Chapter 23 carbonyl condensation reactions
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Chapter 23. Carbonyl Condensation Reactions. Based on McMurry’s Organic Chemistry , 6 th edition. Condensation Reactions. Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions. 23.1 Mechanism of Carbonyl Condensation Reactions.

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Chapter 23 carbonyl condensation reactions

Chapter 23. Carbonyl Condensation Reactions

Based on McMurry’s Organic Chemistry, 6th edition

Condensation reactions
Condensation Reactions

  • Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions

23 1 mechanism of carbonyl condensation reactions
23.1 Mechanism of Carbonyl Condensation Reactions

  • Carbonyl condensation reactions utilize -substitution steps

  • An enolate ion adds as a nucleophile to the electrophilic acceptor

23 2 condensations of aldehydes and ketones the aldol reaction
23.2 Condensations of Aldehydes and Ketones: The Aldol Reaction

  • Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldhyde

  • The b-hydroxy aldehyde product is aldol (aldehyde + alcohol)

  • This is a general reaction of aldehydes and ketones

The equilibrium of the aldol
The Equilibrium of the Aldol Reaction

  • The aldol reaction is reversible, favoring the condensation product only for aldehydes with no  substituent

  • Steric factors are increased in the aldol product

Mechanism of aldol reactions
Mechanism of Aldol Reactions Reaction

  • Aldol reactions, like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule

  • The addition intermediate is protonated to give an alcohol product

23 3 carbonyl condensation reactions versus alpha substitution reactions
23.3 Carbonyl Condensation Reactions versus Alpha-Substitution Reactions

  • Carbonyl condensations and  substitutions both involve formation of enolate ion intermediates

  • Alpha-substitution reactions are accomplished by converting all of the carbonyl compound to enolate form so it is not an electrophile

  • Immediate addition of an alkyl halide to completes the alkylation reaction

Conditions for condensations
Conditions for Condensations Alpha-Substitution Reactions

  • A small amount of base is used to generate a small amount of enolate in the presence of unreacted carbonyl compound

  • After the condensation, the basic catalyst is regenerated

23 4 dehydration of aldol products synthesis of enones
23.4 Dehydration of Aldol Products: Synthesis of Enones Alpha-Substitution Reactions

  • The -hydroxy carbonyl products dehydrate to yield conjugated enones

  • The term “condensation” refers to the net loss of water and combination of 2 molecules

Dehydration of hydoxy ketones and aldehydes
Dehydration of Alpha-Substitution Reactions-Hydoxy Ketones and Aldehydes

  • The  hydrogen is removed by a base, yielding an enolate ion that expels the OH leaving group

  • Under acidic conditions the OH group is protonated and water is expelled

Driving the equilbrium
Driving the Equilbrium Alpha-Substitution Reactions

  • Removal of water from the aldol reaction mixture can be used to drive the reaction toward products

  • Even if the initial aldol favors reactants, the subsequent dehydration step pushes the reaction to completion

23 5 using aldol reactions in synthesis
23.5 Using Aldol Reactions in Synthesis Alpha-Substitution Reactions

  • If a desired molecule contains either a -hydroxy carbonyl or a conjugated enone, it might come from an aldol reaction

Extending the synthesis
Extending the Synthesis Alpha-Substitution Reactions

  • Subsequent transformations can be carried out on the aldol products

  • A saturated ketone might be prepared by catalytic hydrogenation of the enone product

23 6 mixed aldol reactions
23.6 Mixed Aldol Reactions Alpha-Substitution Reactions

  • A mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products

  • This is not useful

Practical mixed aldols
Practical Mixed Aldols Alpha-Substitution Reactions

  • If one of the carbonyl partners contains no  hydrogens and the carbonyl is unhindered (such as benzaldehyde and formaldehyde) it is a good electrophile and can react with enolates hen a mixed aldol reaction is likely to be successful

  • 2-methylcyclohexanone gives the mixed aldol product on reaction with benzaldehyde

Mixed aldols with acidic carbonyl compounds
Mixed Aldols With Acidic Carbonyl Compounds Alpha-Substitution Reactions

  • Ethyl acetoacetate is completely converted into its enolate ion under less basic conditions than monocarbonyl partners

  • Aldol condensations with ethyl acetoacetate occur preferentially to give the mixed product

23 7 intramolecular aldol reactions
23.7 Intramolecular Aldol Reactions Alpha-Substitution Reactions

  • Treatment of certain dicarbonyl compounds with base produces cyclic products by intramolecular reaction

Mechanism of intramolecular aldol reactions
Mechanism of Intramolecular Aldol Reactions Alpha-Substitution Reactions

  • Both the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor are now in the same molecule.

