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Chapter 21 Ester Enolates. O. O. C. C. R. C. OR'. H. H. Introduction. The preparation and reactions of b -dicarbonyl compounds, especially b -keto esters, is the main focus of this chapter.
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O O C C R C OR' H H Introduction • The preparation and reactions of b-dicarbonyl compounds, especially b-keto esters, is the main focus of this chapter. • A proton on the carbon flanked by the two carbonyl groups is relatively acidic, easily and quantitatively removed by alkoxide ions.
O O C C R C OR' H H – CH3CH2O O O C C •• R C OR' – H Introduction pKa ~ 11
•• •• •• •• – O O O O •• •• •• •• •• C C C C •• R C OR' R C OR' – H H Introduction • The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups.
– •• •• O O O O •• •• •• •• •• C C C C •• R C OR' R C OR' – H H Introduction •• •• • The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups.
O O O 2RCH2COR' RCH2CCHCOR' R The Claisen Condensation 1. NaOR' • b-Keto esters are made by the reaction shown, which is called the Claisen condensation. • Ethyl esters are typically used, with sodium ethoxide as the base. + R'OH 2. H3O+
O O O 2CH3COCH2CH3 CH3CCH2COCH2CH3 Example 1. NaOCH2CH3 • Product from ethyl acetate is called ethylacetoacetateor acetoaceticester. 2. H3O+ (75%)
•• O •• – •• CH3CH2 CH2 O H COCH2CH3 •• •• Mechanism Step 1:
•• O •• – •• CH3CH2 CH2 O H COCH2CH3 •• •• O •• CH3CH2 O H •• Mechanism Step 1: •• •• – CH2 COCH2CH3 ••
– •• O •• •• CH2 COCH2CH3 •• O •• – CH2 COCH2CH3 •• Mechanism Step 1: • Anion produced is stabilized by electron delocalization; it is the enolate of an ester.
•• O O •• – CH2 COCH2CH3 •• Mechanism Step 2: •• •• CH3COCH2CH3
•• – •• O O •• •• •• CH3C CH2 COCH2CH3 •• O O •• – CH2 COCH2CH3 •• Mechanism Step 2: OCH2CH3 •• •• •• •• CH3COCH2CH3
•• – •• O O •• •• •• CH3C CH2 COCH2CH3 OCH2CH3 •• •• Mechanism Step 2:
•• – •• O O •• •• •• CH3C CH2 COCH2CH3 OCH2CH3 •• •• •• •• O O •• •• – •• CH3C CH2 OCH2CH3 COCH2CH3 •• •• Mechanism Step 3: +
•• •• O O •• •• – •• CH3C CH2 OCH2CH3 COCH2CH3 •• •• Mechanism Step 3: • The product at this point is ethyl acetoacetate. • However, were nothing else to happen, the yield of ethyl acetoacetate would be small because the equilibrium constant for its formation is small. • Something else does happen. Ethoxide abstracts a proton from the CH2 group to give a stabilized anion. The equilibrium constant for this reaction is favorable. +
•• •• O O •• •• •• – OCH2CH3 CH3C CH H COCH2CH3 •• •• •• •• O O •• •• – •• CH3C CH2 OCH2CH3 COCH2CH3 •• •• Mechanism Step 4: + +
•• O O •• CH3C CH Mechanism Step 5: •• • In a separate operation, the reaction mixture is acidified. This converts the anion to the isolated product, ethyl acetoacetate. – COCH2CH3 ••
•• H O O •• + O CH3C CH H •• H •• •• O H O •• •• CH3C CH O COCH2CH3 •• •• H H Mechanism Step 5: •• – COCH2CH3 •• +
O 2CH3CH2COCH2CH3 1. NaOCH2CH3 2. H3O+ O O CH3CH2CCHCOCH2CH3 CH3 Another example • Reaction involves bond formation between the a-carbon atom of one ethyl propanoate molecule and the carbonyl carbon of the other. (81%)
21.2Intramolecular Claisen Condensation:The Dieckmann Reaction
O O 1. NaOCH2CH3 2. H3O+ O O COCH2CH3 Example CH3CH2OCCH2CH2CH2CH2COCH2CH3 (74-81%)
•• O O •• •• •• O O •• •• – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• via CH3CH2OCCH2CH2CH2CH2COCH2CH3 NaOCH2CH3
•• •• O O •• •• – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• via
•• •• – O CH3CH2O •• •• •• •• O •• C CHCOCH2CH3 H2C H2C CH2 •• •• O O •• •• – CH3CH2OCCH2CH2CH2CHCOCH2CH3 •• via
•• •• – O CH3CH2O •• •• •• •• O •• C CHCOCH2CH3 H2C H2C CH2 via
•• •• – O CH3CH2O •• •• •• •• O •• C CHCOCH2CH3 H2C H2C CH2 •• O •• •• O •• C •• – CH3CH2O CHCOCH2CH3 H2C •• •• H2C CH2 via +
Mixed Claisen Condensations • As with mixed aldol condensations, mixedClaisen condensations are best carried outwhen the reaction mixture contains one compound that can form an enolate and another that cannot.
O O O O HCOR ROCOR ROC COR O COR Mixed Claisen Condensations • These types of esters cannot form an enolate.
O O COCH3 CH3CH2COCH3 O O CCHCOCH3 CH3 Example + 1. NaOCH3 2. H3O+ (60%)
Acylation of Ketones with Esters • Esters that cannot form an enolate can be used to acylate ketone enolates.
O O CH3CH2OCOCH2CH3 O O COCH2CH3 Example + 1. NaH 2. H3O+ (60%)
O O COCH2CH3 CH3C O CCH2C Example + 1. NaOCH2CH3 2. H3O+ O (62-71%)
O O CH3CH2CCH2CH2COCH2CH3 O O CH3 Example 1. NaOCH3 2. H3O+ (70-71%)
O O O RCH2CCHCOH R Ketone Synthesis • b-Keto acids decarboxylate readily to give ketones (Section 19.17). + RCH2CCH2R CO2
O O O O RCH2CCHCOR' RCH2CCHCOH R R Ketone Synthesis H2O • b-Keto acids decarboxylate readily to give ketones (Section 19.17). • b-Keto acids are available by hydrolysis of b-keto esters. + R'OH
O O O 2RCH2COR' RCH2CCHCOR' R Ketone Synthesis 1. NaOR' • b-Keto acids decarboxylate readily to give ketones (Section 19.17). • b-Keto acids are available by hydrolysis of b-keto esters. • b-Keto esters can be prepared by the Claisen condensation. + R'OH 2. H3O+
O 2 CH3CH2CH2CH2COCH2CH3 O O CH3CH2CH2CH2CCHCOCH2CH3 CH2CH2CH3 Example 1. NaOCH2CH3 2. H3O+ (80%)
O O CH3CH2CH2CH2CCHCOH CH2CH2CH3 O O CH3CH2CH2CH2CCHCOCH2CH3 CH2CH2CH3 Example 1. KOH, H2O, 70-80°C 2. H3O+
O O CH3CH2CH2CH2CCHCOH CH2CH2CH3 O CH3CH2CH2CH2CCH2CH2CH2CH3 Example 70-80°C (81%)