Directed Aldol Lda

Directed Aldol with LDA (Crossed Aldol)

Directed aldol reactions use lithium diisopropylamide (LDA) at −78 °C to form the kinetic enolate, then add an aldehyde or ketone electrophile for a crossed aldol (C–C bond formation without messy self-aldol mixtures).


Quick Summary

  • Order matters: 1) LDA 2) electrophile 3) H3O+
  • Why it’s clean: enolate forms first, so self‑aldol side reactions are minimized
  • Product: β-hydroxy carbonyl (usually no dehydration at −78 °C)

Why LDA Instead of NaOH?

Problem with NaOH LDA solution
Both carbonyls present together → mixtures Enolate formed first, electrophile added second
Self-condensation competes No electrophile present during enolate formation
Heat causes dehydration −78 °C keeps β-hydroxy product

Mechanism (4 Steps)

Step 1: Form the kinetic enolate

LDA (strong, bulky base) removes an α‑H at −78 °C → kinetic enolate (less substituted side).

Directed aldol step 1: LDA forms the kinetic enolate

Step 2: Add the electrophile

Add an aldehyde (common) or ketone after the enolate is formed.

Directed aldol step 2: add the aldehyde or ketone electrophile

Step 3: Make the C–C bond

The enolate attacks the electrophile carbonyl → lithium alkoxide.

Directed aldol step 3: carbon-carbon bond formation

Step 4: Aqueous workup

Protonate the alkoxide → β-hydroxy carbonyl.

Directed aldol step 4: aqueous workup gives the beta-hydroxy carbonyl

Worked Examples

Example A: Acetone + Benzaldehyde

Ketone

Acetone (ketone)
+

Electrophile

Benzaldehyde (electrophile)
LDA, then aldehyde (two-step)
→
Beta-hydroxy ketone product

β-hydroxy ketone (4-hydroxy-4-phenylbutan-2-one)

Example B: Cyclohexanone + Acetaldehyde

Ketone

Cyclohexanone (ketone)
+

Electrophile

Acetaldehyde (electrophile)
LDA, then aldehyde (two-step)
→
Beta-hydroxy ketone product

β-hydroxy ketone

Example C: 2-Butanone (Kinetic Enolate)

Unsymmetric ketones → LDA gives kinetic enolate (less substituted α-carbon)

Ketone

2-Butanone (ketone)
+

Electrophile

Benzaldehyde (electrophile)
LDA, then aldehyde (two-step)
→
Beta-hydroxy ketone product

Deprotonation at CH₃ (less hindered) → kinetic enolate attacks benzaldehyde


Kinetic vs. Thermodynamic Enolate

  Kinetic Thermodynamic
Conditions Bulky base (LDA), low temp (−78 °C), short time Smaller base (NaOEt/NaOMe), warmer temp, longer time
Site Less substituted α‑C More substituted α‑C
Why Steric control (bulky LDA) Stability (more substituted)

Exam Quick Reference

Clue in ProblemWhat to Do
"1) LDA, 2) aldehyde"Directed aldol → β-hydroxy ketone
"−78 °C"Kinetic enolate (less substituted)
Unsymmetric ketone + LDADraw kinetic enolate at CH₃ side
"Why LDA not NaOH?"Prevents self-condensation; enolate first, electrophile second

Key points:

  • Product is β-hydroxy carbonyl (no dehydration)
  • Kinetic enolate = less substituted α-carbon
  • New stereocenters → often mixture of diastereomers

Interactive Toolbox

1) LDA 2) aldehyde: directed aldol conditions

In problems, look for 1) LDA 2) aldehyde 3) H3O+ to recognize a directed (crossed) aldol.

1) LDA 2) ketone: directed aldol with ketone electrophile

Ketones are less electrophilic than aldehydes, but the same enolate first → electrophile second logic applies.

  • Mechanism Solver — replay directed aldol with LDA and see kinetic enolate control.
  • Reaction Solver — predict crossed aldol products (and avoid self-aldol traps).
  • IUPAC Namer — name the β-hydroxy carbonyl products.

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