CHAPTER TWENTY-ONE Ester Enolates (c)CH3CH2 OCCHCH2 CH2CH2 COCH2CH SAMPLE SOLUTION (a)Diethyl heptanedioate has one more methylene group in its chain than the diester cited in the example(diethyl hexanedioate). Its Dieckmann cyclization product contains a six-membered ring instead of the five- membered ring formed from diethyl hexanedioate COCH2 CH3 NaoH,CI CHaCHzOCCH2 CH2 CH2CH2CH2 COCH2 CH32 HO ethyl he hyl(2-0) 21.3 MIXED CLAISEN CONDENSATION Analogous to mixed aldol condensations. mixed Claisen condensations involve car- bon-carbon bond formation between the a-carbon atom of one ester and the carbonyl RCOCH, CH3 t r't CH, COCH,CH3 -aoCH RCCHCOCH,CH β- Keto ester The best results are obtained when one of the ester components is incapable of forming an enolate. Esters of this type include the following HCOR ROCOR ROCCOR Formate esters Carbonate esters Oxalate esters The following equation shows an example of a mixed Claisen condensation in which a benzoate ester is used as the nonenolizable component COCH3 CH3CHyCOCH32 ho CCHCOCH3 CH3 Methyl benzoate ethyl propan ethyl-3-0XO- (cannot form an enolate) PROBLEM 21. 3 Give the structure of the product obtained when ethyl phenyl- acetate(CHs CH2 CO, CH2 CH3)is treated with each of the following esters under conditions of the mixed claisen condensation: (a)Diethyl carbonate (c) Ethyl formate (b)Diethyl oxalate Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
(c) SAMPLE SOLUTION (a) Diethyl heptanedioate has one more methylene group in its chain than the diester cited in the example (diethyl hexanedioate). Its Dieckmann cyclization product contains a six-membered ring instead of the fivemembered ring formed from diethyl hexanedioate. 21.3 MIXED CLAISEN CONDENSATIONS Analogous to mixed aldol condensations, mixed Claisen condensations involve carbon–carbon bond formation between the -carbon atom of one ester and the carbonyl carbon of another. The best results are obtained when one of the ester components is incapable of forming an enolate. Esters of this type include the following: The following equation shows an example of a mixed Claisen condensation in which a benzoate ester is used as the nonenolizable component: PROBLEM 21.3 Give the structure of the product obtained when ethyl phenylacetate (C6H5CH2CO2CH2CH3) is treated with each of the following esters under conditions of the mixed Claisen condensation: (a) Diethyl carbonate (c) Ethyl formate (b) Diethyl oxalate 1. NaOCH3 2. H3O COCH3 O Methyl benzoate (cannot form an enolate) CH3CH2COCH3 O Methyl propanoate CH3 CCHCOCH3 O O Methyl 2-methyl-3-oxo- 3-phenylpropanoate (60%) HCOR O Formate esters ROCOR O Carbonate esters ROCCOR OO Oxalate esters COR O Benzoate esters Ester RCOCH2CH3 O Another ester RCH2COCH2CH3 O 1. NaOCH2CH3 2. H3O -Keto ester RCCHCOCH2CH3 O O R Diethyl heptanedioate CH3CH2OCCH2CH2CH2CH2CH2COCH2CH3 O X O X 1. NaOCH2CH3 2. H3O O O COCH2CH3 Ethyl (2-oxocyclohexane)- carboxylate CH3CH2OCCHCH2CH2CH2COCH2CH3 O X CH3 W O X 836 CHAPTER TWENTY-ONE Ester Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
21.4 Acylation of Ketones with Esters SAMPLE SOLUTION (a) Diethyl carbonate cannot form an enolate but ethyl phenylacetate can. Nucleophilic acyl substitution on diethyl carbonate by the eno- late of ethyl phenylacetate yields a diester. CH3CH2o-C-OCH2 CHa C6H5CH CHsCH COCH2 CH3 o OCHCH Diethyl 2-phenylpropanedioate The reaction proceeds in good yield (86%), and the product is a useful one in fur ther synthetic transformations of the type to be described in Section 21.7 21.4 ACYLATION OF KETONES WITH ESTERS In a reaction related to the mixed Claisen condensation nonenolizable esters are used as acylating agents for ketone enolates. Ketones(via their enolates)are converted to B-keto esters by reaction with diethyl carbonate COCH,CH CH3CH,OCOCH,CH3 he base in this example. it is often used instead of sodium Diethyl carbonat Cycloheptanone Ethyl(2-oxocycloheptane)- ethoxide in these reactions carboxylate(91-94%) Esters of nonenolizable monocarboxylic acids such as ethyl benzoate give B-diketones on reaction with ketone enolates I. NaOCH-CI COCH2CH3+CH3C一 CCH,C- Ethyl benzoate Acetophenone 1, 3-Diphenyl-l propanedione(62-71%) Intramolecular acylation of ketones yields cyclic p-diketones when the ring that is formed is five- or six-membere 1. NaOC CH3 CH, CCH, CH2COCH CHs 2. H3o CH Ethyl 4-oxohexanoate 2-Methyl-1, 3-cycloper 70-71% Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
