1559Tch18323-34311/3/0511:12Page323 EQA 18 Enols,Enolates,and the Aldol Condensation: o,B-Unsaturated Aldehydes and Ketones As the text continues to develop the chemistry of aldehydes and ketones. the nuc ically temed ee them here for aldehydes and ketones:thed additionteof cdpotetcharater. Pay close attention to the structural relationships between starting materials and products.Thesc are the Outline of the Chapter 18-2 Keto-Enol Equilibria 18-3,18-4 Halogenation and Alkylation at the a-Carbon 18-5,18-6,18-7 Aldol Condensation A very important new reaction for synthesis 18-8 through 18-11 a,B-Unsaturated Aldehydes and Ketones The properties of the versatile products of aldol condensation. Keys to the Chapter 18-1.The Acidity of a-Hydrogens:Enolate lons second carbonyl group. 323
18 Enols, Enolates, and the Aldol Condensation: , -Unsaturated Aldehydes and Ketones As the text continues to develop the chemistry of aldehydes and ketones, you will now see how the carbon adjacent to a carbonyl group can become nucleophilic. First, reactions of these new nucleophiles with common electrophiles like haloalkanes will be covered: alkylation reactions. More important are reactions of the nucleophilic -carbons of one carbonyl compound with electrophilic carbonyl carbons of another. They are generically termed carbonyl condensation reactions. You see them here for aldehydes and ketones: the aldol condensation. (In a later chapter you will be introduced to the analogous reaction of carboxylic esters: the Claisen condensation.) The products of aldol condensations are , -unsaturated aldehydes and ketones, which contain additional sites of electrophilic and potential nucleophilic character. Pay close attention to the structural relationships between starting materials and products. These are the reactions of real-world organic synthesis, and they are among the most important ones you will see in this course. Outline of the Chapter 18-1 The Acidity of -Hydrogens: Enolate lons Making a nucleophile at the carbon to a carbonyl group. 18-2 Keto-Enol Equilibria 18-3, 18-4 Halogenation and Alkylation at the -Carbon 18-5, 18-6, 18-7 Aldol Condensation A very important new reaction for synthesis. 18-8 through 18-11 , -Unsaturated Aldehydes and Ketones The properties of the versatile products of aldol condensation. Keys to the Chapter 18-1. The Acidity of -Hydrogens: Enolate lons Hydrogens on carbons adjacent to carbonyl or related functional groups are, as a class, the most acidic of alkanelike hydrogens. A short list of representative pKa values follows. Notice how acidity is enhanced by a second carbonyl group. 323 1559T_ch18_323-343 11/3/05 11:12 Page 323
1559T_ch18_323-34311/3/0511:12Page324 EQA 324.Chapter 18 ENOLS,ENOLATES,AND THE ALDOL CONDENSATION:B-UNSATURATED ALDEHYDES AND KETONES Compound pK. Compound 0 00 RCH.COR 35 ROCCH.COR 13 00 RCH.CR 20 11 RCH-CH 17 RCCH.CR 9 00 RCH.CCI 16 HCCH.CH a盒ethn 09 一-c=c The enolate is nucleophilic able of reaction with the 18-2.Keto-Enol Equilibria In this section more mechanistic detail is provided conceming the isomerization of vinyl alcohols(enols)to compoun tions. similar to d.an cnd)atacks citer halogen or aere ay n th oalkane is methyl or primary.Enamines can be used instead of enolates for 18-5,18-6,and 18-7.Aldol Condensation and pro Smplrtatingmolelesitpoeedsvaddionofhedepoomedacatoaofoaecatonigopothie ce the location of the new carbon- on bone mportant applica t illustration or the ns of nola and caro ful results in aldol condensations. carbonyl strongly affects the reactivity of the alkene fun ctonal group.This
Compound pKa Compound pKa O OO B BB RCH2COR 25 ROCCH2COR 13 O OO B BB RCH2CR 20 RCCH2COR 11 O OO B BB RCH2CH 17 RCCH2CR 9 O OO B BB RCH2CCl 16 HCCH2CH 5 Any of the boldface protons in the structures above may be removed by an appropriate base, thus giving rise to the central participant in the reactions of this chapter, the enolate ion. The enolate is nucleophilic, capable of reaction with the typical electrophiles you’ve seen before. Their reaction with haloalkanes (alkylation) is the most general way to introduce alkyl substituents adjacent to carbonyl carbons. 