CHAPTER 21 ESTER ENOLATES SOLUTIONS TO TEXT PROBLEMS 21.1 Ethyl benzoate cannot undergo the Claisen condensation, because it has no protons on its a-carbon atom and so cannot form an enolate. Ethyl pentanoate and ethyl phenylacetate can undergo the Claisen condensation 1. NaOCH( 2CH,CH, CH,CH,COCH, CH 2.H2O CHa CH, CH,CH,CCHCOCH2 CH3 CH,CH, CH Ethyl pentanoate Ethyl 3-ox0-2-propylheptanoate 2C.H CH, COCH, CH2 CHCHCCHCOCH,CH 21.2 (b) The enolate formed by proton abstraction from the a-carbon atom of diethyl 4-methylhep- anedioate cyclizes to form a six-membered B-keto ester LOCHICH3 OCHCH CH CHCH OCCH CH CHCH. CH COCH, CH, NaccHlCH3, Ch,Ch o H,C CHCH3 Diethyl 4-methy lheptanedioate Ethyl (5-methyl-2-oxocyclohexane)- carboxylate 576 Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
CHAPTER 21 ESTER ENOLATES SOLUTIONS TO TEXT PROBLEMS 21.1 Ethyl benzoate cannot undergo the Claisen condensation, because it has no protons on its -carbon atom and so cannot form an enolate. Ethyl pentanoate and ethyl phenylacetate can undergo the Claisen condensation. 21.2 (b) The enolate formed by proton abstraction from the -carbon atom of diethyl 4-methylheptanedioate cyclizes to form a six-membered -keto ester. CH3CH2OCCH2CH2CHCH2CH2COCH2CH3 CH3 O O CH3CH2O NaOCH2CH3 OCH2CH3 CH3 O O C Ethyl (5-methyl-2-oxocyclohexane)- carboxylate Diethyl 4-methylheptanedioate OCH2CH3 O O C C H2C CHCH3 CH2 CH2 CH 2C6H5CH2COCH2CH3 O Ethyl phenylacetate Ethyl 3-oxo-2,4-diphenylbutanoate C6H5CH2CCHCOCH2CH3 O O C6H5 1. NaOCH2CH3 2. H3O 2CH3CH2CH2CH2COCH2CH3 O Ethyl pentanoate Ethyl 3-oxo-2-propylheptanoate CH3CH2CH2CH2CCHCOCH2CH3 O O CH2CH2CH3 1. NaOCH2CH3 2. H3O 576 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
ESTER EN。 LATES 577 (c) The two a carbons of this diester are not equivalent Cyclization by attack of the enolate at C-2 gives NaOCH. CH CH CHOC CHa CH,OCCHCH2 CH,CH,COCH,CH3 H3 yclopentane) This B-keto ester cannot form a stable enolate by deprotonation. It is present in only small amounts at equilibrium. The major product is formed by way of the other enolate OCHCH CH,CH,OCCHCH, CH,CH,COCH, CH3 NaOCH, CH, O CH3 Site of this carbon This B-keto ester is converted to a stable enolate on deprotonation, causing the equilibrium to shift in its favor 21.3(b) Both yl groups of diethyl oxalate are equivalent. The enolate of ethyl phenylacetate attack of them C6HSCHCOCH, CH3 CHa CH,O-CCOCH2CH3 C6HSCHCCOCH,CH Diethyl 2-0X0-3- phenylbutanedioate (c) The enolate of ethyl phenylacetate attacks the carbonyl group of ethyl formate O C6HSCHCOCH,CH3 HC--OCH, CH3 C6HSCHCH OCH, CH3 21. 4 In order for a five-membered ring to be formed c-5 must be the carbanionic site that attacks the H3C CHCH CH CH CHO Enolate of ethyl 4-oxohe Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
