Untitled Quiz

Reactions at the α Carbon of Carbonyl Compounds

• Reactions at the α carbon of carbonyl compounds arise from the weak acidity of hydrogen atoms adjacent to the carbonyl group.
• These hydrogen atoms are called α hydrogens.
• The carbon to which they are attached is called the α carbon.
• α hydrogens are weakly acidic (pKa = 19-20).

The Acidity of α Hydrogens of Carbonyl Compounds: Enolate Anions

• α hydrogens of carbonyl compounds are unusually acidic for hydrogen atoms attached to carbon.
• The pKa values for α hydrogens of simple aldehydes or ketones are around 19-20.
• This is more acidic than ethyne (pKa= 25), ethene (pKa = 44), or ethane (pKa = 50).
• The carbonyl group is strongly electron withdrawing.
• When an α proton is lost, the resulting anion (enolate) is stabilized by delocalization.
• Two resonance structures can be written for an enolate, one with the negative charge on carbon and the other on oxygen.
• Although A is favored due to the stronger carbon-oxygen bond, resonance structure B makes a larger contribution due to oxygen being electronegative allowing it to better accomodate the negative charge.
• The enolate hybrid shows a delocalized negative charge.

Keto and Enol Tautomers

• Keto and enol forms of carbonyl compounds are constitutional isomers; they are easily interconverted in the presence of acids and bases.
• Interconvertible keto and enol forms are called tautomers, and their interconversion is called tautomerization.
• Under most circumstances, keto-enol tautomers exist in equilibrium.
• For simple carbonyl compounds like acetone and acetaldehyde, the amount of the enol form is very small.
• The greater stability of the keto form in these compounds is due to the stronger carbon-oxygen bond compared to the carbon-carbon bond. (~364 versus ~250 kJ mol⁻¹).
• In β-dicarbonyl compounds, the enol form is significantly more stable due to resonance stabilization and hydrogen bonding.

Racemization

• Racemization at alpha carbons occurs in the presence of acids or bases.
• The keto form reversibly converts to the enol form.
• The enol form is achiral, leading to the production of equal amounts of the two enantiomers when it reverts to the keto form.
• A base catalyzes the formation of an enol via an enolate anion intermediate.

Halogenation at the α Carbon

• Carbonyl compounds with an α hydrogen can undergo halogen substitution in the presence of an acid or base.
• In the presence of a base, halogenation happens through the slow formation of an enolate anion or enol, followed by a rapid reaction of the enolate or enol with a halogen.
• The reaction produces a racemic mixture of products.

The Haloform Reaction

• Methyl ketones react with halogens in the presence of excess base to produce multiple halogenations at the methyl group.
• The first halogenation makes the remaining alpha hydrogens more acidic.
• A resulting CX3 group (chloroform, bromoform, or iodoform) attached to the carbonyl carbon can act as a leaving group, leading to a carboxylate salt and a haloform.
• The trihalomethyl anion, unusually stable, is the leaving group.
• The reaction can be used to convert methyl ketones into carboxylic acids.

α-Halo Carboxylic Acids: The Hell-Volhard-Zelinski Reaction

• Carboxylic acids reacting with bromine or chlorine in presence of phosphorous yields alpha-halo carboxylic acids in the Hell-Volhard-Zelinski (HVZ) reaction.
• This reaction is suitable for introducing a halogen at the alpha position of carboxylic acids.

Lithium Enolates

• Lithium diisopropylamine (LDA) is a strong base for converting carbonyl compounds to enolates.
• The equilibrium position depends on the base strength.
• A stronger base shifts the equilibrium toward the enolate form.
• Preparation involves dissolving diisopropylamine in a solvent such as diethyl ether or THF and treating it with an alkyllithium to generate LDA.

Regioselective Formation of Enolates

• The stability of the enolate depends on the substitution pattern of the double bond. More substituted alkenes are generally more stable.
• The equilibrium generally favors the more stable enolate. These reactions provide useful means for controlling regioselectivity.

Direct Alkylation of Ketones via Lithium Enolates

• Lithium enolates provide a way to alkylate ketones selectively.
• Reaction of LDA followed by methyl iodide or benzyl bromide can yield alkylated ketones.

Direct Alkylation of Esters

• Direct alkylation of esters.
• LDA can be used to alkylate esters.

Enolates of β-Dicarbonyl Compounds

• β-dicarbonyl compounds (compounds with two carbonly groups separated by a single carbon atom) exhibit enhanced acidity of their α hydrogens because the negative charge can be delocalized to the two carbonyl oxygens.
• They have pKa values in the range of 9-11, showing increased acidity compared to single carbonyl groups (18-20).

Synthesis of Methyl Ketones: The Acetoacetic Ester Synthesis

• Acetoacetic ester, a β-dicarbonyl compound, can easily be converted to an enolate using sodium ethoxide.
• This enolate can then be alkylated with an alkyl halide to produce a monoalkylacetoacetic ester.
• Using primary alkyl halides or methyl halides provides optimal yields; secondary halides result in lower yields, and tertiary halides yield mostly elimination.
• Further alkylation is possible by using a stronger base than ethoxide ion.

Synthesis of y-keto acids and y-diketones

• Acetoacetic ester synthesis can be used for synthesizing y-keto acids using halo esters.
• The reaction proceeds through halogenation at the alpha position, basic hydrolysis of the ester, acidification, and heating to cause decarboxylation.

Acylation

• Anions from acetoacetic esters can undergo acylation with acyl chlorides or acid anhydrides in aprotic solvents.

Synthesis of Substituted Acetic Acids: The Malonic Ester Synthesis

• The malonic ester synthesis is a method for preparing mono- and disubstituted acetic acids.
• The starting compound is diethyl malonate (a dicarboxylic acid diester)

Further Reactions of Active Hydrogen Compounds

• Active hydrogen compounds—compounds with electron-withdrawing groups on the same carbon atom—have increased acidity in their alpha positions.
• Compounds like ethyl cyanoacetate are examples of active methylene compounds. Ethyl cyanoacetate can be dialkylated with isopropyl iodide.

Synthesis of Enamines: Stork Enamine Reactions

• Enamines are formed from ketones or aldehydes and secondary amines.

The Nucleophilicity of Enamines

• Enamines can undergo a variety of reactions including acylation and alkylation, as well as Michael additions.

Synthesis of y-keto esters

• Enamines can be used in the synthesis of y-keto esters.