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22.5 Condensation Reactions Involving Ester Enolate Ions 1073

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22.5 Condensation Reactions Involving Ester Enolate Ions 1073 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1072 1072 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS (c) CHA O (d) O (e) O S S % CH 3 Ph " " Ph " % " %CH3 Ph Ph (f) O (g) (CH3)2CAA CH CH O S L PhCHAA CH C CH CH Ph L LL L (h) O S 22.23 Analyze the aldol condensation in Eq. 22.49 on p. 1069 using the method given in Eq. 22.50. Show that four possible aldol condensation products might in principle result from the start- ing material. Explain why the observed product is the most reasonable one. CONDENSATION REACTIONS 22.5 INVOLVING ESTER ENOLATE IONS With this section, we begin the use of more compact abbreviations for several commonly oc- curring organic groups. These abbreviations, shown in Table 22.1, not only save space but also make the structures of large molecules less cluttered and easier to read. Just as Ph is used to symbolize the phenyl ring, Me can be used for methyl, Et for ethyl, Pr forL propyl, and L L L so on. Thus, ethyl acetate is abbreviated EtOAc; sodium ethoxide (Na|_OC2H5) is simply written as NaOEt; and methanol is abbreviated as MeOH. PROBLEM 22.24 Write the structure that corresponds to each of the following abbreviations. (See Table 22.1.) (a) Et3C OH (b) i-Pr Ph (c) t-BuOAc (d) Pr LOH (e) Ac2OL (f) Ac Ph L L A. Claisen Condensation The base-catalyzed aldol reactions discussed in the previous section involve enolate ions de- rived from aldehydes and ketones. This section discusses condensation reactions that involve the enolate ions of esters. Ethyl acetate undergoes a condensation reaction in the presence of one equivalent of sodium ethoxide in ethanol to give ethyl 3-oxobutanoate, which is known commonly as ethyl acetoacetate. O O O S NaOEt S S (1 equiv.) H O 3 | (22.51) 2H3C C OEt EtOH H3CCCH2 C OEt EtOH LL LL LL + ethyl acetate ethyl acetoacetate (75–76% yield) 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1073 22.5 CONDENSATION REACTIONS INVOLVING ESTER ENOLATE IONS 1073 TABLE 22.1 Abbreviations of Some Common Organic Groups Group Structure Abbreviation methyl H3C Me L ethyl CH3CH2 Et L propyl CH3CH2CH2 Pr L isopropyl (CH3)2CH i-Pr L butyl CH3CH2CH2CH2 Bu L isobutyl (CH3)2CHCH2 i-Bu L tert-butyl (CH3)3C t-Bu L O S acetyl H3CC Ac L L O S acetate (or acetoxy)H3CCO AcO LLL This is the best-known example of a Claisen condensation, which is named for Ludwig Claisen (1851–1930), who was a professor at the University of Kiel. (Don’t confuse this reaction with the Claisen–Schmidt condensation in the previous section—same Claisen, different reaction.) The product of this reaction, ethyl acetoacetate, is an example of a b-keto ester: a compound with a ketone carbonyl group b to an ester carbonyl group. a ketone group b to an ester group O O S S H3CCCH2 C OEt LLbaLL Thus, a Claisen condensation is the base-promoted condensation of two ester molecules to give a b-keto ester. The first step in the mechanism of the Claisen condensation is formation of an enolate ion by the reaction of the ester with the ethoxide base. EtO _ 2 3 H O O 1 2 S S _ H2"CC OEt H2C C OEt EtOH (22.52a) pLLKa ≈ 25 2enolateLL ion + 1 Because ethoxide ion is a nucleophile, we might ask whether it can also react at the carbonyl group of the ester to give the usual nucleophilic acyl substitution reaction. This reaction un- doubtedly takes place, but the products are the same as the reactants! This is why ethoxide ion is used as a base with ethyl esters in the Claisen condensation (see Study Guide Link 22.1 and Problem 22.26). Although the ester enolate ion is formed in very low concentration, it is a strong base and good nucleophile, and it undergoes a nucleophilic acyl substitution reaction with a second 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1074 1074 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS molecule of ester (Eq. 22.52b). The usual two-step substitution mechanism is observed—that is, formation of a tetrahedral addition intermediate followed by loss of a leaving group: 1 O O O O _ S3 3 S 3 3 S _ H3CC OEt H2C C OEt H3C"C CH2 C OEt LL 2 LL L L LL "OEt 1 tetrahedral3 addition intermediate O O 1 S3 3 S (22.52b) H3CC CH2 C OEt EtO _ LL LL + 1 3 The overall equilibrium as written in Eqs. 22.52a–b lies far on the side