ESTER ENOLATES 577 (c) The two carbons of this diester are not equivalent. Cyclization by attack of the enolate at C-2 gives This -keto ester cannot form a stable enolate by deprotonation. It is present in only small amounts at equilibrium. The major product is formed by way of the other enolate. This -keto ester is converted to a stable enolate on deprotonation, causing the equilibrium to shift in its favor. 21.3 (b) Both carbonyl groups of diethyl oxalate are equivalent. The enolate of ethyl phenylacetate attacks one of them. (c) The enolate of ethyl phenylacetate attacks the carbonyl group of ethyl formate. 21.4 In order for a five-membered ring to be formed, C-5 must be the carbanionic site that attacks the ester carbonyl. O O H3C CH3CH2O Enolate of ethyl 4-oxohexanoate CH2 CH2 C C CH3CH2O O O H3C CH HC OCH2CH3 O C6H5CHCOCH2CH3 O Ethyl 3-oxo-2- phenylpropanoate C6H5CHCH O COCH2CH3 O C6H5CHCOCH2CH3 CH3CH2O CCOCH2CH3 O OO C6H5CHCCOCH2CH3 COCH2CH3 OO O Diethyl 2-oxo-3- phenylbutanedioate CH3CH2OCCHCH2CH2CH2COCH2CH3 NaOCH2CH3 O O CH3 Site of carbanion Enolate attacks this carbon. Ethyl (3-methyl-2- oxocyclopentane)- carboxylate O CH3 OCH2CH3 O C CH3CH2OCCHCH2CH2CH2COCH2CH3 NaOCH2CH3 O O CH3 Site of carbanion Enolate attacks this carbon. Ethyl (1-methyl-2- oxocyclopentane)- carboxylate O O CH3CH2OC H3C Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
578 ESTER EN。 LATES H3C- H. +“ OCH.CH CH3CH 21.5 The desired ketone, cyclopentanone, is derived from the corresponding B-keto ester. This key intermediate is obtained from a Dieckmann cyclization of the starting material, diethyl hexanedioate. COCH. CH CHaCH,O, C(CH,), CH First treat the diester with sodium ethoxide to effect the Dieckmann cyclization L. NaOCHCI COCHCH CH, CH,OCCH, CH, CH, CH,COCH Ch3 2Hao Diethyl hexanedioate Ethyl (2-oxo Next convert the B-keto ester to the desired product by saponification and decarboxylation. COCHCH 3. heat Ethyl (2-oxocyclopentane)- 21.6(b) Write a structural formula for the desired product; then disconnect a bond to the a-carbon CH,3CH,CCH CH CHCCH Derived from alkyl halide Therefore 1. NaOCH, CH -CH Br+CH, CCH,COCH- CH, 2.HO",H,0 CH,CH,CCH3 4. heat Benzyl bromide Ethyl acetoacetate pheny l-2-butano Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
578 ESTER ENOLATES 21.5 The desired ketone, cyclopentanone, is derived from the corresponding -keto ester. This key intermediate is obtained from a Dieckmann cyclization of the starting material, diethyl hexanedioate. First treat the diester with sodium ethoxide to effect the Dieckmann cyclization. Next convert the -keto ester to the desired product by saponification and decarboxylation. 21.6 (b) Write a structural formula for the desired product; then disconnect a bond to the -carbon atom. Therefore CH2CH2CCH3 O Benzyl bromide 4-Phenyl-2-butanone CH2Br Ethyl acetoacetate CH3CCH2COCH2CH3 O O 1. NaOCH2CH3 2. HO, H2O 3. H 4. heat CH2 CH2CCH3 O Required alkyl halide CH2 X Derived from ethyl acetoacetate CH2CCH3 O COCH2CH3 O O Ethyl (2-oxocyclopentane)- carboxylate O Cyclopentanone 1. HO, H2O 2. H 3. heat CH3CH2OCCH2CH2CH2CH2COCH2CH3 O O 1. NaOCH2CH3 2. H3O COCH2CH3 O O Ethyl (2-oxocyclopentane)- carboxylate Diethyl hexanedioate CH3CH2O2C(CH2)4CO2CH2CH3 O COCH2CH3 O O O O H3C OCH2CH3 O O H3C CH3CH2O 2-Methyl-1,3- cyclopentanedione Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
