23.9 Intramolecular Claisen Condensations: The Dieckmann Cyclization
2 min read•may 7, 2024
The is a powerful tool for creating cyclic compounds from linear molecules. This reaction transforms diesters into cyclic β-ketoesters through an process, allowing chemists to build complex ring structures efficiently.
Understanding the opens doors to synthesizing a wide range of cyclic ketones. By manipulating the starting materials and reaction conditions, chemists can create five- and six-membered rings with various substituents, expanding the toolkit for organic synthesis.
Dieckmann Cyclization
Mechanism of Dieckmann cyclization
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- reaction forms cyclic β-ketoesters from diesters
- Diesters contain two ester functional groups within the same molecule ()
- Mechanism involves base-promoted followed by
- Strong base () deprotonates α-carbon of one ester group forming resonance-stabilized ion
- Enolate ion acts as nucleophile and attacks electrophilic carbonyl carbon of the other ester group
- Intramolecular reaction leads to formation of cyclic ()
- () released as leaving group
- Size of ring formed depends on number of carbons separating two ester groups in starting (1,6-diesters form 5-membered rings)
Products of 1,6-diesters vs 1,7-diesters
- 1,6-diesters () undergo to form 5-membered cyclic β-ketoesters
- Enolate ion attacks carbonyl group forming 5-membered ring with ketone and ester functional group (methyl 2-oxocyclopentanecarboxylate)
- 1,7-diesters () undergo Dieckmann cyclization to form 6-membered cyclic β-ketoesters
- Enolate ion attacks carbonyl group forming 6-membered ring with ketone and ester functional group ()
- Ring formation favored for 5- and 6-membered rings due to stability and minimal
Synthesis of substituted cyclic ketones
- Dieckmann cyclization
- Start with 1,6-diester (for ) or 1,7-diester (for )
- Treat diester with strong base to promote enolate formation and intramolecular nucleophilic acyl substitution
- Forms cyclic β-ketoester (5-membered ring for cyclopentanones, 6-membered ring for cyclohexanones)
-
- Treat cyclic β-ketoester with strong base (NaH) to form enolate ion
- Add alkyl halide (R-X) to introduce desired substituent (R) at α-carbon position (methyl iodide)
- Forms 2-alkylated cyclic β-ketoester (methyl 2-methyl-2-oxocyclopentanecarboxylate)
-
- Heat 2-alkylated cyclic β-ketoester in presence of strong acid (H2SO4) or base (NaOH)
- Ester group hydrolyzed and resulting β-keto acid undergoes decarboxylation releasing CO2
- Forms final product: 2-substituted (from 1,6-diesters) or 2-substituted (from 1,7-diesters) ()
Tautomerization and Keto-Enol Equilibrium
- Cyclic β-ketoesters formed in Dieckmann cyclization exist in
- occurs between keto form (cyclic β-ketoester) and enol form
- Keto form typically predominates at equilibrium due to greater stability
- Enol form can participate in further reactions, such as alkylation at the α-carbon
- Understanding keto-enol equilibrium is crucial for predicting reactivity and designing synthetic strategies () involving Dieckmann cyclization products
Key Terms to Review (37)
2-methylcyclopentanone: 2-methylcyclopentanone is a cyclic ketone with a methyl group attached to the second carbon of the cyclopentane ring. It is an important intermediate in organic chemistry, particularly in the context of intramolecular Claisen condensations and the Dieckmann cyclization.
Adipic Acid Dimethyl Ester: Adipic acid dimethyl ester is an organic compound with the chemical formula CH3OOC(CH2)4COOCH3. It is a diester formed from the reaction of adipic acid and methanol. This compound is particularly relevant in the context of intramolecular Claisen condensations and the Dieckmann cyclization, as it can undergo these types of reactions to form cyclic structures.
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.
Carbon-Carbon Bond Formation: Carbon-carbon bond formation is a fundamental process in organic chemistry that involves the creation of new carbon-carbon bonds, which are the backbone of organic molecules. This term is particularly relevant in the context of various reactions and mechanisms that facilitate the construction of more complex organic structures from simpler starting materials.
