting of a sulfur atom double-bonded to two oxygen atoms. It is commonly found in organic compounds and plays a crucial role in various chemical reactions, including the Michael reaction, which is a type of conjugate carbonyl addition.
α,β-unsaturated amide: An α,β-unsaturated amide is a type of organic compound that features a carbonyl group (C=O) directly attached to a nitrogen atom, forming an amide functional group, and an additional carbon-carbon double bond in the α,β-position relative to the carbonyl. This structural feature is important in the context of conjugate carbonyl additions, specifically the Michael reaction.
Cyano: The cyano group, represented by the chemical formula -C≡N, is a functional group consisting of a carbon atom triple-bonded to a nitrogen atom. This group is commonly found in organic compounds and plays a crucial role in various chemical reactions, particularly in the context of conjugate carbonyl additions and the Michael reaction.
α,β-unsaturated ester: An α,β-unsaturated ester is a type of organic compound that features a carbonyl group (ester) directly attached to a carbon-carbon double bond. This structural arrangement creates a system of conjugated double bonds, which gives rise to unique reactivity and properties.
Michael Acceptor: A Michael acceptor is an electrophilic species that can undergo conjugate addition reactions, also known as the Michael reaction. It is a key concept in understanding the reactivity and applications of carbonyl compounds in organic chemistry.
α,β-unsaturated aldehyde: An α,β-unsaturated aldehyde is a type of organic compound that contains a carbonyl group (a carbon-oxygen double bond) adjacent to an alkene (a carbon-carbon double bond). This structural feature gives these aldehydes unique reactivity and makes them important intermediates in organic synthesis, particularly in the context of conjugate carbonyl additions.
Enolate Stability: Enolate stability refers to the relative stability of the enolate ion, which is a key intermediate in many organic reactions, including the Michael reaction. The enolate ion is a nucleophilic species formed by the deprotonation of a carbonyl compound, and its stability can have a significant impact on the outcome of the reaction.
1,4-diketone: A 1,4-diketone is a type of organic compound that contains two carbonyl (C=O) groups separated by two carbon atoms. These compounds are of particular interest in the context of conjugate carbonyl additions, specifically the Michael reaction.