Chapter 22
Additions and Condensations of Enolate Ions
22-00-01UN

Labeled
Title
 Alpha Substitution
Caption
 Alpha substitution involves the replacement of a hydrogen atom at the a carbon atom (the carbon atom next to the carbonyl) by some other group. Alpha substitution generally takes place when the carbonyl compound is converted to its enolate ion or enol tautomer.
Notes
 The base abstracts the a proton, making that carbon nucleophilic. The negative charge can be delocalized on the oxygen as well. The carbon will attack an electrophile and complete the substitution reaction.
Keywords
 alpha substitution, enolate ion, enol tautomer
22-00-02UN

Labeled
Title
 Condensation Reactions
Caption
 Carbonyl condensations are alpha substitutions wherre the electrophile is another carbonyl compound.
Notes
 The enolate carbon attacks the carbonyl carbon of a ketone or aldehyde produces, after protonation, a b-hydroxy carbonyl compound. When the enolate attacks an ester, the product will be a b-dicarbonyl compound.
Keywords
 enolate, condensation, b-dicarbonyl compound, b-hydroxy carbonyl compound
22-00-03UN

Labeled
Title
 Base-Catalyzed Keto-Enol Tautomerism
Caption
 In the presence of strong bases, ketones and aldehydes act as weak proton acids. A proton on the a carbon is abstracted to form a resonance stabilized enolate-ion with the negative charge spread over a carbon atom and an oxygen atom.
Notes
 The equilibrium favors the keto form over the enolate ion.
Keywords
 keto, enolate, enol form, tautomerism
22-00-05UN

Labeled
Title
 Acid-Catalyzed Keto-Enol Tautomerism
Caption
 Keto-enol tautomerism is also catalyzed by acid.
Notes
 In acid, a proton is moved from the a carbon to oxygen by first protonating oxygen and then removing a proton from carbon.
Keywords
 keto, enolate, enol form, tautomerism
22-00-06UN

Labeled
Title
 Racemization
Caption
 If a chiral carbon has enolizable hydrogen atom, a trace of acid or base allows that carbon to invert its configuration, with the enol serving as the intermediate.
Notes
 The intermediate enol is achiral.
Keywords
 chiral, enol, enolization, achiral, chiral, racemization
22-01

Labeled
Title
 Energy Diagram of Enolate Reaction with an Electrophile
Caption
 Figure 22-1 Reaction of the enolate ion with an electrophile removes it from equilibrium.
Notes
 Eventhough the keto-enol tautomerism equilibrium favors the keto form, addition of an electrophile shifts the equilibrium toward the formation of more enol.
Keywords
 enol, enolate, keto form
22-01-04UN

Labeled
Title
 Alpha Halogenation of Ketones
Caption
 When a ketone is treated with a halogen and base, an a-halogenation reaction occurs.
Notes
 The reaction is called base-promoted, rather than base-catalyzed, because a full equivalent of the base is consumed in the reaction.
Keywords
 alpha halogenation, base-catalyzed, base-promoted
22-01-12UN

Labeled
Title
 Mechanism of Haloform Formation
Caption
 The trihalomethyl ketone reacts with hydroxide ion to give a carboxylic acid. A fast proton exchange gives a carboxylate ion and a haloform.
Notes
 When chlorine is used, chloroform is formed; bromine, bromoform; iodine, iodoform.
Keywords
 trihalomethyl ketone, haloform, chloroform, bromoform, iodoform
22-01-13UN

Labeled
Title
 Bromoform Reaction
Caption
 A methyl ketone reacts with a halogen under strongly basic conditions to give a carboxylate ion and a haloform.
Notes
 The trihalomethyl intermediate is not isolated. Iodoform is a yellow solid and its formation is used as a qualitative test for methyl ketones.
Keywords
 trihalomethyl ketone, haloform, iodoform
22-01-15UN

Labeled
Title
 Iodoform Reaction with a Secondary Alcohol
Caption
 Iodine is an oxidizing agent, and an alcohol can give a positive iodorform test if it oxidizes to a methyl ketone.
Notes
 The iodoform reaction can concert such an alcohol to a carboxylic acid with one less carbon.
Keywords
 iodoform
22-01-18UN

Labeled
Title
 Mechanism of Acid-Catalyzed a-Halogenation
Caption
 The mechanism of acid-catalyzed halogenation involves attack of the enol form of the ketone on the electrophile halogen molecule. Loss of a proton gives the haloketone and the hydrogen halide.
Notes
 Acidic halogenation may replace one or more a-hydrogens depending on how much halogen is used.
Keywords
 a-halogenation
22-01-24UN

Labeled
Title
 Hell-Volhard-Zelinsky Reaction
Caption
 The Hell-Volhard-Zelinsky reaction replaces a hydrogen atom with a bromine atom on the a carbon of a carboxylic acid.
Notes
 The carboxylic acid is reacted with bromine and phosphorus tribromide.
Keywords
 Hell-Volhard-Zelinski, phosphorus tribromide
22-01-25UN

