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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. The intramolecular Claisen conden- sation reaction is called the Dieckmann condensation.

O

S O Na O 1 | CH2 CH2 C OEt NaOEt S S H L L L (1 equiv.) _ CO2Et AcOH CH) 2 ) toluene ) CO2Et (22.55) (solvent) $ $CH2 C OEt LLS ethyl 2-oxocyclopentane- O carboxylate (74–81% yield) diethyl adipate

Like the Claisen condensation, the Dieckmann condensation requires one full equivalent of base to form the enolate ion of the product and thus to drive the reaction to completion.

PROBLEM 22.27 (a) Explain why compound A, when treated with one equivalent of NaOEt, followed by acidification, is completely converted into compound B. (b) Give the structure of the only product formed when diethyl a-methyladipate (compound C) reacts in the Dieckmann condensation. Explain your reasoning. O O S CH3 S H3C CO2Et EtO2C(CH2)3CHCO2Et ) CO2Et % % % "CH3 C A B for part (b) for part (a)

C. Crossed Claisen Condensation The Claisen condensation of two different esters is called a crossed Claisen condensation. The crossed Claisen condensation of two esters that both have a-hydrogens gives a mixture of four compounds that are typically difficult to separate. Such reactions in most cases are not synthetically useful.

O O S S NaOEt H3O| H3C CO2Et C2H5 CO2Et H3C C CH2 C OEt LL+ LL LL + O O O O O O S S S S S S CH3CH2 C CH2 C OEt H3C C CHC OEtCH3CH2 C CH C OEt LL LL + LL LL+ LL LL "CH3 "CH3 (22.56)

This problem is conceptually similar to the problem with crossed aldol reactions, discussed in Study Problem 21.1 on p. 1026. 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1077

22.5 CONDENSATION REACTIONS INVOLVING ESTER ENOLATE IONS 1077

Crossed Claisen condensations are useful, however, if one ester is especially reactive or has no a-hydrogens. For example, formyl groups ( CHAO) are readily introduced with esters of formic acid such as ethyl formate: L

O S CO2Et O HC CO2Et CH S Na (1 equiv.) CH 2% EtOH (trace) H O % % HCOEt 3 | EtOH (22.57) toluene "CH2 + L L (solvent) "CH2 + CO Et ethyl formate CO Et % 2 % 2 diethyl succinate diethyl formylsuccinate (60–70% yield)

Formate esters fulfill both of the criteria for a crossed Claisen condensation. First, they have no a-hydrogens; second, their carbonyl reactivity is considerably greater than that of other esters. The reason for their higher reactivity is that the carbonyl group in a formate ester is “part alde- hyde,” and aldehydes are particularly reactive toward nucleophiles (Eq. 21.60, p. 1029). A less reactive ester without a-hydrogens can be used if it is present in excess. For example, an ethoxycarbonyl group can be introduced with diethyl carbonate.

ethoxycarbonyl group O OEt O O C % O S S # S heat H3O| PhCH2 C OEt EtO C OEt (excess) NaOEt Ph "CHC OEt EtOH LL + L L (1 equiv.) LLL + ethyl phenylacetate diethyl carbonate diethyl phenylmalonate (86% yield) (22.58)

In this example, the enolate ion of ethyl phenylacetate condenses preferentially with diethyl carbonate rather than with another molecule of itself because of the much higher concentration of diethyl carbonate. The excess diethyl carbonate must then be separated from the product. Another type of crossed Claisen condensation is the reaction of ketones with esters. In this type of reaction, the enolate ion of a ketone reacts at the carbonyl group of an ester. O O O S O S S S NaOEt CH (1 equiv.) H3O L EtO C H | % EtOH (22.59) ether L L + + ethyl formate cyclohexanone 2-oxocyclohexanecarbaldehyde (70–74% yield)

O O O O S S NaOEt S S (1 equiv.) H O PhC CH EtOC CH 3 | PhC CH C CH EtOH (22.60) 3 3 xylene 2 3 LL ++L L LL L L acetophenone ethyl acetate 1-phenyl-1,3-butanedione (large excess) (a b-diketone) (64–70% yield) In Eq. 22.59, the enolate ion derived from the ketone cyclohexanone is acylated by the ester ethyl formate. In Eq. 22.60, the enolate ion of the ketone acetophenone is acylated by the ester 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1078