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.
Cyclic Compound: A cyclic compound is a type of organic compound in which the carbon atoms are arranged in a closed loop or ring structure. These compounds are an important class of molecules that play a crucial role in the context of intramolecular Claisen condensations and the Dieckmann cyclization.
Cyclization: Cyclization is the process of forming a cyclic structure from an acyclic precursor molecule. This term is particularly relevant in the context of various organic chemistry reactions and processes, where the formation of rings plays a crucial role in the synthesis of complex molecules and the understanding of biological systems.
Cyclohexanone: Cyclohexanone is a cyclic ketone compound with the chemical formula C₆H₁₀O. It is a key intermediate in the synthesis of various organic compounds and is widely used in the chemical industry.
Cyclohexanones: Cyclohexanones are a class of organic compounds containing a six-membered carbon ring with a carbonyl (C=O) group attached. They are important intermediates in organic synthesis, particularly in the context of intramolecular Claisen condensations and the Dieckmann cyclization.
Cyclopentanone: Cyclopentanone is a cyclic ketone compound with a five-membered carbon ring structure. It is an important organic compound that plays a key role in various reactions and synthetic processes discussed in the context of the specified topics.
Cyclopentanones: Cyclopentanones are a class of organic compounds consisting of a five-membered ring structure with a carbonyl (C=O) group. These cyclic ketones are important intermediates in various organic reactions, particularly in the context of intramolecular Claisen condensations and the Dieckmann cyclization.
Decarboxylation: Decarboxylation is a chemical reaction that involves the removal of a carboxyl group (–COOH) from a molecule, typically resulting in the release of carbon dioxide (CO2). This process is important in various organic chemistry reactions and metabolic pathways.
Dieckmann: The Dieckmann reaction is a method of intramolecular Claisen condensation that allows for the formation of cyclic ketones from linear diester precursors. It is a powerful synthetic tool for the construction of carbocyclic and heterocyclic ring systems.
Dieckmann cyclization: Dieckmann cyclization is a chemical reaction where a diester undergoes intramolecular condensation in the presence of a base, resulting in the formation of a cyclic β-keto ester. It's a specific type of intramolecular Claisen condensation that is useful for synthesizing five or six-membered rings.
Dieckmann Cyclization: The Dieckmann cyclization is an intramolecular Claisen condensation reaction that forms cyclic β-keto esters from linear diester precursors. It is a powerful synthetic tool for the construction of carbocyclic and heterocyclic compounds.
Dieckmann cyclization reaction: The Dieckmann cyclization reaction is an intramolecular chemical process in Organic Chemistry where a dicarboxylic acid ester undergoes condensation to form a cyclic β-keto ester under the influence of a base. It serves as a specific example of intramolecular Claisen condensation, crucial for synthesizing five- or six-membered rings.
Diester: A diester is a type of organic compound that contains two ester functional groups. Esters are formed when an alcohol reacts with a carboxylic acid, and a diester is the result when this reaction occurs twice, creating a molecule with two ester groups. Diesters are important intermediates in the context of Intramolecular Claisen Condensations and the Dieckmann Cyclization.
Dimethyl Adipate: Dimethyl adipate is a diester compound formed by the esterification of adipic acid with methanol. It is an important intermediate in the synthesis of various chemicals and materials, particularly in the context of intramolecular Claisen condensations and the Dieckmann cyclization reaction.
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.
Enolate Formation: Enolate formation is a key process in organic chemistry where a carbonyl compound, such as a ketone or aldehyde, is converted into an enolate ion through the removal of a proton from the alpha carbon. This enolate ion can then participate in various reactions, including the Dieckmann cyclization, a type of intramolecular Claisen condensation.
Ethoxide: Ethoxide is a functional group consisting of an ethyl group (CH3CH2-) bonded to an oxygen atom. It is an important intermediate in various organic reactions, particularly in the context of E2 reactions, ester chemistry, and Claisen condensations.
