ch21pp - Chapter 21 Ester Enolates 21.1 O OR H Introduction...

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Unformatted text preview: Chapter 21 Ester Enolates 21.1 O OR H Introduction O OR H H O OR Hydrogens to an ester carbonyl group are less acidic, pKa 24, than of aldehydes and ketones, pKa 16-20. The decreased acidity is due the decreased electron withdrawing ability of an ester carbonyl. This is because the electrons of an ester are delocalized more and the carbonyl is less polarized. (see above) Introduction O R C H C O C H OR' The preparation and reactions of -dicarbonyl compounds, especially -keto esters, is the main focus of this chapter. Doubly alpha protons are relatively acidic, and can be easily and quantitatively removed by alkoxide ions. Introduction O R C C O C H Remember: ethanol pKa is 16 OR' pKa ~ 11 H CH3CH2O O R C C H O C OR' We make an ester enolate Introduction O R C C H O O C OR' R C O C H C OR' The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups. Introduction O O R C C H O O OR' R C C C H C OR' The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups. 21.2 O The Claisen Condensation O 1. NaOR' 2. H3O + O 2 RCH2COR' RCH2CCHCOR' + R'OH R -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. Example O 2 CH3COCH2CH3 O 1. NaOCH2CH3 2. H3O + O CH3CCH2COCH2CH3 (75%) Product from ethyl acetate is called ethyl acetoacetate or acetoacetic ester. Mechanism Step 1: CH3CH2 O O H CH2 COCH2CH3 CH3CH2 O H CH2 O COCH2CH3 Mechanism Step 2: O O CH COCH CH 2 3 CH3C OCH2CH3 2 O CH3COCH2CH3 CH 2 O COCH CH 2 3 Mechanism O O CH2 COCH2CH3 Under basic conditions ethoxide is ok leaving group CH3C OCH2CH3 O CH3C O CH2 COCH2CH3 + OCH2CH3 product is then attacked by ethoxide again Mechanism Step 4: O CH3C CH O COCH2CH3 + H OCH2CH3 Acidify with H3O+ O CH3C O CH2 COCH2CH3 + HOH Another example O 2CH3CH2COCH2CH3 Reaction involves bond formation between the carbon atom of one ethyl propanoate molecule and the carbonyl carbon of the other. 1. NaOCH2CH3 2. H3O+ O O CH3CH2CCHCOCH2CH3 CH3 (81%) Example O 21.3 O CH3CH2OCCH2CH2CH2CH2COCH2CH3 1. NaOCH2CH3 2. H3O+ O O COCH2CH3 (74-81%) via CH3CH2O H2C H2C O O C CHCOCH2CH3 CH2 O O CH3CH2OCCH2CH2CH2CHCOCH2CH3 21.4 Mixed Claisen Condensations As with mixed aldol condensations, mixed Claisen condensations are best carried out when the reaction mixture contains one compound that can form an enolate and another that cannot. Mixed Claisen Condensations These types of esters cannot form an enolate. O HCOR O ROCOR O ROC O COR O COR Example O COCH3 + O CH3CH2COCH3 1. NaOCH3 2. H3O+ O O (60%) CCHCOCH3 CH3 21.5 Acylation of Ketones with Esters Esters that cannot form an enolate can be used to acylate ketone enolates. Example O CH3CH2OCOCH2CH3 1. NaH 2. H3O+ O O COCH2CH3 (60%) + O Example O COCH2CH3 + O CH3C 1. NaOCH2CH3 2. H3O+ O O CCH2C (62-71%) Example O O CH3CH2CCH2CH2COCH2CH3 1. NaOCH3 2. H3O+ O CH3 O (70-71%) 21.6 O O Ketone Synthesis O RCH2CCH2R + CO2 RCH2CCHCOH R -Keto acids decarboxylate readily to give ketones (Section 