scoresvideos
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

Intramolecular aldol reactions create cyclic compounds by joining carbonyl groups within a molecule. These reactions are faster and more selective than their intermolecular counterparts, forming 5- or 6-membered rings most commonly.

Product selectivity depends on factors like ring size, enolate stability, and starting material stereochemistry. The mechanism involves base-catalyzed enolate formation and nucleophilic addition to a carbonyl group, sometimes followed by dehydration to form α,β-unsaturated products.

Intramolecular Aldol Reactions

Intramolecular vs intermolecular aldol reactions

  • Intramolecular aldol reactions occur within the same molecule involve reaction between a ketone or aldehyde and an enolate
    • Enolate attacks the carbonyl group forming a new carbon-carbon bond resulting in a cyclic product (cyclopentanone, cyclohexanone)
  • Intermolecular aldol reactions involve two separate molecules one containing the enolate and the other the ketone or aldehyde
    • Leads to formation of a linear product (β-hydroxyketone, β-hydroxyaldehyde)
  • Intramolecular aldol reactions are typically faster than intermolecular due to reacting groups being in close proximity increasing likelihood of collision and reaction
  • Intramolecular aldol reactions are often more selective than intermolecular reactions as the cyclic transition state limits possible orientations of reacting groups

Products of intramolecular aldol reactions

  • Ring size formed depends on number of carbon atoms separating the two carbonyl groups
    • 5- or 6-membered rings are most common and stable (cyclopentanone, cyclohexanone)
    • 3- and 4-membered rings are less common due to ring strain (cyclobutanone)
    • Rings larger than 6 members are less favored due to entropic factors (cycloheptanone, cyclooctanone)
  • Relative position of carbonyl groups influences product formed
    • 1,4-dicarbonyl compounds (two carbons separating carbonyl groups) form 5-membered rings
    • 1,5-dicarbonyl compounds (three carbons separating carbonyl groups) form 6-membered rings
  • Nature of carbonyl groups (aldehyde or ketone) affects product
    • Reactions involving aldehydes may lead to further dehydration forming α,β-unsaturated carbonyl compounds (enones, enals)
  • Intramolecular aldol reactions can lead to cyclization, forming cyclic products through carbon-carbon bond formation

Selectivity factors in intramolecular aldols

  • Ring size is a major factor in determining product selectivity
    • 5- and 6-membered rings are favored due to stability and minimal ring strain
    • Formation of 3- and 4-membered rings is less favored due to high ring strain
    • Larger rings (>6 members) are less likely to form due to entropic factors
  • Relative stability of enolate intermediate influences product selectivity
    • More substituted enolates are typically more stable and react preferentially (tertiary > secondary > primary)
    • Formation of thermodynamic enolate is favored under equilibrium conditions
  • Stereochemistry of starting material can impact product selectivity
    • Configuration of existing stereocenters may influence facial selectivity of aldol reaction (syn vs anti addition)
    • Substrate control can lead to preferential formation of one diastereomer over another
  • Reaction conditions such as temperature and solvent can affect product selectivity
    • Lower temperatures often favor kinetic products while higher temperatures favor thermodynamic products
    • Polar solvents can stabilize charged intermediates and influence reaction outcome (protic vs aprotic)

Mechanism and Catalysis

  • Intramolecular aldol reactions involve nucleophilic addition of an enolate to a carbonyl compound
  • The reaction is typically catalyzed by a base catalyst, which facilitates enolate formation
  • The process can lead to aldol condensation, where water is eliminated to form an α,β-unsaturated carbonyl product

Key Terms to Review (28)

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.
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.
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.
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.
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.
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.
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.
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.
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.
Enones: Enones are a class of organic compounds containing a carbonyl group (C=O) conjugated with a carbon-carbon double bond. They are characterized by the presence of this extended $\pi$-conjugated system, which gives them unique chemical and physical properties.
Carbonyl Compound: A carbonyl compound is a class of organic compounds that contain a carbonyl group, which is a carbon atom double-bonded to an oxygen atom. These compounds are fundamental in organic chemistry and play a crucial role in various reactions and transformations, including the topics of alcohols from carbonyl compounds, the Wolff-Kishner reduction, nucleophilic acyl substitution, enolate ion formation, alkylation of enolate ions, and intramolecular aldol reactions.
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.
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.
Cyclooctanone: Cyclooctanone is a cyclic ketone compound with a ring structure consisting of eight carbon atoms. It is an important intermediate in organic chemistry and is particularly relevant in the context of intramolecular aldol reactions.
Kinetic Products: Kinetic products are the initial products formed in a reaction that are determined by the reaction's kinetics, or the speed and mechanism by which the reactants are converted into products. These products are often the thermodynamically less stable species, but are formed more rapidly than the thermodynamically favored products.
Intramolecular Aldol Reaction: An intramolecular aldol reaction is a type of organic reaction where a carbonyl compound within the same molecule acts as both the nucleophile and the electrophile, leading to the formation of a new carbon-carbon bond and the creation of a cyclic product.
Thermodynamic Products: Thermodynamic products refer to the most stable and lowest energy chemical compounds formed as the end result of a reaction, determined by the overall thermodynamic favorability of the reaction pathway. These products represent the global minimum on the potential energy surface and are the final, equilibrium-favored outcome of a chemical transformation.
Enals: Enals, short for 'α,β-unsaturated aldehydes', are a class of organic compounds characterized by the presence of a carbon-carbon double bond adjacent to the carbonyl group of an aldehyde. These compounds are of great importance in organic chemistry, particularly in the context of reactions involving aldol condensation and the synthesis of enones.
Intermolecular Aldol Reaction: The intermolecular aldol reaction is a type of carbon-carbon bond-forming reaction that occurs between two separate carbonyl-containing compounds, resulting in the formation of a new β-hydroxy carbonyl product. This reaction is a key step in many organic synthesis pathways and is widely used in the construction of more complex molecules.
Cyclobutanone: Cyclobutanone is a four-membered cyclic ketone compound, consisting of a ring of four carbon atoms with a carbonyl group (C=O) attached. It is an important intermediate in organic chemistry, particularly in the context of intramolecular aldol reactions.
Thermodynamic Enolate: A thermodynamic enolate is a type of enolate ion that is formed under thermodynamic control, where the most stable enolate isomer is produced. This is in contrast to kinetic enolates, which are formed under kinetic control and may not be the most thermodynamically stable product.
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.
1,4-Dicarbonyl: A 1,4-dicarbonyl is a functional group in organic chemistry that consists of two carbonyl groups (C=O) separated by two carbon atoms. This structural feature is particularly important in the context of intramolecular aldol reactions, as it can facilitate the formation of cyclic products.
Base Catalyst: A base catalyst is a type of catalyst that increases the rate of a chemical reaction by providing a basic (proton-accepting) environment. It facilitates the reaction by increasing the nucleophilicity of reactants, making them more reactive towards electrophilic centers.
Cycloheptanone: Cycloheptanone is a cyclic ketone compound with a seven-membered ring structure. It is an important intermediate in organic synthesis and is relevant in the context of intramolecular aldol reactions.
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.
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.