22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1063 22.4 ALDOL ADDITION AND ALDOL CONDENSATION 1063 O O H3C H3C | S3 3 3 3 $CC| CH3 $CCA" CH3 (22.38) LL L H3C) H3C) not an important structure In addition, the carbocation is destabilized by its unfavorable electrostatic interaction with the bond dipole of the carbonyl group—that is, with the partial positive charge on the carbonyl carbon atom. d– O S3 3 C d+ (CH3)2C CH3 | destabilizing electrostatic interaction PROBLEMS 22.16 What product is formed when (a) phenylacetic acid is treated first with Br2 and one equivalent of PBr3, then with a large excess of ethanol? (b) propionic acid is treated first with Br2 and one equivalent of PBr3, then with a large ex- cess of ammonia? 22.17 Give the structure of the product expected in each of the following reactions. (a) O S CH3CH2CCH2Br + 1-bromo-2-butanone N pyridine2 (b) O O S S BrCH2C Ph CH3CO_ Na| a-bromoacetophenoneL + sodiumL acetate 22.18 Give a curved-arrow mechanism for the reaction in Eq. 22.34. Your mechanism should show why two equivalents of NaOH must be used. 22.4 ALDOL ADDITION AND ALDOL CONDENSATION A. Base-Catalyzed Aldol Reactions In aqueous base, acetaldehyde undergoes a reaction called the aldol addition. O OH O S NaOH S 2H3C CH H3C"CH CH2 CH (22.39) H2O acetaldehydeL 3-hydroxybutanalL L L (aldol) (50% yield) 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1064 1064 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS The term aldol is both a traditional name for 3-hydroxybutanal and a generic name for b- hydroxy aldehydes. An aldol addition is a reaction of two aldehyde molecules to form a b-hydroxy aldehyde. The aldol addition is a very important and general reaction of aldehydes and ketones that have a-hydrogens. Notice that this reaction provides another method of form- ing carbon–carbon bonds. The base-catalyzed aldol addition involves an enolate ion as an intermediate. In this reac- tion, an enolate ion, formed by the reaction of acetaldehyde with aqueous NaOH, adds to a second molecule of acetaldehyde. 1 1 O O S S _ (22.40a) HO _ H CH2 CH H2C CH H2O 1 3 L L enolate2 L ion + 1 1 O O O _ O OH O 1 S3 3 S3 3 3 2 3 S3 3 H OH 3 2 S3 3 _ _ H3C CH H2C CH H3C "CH CH2 CH L 1 H3C "CH CH2 CH OH L enolate2 L ion L L L L L L + 3 1 (22.40b) The aldol addition is another nucleophilic addition to a carbonyl group. In this reaction, the nucleophile is an enolate ion. The reaction may look more complicated than some additions be- cause of the number of carbon atoms in the product. However, it is not conceptually different from other nucleophilic additions, such as cyanohydrin formation. Cyanohydrin formation: Aldol addition: 1 nucleophile H C CH A O _ CN 2 L 3 _ 3 + 2 aldehyde H3C CH A O H3C CH A O L 1 3 L 1 3 1 CN H2C CH A O L 3 protonation 1 H C" CH O1 H3C" CH O _ 3 _ LL1 3 LL1 3 H CN H O1 H L L 1 1 CN H2C CH A O addition L 3 product 1 H C" CH O1 H O_1 H (22.41) H3C" CH OH _ CN 3 L L 1 + 3 LL1 + 3 1 PROBLEM 22.19 Use the reaction mechanism to deduce the product of the aldol addition reaction of (a) phenylacetaldehyde; (b) propionaldehyde. The aldol addition is reversible. Like many other carbonyl addition reactions (Sec. 19.7B), the equilibrium for the aldol addition is more favorable for aldehydes than for ketones. 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1065 22.4 ALDOL ADDITION AND ALDOL CONDENSATION 1065 O OH O S S Ba(OH)2 2CH3C CH3 H3CC" CH2 C CH3 (22.42) LL LL LL acetone (equilibrium "CH3 lies to the left) 4-hydroxy-4-methyl-2-pentanone (diacetone alcohol) In this aldol addition reaction of acetone, the equilibrium favors the ketone reactant rather than the addition product, diacetone alcohol. This product can be isolated in good yield only if an apparatus is used that allows the product to be removed from the base catalyst as it is formed. Under more severe conditions (higher base concentration, or heat, or both), the product of aldol addition undergoes a dehydration reaction. 