Intramolecular: Intramolecular refers to processes or interactions that occur within a single molecule, as opposed to intermolecular which involves interactions between different molecules. This term is particularly relevant in the contexts of Claisen condensations and peptide/protein structures.
Intramolecular Claisen Condensation: The intramolecular Claisen condensation, also known as the Dieckmann cyclization, is a powerful organic reaction that allows for the formation of cyclic ketones from linear diester precursors. This reaction involves the intramolecular condensation of two ester groups within the same molecule, resulting in the creation of a new carbon-carbon bond and the formation of a cyclic structure.
Intramolecular, intermolecular: Intramolecular reactions involve the chemical changes that occur within a single molecule, resulting in a rearrangement of its atoms to form a new product. In the context of organic chemistry and specifically carbonyl condensation reactions, these are reactions where two functional groups within the same molecule react with each other.
Keto-Enol Equilibrium: Keto-enol equilibrium is a reversible chemical process in which a molecule containing a carbonyl group (C=O) can exist in two different structural forms - the keto form and the enol form. This equilibrium plays a crucial role in various organic chemistry reactions, including the Aldol Reaction and the Dieckmann Cyclization.
Methyl 2-oxocyclohexanecarboxylate: Methyl 2-oxocyclohexanecarboxylate is a cyclic ester compound that contains a cyclohexane ring with a carbonyl group and a methyl ester group. It is a key intermediate in the Dieckmann cyclization, a type of intramolecular Claisen condensation reaction.
Methyl 2-oxocyclopentanecarboxylate: Methyl 2-oxocyclopentanecarboxylate is a cyclic ketone compound with a methyl ester group attached. It is a key intermediate in the Dieckmann cyclization, a type of intramolecular Claisen condensation reaction used to construct cyclic ketones.
Nucleophilic Acyl Substitution: Nucleophilic acyl substitution is a type of organic reaction where a nucleophile attacks the carbonyl carbon of a carboxylic acid derivative, such as an acid chloride, anhydride, or ester, leading to the replacement of the leaving group with the nucleophile. This process is central to the reactivity and transformations of carboxylic acid derivatives.
Nucleophilic acyl substitution reaction: A nucleophilic acyl substitution reaction is a type of chemical reaction where a nucleophile replaces the leaving group in an acyl compound. This reaction is fundamental in organic chemistry for modifying carboxylic acid derivatives into other functional groups.
Pimelic Acid Dimethyl Ester: Pimelic acid dimethyl ester is an organic compound with the chemical formula CH3OOC(CH2)5COOCH3. It is a diester derived from the dicarboxylic acid, pimelic acid, and is a key intermediate in various organic reactions, particularly in the context of intramolecular Claisen condensations and the Dieckmann cyclization.
Retrosynthesis: Retrosynthesis is a conceptual tool used in organic chemistry to plan the synthesis of a target molecule. It involves working backwards from the desired product to identify simpler starting materials and key transformations that can be used to construct the target compound.
Ring Closure: Ring closure is a fundamental organic chemistry reaction where a linear molecule cyclizes to form a ring structure. This process is crucial in the context of intramolecular Claisen condensations and the Dieckmann cyclization, where the formation of a cyclic product is the desired outcome.
Ring Strain: Ring strain refers to the inherent instability and high-energy state of cyclic organic compounds, particularly those with small ring sizes, due to the distortion of bond angles and bond lengths from their ideal values. This concept is central to understanding the properties and reactivity of cycloalkanes and other cyclic structures.
Sodium Ethoxide: Sodium ethoxide is an alkoxide compound with the chemical formula C₂H₅ONa. It is a strong nucleophile and base used in various organic reactions, including the preparation of alkenes, the Wittig reaction, and Claisen condensations.
Tautomerization: Tautomerization is a type of isomerization in organic chemistry where a molecule can exist in two or more different structural forms that are in equilibrium with each other. These different forms, called tautomers, have the same molecular formula but differ in the location of a hydrogen atom and a double bond.
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.