《有机化学》课程教学资源（教材文献，英文版）CHAPTER 21 ESTER ENOLATES.pdf_大学文库

CHAPTER TWENTY-ONE Ester Enolates H Principal resonance structures of the anion of a p-keto ester We'll begin by describing the preparation and properties of B-keto esters, proceed to a discussion of their synthetic applications, continue to an examination of related species and conclude by exploring some recent developments in the active field of synthetic car- banion chemistry. 21.1 THE CLAISEN CONDENSATION Before describing how B-keto esters are used as reagents for organic synthesis, we need to see how these compounds themselves are prepared. The main method for the prepa dig Claisen was a Ger. ration of B-keto esters is a reaction known as the Claisen condensation man chemist who worked of the nineteenth centu and the first two decades of 2RCHCOR,,,+ R'OH the twentieth. His name is R presented in Ester β- Keto ester Alcohol 8.10 the Claisen On treatment with alkoxide bases, esters undergo self-condensation to give a B-keto ester his section and the Claisen and an alcohol. Ethyl acetate, for example, undergoes a Claisen condensation on treat duced in Section 24. 13 ment with sodium ethoxide to give a B-keto ester known by its common name ethyl ace toacetate(also called acetoacetic ester): 2CH COCH, CH3-2HO CH3 CCH,COCH, CH3+ CH3CH,OH Ethyl acetate Ethyl acetoacetate (75%) Ethanol (acetoacetic ester) The systematic IUPAC name of ethyl acetoacetate is ethyl 3-oxobutanoate. The presence of a ketone carbonyl group is indicated by the designation"oxo"along with the appro- riate locant. Thus, there are four carbon atoms in the acyl group of ethyl 3-oxobutanoate, C-3 being the carbonyl carbon of the ketone function. The mechanism of the cl ure 21.1. The first two steps of the mechanism are analogous to those of aldol addition (Section 18.9). An enolate ion is generated in step l, which undergoes nucleophilic addi- tion to the carbonyl group of a second ester molecule in step 2. The species formed in this step is a tetrahedral intermediate of the same type that we encountered in our dis- ussion of nucleophilic acyl substitution of esters. It dissociates by expelling an ethox ide ion, as shown in step 3, which restores the carbonyl group to give the p-keto ester. Steps 1 to 3 show two different types of ester reactivity: one molecule of the ester gives rise to an enolate; the second molecule acts as an acylating agent. Claisen condensations involve two distinct experimental operations. The first stage concludes in step 4 of Figure 21.1, where the base removes a proton from C-2 of the B-keto ester. Because this proton is relatively acidic, the position of equilibrium for step 4 lies far to the right Back Forward Main MenuToc Study Guide ToC Student o MHHE Website

We’ll begin by describing the preparation and properties of -keto esters, proceed to a discussion of their synthetic applications, continue to an examination of related species, and conclude by exploring some recent developments in the active field of synthetic carbanion chemistry. 21.1 THE CLAISEN CONDENSATION Before describing how -keto esters are used as reagents for organic synthesis, we need to see how these compounds themselves are prepared. The main method for the preparation of -keto esters is a reaction known as the Claisen condensation: On treatment with alkoxide bases, esters undergo self-condensation to give a -keto ester and an alcohol. Ethyl acetate, for example, undergoes a Claisen condensation on treatment with sodium ethoxide to give a -keto ester known by its common name ethyl acetoacetate (also called acetoacetic ester): The systematic IUPAC name of ethyl acetoacetate is ethyl 3-oxobutanoate. The presence of a ketone carbonyl group is indicated by the designation “oxo” along with the appropriate locant. Thus, there are four carbon atoms in the acyl group of ethyl 3-oxobutanoate, C-3 being the carbonyl carbon of the ketone function. The mechanism of the Claisen condensation of ethyl acetate is presented in Figure 21.1. The first two steps of the mechanism are analogous to those of aldol addition (Section 18.9). An enolate ion is generated in step 1, which undergoes nucleophilic addition to the carbonyl group of a second ester molecule in step 2. The species formed in this step is a tetrahedral intermediate of the same type that we encountered in our discussion of nucleophilic acyl substitution of esters. It dissociates by expelling an ethoxide ion, as shown in step 3, which restores the carbonyl group to give the -keto ester. Steps 1 to 3 show two different types of ester reactivity: one molecule of the ester gives rise to an enolate; the second molecule acts as an acylating agent. Claisen condensations involve two distinct experimental operations. The first stage concludes in step 4 of Figure 21.1, where the base removes a proton from C-2 of the -keto ester. Because this proton is relatively acidic, the position of equilibrium for step 4 lies far to the right. Ethyl acetate 2CH3COCH2CH3 O Ethyl acetoacetate (75%) (acetoacetic ester) CH3CCH2COCH2CH3 O O Ethanol CH3CH2OH 1. NaOCH2CH3 2. H3O Ester 2RCH2COR O -Keto ester RCH2CCHCOR O R O Alcohol ROH 1. NaOR 2. H3O C C R OR O H O C R C C OR O O H C R C C OR O O H C Principal resonance structures of the anion of a -keto ester 832 CHAPTER TWENTY-ONE Ester Enolates Ludwig Claisen was a German chemist who worked during the last two decades of the nineteenth century and the first two decades of the twentieth. His name is associated with three reactions. The Claisen–Schmidt reaction was presented in Section 18.10, the Claisen condensation is discussed in this section, and the Claisen rearrangement will be introduced in Section 24.13. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website