ESTER EN。 LATES 579 (c) The disconnection approach to retrosynthetic analysis reveals that the preparation of 5-hexen- 2-one by the acetoacetic ester synthesis requires an allylic halide H,C=CHCH,$CH, CCH3 H,C=CHCH, CH,CCH Derived from alkyl halide H_C=CHCH2Br CHaCCHCOCH CH3 2.HO-HO .NaoCHCH3 HC=CHCH, CH, CCH 4. heat Allyl bromide hyl 21.7(b) Nonanoic acid has a CH3(CH,)CH attached to the CH, COH synthon CH,(CH),,+-CH, COH> CH,CH,),CH,X+: CH,COH Required alkyl halide Derived from Therefore the anion of diethyl malonate is alkylated with a l-haloheptane CH3(CH2)5 CH2 Br CH2(COOCHCH3)2- cthanol CH3(CH2)sCH CH(COOCH2CH3) Diethyl malonate Diethyl 2-heptylmalonate CHa(CH2)5CH,CH,CO,H Nonanoic acid (c) Disconnection of the target molecule adjacent to the a carbon reveals the alkyl halide needed to react with the enolate derived from diethyl malonate. CH,CH, CHCH, CH, COH CHCH,CHCH,X CH, COH Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(c) The disconnection approach to retrosynthetic analysis reveals that the preparation of 5-hexen- 2-one by the acetoacetic ester synthesis requires an allylic halide. 21.7 (b) Nonanoic acid has a CH3(CH2)5CH2@ unit attached to the synthon. Therefore the anion of diethyl malonate is alkylated with a 1-haloheptane. (c) Disconnection of the target molecule adjacent to the carbon reveals the alkyl halide needed to react with the enolate derived from diethyl malonate. Derived from diethyl malonate CH2COH O Required alkyl halide CH3CH2CHCH2X CH3 CH3CH2CHCH2 O CH2COH CH3 1-Bromoheptane CH3(CH2)5CH2Br Diethyl malonate CH2(COOCH2CH3)2 Diethyl 2-heptylmalonate CH3(CH2)5CH2CH(COOCH2CH3)2 Nonanoic acid CH3(CH2)5CH2CH2CO2H NaOCH2CH3 ethanol 1. HO, H2O 2. H 3. heat Derived from diethyl malonate CH2COH O Required alkyl halide CH3(CH2) CH3(CH2)5CH2 5CH2X O CH2COH CH2COH O Allyl bromide H CHCH2Br 2C 5-Hexen-2-one CHCH2CH2CCH3 O H2C Ethyl acetoacetate CH3CCH2COCH2CH3 O O 1. NaOCH2CH3 2. HO, H2O 3. H 4. heat Required alkyl halide H2C CHCH2 X Derived from ethyl acetoacetate CH2CCH3 O H2C CHCH2 O CH2CCH3 ESTER ENOLATES 579 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
580 ESTER EN。 LATES The necessary alkyl halide in this synthesis is l-bromo-2-methylbutane CH, CH,CHCH,Br +CH,(COOCH, CH,)2-od+ CH, CH, CHCH, CH(COOCH, CH, ) I-Bromo-2-methylbutane Diethyl malonate Diethyl 2-(2-methylbutyl)malonate 1. HO. H-O 3. heat CH, CH,CHCH,CH,COH 4-Methy hexanoic acid (d) Once again disconnection reveals the necessary halide, which is treated with diethyl malonate CsH.CH,&CH,COH CsHCH,X CH,COH Alkylation of diethyl malonate with benzyl bromide is