19.17). Ketone Synthesis O O O O RCH2CCHCOR' H2O RCH2CCHCOH + R'OH R R -Keto acids decarboxylate readily to give ketones (Section 19.17). -Keto acids are available by hydrolysis of keto esters. Ketone Synthesis O 2RCH2COR' O 1. NaOR' 2. H3O + O RCH2CCHCOR' + R'OH R -Keto acids decarboxylate readily to give ketones (Section 19.17). -Keto acids are available by hydrolysis of keto esters. -Keto esters can be prepared by the Claisen condensation. Example O 2 CH3CH2CH2CH2COCH2CH3 Claisen condensation O 1. NaOCH2CH3 2. H3O+ O CH3CH2CH2CH2CCHCOCH2CH3 CH2CH2CH3 (80%) Example O O CH3CH2CH2CH2CCHCOH CH2CH2CH3 Hydrolysis of ester under base conditions O 1. KOH, H2O, 70-80C 2. H3O+ O CH3CH2CH2CH2CCHCOCH2CH3 CH2CH2CH3 Example O O CH3CH2CH2CH2CCHCOH CH2CH2CH3 Decarboxylation step O CH3CH2CH2CH2CCH2CH2CH2CH3 (81%) 70-80C 21.7 Acetoacetic Ester O H3C C H C O C H OCH2CH3 Acetoacetic ester is another name for ethyl acetoacetate. The "acetoacetic ester synthesis" uses acetoacetic ester as a reagent for the preparation of ketones. Deprotonation of Ethyl Acetoacetate O H3C C C O C OCH2CH3 + CH3CH2O H H pKa ~ 11 O H3C C C H O C Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. OCH2CH3 + CH3CH2OH pKa ~ 16 Alkylation of Ethyl Acetoacetate O H3C C C H R O H3C C H C O C R OCH2CH3 X O C OCH2CH3 The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination). Conversion to Ketone O H3C C H C O C OH Saponification and acidification convert the alkylated derivative to the corresponding keto acid. The -keto acid then undergoes decarboxylation to form a ketone. R 1. HO, H2O 2. H+ O C C R OCH2CH3 O H3C C H Conversion to Ketone O H3C C H C O C R OH Saponification and acidification convert the alkylated derivative to the corresponding keto acid. The -keto acid then undergoes decarboxylation to form a ketone. O H3C C CH2R + CO2 Example O O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH CH CH CH Br O O 3 2 2 2 CH3CCHCOCH2CH3 CH CH CH CH (70%) 2 2 2 3 Example O CH3CCH2CH CH CH CH 2 2 2 1. NaOH, H2O 3 2. H+ 3. heat, -CO2 (60%) O O CH3CCHCOCH2CH3 CH CH CH CH 2 2 2 3 Example: Dialkylation O O CH3CCHCOCH2CH3 CH2CH CH2 1. NaOCH2CH3 2. CH CH I O O 3 2 CH3CCCOCH2CH3 CH CH 3 2 CH2CH (75%) CH2 Example: Dialkylation O CH3CCH CH CH 3 CH2CH CH2 1. NaOH, H2O 2 2. H+ 3. heat, -CO2 O O CH3CCCOCH2CH3 CH CH 3 2 CH2CH CH2 Another Example O O COCH2CH3 H -Keto esters other than ethyl acetoacetate may be used. Another Example O O COCH2CH3 H 1. NaOCH2CH3 2. H C CHCH Br O O2 COCH2CH3 CH CH 2 CH (89%) Another Example O H CH CH CH 2 (66%) O 2 1. NaOH, H2O 2. H+ 3. heat, -CO2 O COCH2CH3 CH CH CH 21.8 Malonic Ester O CH3CH2O C H C O C H OCH2CH3 Malonic ester is another name for diethyl malonate. The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids. An Analogy The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids. O O O O CH3CCH2COCH2CH3 CH3CH2OCCH2COCH2CH3 O CH3CCH2R O HOCCH2R Example O O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. H C O O2 CHCH CH CH Br 2 2 2 CH3CH2OCCHCOCH2CH3 CH CH CH CH (85%) 2 2 2 CH 