23.5 Mixed Aldol Reactions

Mixed aldol reactions combine two different carbonyl compounds to form new carbon-carbon bonds. One compound acts as a nucleophile, forming an enolate, while the other serves as an electrophile. This process requires specific conditions, including strong bases and anhydrous environments.

The reaction yields β-hydroxy carbonyl products, with regioselectivity and stereochemistry depending on the reactants' structure. Mixed aldol reactions are valuable in organic synthesis, allowing for the creation of complex molecules through careful selection of reactants and control of reaction conditions.

Mixed Aldol Reactions

Conditions for mixed aldol reactions

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• Two different carbonyl compounds are required
  • One carbonyl compound acts as the nucleophile (enolate) must have an $\alpha$-hydrogen to form the enolate typically an aldehyde (propanal) or ketone (acetone)
  • The other carbonyl compound acts as the electrophile can be an aldehyde (benzaldehyde) or ketone (cyclohexanone)
• Strong base is needed to deprotonate the nucleophilic carbonyl compound
  • Common bases: LDA (lithium diisopropylamide), NaH (sodium hydride), NaOEt (sodium ethoxide)
• Anhydrous conditions are necessary to prevent side reactions water can react with the base or enolate, reducing the yield use of dry solvents (THF, diethyl ether) and inert atmosphere (N2 or Ar)
• Low temperatures (-78\,^{\circ}\mathrm{C}) are often used to control the reaction and improve selectivity achieved using dry ice/acetone bath or liquid nitrogen/ethyl acetate bath

Products of mixed aldol reactions

• The enolate of the nucleophilic carbonyl compound attacks the electrophilic carbonyl carbon forms a new carbon-carbon bond between the $\alpha$-carbon of the nucleophile and the carbonyl carbon of the electrophile
• The resulting alkoxide intermediate is protonated during workup to give the aldol product a $\beta$-hydroxy carbonyl compound is formed (3-hydroxybutanal from acetaldehyde and formaldehyde)
• Regioselectivity depends on the structure of the nucleophilic carbonyl compound
  • Aldehydes (propanal) and unsymmetrical methyl ketones (2-butanone) form enolates at the least substituted $\alpha$-carbon
  • Ketones with two different $\alpha$-substituents (2-pentanone) can form two different enolates, leading to a mixture of products
• Stereochemistry of the product depends on the reaction conditions and the structure of the reactants
  • The addition of the enolate to the electrophile can occur from either the re or si face, leading to diastereomers (syn and anti aldol products)
  • The Zimmerman-Traxler model can be used to predict the stereochemistry of aldol reactions

Synthesis via mixed aldol reactions

• Retrosynthetic analysis can be used to plan a synthesis route
  1. Identify the target molecule (4-hydroxy-4-phenylbutan-2-one) and work backwards
  2. Disconnect the carbon-carbon bond formed in the aldol reaction to determine the required reactants (acetone and benzaldehyde)
• Consider the reactivity and selectivity of the carbonyl compounds choose the nucleophilic (acetone) and electrophilic (benzaldehyde) components based on their structure and the desired product
• Protect functional groups that may interfere with the reaction
  • Alcohols can be protected as silyl ethers (TBS) or acetates
  • Amines can be protected as carbamates (Boc) or amides
• Use appropriate reaction conditions to control the regio- and stereoselectivity
  • Select the base (LDA), temperature (-78\,^{\circ}\mathrm{C}), and solvent (THF) to optimize the yield and selectivity
• Perform additional transformations as needed to obtain the target molecule
  • Oxidation (Swern), reduction (NaBH4), or elimination (dehydration using H2SO4) of the aldol product may be required
  • Deprotection of functional groups (TBAF for silyl ethers, LiAlH4 for acetates) may be necessary

Enolate formation and reactivity

• Enolization is the process of forming an enolate from a carbonyl compound
• Kinetic vs. thermodynamic enolates:
  • Kinetic enolates form quickly and are favored at low temperatures
  • Thermodynamic enolates are more stable and form under equilibrium conditions
• Aldol addition occurs when an enolate attacks another carbonyl compound
• Crossed aldol condensation involves two different carbonyl compounds and can lead to multiple products
• E1cB elimination can occur after aldol addition, resulting in an α,β-unsaturated carbonyl compound