Chapter 21: Alpha Carbon Chemistry

Enol & Enolate Intermediates

reactions occur either through enol or enolate intermediates

*must have ⍺ carbon

enolates are more reactive than enols b/c the ⊖ charge on O

Enol Intermediates

in presence of catalytic base or acid

→ ketone exists in equilibrium w/ enol

ketone & enol are tautomers

(not resonance structures)

equilibrium favors ketone (99%) unless:

1) conjugated system → favors enol

2) intramolecular H-bond (like in diketone) → favors enol

enol is very reactive b/c its ⍺ carbon is very nucleophilic

(OH activates carbon)

Acid-Catalyzed Tautomerization

Starting Material: Ketone

Acidic Tautomerization → Enol

Reagents: H3O+

*assume tautomerization will occur if possible

Base-Catalyzed Tautomerization

Starting Material: Ketone

Basic Tautomerization → Enol

Reagents: OH-

*assume tautomerization will occur if possible

Enolate Intermediates

⍺ carbon of ketone treated w/ strong base → enolate intermediate

enolates have 2 nucleophilic sites: O & C

(C attacks are more common)

pKa Values Predicting Equilibrium Shift

similar pKa values (milder base)

→ both reactants & enolate present

strong base like NaH/LDA used

→ only enolate present (irreversible)

diketone reactant → mild base is sufficient to ensure irreversible enolate

Alpha Halogenation in Basic Conditions

Starting Material: Aldehyde/Ketone

Basic Alpha Halogenation → all ⍺ protons replaced w/ Br

Reagents: NaOH, Br2

Intermediate: Enolate

*if unsymmetrical, Br added to more substituted side

Haloform Reaction

Starting Material: Tribromomethyl

Haloform Reaction → Carboxylic Acid

Reagents: 1) NaOH, Br2 / 2) H3O+

Intermediate: -CBr3 (good LG)

Alpha Halogenation in Acidic Conditions

Starting Material: Aldehyde/Ketone

Acidic Alpha Halogenation → 1 ⍺ proton replaced w/ Br

Reagents: H3O+, Br2

Intermediate: Enol

*if unsymmetrical, Br added to more substituted side

Aldol Addition Reaction

Starting Material: Aldehyde

Aldol Addition → ꞵ-Hydroxy Aldehyde/Ketone (OH at ꞵ)

Reagents: H3O+, Br2

Intermediate: Enolate

*reversible → retro-aldol reaction

Aldol Condensation Reaction

aldol condensation = aldol addition + elimination

Starting Material: Aldehyde/Ketone

Aldol Condensation → ⍺,ꞵ-Unsaturated Aldehyde/Ketone

Reagents: NaOH, H2O, heat

*driving force → increased conjugation

Crossed Aldol Reaction

getting 1 product btwn different aldehydes/ketones

1) 1 Aldehyde/Ketone Lacks ⍺ Proton → Not Enolizable

Reagents: NaOH, H2O

2) Strong Base (NaH or LDA) → 3 Steps

Reagents: 1) NaH (or LDA) / 2) Aldehyde/Ketone / 3) H2O

Claisen Condensation Reaction

Starting Material: Ester

Claisen Condensation → ꞵ-Keto Estr

Reagents: 1) NaOEt / 2) H3O+

Intermediate: Ester Enolate

*RO groups must be the same

Crossed Claisen Condensation Reaction

getting 1 product btwn different esters

1) 1 Ester Lacks ⍺ Proton → Not Enolizable

Reagents: 1) NaOMe / 2) H3O+

2) Strong Base (NaH or LDA) → 3 Steps

Reagents: 1) NaH (or LDA) / 2) Ester / 3) H3O+

Alkylation of ⍺ Position

Starting Material: Ketone

1) Small Base (NaH) → R Added at More Substituted

Reagents: 1) NaH / 2) RX

2) Bulky Base (LDA) → R Added at Least Substituted

Reagents: 1) LDA / 2) RX

Malonic Ester Synthesis

Starting Material: Large Ester Compound

Malonic Ester Synthesis → Basic Carboxylic Acid

Reagents: 1) NaOMe, MeOH / 2) MeBr / 3) NaOMe, MeOH / 4) EtBr / 5) H3O+, heat

*forms CO2 by-product

Michael Acceptors vs Donors

Michael Acceptor (E+) → ⍺,ꞵ-Unsaturated Compound

*unique reactivity: 2 E+ positions

Michael Donor (Nuc-) → Enolate Ion

*large & weak compound (favors attack at ꞵ carbon)

Michael Synthesis

Starting Material: Michael Donor (Nuc-)

Michael Synthesis → Combines Donor + Acceptor

Reagents: 1) KOH / 2) Michael Acceptor (E+) / 3) H3O+

*keto-enol tautomerization occurs after product is formed