Labeled
Title
 Hell-Volhard-Zelinski Reaction: Step 1
Caption
 The enol form of the acyl bromide serves as a nucleophilic intermediate. The first step is the formation of acyl bromide, which enolizes more easily than does the acid.
Notes
 The equilibrium favors the keto form (acyl bromide).
Keywords
 acyl bromide
22-01-26UN

Labeled
Title
 Hell-Volhard-Zelinski Reaction: Step 2
Caption
 The enol is nucleophilic, attacking bromine to give the a-brominated acyl bromide.
Notes
 Reaction of the a-brominated acyl bromide with a second molecule of acid will give the a-brominated carboxylic acid and a molecule of acyl bromide.
Keywords
 a-halogenated acyl bromide
22-01-27UN

Labeled
Title
 Alkylation of Enolate Ions
Caption
 Because the enolate has two nucleophilic sites (the oxygen and the a carbon), it can react at either of these sites. The reaction usually takes place primarily at the a carbon, forming a new C-C bond.
Notes
 The enolate for this reaction must be formed with bases other than hydroxide or alkoxides to prevent side reactions.
Keywords
22-01-34UN

Labeled
Title
 Mechanism of Enolate Formation
Caption
 An enamine results from the reaction of a ketone or aldehyde with a secondary amine.
Notes
 The 2o carbinolamine is protonated and water is eliminated. Removal of a proton from the a carbon gives the enamine.
Keywords
 enamine, carbinolamine
22-01-36UN

Labeled
Title
 Alkylation of an Enamine
Caption
 Enamines diplace halides from reactive alkyl halides, giving alkylated iminium salts.
Notes
 The alkylated iminium salt can be hydrolyzed to the ketone under acidic conditions.
Keywords
 iminium salts, enamines
22-01-39UN

Labeled
Title
 Acylation of Enamines
Caption
 The initial acylation gives an acyl iminium salt, which hydrolyzes to the b-diketone product.
Notes
 b-Dicarbonyl compounds can be further alkylated.
Keywords
 acyl iminium salt, b-diketone
22-01-41UN

Labeled
Title
 Aldol Condensation
Caption
 Under basic conditions, the aldol condensation involves the nucleophilic addition of an enolate ion to another carbonyl group.
Notes
 When the reaction is carried out at low temperatures, the b-hydroxy carbonyl compound can be isolated. Heating will dehydrate the aldol product to the a,b-unsaturated compound.
Keywords
 b-hydroxy carbonyl, a,b-unsaturated compound, aldol condensation
22-01-42UN

Labeled
Title
Caption
Notes
Keywords
22-01-43

Labeled
Title
 Mechanism of Base-Catalyzed Aldol Condensation
Caption
 Deprotonation of the acetaldehyde gives an enolate ion, which acts as a strong nucleophile. Attack on the carbonyl group of another acetaldehyde molecule gives addition across the carbonyl double bond, forming the aldol product.
Notes
 The aldol condensation reaction is reversible.
Keywords
 aldol condensation
22-02

Labeled
Title
 Aldol Condensation of Acetone
Caption
 Figure 22-2 Acetone refluxes onto a basic catalyst such as Ba(OH)2. The non-volatile diacetone alcohol does not reflux, so its equilibrium concentration gradually increases until all the acetone is converted to the diacetone alcohol.
Notes
 Yields for the aldol condensation of ketones is very low so heating is essential to increase the yield of product.
Keywords
 diacetone, reflux
22-02-06

Labeled
Title
 Crossed Aldol Condensation
Caption
 When the enolate of one aldehyde (or ketone) adds to the carbonyl group of another, the result is called a crossed aldol condensation.
Notes
 A mixture of products can be obtained if more than one enolate can be formed.
Keywords
 crossed aldol condensation
22-02-07UN

Labeled
Title
 Successful Crossed Aldol Condensations
Caption
 A crossed aldol condensation can be effective if it is planned so that only one of the reactants can form an enolate ion so that the other compound is more likely to react with the enolate.
Notes
 To carry out these reactions slowly add the compound with protons to a basic solution of the compound with no a protons.
Keywords
 crossed aldol condensation
22-02-09UN

Labeled
Title
Caption
Notes
Keywords
22-02-14UN

Labeled
Title
 Aldol Cyclization
Caption
 Intramolecular aldol reactions of diketones are often used for making five- and six-membered rings.
Notes
 Rings smaller or larger than 5- or 6-membered are not favored due to ring strain or entropy.
Keywords
 cyclization, diketone
22-03

Labeled
Title
 Retrosynthesis of Aldol Condensation
Caption
 Figure 22-3 Aldol products are b-hydroxyl aldehydes and ketones, or a,b-unsaturated aldehydes and ketones.
Notes
 Imaginary breaking the a,b C-C bond gives the starting products from the aldol condensation.
Keywords
 b-hydroxyl, a,b-unsaturation
22-03-03UN

