23.2 Carbonyl Condensations versus Alpha Substitutions

Carbonyl compounds can undergo two key reactions: condensations and alpha substitutions. These processes involve different mechanisms, conditions, and outcomes, shaping how carbonyl groups transform and form new bonds.

Understanding these reactions is crucial for manipulating carbonyl compounds. Condensations join two carbonyls, while alpha substitutions replace hydrogens next to the carbonyl. Mastering these opens up a world of synthetic possibilities in organic chemistry.

Carbonyl Condensations and Alpha Substitutions

Carbonyl condensations vs alpha substitutions

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Carbonyl condensations:

• Reaction between two carbonyl compounds (aldehydes or ketones)
• Catalytic amount of base required (NaOH, KOH, NaOEt)
• Proceeds through aldol condensation mechanism
  • Enolate formation of one carbonyl compound
  • Nucleophilic addition of enolate to second carbonyl compound
  • Dehydration of resulting [object Object],[object Object]-hydroxy carbonyl compound forms [object Object],[object Object]-unsaturated carbonyl product
• Unreacted carbonyl compounds remain in reaction mixture (acetaldehyde, acetone) Alpha substitutions:
• Reaction between carbonyl compound and alkyl halide (methyl iodide, ethyl bromide)
• Strong base required (LDA, NaH, NaNH2)
• Proceeds through SN2 mechanism
  • Enolate formation of carbonyl compound
  • SN2 reaction between enolate and alkyl halide
• All carbonyl compounds consumed during reaction
• Involves a leaving group in the alkyl halide

Conditions for alpha-substitution reactions

Base strength:

• Strong bases required for complete enolate formation of carbonyl compound
  • Lithium diisopropylamide (LDA)
  • Sodium hydride (NaH)
  • Sodium amide (NaNH2) Temperature:
• Carried out at low temperatures (-78°C to 0°C)
• Low temperatures favor kinetic enolate formation and minimize side reactions Reactant addition order:

1. Carbonyl compound first treated with strong base to form enolate
2. Alkyl halide then added to reaction mixture

• Ensures enolate present before alkyl halide introduced, favoring desired SN2 reaction

Process of carbonyl condensation reactions

Process:

1. Two carbonyl compounds mixed with catalytic amount of base
2. Base facilitates enolate formation from one carbonyl compound
3. Enolate acts as nucleophile and attacks second carbonyl compound
4. Resulting aldol product undergoes dehydration to form $\alpha,\beta$-unsaturated carbonyl compound

Conditions:

• Catalytic amount of base sufficient (NaOH, KOH, NaOEt)
  • Base regenerated during dehydration step, allowing further reaction catalysis
• Unreacted carbonyl compounds remain
  • Nucleophilic carbonyl compound (enolate precursor) used in excess
  • Ensures complete reaction of electrophilic carbonyl compound
  • Unreacted nucleophilic carbonyl compounds (acetone, cyclohexanone) remain in reaction mixture after condensation complete

Keto-Enol Tautomerism and Enolates

• Keto-enol tautomerism involves the interconversion between keto and enol forms
• Enols are unstable tautomers of carbonyl compounds
• Thermodynamic enolate formation occurs under equilibrium conditions
• Kinetic enolate formation is favored at low temperatures and with strong, hindered bases