1 M NaOH OH 80 °C 2 CH3CH2CH2CHA O CH3CH2CH2"CH CHCHA O L butanal "CH2CH3 2-ethyl-3-hydroxyhexanal (the aldol addition product) CH3CH2CH2CHA CCHA O H2O (22.43) + "CH2CH3 2-ethyl-2-hexenal (86% yield) The sequence of reactions consisting of the aldol addition followed by dehydration, as in Eq. 22.43, is called the aldol condensation. (A condensation is a reaction in which two mole- cules combine to form a larger molecule with the elimination of a small molecule, in many cases water.) The term aldol condensation has been used historically to refer to the aldol addition reaction as well as to the addition and dehydration reactions together. To eliminate ambiguity, aldol condensation is used in this text only for the addition-dehydration sequence. The term aldol reactions is used to refer generically to both addition and condensation reactions. The dehydration part of the aldol condensation is a b-elimination reaction catalyzed by base, and it occurs in two distinct steps through an enolate-ion intermediate. 1 _ OH O 3 1 S H O 1 O C S S L _1 A 1 (22.44) "C "C C H2O "C C C $CC$ _ OH L L LL 3 + LLLL + 3 1 "OH " "OH " a),b-unsaturated) 1 1 aldol3 addition 3 carbanion carbonyl compound product intermediate This is not a concerted b-elimination. In this respect, it differs from the E2 reaction. (See Problem 9.16, p. 402.) 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1066 1066 CHAPTER 22 • THE CHEMISTRY OF ENOLATE IONS, ENOLS, AND a,b-UNSATURATED CARBONYL COMPOUNDS A base-catalyzed dehydration reaction of simple alcohols is unknown; ordinary alcohols do not dehydrate in base. However, b-hydroxy aldehydes and b-hydroxy ketones do for two rea- sons. First, their a-hydrogens are relatively acidic. Recall that base-promoted b-eliminations are particularly rapid when acidic hydrogens are involved (Secs. 17.3B and 9.5B). Second, the product is conjugated and therefore is particularly stable. To the extent that the transition state of the dehydration reaction resembles the a,b-unsaturated ketone, it too is stabilized by con- jugation, and the elimination reaction is accelerated (Hammond’s postulate). The product of the aldol condensation is an a,b-unsaturated carbonyl compound. The aldol condensation is an important method for the preparation of certain a,b-unsaturated carbonyl compounds. Whether the aldol addition product or the condensation product is formed de- pends on reaction conditions, which must be worked out on a case-by-case basis. You can as- sume for purposes of problem-solving, unless stated otherwise, that either the addition prod- uct or the condensation product can be prepared. Musical History of the Aldol Condensation Discovery of the aldol condensation is usually attributed solely to Charles Adolphe Wurtz, a French chemist who trained Friedel and Crafts. However, the reaction was first investigated during the pe- riod 1864–1873 by Aleksandr Borodin (1833–1887), a Russian chemist who was also a self-taught and proficient musician and composer.(Borodin’s musical themes were used as the basis of songs in the musical Kismet.) Borodin found it difficult to compete with Wurtz’s large, modern, well-funded laboratory. Borodin also lamented that his professional duties so burdened him with “examinations and commissions” that he could only compose when he was at home ill. Knowing this, his musical friends used to greet him,“Aleksandr, I hope you are ill today!” B. Acid-Catalyzed Aldol Condensation Aldol condensations are also catalyzed by acid. O H C O S 3 S acid 2H3C C CH3 $CA CHC CH3 H2O (22.45) LL LL + acetone H3C) mesityl oxide (79% yield) Acid-catalyzed aldol condensations, as in this example, generally give a,b-unsaturated car- bonyl compounds as products; addition products cannot be isolated. In acid-catalyzed aldol condensations, the conjugate acid of the aldehyde or ketone is a key reactive intermediate. H OH| 2 H L | O O % 33S 2 3S H3CC CH3 H3CC CH3 OH2 (22.46a) LL LL + 2 This protonated ketone plays two roles. First, it serves as a source of the2 enol, as shown in Eq. 22.17b on p. 1056. Second, the protonated ketone is the electrophilic species in the reaction. It reacts as an electrophile with the p electrons of the enol to give an a-hydroxy carbocation, which is also the conjugate acid of the addition product: 22_BRCLoudon_pgs4-4.qxd 11/26/08 12:27 PM Page 1067 22.4 ALDOL ADDITION AND ALDOL CONDENSATION 1067 OH| S3 one molecule of the H3CC CH3 protonated ketone a second molecule LL of the protonated H O H O ketone 2 3 | 1 1 1 H CH3 OH 1 CH3 O H 3 3 L OH2 $O| A"C H2C "C CH3 HO" C CH2 "C CH3 3 3 enolL 1 L L L | L "CH3 "CH3 an a-hydroxy carbocation the carbonyl carbon accepts (a protonated ketone; Sec.