SAMPLE SOLUTION (a) Diethyl carbonate cannot form an enolate, but ethyl phenylacetate can. Nucleophilic acyl substitution on diethyl carbonate by the enolate of ethyl phenylacetate yields a diester. The reaction proceeds in good yield (86%), and the product is a useful one in further synthetic transformations of the type to be described in Section 21.7. 21.4 ACYLATION OF KETONES WITH ESTERS In a reaction related to the mixed Claisen condensation, nonenolizable esters are used as acylating agents for ketone enolates. Ketones (via their enolates) are converted to -keto esters by reaction with diethyl carbonate. Esters of nonenolizable monocarboxylic acids such as ethyl benzoate give -diketones on reaction with ketone enolates: Intramolecular acylation of ketones yields cyclic -diketones when the ring that is formed is five- or six-membered. 1. NaOCH3 2. H3O CH3CH2CCH2CH2COCH2CH3 O O Ethyl 4-oxohexanoate CH3 O O 2-Methyl-1,3-cyclopentanedione (70–71%) COCH2CH3 O Ethyl benzoate O CH3C Acetophenone 1. NaOCH2CH3 2. H3O CCH2C O O 1,3-Diphenyl-1,3- propanedione (62–71%) 1. NaH 2. H3O CH3CH2OCOCH2CH3 O Diethyl carbonate O Cycloheptanone COCH2CH3 O O Ethyl (2-oxocycloheptane)- carboxylate (91–94%) CH3CH2O C C6H5CH COCH2CH3 O O OCH2CH3 C OCH2CH3 C6H5CH O C O OCH2CH3 Diethyl 2-phenylpropanedioate (diethyl phenylmalonate) 21.4 Acylation of Ketones with Esters 837 Sodium hydride was used as the base in this example. It is often used instead of sodium ethoxide in these reactions. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-ONE Ester Enolates PROBLEM 21.4 Write an equation for the carbon-carbon bond-forming step in the cyclization reaction just cited show clearly the structure of the enolate ion, and use curved arrows to represent its nucleophilic addition to the appropriate carbonyl group. Write a second equation showing dissociation of the tetrahedral intermediate formed in the carbon-carbon bond-forming step recal, even though ketones have the potential to react with themselves by aldol addition, that the position of equilibrium for such reactions lies to the side of the startin materials(Section 18.9). On the other hand, acylation of ketone enolates gives products (B-keto esters or B-diketones) that are converted to stabilized anions under the reaction conditions. Consequently, ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base in the presence of esters 21.5 KETONE SYNTHESIS VIA B-KETO ESTERS The carbon-carbon bond-forming potential inherent in the Claisen and Dieckmann reac tions has been extensively exploited in organic synthesis. Subsequent transformations of the B-keto ester products permit the synthesis of other functional groups. One of these transformations converts B-keto esters to ketones; it is based on the fact that B-keto acids (not esters! undergo decarboxylation readily (Section 19.17). Indeed, B-keto acids, and their corresponding carboxylate anions as well, lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation. H HR β- Keto acid Enol form of ketone Ketone Thus, 5-nonanone has been prepared from ethyl pentanoate by the sequence CH2 CH,CH, CH,COCHCH3-,CHCH,CH, CH,CCHCOCHCH CH,CH, CH3 Ethyl pentanoate KOH.H2O.70-80°C CH3CH2 CH2 CH2 CCH2 CH2 CH2 CH3 -CO. CH3CH2CH-CH2CCHCOH CH2CH2CH3 Nonanone(81%) 3-0xo-2-propy heptanoic acid (not isolated; decarboxylates under conditions of its formation) Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
PROBLEM 21.4 Write an equation for the carbon–carbon bond-forming step in the cyclization reaction just cited. Show clearly the structure of the enolate ion, and use curved arrows to represent its nucleophilic addition to the appropriate carbonyl group. Write a second equation showing dissociation of the tetrahedral intermediate formed in the carbon–carbon bond-forming step. Even though ketones have the potential to react with themselves by aldol addition, recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18.9). On the other hand, acylation of ketone enolates gives products (-keto esters or -diketones) that are converted to stabilized anions under the reaction conditions. Consequently, ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base in the presence of esters. 21.5 KETONE SYNTHESIS VIA -KETO ESTERS The carbon–carbon bond-forming potential inherent in the Claisen and Dieckmann reactions has been extensively exploited in organic synthesis. Subsequent transformations of the -keto ester products permit the synthesis of other functional groups. One of these transformations converts -keto esters to ketones; it is based on the fact that -keto acids (not esters!) undergo decarboxylation readily (Section 19.17). Indeed, -keto acids, and their corresponding carboxylate anions as well, lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation. Thus, 5-nonanone has been prepared from ethyl pentanoate by the sequence CH3CH2CH2CH2COCH2CH3 O Ethyl pentanoate 1. NaOCH2CH3 2. H3O 1. KOH, H2O, 70–80°C 2. H3O CH3CH2CH2CH2CCHCOCH2CH3 O O CH2CH2CH3 Ethyl 3-oxo-2-propylheptanoate (80%) CH3CH2CH2CH2CCH2CH2CH2CH3 O 5-Nonanone (81%) 70–80°C CO2 3-Oxo-2-propylheptanoic acid (not isolated; decarboxylates under conditions of its formation) CH3CH2CH2CH2CCHCOH O O CH2CH2CH3 R C O CH2R Ketone heat CO2 -Keto acid R C C O O O H R H C Enol form of ketone C R R O H C H 838 CHAPTER TWENTY-ONE Ester Enolates Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