1078 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS

ethyl acetate. In these reactions, several side reactions are possible in principle but in fact do not interfere. The analysis of these cases again highlights important principles of carbonyl- compound reactivity. In Eq. 22.59, a possible side reaction is the aldol addition of cyclohexanone with itself. However, the equilibrium for the aldol addition of two ketones favors the reactants, whereas the Claisen condensation is irreversible because one equivalent of base is used to form the eno- late ion of the product. Because the ester has no a-hydrogens, it cannot condense with itself. The ester in Eq. 22.60, however, does have a-hydrogens and is known to condense with itself (Eq. 22.51, p. 1072). Why is such a condensation not an interfering side reaction? The answer is

that ketones are far more acidic than esters (by about 5–7 pKa units; see Eqs. 22.3–22.4 on p. 1048). Thus, the enolate ion of the ketone is formed in much greater concentration than the enolate ion of the ester. The ketone enolate ion can react with another molecule of ketone—an unfavorable equilibrium—or it can be intercepted by the excess of ethyl acetate to give the ob- served product, which is a b-diketone. Even though esters are less reactive than ketones, a b- diketone is especially acidic (like a b-keto ester) and is ionized completely by the one equiva- lent of NaOEt. (Be sure to identify the acidic hydrogens of the product in Eq. 22.60.) Hence, b-diketone formation is observed because ionization makes this an irreversible reaction. These examples illustrate that the crossed Claisen condensation can be used for the synthe- sis of a wide variety of b-dicarbonyl compounds.

PROBLEM 22.28 Complete the following reactions. Assume that one equivalent of NaOEt is present in each case. (a) O O S S NaOEt H3O| H3C C CMe3 EtO C OEt (excess) LL + LL (b) O O S S NaOEt H3O| Ph C CH3 Ph C OEt (excess) LL + LL (c) O CO2Et S NaH H3O| H3C C CH2 C(Me)2 "CH CO2Et (C11H16O4) LL LLL

D. Synthesis with the Claisen Condensation As the examples in the previous sections have shown, the Claisen condensation and related re- actions can be used for the synthesis of b-dicarbonyl compounds: b-keto esters, b-diketones, and the like. Compare these types of compounds with those prepared by the aldol condensa- tion, and note the differences carefully. In planning the synthesis of a b-dicarbonyl compound, we adopt the usual two-step strat- egy: examine the target molecule and work backward to reasonable starting materials. Then we mustn’t forget to analyze the reaction of these starting materials to see whether the desired reaction is reasonable or whether other reactions will occur instead. To determine the starting materials for a Claisen condensation, mentally reverse the conden- sation by adding the elements of ethanol (or another alcohol) across either of the carbon–car- bon bonds between the carbonyl groups. Because there are two such bonds, we will generally find two possible “disconnections” (labeled (a) and (b) in the following equation) and two cor- responding sets of starting materials by this procedure. 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1079

22.5 CONDENSATION REACTIONS INVOLVING ESTER ENOLATE IONS 1079

enolate acceptor component carbonyl compound (a) R1 O R3 O H OEt (a) S S L HC" C "C H EtO C OEt R1 O R3 O LLL + LL S S "R2 "H HC" CC" C OEt (22.61) LLL L R1 O R3 O "R2 "H S S HC" C OEt H "C C OEt EtO H (b) LL + L LL L "R2 "H (b) acceptor enolate carbonyl compound component

A b-diketone can be similarly analyzed in two different ways:

(a) O R2 O H OEt (a) S S L R1 C "C H EtO C R3 2 O R O LLL + LL S S "H R1 CC" C R3 (22.62) LLL L O R2 O "H S S R1 C OEt H "C C R3 EtO H (b) LL + L LL L "H (b)

Having determined the starting materials required in a Claisen condensation, we then ask whether the Claisen condensation of the required materials will give mostly the desired prod- uct or a complex mixture. Such an analysis of a target b-keto ester is illustrated in Study Prob- lem 22.3.

Study Problem 22.3 Determine whether the following compound can be prepared by a Claisen condensation or one of its variations; if so, give the possible starting materials.