the first step in the preparation of 3-phenylpropanoic acid CGHSCHBr CH2(COOCH2CH3)ethanol C&HS CH CH(COOCH2 CH3)2 H+ CsH,CH, CH, COH Diethyl malonate Diethyl 2-benzylmalonate 3-Phenylpropanoic acid 21.8 Retrosynthetic analysis of the formation of 3-methyl-2-butanone is carried out in the same way as for other ketones CH CCH&CH CH, CCH 2CH,X H3 Derived from The two alkylation steps are carried out sequentially CHaCCH,COCH_CH3-ch.BT CH,CCHCOCH、NocH2 CHICCCOCH2CH3 3 hea CH,CCH(CH3) CH HC Eth Ethyl 2- methyl-3-oxobutanoate 2, 2-dimethyl-3-oxobutanoate Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
The necessary alkyl halide in this synthesis is 1-bromo-2-methylbutane. (d) Once again disconnection reveals the necessary halide, which is treated with diethyl malonate. Alkylation of diethyl malonate with benzyl bromide is the first step in the preparation of 3-phenylpropanoic acid. 21.8 Retrosynthetic analysis of the formation of 3-methyl-2-butanone is carried out in the same way as for other ketones. The two alkylation steps are carried out sequentially. CH3CCHCOCH2CH3 NaOCH2CH3 CH3Br O O CH3 CH3CCH2COCH2CH3 NaOCH2CH3 CH3Br O O Ethyl acetoacetate Ethyl 2-methyl-3-oxobutanoate 1. HO, H2O 2. H CH3CCCOCH2CH3 O O H3C CH3 Ethyl 2,2-dimethyl-3-oxobutanoate CH3CCH(CH3)2 O 3-Methyl-2-butanone 3. heat CH3CCH 2CH3X O O CH3CCH CH3 CH3 3-Methyl-2-butanone (two disconnections as shown) Derived from ethyl acetoacetate Benzyl bromide C6H5CH2Br Diethyl malonate CH2(COOCH2CH3)2 NaOCH2CH3 ethanol Diethyl 2-benzylmalonate C6H5CH2CH(COOCH2CH3)2 1. HO, H2O 3-Phenylpropanoic acid C6H5CH2CH2COH O 2. H 3. heat Derived from diethyl malonate CH2COH O Required halide C6H5CH2 C6H5CH2X O CH2COH Diethyl malonate CH2(COOCH2CH3)2 NaOCH2CH3 ethanol 1-Bromo-2-methylbutane CH3CH2CHCH2Br CH3 1. HO, H2O 2. H 3. heat Diethyl 2-(2-methylbutyl)malonate CH3CH2CHCH2CH(COOCH2CH3)2 CH3 4-Methylhexanoic acid CH3CH2CHCH2CH2COH CH3 O 580 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
ESTER EN。 LATES 581 21.9 Alkylation of ethyl acetoacetate with 1, 4-dibromobutane gives a product that can cyclize to a five CH3,, CH3 BrCHlCH,CH,CH,Br BrCH, CH, CH, CH,CHCCH3 Ethyl acetoacetate 1.4-Dibromobutane COCHCH NaOCH CH, CCH CCH COCH,CH H2C、 COCH, CH3 Ethyl 1-acetylcyclopentane- Saponification followed by decarboxylation gives cyclopentyl methyl ketone. CCH 1. HO.H,O CCH COCH 3. heat Ethyl l-acetylcyclopentane- carboxylate Cycloketonlemethyl 21.10 The last step in the synthesis of pentobarbital is the reaction of the appropriately substituted deriva- tive of diethyl malonate with urea. CHCH2CH2CH、OcHH CHCH,CH,CH H,NCNH2 CHCH, COCH,CH CH- CH Diethyl 2-ethyl-2-(1-methylbutyl)malonate U Pentobarbital The dialkyl derivative of diethyl malonate is made in the usual way. It does not matter whether the ethyl group or the 1-methylbutyl group is introduced first CH 1. NaoCH CH3, CH, CH,CH, CHCH CH3CH2CH2CH、 CH2(COOCH_ CH3)2 2.NaOCHCHCHCHBT C(COOCH, CH3)2 Diethyl malonate Diethyl 2-ethyl-2-(1-methylbutyl)malonate Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