Labeled
Title
 Claisen Condensation
Caption
 The Claisen condensation results when an ester molecule undergoes nucleophilic acyl substitution by an enolate.
Notes
 The product of the reaction is a b-keto ester.
Keywords
 Claisen condensation, ester, nucleophilic acyl substitution
22-03-19UN

Labeled
Title
 Dieckman Condensation
Caption
 An internal Claisen condensation of a diester forms a ring. Such a reaction is called a Dieckman condensation or a Dieckman cyclization.
Notes
 The formation of 5- or 6-membered rings is favored.
Keywords
 Claisen condensation, Dieckman condensation, cyclization
22-03-25UN

Labeled
Title
 Crossed Claisen Condensation
Caption
 In a crossed Claisen condensation, an ester without a hydrogens serves as the electrophilic component.
Notes
 The ethyl acetate reacts with the base to form an enolate, which condenses with ethyl benzoate.
Keywords
 crossed Claisen condensation
22-03-38UN1-2

Labeled
Title
 Crossed Claisen Condensation with Ketones and Esters
Caption
 Crossed Claisen condensation between ketones and ester are also possible. Ketones are more acidic than esters, and the ketone component is more likely to deprotonate and serve as the enolate component in the condensation.
Notes
 The ester acts as an acylating agent in the reaction producing a b-diketone.
Keywords
 acylating agent
22-03-52UN

Labeled
Title
 Malonic Ester Synthesis
Caption
 The malonic ester synthesis makes substituted derivatives of acetic acids. Malonic ester is alkylated or acylated on the carbon that is s to both carbonyl groups, and the resulting derivative is hydrolyzed and allowed to decarboxylate.
Notes
 The products of the reaction are a substituted acetic acid derivatives and CO2.
Keywords
 malonic ester
22-03-55UN

Labeled
Title
 Decarboxylation of the Alkylmalonic Acid
Caption
 Decarboxylation takes place through a cyclic transition state, initially giving an enol form that quickly tautomerizes to the product.
Notes
 Any carboxylic acid with a carbonyl group in the b position is prone to decarboxylate.
Keywords
 decarboxylation, tautomerization, enol form
22-04-05UN

Labeled
Title
 Acetoacetic Ester Synthesis
Caption
 The acetoacetic ester synthesis is similar to the malonic ester synthesis, but the final products are ketones; substituted derivatives of acetone.
Notes
 The a substitution is followed by hydrolysis and decarboxylation by heating in acidic media.
Keywords
 acetoacetic ester synthesis, ehyl acetoacetate, acetoacetic ester
22-04-20UN

Labeled
Title
 Conjugate Additions: The Michael Reaction
Caption
 a,b-Unsaturated carbonyl compounds have unusually electrophilic double bonds. The b carbon is electrophilic because it shares the partial positive charge of the carbonyl carbon through resonance.
Notes
 Addition can occur at either one of the electrophilic sites, depending on the nucleophile used.
Keywords
 a,b-unsaturated compound, Michael reaction, conjugate addition
22-04-21UN

Labeled
Title
 1,2-Addition and 1,4-Addition
Caption
 When attack occurs at the carbonyl group, protonation of the oxygen leads to a 1,2-addition. When attack occurs at the b-position, the oxygen atom is the fourth atom counting from the nucleophile, and the addition is called a 1,4-addition.
Notes
 The 1,4-addition is also called a conjugate addition.
Keywords
 Michael addition, conjugate addition, 1,2-addition, 1,4-addition
22-04-23UN

Labeled
Title
 1,4-Addition of an Enolate to MVK
Caption
 The crucial step is the attack of the enolate at the carbon. The resulting enolate is strongly basic, and it gets quickly protonated.
Notes
 If malonic ester enolate is used, the addition product can be decarboxylated to produce a d-keto acid.
Keywords
 d-keto acid, methyl vinyl ketone (MVK), 1,4-addition
22-04-36UN

Labeled
Title
 Robinson Annulation
Caption
 If the conjugate addition takes place under strongly basic or acidic conditions, the d-diketone undergoes a spontaneous intramolecular aldol condensation, usually with dehydration, to give a six-membered ring; a conjugated cyclohexenone.
Notes
 Sir Robert Robinson invented this reaction to form complicated ring systems.
Keywords
 Robinson annulation, Michael addition
22-04-37UN

Labeled
Title
 Step 1: Michael Addition
Caption
 The mechanism begins with addition of the enolate of the cyclohexanone to MVK, forming a d-diketone.
Notes
Keywords
 d-diketone, Michael addition
22-04-38UN

Labeled
Title
 Steps 2 and 3: Cyclic Aldol and Dehydration
Caption
 To form a six-membered ring, the enolate of the methyl ketone attacks the cyclohexanone carbonyl. The aldol product dehydrates to give a cyclohexenone.
Notes
Keywords
 aldol cyclization, cyclohexenone
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