O O S S C CH3 L ) H %

Solution This is a b-diketone, a type of compound for which a Claisen or Dieckmann condensa- tion might be appropriate. To determine the possible starting materials, follow the foregoing procedure: Add EtOH in turn across each of the bonds indicated:

O O S S C CH (a) (b)% % 3 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1080

1080 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS

Addition across bond (a) gives the following possible starting material:

O B OEt O C S (3) # % CH2 C CH3 (1) LLA (2)

Now let’s think about all possible Dieckmann condensation reactions that can occur with this compound. Three possible sets of a-hydrogens could ionize to give enolate ions. Hydrogens (1) and (2), because they are adjacent to a ketone carbonyl, are more acidic than hydrogens (3), which are adjacent to an ester carbonyl. Formation of an enolate ion at (1) and reaction of this enolate at carbonyl B give the desired product, and this reaction is driven to completion by using one equiva- lent of NaOEt. Formation of an enolate ion at (2) and reaction of this enolate at carbonyl B would give a b-diketone product containing a seven-membered ring:

O O A A

Because five-membered rings usually form much more rapidly than seven-membered rings (Sec. 11.7), the desired product should be the major one, although formation of the seven- membered ring is a potential complication. Breaking bond (b) in the target gives the following starting materials:

O S H O S ) EtO C CH3 %H + LL ethyl acetate cyclopentanone

In this case, the ketone, cyclopentanone, is more acidic than the ester, ethyl acetate. Because of its symmetry, cyclopentanone can give only one enolate ion. Aldol addition of this enolate ion to another molecule of cyclopentanone is an unfavorable equilibrium; recall that the equilibria for aldol additions of ketones are unfavorable. If an excess of ethyl acetate is used, this potential side reaction can be further suppressed, if it occurs at all. The desired Claisen condensation can be made irreversible by use of one equivalent of NaOEt to ionize the products. Consequently, this set of starting materials—cyclopentanone and ethyl acetate—should give the desired reaction. Evidently, both sets of potential starting materials would work, and in fact are acceptable answers. Which would be best in practice? Cyclopentanone and ethyl acetate are inexpensive and STUDY GUIDE LINK 22.5 readily available. The other starting material would probably have to be prepared in a multistep Variants of the synthesis. Consequently, cyclopentanone and ethyl acetate are the starting materials of choice. Aldol and Claisen Condensations (This synthesis is conceptually the same as the one in Eq. 22.60.)

PROBLEMS 22.29 Analyze each of the following compounds and determine what starting materials would be required for its synthesis by a Claisen condensation. Then decide which if any of the possi- ble Claisen condensations would be a reasonable route to the desired product. 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1081

22.6 BIOSYNTHESIS OF FATTY ACIDS 1081

(a) O O (b) O O S S S S H3CC CHC CH2CH3 EtC CHC OEt LL LL LL LL "CH3 "CH3

(c) O (d) O O S S S CO2Et PhCH2 C CHC OEt LL LL ) CH3 $ "CH2CH2CH3

22.30 Give the starting material required for the synthesis of each of the following compounds by a Dieckmann condensation. (a) O (b) O S CH3

* " * O ( O

22.6 BIOSYNTHESIS OF FATTY ACIDS

The utility of the Claisen condensation and the aldol reactions is not confined to the labora- tory; these reactions are also important in the biological world. The biosynthesis of fatty acids (Sec. 20.5) illustrates how nature uses a reaction very similar to the Claisen condensation to build long carbon chains. The starting material for the biosynthesis of fatty acids is a thiol ester of acetic acid called acetyl-CoA. O S H3CC S CoA LLL acetyl-CoA The abbreviated name acetyl-CoA stands for acetyl-coenzyme A, the complete structure of which is shown in Fig. 22.3. The complex functionality in this molecule is required for its recognition by enzymes. However, this complexity has no direct role in its chemical transfor- mations and can be ignored for our purposes.

NH2 N O O OH CH3 O O N H C C S(CH ) NHC(CH ) NHC CHCCH O P O P O CH N 3 2 2 2 2 2 2 O N abbreviated CH O O R configuration 3 HH O H 2– O3PO OH H3C C SCoA

Figure 22.3 Structure of acetyl-CoA, the basic building block for fatty acid biosynthesis