21.9 Alkylation of ethyl acetoacetate with 1,4-dibromobutane gives a product that can cyclize to a fivemembered ring. Saponification followed by decarboxylation gives cyclopentyl methyl ketone. 21.10 The last step in the synthesis of pentobarbital is the reaction of the appropriately substituted derivative of diethyl malonate with urea. The dialkyl derivative of diethyl malonate is made in the usual way. It does not matter whether the ethyl group or the 1-methylbutyl group is introduced first. CH2(COOCH2CH3)2 Diethyl malonate CH3CH2CH2CH CH3 CH3CH2 C(COOCH2CH3)2 Diethyl 2-ethyl-2-(1-methylbutyl)malonate 2. NaOCH2CH3, CH3CH2Br 1. NaOCH2CH3, CH3CH2CH2CHCH3 Br COCH2CH3 COCH2CH3 CH3CH2CH2CH CH3 CH3CH2 C O O Diethyl 2-ethyl-2-(1-methylbutyl)malonate H2NCNH2 O Urea CH3CH2CH2CH CH3CH2 O N N O O CH3 Pentobarbital H H 1. HO, H2O 2. H 3. heat CCH3 COCH2CH3 O O Ethyl 1-acetylcyclopentanecarboxylate CCH3 H O Cyclopentyl methyl ketone NaOCH2CH3 ethanol CCH3 O COCH2CH3 O BrCH2CH2CH2CH2CHCCH3 COCH2CH3 O O CH2 CH2 Br H2C C H2C CCH3 O COCH2CH3 O NaOCH2CH3 CH3CCH2COCH2CH3 O O Ethyl acetoacetate BrCH2CH2CH2CH2Br 1,4-Dibromobutane Ethyl 1-acetylcyclopentanecarboxylate ESTER ENOLATES 581 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
582 ESTER EN。 LATES 21.11 The carbonyl oxygen at C-2 of pentobarbital is replaced by sulfur in Pentothal( thiopental) CH3o CH3 CH..CH CH2CHCH2CH、 CH3 CH2 6 CHCH Pentobarbital; prepared from urea, (HNC=O The sodium salt of Pentothal is formed by removal of a proton from one of the N-H groups by odium hydroxide O H3 CH, CHCHCH CH, CHCH、>NNa CH-C CH3 CH2 Pentothal sodium 21.12 The synthesis of phenobarbital requires diethyl 2-phenylmalonate as the starting material NaTCH.C HN C6HS CH(COOCH_ CH3)2 CHCHBr CHSC(COOCH2 CH3)2 H3 CH2 CH- CH3 Diethyl Phenobarbital -ethyl-2-phenylmalonate ethyl 2-phenylmalonate is prepared by a mixed Claisen condensation between ethyl phenyl- acetate and diethyl carbonate. C6H-CH, COCH, CH3+ CH3 CH,OCOCH, CH C6H_CH(COOCH,CH3) Diethyl carbonate Diethyl 2-phenylmalonate 21.13 Like diethyl malonate, ethyl acetoacetate undergoes Michael addition to an a, B-unsaturated ke NaoCH, CH, CHa CCH,COCH,CH3 CH,CH,OH CHCOCHCH Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
21.11 The carbonyl oxygen at C-2 of pentobarbital is replaced by sulfur in Pentothal (thiopental). The sodium salt of Pentothal is formed by removal of a proton from one of the N@H groups by sodium hydroxide. 21.12 The synthesis of phenobarbital requires diethyl 2-phenylmalonate as the starting material. Diethyl 2-phenylmalonate is prepared by a mixed Claisen condensation between ethyl phenylacetate and diethyl carbonate. 