CHEMY421 (Organic Chemistry III) Carbonyl Condensation Reactions 1st sem 2023-2024, Dr. Suad AlRashdan Aldol condensation • Carbonyl reactions condensation are the between two compounds and reactions carbonyl involve a combination of Nu- addition and α-substitution steps. • The general mechanism is as follow: 11/12/2023 2 Mechanism of Aldol Condensation 11/12/2023 3 Carbonyl condensation versus Alpha substitutions • Both carbonyl condensation and alpha substitution reaction take place in basic conditions and involve enolation intermediates. • Alpha substitution reactions require full equivalent of strong base and the E+ is added rapidly to ensure that enolate ion is quenched quickly. • Carbonyl condensation reactions require only a catalytic amount of a weak base. 11/12/2023 4 Dehydration of Aldol Products: Synthesis of Enones • The β-hydroxy aldehydes and β-hydroxy ketones formed in aldol reactions are easily dehydrated to yield ,-unsaturated products, or conjugated enones (ene -one). It’s this loss of water that gives the aldol condensation its name. 11/12/2023 5 Dehydration of Aldol Products: Synthesis of Enones • Most alcohols are resistant to dehydration by dilute acid or base because hydroxide ion is a poor leaving group, but β-hydroxy carbonyl compounds dehydrate easily because of the carbonyl group. • Under basic conditions, a hydrogen is abstracted and the resultant enolate ion expels the OH leaving group in an E1cB reaction). Under acidic conditions, an enol is formed, the OH group is protonated, and H2O is then expelled in an E1 or E2 reaction. • Conjugated enones are more stable than nonconjugated eneons. 11/12/2023 6 Dehydration of Aldol Products: Synthesis of Enones 11/12/2023 7 Intramolecular Aldol Reactions 11/12/2023 8 Intramolecular Aldol Reactions 11/12/2023 9 Mixed Aldol Reactions • A mixed Aldol reaction leads to a mixture of different products. • Mixed Aldol reaction can lead to a single product if either of the two conditions is met: If one of the carbonyl compound contains no alpha hydrogen. Neither benzaldehyde nor formaldehyde can form an enolate ion. If one of the carbonyl compounds is much more acidic than the other and so it transformed into its enolate ion in preference to the other. Example: 11/12/2023 10 Mixed Aldol Condensation Reaction 11/12/2023 11 Condensations of Esters: The Claisen Condensation Reaction • Esters are weakly acidic. When an ester with an α-hydrogen is treated with a base such as sodium ethoxide, a carbonyl condensation • reaction occurs to yield a -keto ester. This reaction between two ester molecules is known as the Claisen condensation reaction. • Example: 11/12/2023 12 Claisen Condensation Mechanism 11/12/2023 13 Intramolecular Claisen Reactions 11/12/2023 14 Intramolecular Claisen Reactions 11/12/2023 15 Conjugate carbonyl addition: Michael Addition 11/12/2023 16 Michael Reaction 11/12/2023 17 Michael Addition Reaction 11/12/2023 18 Carbonyl Condensation with Enamines: Stork Reaction 11/12/2023 19 Stork Reaction Mechanism 11/12/2023 20 Carbonyl Condensation with Enamines: Stork Reaction 11/12/2023 21 The Robinson Annulation Reaction The Robinson Annulation is a useful reaction for the formation of six-membered rings in polycyclic compounds, such as steroids. It combines two reactions: the Michael Addition and the Aldol Condensation. 11/12/2023 22