Química Orgânica 2 · Adição e condensação aldólica
Directed crossed aldol addition of propiophenone to pivalophenone (LDA)
Condições: Propiophenone, LDA (1.05 equiv), THF, −78 °C; then pivalophenone (1.0 equiv), −78 °C; then sat. aq. NH4Cl
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LDA forms the propiophenone enolate
Diisopropylamide removes a proton from the CH2 next to the propiophenone carbonyl. The C–H pair becomes the C=C π bond and the carbonyl π pair moves onto oxygen. Diisopropylamine is about 17 pKa units less acidic than the ketone, so the deprotonation is complete and irreversible at −78 °C.
As setas curvas
- A nitrogen lone pair of diisopropylamide takes an α-hydrogen of propiophenone.
- The C–H pair forms the enolate C=C π bond.
- The carbonyl π pair moves onto oxygen.
Why preform the enolate?
LDA makes the enolate quantitatively and irreversibly, and the addition at −78 °C to the lithium alkoxide is not reversed before the quench. Under catalytic NaOH the ketone–ketone aldol is reversible and uphill, so retro-aldol would return mostly the starting ketones.
The enolate adds to pivalophenone
Pivalophenone is added to the preformed enolate at −78 °C. The enolate α-carbon attacks the pivalophenone carbonyl carbon, forming the new C–C bond and a tertiary alkoxide, held as its lithium chelate until the quench.
As setas curvas
- The oxygen lone pair reforms the propiophenone C=O.
- The enolate π pair forms the C–C bond to the pivalophenone carbonyl carbon.
- The C=O π pair moves onto oxygen as an alkoxide.
Ammonium protonates the alkoxide
The saturated NH4Cl quench supplies ammonium, a mild acid that protonates the alkoxide to give the β-hydroxy ketone and ammonia while the mixture is still cold, so neither retro-aldol nor dehydration occurs.
As setas curvas
- The alkoxide lone pair takes a proton from ammonium.
- The N–H pair stays on nitrogen as ammonia.
3-Hydroxy-2,4,4-trimethyl-1,3-diphenylpentan-1-one
The aldol adduct joins the propiophenone α-carbon to the former pivalophenone carbonyl carbon, which now carries OH, phenyl and tert-butyl groups.
O que você vai praticar
Draw the directed crossed aldol addition: LDA converts propiophenone completely into its enolate, the enolate adds to pivalophenone at −78 °C, and the ammonium chloride quench protonates the alkoxide to give 3-hydroxy-2,4,4-trimethyl-1,3-diphenylpentan-1-one.
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