Condensations and a Substitutions of Carbonyl Compounds

Alpha Substitution

• Alpha substitution involves replacing a hydrogen atom on the α carbon with an electrophile.
• This reaction proceeds through an enolate ion intermediate.

Condensation Reactions

• Condensation reactions combine two or more molecules, often with the loss of a small molecule like water or an alcohol.

Enolate Condensation with Aldehydes or Ketones

• The enolate ion attacks the carbonyl group, leading to the formation of an alkoxide.
• Protonation of the alkoxide yields a β-hydroxy carbonyl compound.

Condensation with Esters

• The enolate adds to the ester, forming a tetrahedral intermediate.
• Elimination of the leaving group (alkoxide) produces a β-dicarbonyl compound.

Keto-Enol Tautomerism

• Tautomerization is the interconversion of isomers through proton migration and double bond movement.
• Tautomers are not resonance forms.

Base-Catalyzed Tautomerism

• A proton on the α carbon is abstracted to form a resonance-stabilized enolate ion.
• The equilibrium favors the keto form over the enolate ion.

Acid-Catalyzed Tautomerism

• In acidic conditions, the oxygen is first protonated, followed by the removal of a proton from the α carbon.

Racemization

• For aldehydes and ketones, the keto form is highly favored at equilibrium.
• If a chiral α carbon has an enolizable hydrogen atom, a trace of acid or base can cause inversion of configuration through an enol intermediate; this is called racemization.

Acidity of Alpha Hydrogens

• The pK_a of an α H of an aldehyde or ketone is approximately 20.
• α hydrogens are more acidic than alkanes, alkenes (pKa > 40), or alkynes (pKa = 25).
• α hydrogens are less acidic than water (pKa = 15.7) or alcohols (pKa = 16-19).
• Only a small fraction of enolate ion is present at equilibrium.

Formation and Stability of Enolate Ions

• The equilibrium mixture contains only a small fraction of the deprotonated enolate form.

Energy Diagram of Enolate Reaction

• Even though the keto-enol tautomerism equilibrium favors the keto form, the addition of an electrophile shifts the equilibrium toward enol formation.

Synthesis of Lithium Diisopropylamide (LDA)

• LDA is synthesized by deprotonating diisopropylamine using an alkyllithium reagent.
• LDA can quantitatively convert a carbonyl compound to its enolate.

Enolate of Cyclohexanone

• LDA reacts with a ketone, abstracting the α proton to form the lithium salt of the enolate.

Alkylation of Enolate Ions

• Enolates have two nucleophilic sites (oxygen and α carbon) and can react at either site.
• The reaction usually occurs predominantly at the α carbon, forming a C-C bond.

Alpha Alkylation of Enolate Ions

• LDA forms the enolate.
• The enolate acts as a nucleophile, attacking the partially positive carbon of the alkyl halide, displacing the halide and forming a C-C bond.

Enamine Formation

• Ketones or aldehydes react with a secondary amine to form enamines.
• Enamines have a nucleophilic α carbon that can attack electrophiles.

Electrostatic Potential Map of an Enamine

• The EPM shows a high negative electrostatic potential (red) near the α carbon atom of the double bond, indicating the nucleophilic carbon atom of the enamine.

Mechanism of Enamine Formation

• Enamines result from the reaction between a ketone or aldehyde and a secondary amine.

Alkylation of Enamines

• Enamines displace halides from reactive alkyl halides, yielding alkylated iminium salts.
• The alkylated iminium salt can be hydrolyzed to the ketone under acidic conditions.

Acylation of Enamines

• The enamine attacks the acyl halide, forming an acyl iminium salt.
• Hydrolysis of the iminium salt produces the β-diketone as the final product.

Alpha Halogenation of Ketones

• Ketones undergo α halogenation when treated with a halogen and a base.
• The reaction is base-promoted because a full equivalent of the base is consumed.

Base-Promoted Halogenation Mechanism

• Base-promoted halogenation involves a nucleophilic attack of an enolate ion on the electrophilic halogen molecule.
• The products are the halogenated ketone and a halide ion.

Multiple Halogenations

• α-haloketones are more reactive than ketones due to the electron-withdrawing halogen stabilizing the enolate ion.
• The second halogenation occurs faster than the first.
• Due to the tendency for multiple halogenations, this method is not typically used to prepare monohalogenated ketones.

Haloform Reaction

• Methyl ketones react with a halogen under strongly basic conditions to yield a carboxylate ion and a haloform.
• The trihalomethyl intermediate is not isolated.

Final Steps of the Haloform Reaction

• The trihalomethyl ketone reacts with a hydroxide ion to give a carboxylic acid.
• A fast proton exchange gives a carboxylate ion and a haloform.
• Cl2 forms chloroform, Br2 forms bromoform, and I_2 forms iodoform.

Positive Iodoform Test for Alcohols

• The iodoform test is used to identify methyl ketones.
• Alcohols can also give a positive iodoform test.
• Iodoform (CHI_3) is a yellow solid that precipitates out of solution.

Acid-Catalyzed Alpha Halogenation

• Ketones also undergo acid-catalyzed α halogenation.
• Acidic halogenation may replace one or more alpha hydrogens, depending on the amount of halogen used.

Mechanism of Acid-Catalyzed Alpha Halogenation

• Acid-catalyzed halogenation involves the attack of the enol form of the ketone on the electrophile halogen molecule.
• Loss of a proton gives the haloketone and the hydrogen halide.

Hell-Volhard-Zelinsky (HVZ) Reaction

• The HVZ reaction replaces a hydrogen atom with a bromine atom on the α carbon of a carboxylic acid (α-bromoacid).
• The acid is treated with bromine and phosphorus tribromide, followed by hydrolysis.

