23.11 Carbonyl Condensations with Enamines: The Stork Enamine Reaction
2 min read•may 7, 2024
Enamines are powerful tools in organic synthesis, formed by reacting ketones with secondary amines. They're more nucleophilic than enolates, making them ideal for creating new carbon-carbon bonds. Their unique structure and reactivity open up exciting possibilities for building complex molecules.
The showcases enamines in action, allowing for selective α- of compounds. This three-step process - formation, , and - offers advantages over traditional enolate chemistry, including milder conditions and fewer side reactions.
Carbonyl Condensations with Enamines
Formation and structure of enamines
Top images from around the web for Formation and structure of enamines
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
1 of 3
Top images from around the web for Formation and structure of enamines
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
21.4. Imine formation | Organic Chemistry II View original
Is this image relevant?
1 of 3
- Enamines form by reaction between and secondary amine (, )
- Equilibrium process involves of secondary amine to ketone followed by elimination of water
- Reaction catalyzed by acid which protonates ketone making it more electrophilic
- Enamines have carbon-carbon double bond conjugated with nitrogen atom
- Nitrogen atom typically part of secondary amine or cyclic amine
- Carbon-carbon double bond usually located at -position relative to original carbonyl group
- Structure of enamines represented by two forms
- One form has carbon-carbon double bond and neutral nitrogen atom
- Other form has carbon-nitrogen double bond and negatively charged -carbon atom
- Enamines more nucleophilic than corresponding enolate ions due to higher electron density on -carbon atom
Mechanism of Stork enamine reaction
- is method for of ketones or aldehydes via enamine intermediate
- Reaction involves three main steps:
- Enamine formation: Ketone or reacts with secondary amine to form enamine intermediate in acid-catalyzed equilibrium process
- Michael addition: Enamine (acting as a ) undergoes 1,4-addition with -unsaturated carbonyl compound ( or ) to give after protonation of resulting enolate intermediate
- Hydrolysis: Iminium ion hydrolyzed by water under acidic conditions (aqueous acetic acid) to regenerate secondary amine catalyst and give final -alkylated carbonyl product
Enamines vs enolate ions in synthesis
- Enamines have advantages over enolate ions in Michael-like reactions for synthesis of
- More nucleophilic leading to faster reaction rates and higher yields
- Less basic reducing risk of side reactions (self-condensation, polymerization)
- Neutral species more compatible with wider range of electrophiles and reaction conditions
- Enolate ions have disadvantages compared to enamines
- More basic and can lead to side reactions especially with acidic protons present
- Charged species can limit solubility and reactivity in certain solvents or with certain electrophiles
- Often require strong bases (LDA, ) for generation which can be incompatible with sensitive functional groups
- Overall, use of enamines in Michael-like reactions offers milder and more selective approach for synthesis of 1,5-dicarbonyl compounds compared to use of enolate ions
Resonance and Conjugation in Enamines
- Resonance stabilization contributes to the reactivity of enamines
- Extended in enamines enhances their nucleophilicity
- Alkylation occurs at the α-carbon due to resonance effects
- Electrophiles preferentially attack the most electron-rich position in the conjugated system
Key Terms to Review (28)
$\alpha$-Alkylation: $\alpha$-Alkylation is a type of organic reaction in which a hydrogen atom attached to the $\alpha$-carbon (the carbon adjacent to a carbonyl group) is replaced with an alkyl group. This reaction is particularly relevant in the context of carbonyl condensations with enamines, specifically the Stork Enamine Reaction.
1,5-Dicarbonyl Compounds: 1,5-Dicarbonyl compounds are organic molecules that contain two carbonyl groups (C=O) separated by three carbon atoms. These compounds are of particular interest in the context of carbonyl condensations with enamines, specifically the Stork enamine reaction.
Aldaric acid: Aldaric acid is a type of dicarboxylic acid obtained by oxidizing both the aldehyde and primary alcohol groups of an aldose to carboxylic acids. It represents the fully oxidized form of a monosaccharide where all potential reactive sites have been converted to carboxyl groups.
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.
Alkylation: Alkylation is the process of introducing an alkyl group (a hydrocarbon chain) into a molecule, typically through the reaction of a nucleophile with an alkyl halide or other alkylating agent. This versatile reaction is employed in various organic chemistry contexts, including the formation of new carbon-carbon bonds, the synthesis of more complex molecules, and the modification of existing functional groups.
Carbonyl: The carbonyl group is a functional group consisting of a carbon atom double-bonded to an oxygen atom. It is a key structural feature in many organic compounds, including aldehydes, ketones, carboxylic acids, and esters, and plays a crucial role in their chemical reactivity and properties.
Carbonyl condensation reactions: Carbonyl condensation reactions are chemical processes where two carbonyl-containing molecules combine, with the loss of a small molecule such as water, to form a larger molecule that contains a carbonyl group. This type of reaction is fundamental in forming carbon-carbon bonds in organic synthesis.