2 Example O HOCCH2CH CH CH CH 2 CH 2 (75%) 2 2 1. NaOH, H2O 2. H+ 3. heat, -CO2 O O CH3CH2OCCHCOCH2CH3 CH CH CH CH 2 2 2 CH 2 Dialkylation O O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. CH Br O O 3 CH3CH2OCCHCOCH2CH3 CH (79-83%) Dialkylation O O CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH 1. NaOCH2CH3 3 2. CH3(CH2)8CH2Br O O CH3CH2OCCHCOCH2CH3 CH Dialkylation O O CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH 1. NaOH, H2O 2. H+ 3. heat, -CO2 O CH3(CH2)8CH2CHCOH CH (61-74%) 3 Another Example O O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. BrCH CH CH Br O O 2 2 2 CH3CH2OCCHCOCH2CH3 CH CH CH Br Another Example O O CH3CH2OCCCOCH2CH3 HC 2 CH C H 2 2 (60-65%) NaOCH2CH3 O This product is not isolated, but cyclizes in the presence of sodium ethoxide. O CH3CH2OCCHCOCH2CH3 CH CH CH Br Another Example O O CH3CH2OCCCOCH2CH3 HC 2 CH C H 1. NaOH, H2O 2 2. H+ 3. heat, -CO2 CO2H C CH C H 2 2 H HC 2 (80%) Stabilized Anions O H3C C C H O CH3CH2O C C H 21.9 O C OCH2CH3 O C OCH2CH3 The anions derived by deprotonation of -keto esters and diethyl malonate are weak bases. Weak bases react with , unsaturated carbonyl compounds by conjugate addition. Example O O O H C CHCCH 2 3 CH3CH2OCCH2COCH2CH3 + KOH, ethanol O O CH3CH2OCCHCOCH2CH3 CH CH CCH 2 2 (85%) O 3 Example O O (42%) CH CCH CH CH2COH 3 2 2 1. KOH, ethanol-water 2. H+ 3. heat O O CH3CH2OCCHCOCH2CH3 CH CH CCH 2 2 O 3 21.10 Reactions of LDA-Generated Ester Enolates 21.10 Deprotonation of Simple Esters Ethyl acetoacetate (pKa ~11) and diethyl malonate (pKa ~13) are completely deprotonated by alkoxide bases. Simple esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts with the original ester, and Claisen condensation occurs. Are there bases strong enough to completely deprotonate simple esters, giving ester enolates quantitatively? Yes LDA which we've seen before. Lithium diisopropylamide CH3 H C CH3 CH3 C CH3 H Li + N Lithium dialkylamides are strong bases (just as NaNH2 is a very strong base). Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups. Lithium diisopropylamide (LDA) Lithium diisopropylamide converts simple esters to the corresponding enolate. O CH3CH2CH2COCH3 + pKa ~ 22 O CH3CH2CHCOCH3 + LiN[CH(CH3)2]2 HN[CH(CH3)2]2 pKa ~ 36 + + Li Lithium diisopropylamide (LDA) Enolates generated from esters and LDA can be alkylated. O CH3CH2CHCOCH3 CH CH O CH3CH2CHCOCH3 CH CH I 3 2 (92%) 2 3 Aldol addition of ester enolates Ester enolates undergo aldol addition to aldehydes and ketones. O CH3COCH2CH3 1. LiNR2, THF 2. (CH ) C 3. H3O+ 3 2 O HO HC 3 O C CH2COCH2CH3 CH (90%) Ketone Enolates Lithium diisopropylamide converts ketones quantitatively to their enolates. O CH3CH2CC(CH3)3 1. LDA, THF O 2. CH CH CH 3. H3O+ O 3 2 CH3CHCC(CH3)3 HOCHCH CH (81%) ...
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This note was uploaded on 04/02/2008 for the course CHEM 332 taught by Professor Kisslings during the Spring '08 term at Binghamton University.

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