23.12 The Robinson Annulation Reaction
2 min read•may 7, 2024
is a powerful two-step process for building complex ring systems. It combines a with an intramolecular , creating new carbon-carbon bonds and forming cyclic structures.
This reaction is crucial for synthesizing molecules, especially those found in steroids and other bioactive compounds. It's a versatile tool that chemists use to construct intricate molecular frameworks, making it essential in organic synthesis.
Robinson Annulation Reaction
Two-step process of Robinson annulation
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- Involves the formation of a new ring system through a two-step process
- Step 1:
- Nucleophilic addition of an () to an -unsaturated carbonyl compound () (e.g., )
- Creates a new carbon-carbon bond and generates a intermediate
- Step 2: Intramolecular aldol reaction
- The 1,5-dicarbonyl intermediate undergoes an intramolecular aldol condensation
- Forms a new carbon-carbon bond and a cyclic -hydroxyketone or -hydroxyaldehyde (e.g., )
- of the -hydroxyketone or -hydroxyaldehyde yields an -unsaturated cyclic ketone or aldehyde
- Step 1:
Reactants and products in Robinson annulation
- Reactants
- An enolate or derived from a ketone or aldehyde (e.g., )
- An -unsaturated carbonyl compound, such as an -unsaturated ketone or aldehyde (e.g., methyl vinyl ketone)
- Products
- A cyclic -hydroxyketone or -hydroxyaldehyde intermediate
- An -unsaturated cyclic ketone or aldehyde as the final product (e.g., Wieland-Miescher ketone)
Applications for polycyclic molecule synthesis
- Enables the synthesis of polycyclic molecules, especially those with a six-membered ring fused to a five-membered ring
- This ring system is prevalent in hormones and other biologically active compounds (e.g., , )
- Example: Synthesis of the Wieland-Miescher ketone, a key intermediate in the synthesis of various steroids
- Michael reaction between 2-methylcyclohexane-1,3-dione (an enolate) and methyl vinyl ketone (an -unsaturated ketone)
- Intramolecular aldol reaction and dehydration to form the bicyclic Wieland-Miescher ketone
- Can be further extended to synthesize more complex polycyclic systems by using the product as a reactant in subsequent annulation reactions (e.g., synthesis of tetracyclic steroid core)
Mechanistic considerations
- The Michael reaction proceeds through , where the nucleophile attacks the β-carbon of the compound
- The intramolecular aldol reaction involves of the 1,5-dicarbonyl intermediate
- of the product is influenced by the reaction conditions and substrate structure
Key Terms to Review (28)
1,5-dicarbonyl: The 1,5-dicarbonyl functional group consists of two carbonyl groups (C=O) separated by three carbon atoms. This structural feature is particularly important in the context of intramolecular aldol reactions and the Robinson annulation reaction, as it can facilitate the formation of cyclic compounds.
2-methylcyclohexane-1,3-dione: 2-methylcyclohexane-1,3-dione is a cyclic organic compound with a 6-membered ring structure containing two carbonyl (C=O) functional groups at the 1 and 3 positions, as well as a methyl (CH3) substituent at the 2 position. This compound is an important intermediate in the Robinson Annulation Reaction, a key transformation in organic synthesis.
Aldol Condensation: Aldol condensation is a type of organic reaction where an aldehyde or ketone undergoes a nucleophilic addition reaction with another aldehyde or ketone, followed by a dehydration step to form an α,β-unsaturated carbonyl compound known as an enone.
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.
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.
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.
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.
Dehydration: Dehydration is a chemical process in which water is removed from a compound, typically resulting in the formation of a new compound with fewer hydrogen and oxygen atoms. This term is particularly relevant in the context of various organic reactions and transformations, where dehydration plays a crucial role in the preparation and interconversion of different functional groups.
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.
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.
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.
Methyl Vinyl Ketone: Methyl vinyl ketone is an organic compound with the chemical formula CH3C(O)CH=CH2. It is a colorless liquid with a sharp, unpleasant odor and is used as a building block in various organic synthesis reactions, including the Robinson Annulation Reaction.
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.
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.
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.
Polycyclic: Polycyclic refers to a chemical compound or structure that contains multiple interconnected ring systems. This term is particularly relevant in the context of organic chemistry, where it describes the presence of fused or bridged cyclic structures within a molecule.
Polycyclic molecule: A polycyclic molecule consists of two or more interconnected ring structures, which may be either fused together directly, share a common bond, or be linked through a bridge. These compounds display a variety of complex geometrical arrangements and have significant implications in the study of organic chemistry due to their unique properties and reactions.
Progesterone: Progesterone is a steroid hormone that plays a crucial role in the female reproductive system, particularly during the menstrual cycle and pregnancy. It is also involved in the Robinson Annulation Reaction, a synthetic method for the preparation of steroids.
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.
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.
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.
Steroid: Steroids are a class of organic compounds characterized by a unique tetracyclic carbon skeleton. They play crucial roles in various biological processes, including hormone regulation, cell signaling, and structural support within living organisms.
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.
Testosterone: Testosterone is a steroid hormone that is primarily produced in the testes of men and the ovaries of women. It is responsible for the development and maintenance of male sexual characteristics and plays a crucial role in various physiological processes.
Wieland-Miescher Ketone: The Wieland-Miescher ketone is an important intermediate in organic synthesis, particularly in the context of the Robinson annulation reaction. It is a bicyclic compound that serves as a key building block for the construction of more complex natural product-like structures.
α,β-Unsaturated Carbonyl: An α,β-unsaturated carbonyl is a carbonyl compound (such as an aldehyde or ketone) that contains a carbon-carbon double bond adjacent to the carbonyl group. This structural feature has important implications in organic chemistry, particularly in the context of conjugate nucleophilic additions, aldol reactions, and other carbonyl condensation reactions.
β-hydroxyaldehyde: A β-hydroxyaldehyde is a type of organic compound that contains both a hydroxyl (-OH) group and an aldehyde (-CHO) group, with the hydroxyl group positioned on the carbon atom beta (β) to the aldehyde group. These compounds are important intermediates in various organic reactions, particularly in the context of intramolecular aldol reactions and the Robinson annulation reaction.
β-hydroxyketone: A β-hydroxyketone is a type of organic compound that contains a hydroxyl group (-OH) attached to the carbon atom adjacent to a carbonyl group (C=O). These compounds are important intermediates in various organic reactions, particularly in the context of intramolecular aldol reactions and the Robinson annulation reaction.