21.13 Like diethyl malonate, ethyl acetoacetate undergoes Michael addition to an , -unsaturated ketone. NaOCH2CH3 CH3CH2OH CH3CCH2COCH2CH3 O O O CHCOCH2CH3 O CH3 C O O NaOCH2CH3 Ethyl phenylacetate C6H5CH2COCH2CH3 O Diethyl carbonate CH3CH2OCOCH2CH3 O Diethyl 2-phenylmalonate C6H5CH(COOCH2CH3)2 C6H5CH(COOCH2CH3)2 Diethyl 2-phenylmalonate Phenobarbital C6H5 CH3CH2 O N N O O NaOCH2CH3 CH3CH2Br Diethyl 2-ethyl-2-phenylmalonate C6H5C(COOCH2CH3)2 CH2CH3 H2NCNH2 O H H Pentothal sodium CH3CH2CH2CH CH3CH2 O N N O S CH3 Na CH3CH2CH2CH CH3CH2 O N N O S CH3 Na H H Pentobarbital; prepared from urea, (H2N)2C O CH3CH2CH2CH CH3CH2 O N N H H O O CH3 1 3 4 6 5 2 Pentothal; prepared from thiourea, (H2N)2C S CH3CH2CH2CH CH3CH2 O N N H H O S CH3 582 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
ESTER EN。 LATES 583 Basic ester hydrolysis followed by acidification and decarboxylation gives the diketone 3-(2 oxopropyl)cycloheptanone as the major product of the reaction sequence 1. KOH ethanok-water CHCOCHCH CHCCH 3. heat CH3 cycloheptanone (52%o) 21. 14 (b) The a-carbon atom of the ester bears a phenyl substituent and a methyl group. Only the methyl group can be attached to the a carbon by nucleophilic substitution. Therefore generate the enolate of methyl phenylacetate with lithium diisopropylamide (lda)in tetrahydrofuran THF) and then alkylate with methyl iodide CH__ CO, CH,- THE C6HSCH=C → CH CHCO2CH3 OCH Methyl phenylacetate Methyl (c) The desired product corresponds to an aldol addition product CHC6H5 HCCSH Therefore convert cyclohexanone to its enolate and then treat with benzaldehyde CHCH L LDA THF 3.H2O Cyclohexanone 1-(2-Oxocyclohexyl)I (d) This product corresponds to the addition of the enolate of tert-butyl acetate to cyclohexanone OH 0 +: CH, COC(CH3)3 CH,COC(CH3)3 Generate the enolate of tert-butyl acetate with lithium diisopropylamide; then add cyclohexa 1. LDA, THF OH CH3CO2C(CH3)3 2. cyclohexanone 3.H2O CH, CO,C(CH3) tert-Butyl acetate (1-hydroxycyclohexyl)acetate Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
Basic ester hydrolysis followed by acidification and decarboxylation gives the diketone 3-(2- oxopropyl)cycloheptanone as the major product of the reaction sequence. 21.14 (b) The -carbon atom of the ester bears a phenyl substituent and a methyl group. Only the methyl group can be attached to the carbon by nucleophilic substitution. Therefore generate the enolate of methyl phenylacetate with lithium diisopropylamide (LDA) in tetrahydrofuran (THF) and then alkylate with methyl iodide. (c) The desired product corresponds to an aldol addition product. Therefore convert cyclohexanone to its enolate and then treat with benzaldehyde. (d) This product corresponds to the addition of the enolate of tert-butyl acetate to cyclohexanone. Generate the enolate of tert-butyl acetate with lithium diisopropylamide; then add cyclohexanone. 