CHAPTER TWENTY-ONE Ester Enolates Step 5: Acidification of the reaction mixture. This is performed in a separate synthetic operation to give the product in its neutral form for eventual isolatic H CH3CCHCOCH, CH3 →>CH3 CCHCOCH2CH3+:O H ethyl 3-oxobutanoate (stronger acid) (weaker acid) (weaker base (stronger base FIGURE 21.1(Continued) In general, the equilibrium represented by the sum of steps 1 to 3 is not favorable for condensation of two ester molecules to a B-keto ester. (Two ester carbonyl groups are more stable than one ester plus one ketone carbonyl. However, because the B-keto ester is deprotonated under the reaction conditions, the equilibrium represented by the of steps I to 4 does lie to the side of products. On subsequent acidification(step 5), the anion of the B-keto ester is converted to its neutral form and isolated Organic chemists sometimes write equations for the Claisen condensation in a form that shows both stages explicitly: 2CH3 COCH, CH3 CH3CCHCOCHCH3-> CH3CCH,COCH, CH3 Ethyl acetate Sodium sa to Ethyl acetoacetate Like aldol condensations, Claisen condensations always involve bond formation between the a-carbon atom of one molecule and the carbonyl carbon of another: oO NaOCH- C 2CH3CH,COCH CH,2H,o uo> CHCH, CCHCOCH, CH3 CH3 CH,OH Ethyl propanoate Ethyl 2-methyl-3-oxopentanoate Ethanol (81%) PROBLEM 21.1 One of the following esters cannot undergo the Claisen con- densation. Which one? Write structural formulas for the claisen condensation products of the other two CH3 CH2 CH2 CO2 CH2 CH3 C6H5 CO2 CH2 CH3 C6H5 CH2 CO2 CH2 CH Ethyl pentanoate Ethyl benzoate Ethyl phenylacetate Unless the B-keto ester can form a stable anion by deprotonation as in step 4 of Figure 21., the Claisen condensation product is present in only trace amounts at equi librium. Ethyl 2-methylpropanoate, for example, does not give any of its condensation product under the customary conditions of the Claisen condensation Back Forward Main MenuToc Study Guide ToC Student o MHHE Website

In general, the equilibrium represented by the sum of steps 1 to 3 is not favorable for condensation of two ester molecules to a -keto ester. (Two ester carbonyl groups are more stable than one ester plus one ketone carbonyl.) However, because the -keto ester is deprotonated under the reaction conditions, the equilibrium represented by the sum of steps 1 to 4 does lie to the side of products. On subsequent acidification (step 5), the anion of the -keto ester is converted to its neutral form and isolated. Organic chemists sometimes write equations for the Claisen condensation in a form that shows both stages explicitly: Like aldol condensations, Claisen condensations always involve bond formation between the -carbon atom of one molecule and the carbonyl carbon of another: PROBLEM 21.1 One of the following esters cannot undergo the Claisen condensation. Which one? Write structural formulas for the Claisen condensation products of the other two. Unless the -keto ester can form a stable anion by deprotonation as in step 4 of Figure 21.1, the Claisen condensation product is present in only trace amounts at equilibrium. Ethyl 2-methylpropanoate, for example, does not give any of its condensation product under the customary conditions of the Claisen condensation. CH3CH2CH2CH2CO2CH2CH3 Ethyl pentanoate C6H5CH2CO2CH2CH3 Ethyl phenylacetate C6H5CO2CH2CH3 Ethyl benzoate Ethyl propanoate 2CH3CH2COCH2CH3 O Ethanol CH3CH2OH 1. NaOCH2CH3 2. H3O Ethyl 2-methyl-3-oxopentanoate (81%) CH3CH2CCHCOCH2CH3 O O CH3 Ethyl acetate 2CH3COCH2CH3 O NaOCH2CH3 H3O Ethyl acetoacetate CH3CCH2COCH2CH3 O O Sodium salt of ethyl acetoacetate CH3CCHCOCH2CH3 Na O O 834 CHAPTER TWENTY-ONE Ester Enolates Step 5: Acidification of the reaction mixture. This is performed in a separate synthetic operation to give the product in its neutral form for eventual isolation. O CH3CCHCOCH2CH3 O Conjugate base of ethyl 3-oxobutanoate (stronger base) H H O H Hydronium ion (stronger acid) O CH3CCHCOCH2CH3 O Ethyl 3-oxobutanoate (weaker acid) H H O H Water (weaker base) XX XX FIGURE 21.1 (Continued) Back Forward Main Menu TOC Study Guide TOC Student OLC 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

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