Aldehydes and Ketones II: Enolates

Aldehydes and Ketones II: Enolates section provides High Yield information for College Students, Medical Students to succeed in the MCAT exam and Medical School.

General Principles

Acidity of alpha-Hydrogen
  • An a-carbon is adjacent to the carbonyl carbon and the hydrogens connected the a-carbon are termed a-Hydrogen.
    • Oxygen pulls some of the electron density out of these C-H bonds which makes it easier to deprotonate the a-carbon an aldehyde or ketone.
  • Acidity of the alpha hydrogen is increased through the resonance stability provided by the conjugate base
    • Extra electrons that remain after the hydrogen is removed will resonate between the remaining atoms, which subsequently increases the stability of the enolate intermediate.
    • Negative charge is distributed to the more electronegative oxygen atom
    • Electron withdrawing oxygen atom helps stabilize the carbanion
    • Thus alpha hydrogens can easily deprotonate in basic solutions
  • Ketones are slightly less acidic than those of aldehydes due to the electron-donating properties of the additional alkyl group in a ketone.

Steric Hindrance
  • Aldehydes are slightly more reactive to nucleophiles than ketones
  • Additional alkyl group in ketones increases the steric hindrance.
    • Alkyl groups are in the way of the nucleophile trying to attack the carbonyl oxygen.

Enolate Chemistry

  • Ketones and aldehydes exist in solution as a mixture of two isomers: keto & enol forms

Keto-Enol Tautomerization
  • Enol Form: presence of carbon-carbon double bond and an alcohol.
  • The two isomers differ in the placement of a proton and the double bond and they are called tautomers.
  • Equilibrium position lies far to the keto side
  • Enolization or Tautomerization: process of interconverting from the keto to the enol tautomer.
    • Alpha-racemization: any aldehyde or ketone with a chiral alpha carbon will rapidly become a racemix mixture as the keto and enol forms interconvert

Kinetic and Thermodynamic Enolates
  • Two forms of enolates can form if there are two different alkyl groups on a ketone
    • One form with the carbon-carbon double bond between the carbonyl carbon and either the more or less substituted carbon.
  • Kinetically Controlled Product: double bond is on the less substituted alpha-carbon
    • Formed more rapidly but is less stable
    • Favored in reaction that are rapid, irreversible, at lower temperature and with a strong sterically hindered base.
  • Thermodynamically controlled Product: double bond is formed on the more substituted alpha carbon.
    • Favored when there are higher temperature, slow/reversible reactions and with a weaker/smaller base.
    • More stable

  • Tautomers of imines. Same mechanism, i.e. – movement of hydrogen and a double bond.

Aldol Condensation

  • Follows the same general mechanism of nucleophilic addition to a carbonyl
  • An adelhyde/ketone acts both as an electrophile (keto form) and a nucleophile (enolate form) which results in the formation of a carbon-carbon bond.
  • Step 1: aldehyde turns into a enolate ion when catalyzed by a base. This nucleophilic enolate reacts with the electrophilic carbonyl group of another aldehyde molecule.
    • Key is that both species are in the same flask
  • Step 2: A strong base and higher temperature cause dehydration through E1/E2 mechanisms which kicks off a water molecule and forms a double bond.
  • Most useful when only one type of aldehyde or ketone is used, easily controlled.
  • Condensation reaction and a dehydration reaction

Retro-Aldol Reaction
  • Reverse of above reaction.
  • This reaction can be reversed by applying heat and adding aqueous base
  • Useful for breaking bonds between the alpha and beta carbons of a carbonyl