of the reactants; that is, all b-keto esters are less stable than the esters from which they are derived. For this reason, the Claisen condensation must be driven to completion by applying Le Châtelier’s principle. The most common technique is to use one full equivalent of ethoxide catalyst. In the b-keto ester product, the hydrogens on the carbon adjacent to both carbonyl groups (red in Eq. 22.52c) are especially acidic (why?), and the ethoxide removes one of these protons to form quantitatively the conjugate base of the product. O O O O S S S S H CHC C_ C OEt EtOH (22.52c) H3CCC H2 C OEt Na| EtO_ 3 LLpK 10.7LL + LL2 LL +pK 15–16 a Na| a = = The un-ionized b-keto ester product in Eq. 22.51 is formed when acid is added subsequently to the reaction mixture. Notice that ethoxide ion is a catalyst for the reactions in Eqs. 22.52a–b, but it is consumed in Eq. 22.52c. Thus, ethoxide is a reactant rather than a catalyst in the overall reaction, and for this reason one full equivalent of ethoxide must be used in the Claisen condensation. The removal of a product by ionization is the same strategy employed to drive ester saponi- fication to completion (Sec. 21.7A). The importance of this strategy in the success of the Claisen condensation is evident if the condensation is attempted with an ester that has only one a-hydrogen: No condensation product is formed. In this case, the desired condensation product has a quaternary a-carbon, and therefore it has no a-hydrogens acidic enough to react completely with ethoxide. no acidic O O CH3 hydrogen here S S _OEt 2(CH3)2CH C OEt (CH3)2CHCC" CO2Et (22.53) LL EtOH LLL "CH3 (no product observed) Furthermore, if the product of Eq. 22.53 (prepared by another method) is subjected to the con- ditions of the Claisen condensation, it readily decomposes back to starting materials because of the reversibility of the Claisen condensation. The Claisen condensation is another example of nucleophilic acyl substitution. In this re- action, the nucleophile is an enolate ion derived from an ester. Although the reaction may 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1075 22.5 CONDENSATION REACTIONS INVOLVING ESTER ENOLATE IONS 1075 seem complex because of the number of carbon atoms in the product, it is not conceptually different from other nucleophilic acyl substitutions, such as ester saponification: Saponification: Claisen condensation: nucleophile 1 _ OH H2C_ CO2Et 3 1 1 L + ester H3COC A H3C C AO L 1 3 L 1 3 "OEt "OEt 3 1 3 1 H C CO1 Et OH1 1 2 2 3 L tetrahedral H3C "C O H3C "C O _ _ addition LL1 3 LL1 3 intermediate "OEt "OEt 3 1 3 1 H2C CO2Et 1 OH1 1 3 L substitution H C "C AO EtO A 3 _ H3C "C O EtO _ product L 1 3 + 1 3 L 1 3 + 1 3 1 acid-base 1 reaction _ 1 O _ HC CO2Et 1 33 L H3C "C AO EtOH H3C "C AO EtOH (22.54) L 1 3 + 1 L 1 3 + 1 You have now studied two types of condensation reactions: the aldol condensation and the Claisen condensation. These condensations are quite different and should not be confused. To compare: 1. The aldol condensation is an addition reaction of an enolate ion or an enol with an alde- hyde or ketone followed by a dehydration. The Claisen condensation is a nucleophilic acyl substitution reaction of an enolate ion with an ester group. 2. The aldol condensation is catalyzed by both base and acid. The Claisen condensation re- quires a full equivalent of base and is not catalyzed by acid. 3. The aldol addition requires only one a-hydrogen. A second a-hydrogen is required, however, for the dehydration step of the aldol condensation. In the Claisen condensa- tion, the ester starting material must have at least two a-hydrogens, one for each of the ionizations shown in Eqs. 22.52a and 22.52c. PROBLEMS 22.25 Give the Claisen condensation product formed in the reaction of each of the following esters with one equivalent of NaOEt, followed by neutralization with acid. (a) ethyl phenylacetate (b) ethyl butyrate 22.26 Hydroxide ion is about as basic as ethoxide ion. Would NaOH be a suitable base for the Claisen condensation of ethyl acetate? Explain. (Hint: See Study Guide Link 22.1.) 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1076 1076 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS B. Dieckmann Condensation Intramolecular Claisen condensations, like intramolecular aldol condensations, take place readily when five- or six-membered rings can be formed.
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