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Questions and Answers
What is produced when an enolate reacts with an electrophile?
What is produced when an enolate reacts with an electrophile?
Which reaction specifically results in the formation of haloform?
Which reaction specifically results in the formation of haloform?
Racemization of chiral enolates leads to the formation of which type of compound?
Racemization of chiral enolates leads to the formation of which type of compound?
What is the role of a base in the formation of enolates?
What is the role of a base in the formation of enolates?
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Which of the following reactions involves the use of base in the formation of an enolate?
Which of the following reactions involves the use of base in the formation of an enolate?
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What compound is produced from the reaction of a carboxylic acid with X2 and P?
What compound is produced from the reaction of a carboxylic acid with X2 and P?
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What component is typically used to stabilize the resonance of an enolate?
What component is typically used to stabilize the resonance of an enolate?
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Which type of bond does an enolate primarily form with an electrophile?
Which type of bond does an enolate primarily form with an electrophile?
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What is a key characteristic of direct alkylation via lithium enolates?
What is a key characteristic of direct alkylation via lithium enolates?
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In acetoacetic ester synthesis, what role does heat play in the reaction process?
In acetoacetic ester synthesis, what role does heat play in the reaction process?
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During the malonic ester synthesis, which compound is primarily being produced following the initial reactions?
During the malonic ester synthesis, which compound is primarily being produced following the initial reactions?
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What temperature is commonly used during the formation of the kinetic enolate in direct alkylation?
What temperature is commonly used during the formation of the kinetic enolate in direct alkylation?
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In direct alkylation of esters, what is the purpose of adding LDA in THF?
In direct alkylation of esters, what is the purpose of adding LDA in THF?
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What is the correct sequence of steps in acetoacetic ester synthesis?
What is the correct sequence of steps in acetoacetic ester synthesis?
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Which reagent is commonly used in malonic ester synthesis to generate the enolate?
Which reagent is commonly used in malonic ester synthesis to generate the enolate?
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Which statement regarding the direct alkylation of esters is true?
Which statement regarding the direct alkylation of esters is true?
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Study Notes
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.
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