  • The least strained product is formed because the reaction is reversible

23 8 the claisen condensation reaction
23.8 The Claisen Condensation Reaction Alpha-Substitution Reactions

  • Reaction of an ester having an  hydrogen with 1 equivalent of a base to yield a -keto ester

Mechanism of the claisen condensation
Mechanism of the Claisen Condensation Alpha-Substitution Reactions

  • Similar to aldol condensation: nucleophilic acyl substitution of an ester enolate ion on the carbonyl group of a second ester molecule

Features of the claisen condensation
Features of the Claisen Condensation Alpha-Substitution Reactions

  • If the starting ester has more than one acidic a hydrogen, the product -keto ester has a doubly activated proton that can be abstracted by base

  • Requires a full equivalent of base rather than a catalytic amount

  • The deprotonation drives the reaction to the product

23 9 mixed claisen condensations
23.9 Mixed Claisen Condensations Alpha-Substitution Reactions

  • Successful when one of the two ester act as the electrophilic acceptor in reactions with other ester anions to give mixed -keto esters

Esters and ketones
Esters and Ketones Alpha-Substitution Reactions

  • Reactions between esters and ketones, resulting in -diketones

  • Best when the ester component has no  hydrogens and can't act as the nucleophilic donor

23 10 intramolecular claisen condensations the dieckmann cyclization
23.10 Intramolecular Claisen Condensations: The Dieckmann Cyclization

  • Intramolecular Claisen condensation

  • Best with 1,6-diesters (product: 5-membered-ketoester) and 1,7-diesters (product: 6-membered -ketoester)

Alkylation of dieckmann product
Alkylation of Dieckmann Product Cyclization

  • The cyclic -keto ester can be further alkylated and decarboxylated as in the acetoacetic ester synthesis

23 11 the michael reaction
23.11 The Michael Reaction Cyclization

  • Enolates can add as nucleophiles to ,-unsaturated aldehydes and ketones to give the conjugate addition product

Best conditions for the michael reaction
Best Conditions for the Michael Reaction Cyclization

  • When a particularly stable enolate ion

  • Example: Enolate from a -keto ester or other 1,3-dicarbonyl compound adding to an unhindered ,-unsaturated ketone

Mechanism of the michael reaction
Mechanism of the Michael Reaction Cyclization

  • Nucleophilic addition of a enolate ion donor to the  carbon of an ,-unsaturated carbonyl acceptor

Generality of the michael reaction
Generality of the Michael Reaction Cyclization

  • Occurs with a variety of ,-unsaturated carbonyl compounds (aldehydes, esters, nitriles, amides, and nitro compounds)

  • Donors include -diketones, -keto esters, malonic esters, -keto nitriles, and nitro compounds

  • See Table 23.1

23 12 the stork enamine reaction
23.12 The Stork Enamine Reaction Cyclization

  • Enamines are equivalent to enolates in their reactions and can be used to accomplish the transformations under milder conditions

  • Enamines are prepared from a ketone and a secondary amine

Why enamines are nucleophilic
Why Enamines Are Nucleophilic Cyclization

  • Overlap of the nitrogen lone-pair orbital with the double-bond π orbitals increases electron density on the  carbon atom

Enamine addition and hydrolysis
Enamine Addition and Hydrolysis Cyclization

  • Enamine adds to an ,-unsaturated carbonyl acceptor

  • The product is hydrolyzed to a 1,5-dicarbonyl compound

23 13 carbonyl condensation reactions in synthesis the robinson annulation reaction
23.13 Carbonyl Condensation Reactions in Synthesis: The Robinson Annulation Reaction

  • A two-step process: combines a Michael reaction with an intramolecular aldol reaction

  • The product is a substituted 2-cyclohexenone

Robinson annulation in synthesis
Robinson Annulation in Synthesis Robinson Annulation Reaction

  • The sequence is frequently used to create cyclic structures in complex molecules, including the synthesis of steroids

23 14 biological carbonyl condensation reactions
23.14 Biological Carbonyl Condensation Reactions Robinson Annulation Reaction

  • The acetyl CoA molecule as the major building block for synthesis in living systems (Two-carbon acetyl group and large CoA group is connected as thiol ester

  • Acetyl CoA is an electrophilic acceptor, and can become a nucleophilic donor by loss of its  hydrogen

The role of acetyl coa
The Role of Acetyl CoA Robinson Annulation Reaction

  • Acetyl CoA is a source of an acetyl enolate nucleophile in enzyme-catalyzed Claisen-like condensations in the biosynthesis of lipids and in sugar metabolism