Condensation: Condensation is a chemical reaction in which two molecules combine to form a single, larger molecule, often with the loss of a small molecule such as water or alcohol. This process is central to the understanding of two important organic chemistry reactions: the Dieckmann cyclization and the Stork enamine reaction.
Conjugation: Conjugation refers to the overlap or sharing of atomic orbitals, resulting in the delocalization of electrons across a system of connected atoms. This concept is central to understanding resonance, the stability of certain molecules and ions, and the interpretation of various spectroscopic techniques in organic chemistry.
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.
Enal: An enal is a conjugated enone, which is a carbonyl compound containing a carbon-carbon double bond adjacent to a carbonyl group. Enals are important intermediates in many organic reactions, particularly in the context of carbonyl condensations with enamines.
Enamine: An enamine is a type of organic compound formed by the condensation reaction between a primary or secondary amine and a carbonyl compound, such as an aldehyde or ketone. Enamines are important intermediates in various organic reactions, including the Stork Enamine Reaction and the Robinson Annulation Reaction.
Enone: An enone is a functional group consisting of a carbon-carbon double bond adjacent to a carbonyl group (ketone or aldehyde). Enones are important intermediates in organic synthesis, particularly in the context of aldol condensations and enamine reactions.
Hydrolysis: Hydrolysis is a chemical reaction in which a compound is cleaved into smaller molecules by the addition of water. This process involves the breaking of chemical bonds through the insertion of water molecules, often resulting in the formation of new functional groups or the decomposition of larger molecules.
Iminium Ion: An iminium ion is a positively charged species formed by the reaction of an amine with a carbonyl compound, such as an aldehyde or ketone. It is a key intermediate in various organic reactions, including the Stork enamine reaction and the reactions of amines.
Ketone: A ketone is a functional group in organic chemistry that consists of a carbonyl group (a carbon-oxygen double bond) bonded to two alkyl or aryl groups. Ketones are widely encountered in various organic chemistry topics, including the hydration of alkynes, oxidative cleavage of alkynes, organic synthesis, oxidation and reduction reactions, and the chemistry of aldehydes and ketones.
LDA (Lithium Diisopropylamide): LDA, or lithium diisopropylamide, is a powerful organometallic base commonly used in organic chemistry for the deprotonation of alpha-hydrogen atoms, generating highly reactive enolate ions. This key term is closely related to various topics in the study of carbonyl chemistry, including enolate ion formation, reactivity, and subsequent reactions.
Michael Addition: The Michael addition 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 a crucial step in many organic synthesis pathways, particularly in the context of conjugate nucleophilic addition to α,β‑unsaturated aldehydes and ketones, as well as carbonyl condensations with enamines.
Morpholine: Morpholine is a heterocyclic organic compound with the chemical formula C₄H₉NO. It is a colorless liquid with a characteristic amine-like odor and is widely used in the synthesis of various pharmaceuticals, pesticides, and other industrial chemicals.
NaH: NaH, or sodium hydride, is a strong reducing agent and a common base used in organic chemistry. It is a white, crystalline solid that reacts violently with water and is often used to generate enolate ions, a key intermediate in various organic reactions.
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.
Nucleophilic Addition: Nucleophilic addition is a fundamental organic reaction in which a nucleophile, a species that donates electrons, adds to an electrophilic carbon center, typically a carbonyl carbon, to form a new product. This reaction is central to understanding many important topics in organic chemistry, including functional groups, polar reactions, carbocation stability, reaction stereochemistry, and the chemistry of aldehydes, ketones, alcohols, and other carbonyl-containing compounds.
Nucleophilic addition reaction: A nucleophilic addition reaction is a chemical process where a nucleophile forms a bond with an electrophilic carbon atom of a compound, typically found in aldehydes and ketones. This reaction results in the conversion of the carbonyl group into a more complex, often larger, molecule.
Pyrrolidine: Pyrrolidine is a heterocyclic organic compound consisting of a five-membered ring containing four carbon atoms and one nitrogen atom. It is a key structural component in various organic reactions and compounds, particularly in the context of carbonyl condensations with enamines and the naming of amines.
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.
Stork enamine reaction: The Stork enamine reaction is a chemical reaction involving the alkylation of an aldehyde or ketone using an enamine as the nucleophile, followed by hydrolysis to produce a substituted ketone or aldehyde. This process allows for the synthesis of complex carbonyl compounds from simpler ones without overreaction issues.
Stork Enamine Reaction: The Stork enamine reaction is a powerful carbon-carbon bond forming reaction that involves the condensation of an enamine with a carbonyl compound. It is a widely used method in organic synthesis for the construction of complex molecules.
β Diketone: A β-diketone is an organic compound containing two ketone groups separated by a carbon atom, which is the beta (β) position relative to each ketone group. These molecules are characterized by the presence of hydrogen atoms on the carbon between the two carbonyl (C=O) groups, making them acidic and prone to enolate ion formation.