Claisen condensation between Mechanism of the Claisen condensation between Ethyl Benzoate and Ethyl Propanoate Rainer Ludwig Claisen (1851-1930) Developed the “Claisen Condensation” in 1887

ETHYL PROPANOATE ETHYL BENZOATE CARBON ETHOXIDE ION HYDROGEN What are the building blocks? ETHYL PROPANOATE ETHYL BENZOATE CARBON ETHOXIDE ION HYDROGEN

O O C C C O C C sp2 orbitals p orbitals π bond sp3 orbitals α hydrogens C C C O C sp3 orbitals C

FORCE & ENERGY O C C Sites for nucleophilic attacks High Electronegativity of Oxygen Sites for nucleophilic attacks O C C α hydrogens

Resonance Energy “Stabilization energy” FORCE & ENERGY Resonance Energy “Stabilization energy”

Condensation with ethyl benzoate to form β-keto ester FORCE & ENERGY O || Formation of the enolate - Et -O - C - CH – CH3 Condensation with ethyl benzoate to form β-keto ester Loss of 2nd alpha hydrogen on β-keto ester Ethyl propanoate O || Et -O - C - CH2 – CH3

MATHEMATICS 0.06 0.06 0.14 Ethyl Propanoate 0.04 pKa of alpha hydrogens ≈ 24 or Ka ≈ 10-24 0.06 0.06 0.14 0.04 Ethyl Propanoate

MATHEMATICS Bond Angles sp3 orbitals sp2 orbitals 109.5o 120o 90o 180o

Overview of the Claisen Condensation Reaction 2. The enolate of ethyl propanoate is formed. 3. The enolate of ethyl propanoate is a strong nucleophile that attacks the partially positive carbon of the carbonyl group on ethyl benzoate. 1. Ethoxide ion acting as a strong base deprotonates ethyl propanoate. 6. The driving force for this reaction is the transfer of the second alpha hydrogen to the ethoxide ion. This is exothermic. 4. The alpha substitution makes this a carbonyl condensation reaction. Ethyl Propanoate 5. A β-keto ester is formed. Ethoxide ion Ethyl Benzoate +

Deprotonation of Ethyl Propanoate The enolate ion is a strong nucleophile and will attack the partially positive carbon of a carbonyl group. Resonance Ethyl Benzoate + Enolate of Ethyl Propanoate

Self condensation of ethyl propanoate

Claisen condensation between Mechanism of the Claisen condensation between Ethyl Benzoate and Ethyl Propanoate Rainer Ludwig Claisen (1851-1930) Developed the “Claisen Condensation” in 1887