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Home , Claisen condensation, Michael reaction, Robinson annulation

Chapter 23 Reaction Summary Carbonyl Condensation Reactions In all of the following reactions, one carbonyl compound (containing at least one acidic α-proton) will be the () and the other carbonyl compound will be the . Some electrophilic carbonyl compounds do not contain a leaving group ( and ), while other contain a leaving group ( and halides). In the case of no leaving group, an alcohol forms. This alcohol often gets dehydrated to an α,β-unsaturated carbonyl. When there is a leaving group, it will leave to reform the carbonyl functionality.

The • Simple Aldol O O O OH OH 2 R(H) R(H) Both E and Z R(H) H O 2 HO R(H) (H)R β-hydroxycarbonyl α,β-unsaturated carbonyl o Two identical molecules of or in the presence of provide a β- hydroxycarbonyl product. o The aldehyde/ketone must contain at least one alpha proton. o Under basic conditions, the β-hydroxycarbonyl is dehydrated to an α,β-unsaturated carbonyl compound.

• Directed Crossed Aldol

O 1. LDA O OH OH O Both E and Z 2. O R R Ph Ph Ph R H 3. H2O o In a directed aldol two different ketones, two different aldehydes, or an aldehyde and a ketone are reacted together. o In this reaction, base is used to form the enolate of one carbonyl (nucleophile) and the second carbonyl compound (electrophile) is subsequently added. o This process is necessary when both carbonyl compounds have α-protons of similar acidities.

• Intramolecular Aldol O O O O NaOEt HOEt O O HO o This reaction works with: 1,4-dicarbonyl compounds (to form a 5 membered ring) 1,5-dicarbonyl compounds (to form a 6 membered ring) 1,6-dicarbonyl compounds (to form a 5 membered ring) 1,7-dicarbonyl compounds (to form a 6 membered ring) o The negative charge that forms on one of the alpha-carbons will act as a nucleophile and cyclize to give a 5 or 6 membered ring. The Claisen Condensation • Simple Claisen O O 1. NaOR R 2 OR R' 2. H+ OR R' O β-ketoester o A Claisen reaction occurs between two molecules of . One ester is the nucleophile and the other is the electrophile. Since the electrophile contains a leaving group, it is lost to reform the C=O. o The base used (NaOR) should have the same -OR group as the ester. • Crossed Claisen O O 1. NaOEt O O + 2. H+ R OEt R o In a crossed Claisen, two different esters or a ketone and an ester are reacted in the presence of base. o When a ketone and ester are used, the ketone is the nucleophile and the ester is the electrophile. The ketone is more acidic so its enolate is formed preferentially. • Intramolecular Claisen (Dieckmann Condensation) O O OEt 1. NaOEt O EtO 2. H+ O OEt o The Dieckmann Condensation occurs with 1,6 diesters to form 5-membered rings and 1,7-diesters to form 6-membered rings.

The (Conjugate Addition) O O O O O OH + H O R 2 O New Bond E sight R Nu Site • A Michael reaction occurs between an α,β-unsaturated carbonyl compound (Michael Acceptor, Electrophile) and a carbonyl compound (Nucleophile). • The carbonyl compound that is the nucleophile is generally a 1,3-dicarbonyl compound. • The electrophilic carbon in the Michael reaction is not the carbonyl carbon, but is the β- unsaturated carbon. • The base can be either hydroxide (HO−) or alkoxide (RO−)

The R R R R OH -H2O + H2O O O O O O O Michael Aldol OH Dehydration R = H or alkyl - reaction will work R = COCH3 or COOR - best yields • The Robinson Annulation is a tandem Michael Reaction/Aldol Condensation that occurs between an α,β-unsaturated carbonyl compound and a second carbonyl compound.