1. LDA, THF 2. cyclohexanone 3. H3O CH2CO2C(CH3)3 OH tert-Butyl (1-hydroxycyclohexyl)acetate CH3CO2C(CH3)3 tert-Butyl acetate O O CH2COC(CH3)3 OH CH2COC(CH3)3 O 1. LDA, THF 2. C6H5CHO 3. H3O O Cyclohexanone O OH CHC6H5 1-(2-Oxocyclohexyl)-1- phenylmethanol O OH CHC6H5 O HCC6H5 O LDA THF CH3I C6H5CHCO2CH3 CH3 Methyl 2-phenylpropanoate C6H5CH OCH3 OLi C Enolate of methyl phenylacetate C6H5CH2CO2CH3 Methyl phenylacetate CHCOCH2CH3 O O 1. KOH, ethanol–water 2. H 3. heat CH2CCH3 O O 3-(2-Oxopropyl)- CH cycloheptanone (52%) O 3 C ESTER ENOLATES 583 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
584 ESTER EN。 LATES 21.15 To undergo a Claisen condensation, an ester must have at least two protons on the a carbon 2RCH, COCH, CH3 NaOCH, CH3 RCH,CCCOCH2 CH3 Na 2CH CH2OH The equilibrium constant for condensation is unfavorable unless the B-keto ester can be deproton- ated to form a stable anion (a) Among the esters given, ethyl pentanoate and ethyl 3-methylbutanoate undergo the Claisen L Natch. ch CHaCH,,CH,COCH, CH CHa,CH,CH, CCHCOCH,CH Ethyl 3-ox0-2-propylheptanoate 1. NaOCH,CH, (CH3)2CHCH2 COCH CH3 2Ht (CH,) CHCH, CCHCOCH, CH3 CH(CH3h2 Ethyl 3-methylbutanoate Ethyl 2-isopropyl-5-methyl- 3-oxohexanoate (b) The Claisen condensation product of ethyl 2-methylbutanoate cannot be deprotonated; the uilibrium constant for its formation is less than 1 CHCH..CH CH CH, CHCCCOOCH,CH3 CH3 CH,CH Ethyl 2-methylbutanoate No protons on a-carbon atom form stabilized enolate by depr (c) Ethyl 2, 2-dimethylpropanoate has no protons on its a carbon; it cannot form the ester enolate required in the first step of the Claisen condensation H, C CH CCOCH,CH3 OCH,CH no reaction H3 Ethyl 2, 2- dimethylpropanoate 21.16(a) The Claisen condensation of ethyl phenylacetate is given by the equation 00 NaOCH.CH C6H CH,COCH, CH CBHSCH, CCHCOCH,CH Ethyl phenylacetate Ethyl 3-oXo-2, 4-diphenylbutanoat Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
21.15 To undergo a Claisen condensation, an ester must have at least two protons on the carbon: The equilibrium constant for condensation is unfavorable unless the -keto ester can be deprotonated to form a stable anion. (a) Among the esters given, ethyl pentanoate and ethyl 3-methylbutanoate undergo the Claisen condensation (b) The Claisen condensation product of ethyl 2-methylbutanoate cannot be deprotonated; the equilibrium constant for its formation is less than 1. (c) Ethyl 2,2-dimethylpropanoate has no protons on its carbon; it cannot form the ester enolate required in the first step of the Claisen condensation. 21.16 (a) The Claisen condensation of ethyl phenylacetate is given by the equation 1. NaOCH2CH3 2. H C6H5CH2COCH2CH3 O Ethyl phenylacetate C6H5CH2CCHCOCH2CH3 O O C6H5 Ethyl 3-oxo-2,4-diphenylbutanoate OCH2CH3 H3C CH3CCOCH2CH3 O CH3 C no reaction Ethyl 2,2- dimethylpropanoate Ethyl 2-methylbutanoate CH3CH2CHCOCH2CH3 O CH3 No protons on -carbon atom; cannot form stabilized enolate by deprotonation CH3CH2CHCCCOOCH2CH3 O CH3 CH2CH3 CH3 NaOCH2CH3 K 1 1. NaOCH2CH3 2. H (CH3)2CHCH2COCH2CH3 O Ethyl 3-methylbutanoate (CH3)2CHCH2CCHCOCH2CH3 O O CH(CH3)2 Ethyl 2-isopropyl-5-methyl- 3-oxohexanoate 1. NaOCH2CH3 2. H CH3CH2CH2CH2CCHCOCH2CH3 O CH2CH2CH3 O Ethyl 3-oxo-2-propylheptanoate CH3CH2CH2CH2COCH2CH3 O Ethyl pentanoate 2RCH2COCH2CH3 NaOCH2CH3 O Na 2CH3CH2OH RCH2CCCOCH2CH3 R O O 584 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
