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
- 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
Enamines
- 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
