Overview
This lecture covers aldol and Claisen condensation reactions, focusing on their mechanisms, products, and roles in forming carbon-carbon bonds in organic chemistry.
Gluconeogenesis & Aldol Reactions
- Gluconeogenesis creates glucose in the body using aldol reactions, joining carbonyl compounds to form sugars.
- An aldol is a ketone or aldehyde with a beta-hydroxy group (carbonyl near an alcohol group).
- Aldol reactions combine two carbonyl compounds (aldehydes or ketones) to form a larger molecule.
- Aldol reactions were discovered independently by Charles Wertz and Alexander Borodin.
Mechanisms of Aldol Reactions
- Aldol reactions can be acid or base catalyzed.
- Base-catalyzed: A base removes a proton from the alpha carbon, forming an enolate ion.
- The enolate ion attacks another carbonyl, forming a carbon-carbon bond and an alkoxide intermediate.
- The alkoxide is protonated, yielding a beta-hydroxy carbonyl (aldol product).
- Dehydration (elimination of water) often follows, producing an alpha, beta-unsaturated carbonyl.
- Dehydration in base conditions is an E1cb elimination (involves a stabilized carbanion and a poor leaving group).
Acid-Catalyzed Aldol Reactions
- Acid catalysis starts with protonation of the carbonyl and formation of an enol.
- The enol attacks another protonated carbonyl, forming a new C-C bond and aldol product.
- Elimination can proceed via E1, E2, or enol-based mechanisms under acidic conditions, especially if heated.
Claisen Condensation
- Claisen condensation joins two esters (or ester plus carbonyl) using a strong base to make a beta-keto ester.
- The base removes an alpha hydrogen to form an enolate, which attacks another ester.
- The leaving group (alkoxide) is expelled, then the product is deprotonated and finally reprotonated with acid.
- Claisen condensation requires a stoichiometric amount of base; starting ester needs two alpha hydrogens.
- Crossed Claisen condensation uses two different esters, one lacking alpha hydrogens to avoid product mixtures.
Application to Penicillin Synthesis
- Both aldol and Claisen condensations are vital in multi-step syntheses such as penicillin V.
- Intramolecular reactions and E1cb eliminations play roles in forming key bonds and structures.
Key Terms & Definitions
- Aldol — A molecule with a carbonyl and a beta-hydroxy group.
- Enolate — A resonance-stabilized anion formed by deprotonation next to a carbonyl.
- Aldol Condensation — Reaction forming a C-C bond plus elimination of water to give unsaturated carbonyls.
- E1cb — Elimination mechanism with a carbanion intermediate and a poor leaving group.
- Claisen Condensation — Reaction joining two esters (or ester plus carbonyl) yielding a beta-keto ester.
Action Items / Next Steps
- Review mechanisms for aldol and Claisen condensations.
- Prepare for upcoming lessons on crossed aldol reactions and conjugate addition.
- Practice drawing the stepwise mechanisms for E1cb, E1, and E2 eliminations.