Hell-Volhard-Zelinsky Reaction: Step 1

• 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 the acid.

Hell-Volhard-Zelinsky Reaction: Step 2

• The enol is nucleophilic and attacks bromine to give the alpha-brominated acyl bromide.
• In the last step, the acyl bromide is hydrolyzed by water to the carboxylic acid.

Aldol Condensation of Ketones and Aldehydes

• The aldol condensation is the addition of an enolate ion to another carbonyl group under basic or acidic conditions.
• Under basic conditions, the aldol condensation involves the nucleophilic addition of an enolate ion to another carbonyl group.
• When the reaction is carried out at low temperatures, the β-hydroxy carbonyl compound can be isolated.
• Heating will dehydrate the aldol product to the α,β-unsaturated compound.

Base-Catalyzed Aldol Condensation: Step 1

• The base removes the α proton, forming the enolate ion.
• The enolate ion has a nucleophilic α carbon.

Base-Catalyzed Aldol Condensation: Step 2

• The enolate attacks the carbonyl carbon of a second molecule of carbonyl compound.

Base-Catalyzed Aldol Condensation: Step 3

• Protonation of the alkoxide gives the aldol product.

Acid-Catalyzed Aldol Condensation: Step 1

• Formation of the enol by protonation on O, followed by deprotonation on C

Acid-Catalyzed Aldol Condensation: Step 2

• Addition of the enol to the protonated carbonyl

Acid-Catalyzed Aldol Condensation: Step 3

• Deprotonation to give the aldol product

Dehydration of Aldol Products

• Heating a basic or acidic aldol product leads to dehydration of the alcohol functional group.
• The product is an α,β-unsaturated conjugated aldehyde or ketone.

Crossed Aldol Condensations

• When the enolate of one aldehyde (or ketone) adds to the carbonyl group of a different aldehyde or ketone, the result is called a crossed aldol condensation.

Successful Crossed Aldol Condensations

• A crossed aldol condensation can be effective if it is planned so that only one of the reactants can form an enolate ion.

Aldol Cyclization

• Intramolecular aldol reactions of diketones are often used for making five- and six-membered rings.
• Rings smaller or larger than five or six members are not favored due to ring strain or entropy.

Claisen Ester Condensation

• The Claisen condensation results when an ester molecule undergoes nucleophilic acyl substitution by an enolate.

Dieckmann Condensation

• An internal Claisen cyclization is called a Dieckmann condensation or a Dieckmann cyclization.

Crossed Claisen Condensation

• Two different esters can be used, but one ester should have no α hydrogens.
• Useful esters are benzoates, formates, carbonates, and oxalates.
• Ketones (pK_a = 20) may also react with an ester to form a β-diketone.
• In a crossed Claisen condensation, an ester without α hydrogens serves as the electrophilic component.

Crossed Claisen Condensation with Ketones and Esters

• Crossed Claisen condensation between ketones and esters is 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.

Crossed Claisen Mechanism

• The ketone enolate attacks the ester, which undergoes nucleophilic acyl substitution and thereby acylates the ketone.

Syntheses Using B-Dicarbonyl Compounds

• Typical pKa values for carbonyl compounds include simple ketones ($\approx 20) and esters ($\approx 24), while β-dicarbonyl compounds have significantly lower pKa values ($\approx 11-13$$).

Malonic Ester Synthesis

• The malonic ester synthesis makes substituted derivatives of acetic acids.
• Malonic ester is alkylated or acylated on the carbon that is alpha to both carbonyl groups.
• The resulting derivative is hydrolyzed and decarboxylated.

Decarboxylation of the Alkylmalonic Acid

• Decarboxylation takes place through a cyclic transition state, initially giving an enol form that quickly tautomerizes to the product.

Dialkylation of Malonic Ester

• Further alkylation of the alkylmalonic ester results in dialkylmalonic esters, which can be hydrolyzed and decarboxylated to disubstituted acetic acids.

Acetoacetic Ester Synthesis

• The acetoacetic ester synthesis is similar to the malonic ester synthesis, but the final products are ketones.

Alkylation of Acetoacetic Ester

• Ethoxide ion completely deprotonates acetoacetic ester.
• The resulting enolate is alkylated by an unhindered alkyl halide or tosylate to give an alkylacetoacetic ester.

Hydrolysis of Alkylacetoacetic Ester

• Acidic hydrolysis of the alkylacetoacetic ester initially gives an alkylacetoacetic acid, which is a β-keto acid.
• The keto group in the β position promotes decarboxylation to form a substituted version of acetone.

Conjugate Additions - The Michael Reaction

• α,β-Unsaturated carbonyl compounds have unusually electrophilic double bonds.
• The β carbon is electrophilic because it shares the partial positive charge of the carbonyl carbon through resonance.

1,2-Addition and 1,4-Addition

• When attack occurs at the carbonyl group, protonation of the oxygen leads to a 1,2-addition.
• When attack occurs at the β position, the oxygen atom is the fourth atom counting from the nucleophile, and the addition is called a 1,4-addition.
• Common Michael donors include lithium dialkyl cuprates (Gilman reagents), enamines, β-diketones, β-keto esters, α-nitro ketones, and nitroethylene. Common Michael acceptors include conjugated aldehydes, ketones, esters, amides, and nitriles.

1,4-Addition of an Enolate to Methyl Vinyl Ketone (MVK)

• An enolate will do a 1,4-attack on the α,β-unsaturated ketone (MVK).

Robinson Annulation

• With enough base, the product of the Michael reaction undergoes a spontaneous intramolecular aldol condensation, usually with dehydration, to give a six-membered ring—a conjugated cyclohexenone.