ESTER EN。 LATES 585 (b) Saponification and decarboxylation of this B-keto ester gives dibenzyl ketone. 00 1. HO.H C..CCHCOCHCH CsH-CH, CCH,CSH C6H5 Ethyl 3-0Xo-2,4- Dibenzyl ketone (c) This process illustrates the alkylation of a B-keto ester with subsequent ication and decarboxylation OCHCH=CH C6HsCH, CCHCOCH,CH CHCH, Br CH-CH,CCCOOCH, CH- CH CH,CCHCH,CH=CH CsHs (d) The enolate ion of ethyl phenylacetate attacks the carbonyl carbon of ethyl benzoate. CHC OCH,CH C6HSCCHCOCH,CH C6HSCHCOCH,CH O Ethyl 2, 3-diphenyl 3-oxopropanoate (e) Saponification and decarboxylation yield benzyl phenyl ketone 1. HO, H,O CH_CCHCOCU (32.H C6H CCH,C6H5 CsH Ethyl Benzyl phenyl ketone 3-0xo-2, 3-diphenylpropanoate (f This sequence is analogous to that of part(c) OCHCHECH NaOCH, CH, CaH_CCHCOCH2 CH, H,C=CHCH,Br CaH, CCCOOCH2CH, 2HT C6HSCCHCH,CH=CH, CBHs CAHs 3. heat CAHs 1. 2-Diphenyl-4-penten-1-o 21.17(a) The Dieckmann reaction is the intramolecular version of the Claisen condensation. It employs a diester as starting material COCH.CH CH,CH_OC(CH),COCH_CH, L/CH,CHS Diethyl heptanedioat Ethyl (2-oxocyclohexane)- Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(b) Saponification and decarboxylation of this -keto ester gives dibenzyl ketone. (c) This process illustrates the alkylation of a -keto ester with subsequent saponification and decarboxylation. (d) The enolate ion of ethyl phenylacetate attacks the carbonyl carbon of ethyl benzoate. (e) Saponification and decarboxylation yield benzyl phenyl ketone. ( f) This sequence is analogous to that of part (c). 21.17 (a) The Dieckmann reaction is the intramolecular version of the Claisen condensation. It employs a diester as starting material. 1. NaOCH2CH3 2. H Ethyl (2-oxocyclohexane)- carboxylate COCH2CH3 O O Diethyl heptanedioate CH3CH2OC(CH2)5COCH2CH3 O O C6H5CCHCOCH2CH3 O O C6H5 NaOCH2CH3 H CHCH2Br 2C C6H5CCCOOCH2CH3 O C6H5 CH2CH CH2 1. HO, H2O 2. H 3. heat 1,2-Diphenyl-4-penten-1-one C6H5CCHCH2CH O C6H5 CH2 1. HO, H2O 2. H 3. heat O O C6H5 C6H5CCHCOCH2CH3 Ethyl 3-Oxo-2,3-diphenylpropanoate O C6H5CCH2C6H5 Benzyl phenyl ketone C6H5C O O OCH2CH3 C6H5CHCOCH2CH3 O O C6H5 C6H5CCHCOCH2CH3 Ethyl 2,3-diphenyl- 3-oxopropanoate C6H5CH2CCHCOCH2CH3 O O C6H5 Ethyl 3-oxo-2,4- diphenylbutanoate NaOCH2CH3 H CHCH2Br 2C C6H5CH2CCCOOCH2CH3 O C6H5 CH2CH CH2 1. HO, H2O 2. H 3. heat C6H5CH2CCHCH2CH O C6H5 1,3-Diphenyl-5-hexen-2-one CH2 1. HO, H2O 2. H 3. heat C6H5CH2CCH2C6H5 O Dibenzyl ketone C6H5CH2CCHCOCH2CH3 O O C6H5 Ethyl 3-oxo-2,4- diphenylbutanoate ESTER ENOLATES 585 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