21.6 The Acetoacetic Ester Synthesis The sequence begins with a Claisen condensation of ethyl pentanoate to give a -keto ester. The ester is hydrolyzed, and the resulting B-keto acid decarboxylates to yield the desired ketone PROBLEM 21.5 Write appropriate chemical equations showing how you could prepare cyclopentanone from diethyl hexanedioate The major application of B-keto esters to organic synthesis employs a similar pat tern of ester saponification and decarboxylation as its final stage, as described in the fol lowing section 21.6 THE ACETOACETIC ESTER SYNTHESIS Ethyl acetoacetate(acetoacetic ester), available by the Claisen condensation of ethyl acetate, has properties that make it a useful starting material for the preparation of ketones. These properties are 1. The acidity of the a proton 2. The ease with which acetoacetic acid undergoes thermal decarboxylation Ethyl acetoacetate is a stronger acid than ethanol and is quantitatively converted to its anion on treatment with sodium ethoxide in ethanol NaoChoch Na+ CH3CH2OH H3C OCH,CH3 H3C OCH,CH3 Ethyl acetoacetate Sodium ethoxide Sodium salt of ethyl Ethanol (stronger acid) (stronger base) acetoacetate ( weaker acid Ka 10 (pKa Il) (pKa 16) The anion produced by proton abstraction from ethyl acetoacetate is nucleophilic. Adding an alkyl halide to a solution of the sodium salt of ethyl acetoacetate leads to alkylation of the a carbon Na NaX OCH,CH3 H3C OCH.CH Sodium salt of ethyl acetoacetate; 2-Alkyl derivative of Sodiur alkyl halide ethyl acetoacetate halid The new carbon-carbon bond is formed by an Sn2-type reaction. The alkyl halide must therefore be one that is not sterically hindered. Methyl and primary alkyl halides work best; secondary alkyl halides give lower yields. Tertiary alkyl halides react only by elim- ination, not substitution Saponification and decarboxylation of the alkylated derivative of ethyl acetoacetate yields a ketone Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
The sequence begins with a Claisen condensation of ethyl pentanoate to give a -keto ester. The ester is hydrolyzed, and the resulting -keto acid decarboxylates to yield the desired ketone. PROBLEM 21.5 Write appropriate chemical equations showing how you could prepare cyclopentanone from diethyl hexanedioate. The major application of -keto esters to organic synthesis employs a similar pattern of ester saponification and decarboxylation as its final stage, as described in the following section. 21.6 THE ACETOACETIC ESTER SYNTHESIS Ethyl acetoacetate (acetoacetic ester), available by the Claisen condensation of ethyl acetate, has properties that make it a useful starting material for the preparation of ketones. These properties are 1. The acidity of the proton 2. The ease with which acetoacetic acid undergoes thermal decarboxylation Ethyl acetoacetate is a stronger acid than ethanol and is quantitatively converted to its anion on treatment with sodium ethoxide in ethanol. The anion produced by proton abstraction from ethyl acetoacetate is nucleophilic. Adding an alkyl halide to a solution of the sodium salt of ethyl acetoacetate leads to alkylation of the carbon. The new carbon–carbon bond is formed by an SN2-type reaction. The alkyl halide must therefore be one that is not sterically hindered. Methyl and primary alkyl halides work best; secondary alkyl halides give lower yields. Tertiary alkyl halides react only by elimination, not substitution. Saponification and decarboxylation of the alkylated derivative of ethyl acetoacetate yields a ketone. NaX Sodium halide H3C C C OCH2CH3 O O H R C 2-Alkyl derivative of ethyl acetoacetate H3C C C OCH2CH3 O O C Na HRX Sodium salt of ethyl acetoacetate; alkyl halide 21.6 The Acetoacetic Ester Synthesis 839 H3C C C OCH2CH3 O O H H C Ethyl acetoacetate (stronger acid) Ka 1011 (pKa 11) NaOCH2CH3 Sodium ethoxide (stronger base) Sodium salt of ethyl acetoacetate (weaker base) H3C C C OCH2CH3 O O C H Na CH3CH2OH Ethanol (weaker acid) Ka 1016 (pKa 16) Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website