18-2. Keto-Enol Equilibria In this section more mechanistic detail is provided concerning the isomerization of vinyl alcohols (enols) to carbonyl compounds. This isomerization, although it favors the keto structure, allows small concentrations of enols to be in equilibrium with carbonyl compounds, and these enols can lead to productive chemical reactions. 18-3 and 18-4. Halogenation and Alkylation at the -Carbon The reactions in this section are mechanistically very similar to ones you know. The nucleophilic carbon of an enolate (or, in acid, an enol) attacks either a halogen or a haloalkane through an SN2 pathway. Therefore, alkylations succeed best when the haloalkane is methyl or primary. Enamines can be used instead of enolates for alkylation and usually give superior results. 18-5, 18-6, and 18-7. Aldol Condensation These sections cover the first, and probably the most important carbonyl condensation reaction, the aldol condensation. Its significance is due to its ability to make relatively complex structures, including rings, from much simpler starting molecules. It proceeds via addition of the deprotonated -carbon of one carbonyl group to the carbonyl carbon of another. As you read this text section, notice the location of the new carbon–carbon bond in each aldol product. Cover up the starting materials and see if you can deduce their structures solely by looking at their aldol products. Although many aldol reactions between two identical molecules are useful, the most important applications fall into two categories: the so-called crossed aldols, and intramolecular condensations of dicarbonyl compounds. Pay particular attention to the examples in this section, because they provide excellent illustrations for the various permutations of enolate and carbonyl “partners” that give successful and useful results in aldol condensations. 18-8 through 18-11. , -Unsaturated Aldehydes and Ketones You see here logical extensions of carbonyl and alkene chemistry. The carbon–carbon double bond in an , - unsaturated carbonyl compound generally shows the same addition reactions typical of simple alkenes. However, the highly polar nature of the carbonyl strongly affects the reactivity of the alkene functional group. This O base C C H O C C O C C 324 • Chapter 18 ENOLS, ENOLATES, AND THE ALDOL CONDENSATION: , -UNSATURATED ALDEHYDES AND KETONES 1559T_ch18_323-343 11/3/05 11:12 Page 324
1559Tch18323-34311/3/0511:12Page325 Keysohe Chapter325 The wide range of chemistry is unde standable in terms of just three fundamental mechanisti sses 1.Electrophilic addition to carbonyl oxygen,e.g x-2 COH :OH C( 2.Nucleophilic addition to carbonyl carbon.. Co: :0:L c= +一x- 3.Nucleophilic addition to the B-carbon.e.g. Practice by writing mechanisms for examples in the text for which specific mechanisms are not pictured Use the appropriate mechanism above to starand follow it with the behavior expected for the product of that ste you understand the mechanisms. ones or ena ation Micha the retrosynthetic analysis for compounds containing six-membered rings six-membered rings
is best seen by the resonance forms in these compounds: Note in particular the presence of positive character at the -carbon as well as at the carbonyl carbon. The wide range of enone chemistry is understandable in terms of just three fundamental mechanistic processes. 1. Electrophilic addition to carbonyl oxygen, e.g., 2. Nucleophilic addition to carbonyl carbon, e.g., 3. Nucleophilic addition to the -carbon, e.g., Practice by writing mechanisms for examples in the text for which specific mechanisms are not pictured. Use the appropriate mechanism above to start, and follow it with the behavior expected for the product of that step. Once you understand the mechanisms, concentrate on the synthetic applications of the process. Focus on the carbon–carbon bond-forming examples, with particular emphasis on the Michael addition, the 1,4-addition of enolates to enones or enals. The combination Michael addition–aldol condensation provides a powerful means of synthesis of six-membered rings, the Robinson annulation. Don’t worry about all these people’s names; learn the retrosynthetic analysis for compounds containing six-membered rings. Cyclohexenone O 3 3 1 1 2 2 Substituted and functionalized six-membered rings 1,5-Dicarbonyl compound O O O O O O C O O C C C CN C C CN C C O Li O C CH3 CH3 C C Li C C C OH OH OH C C H C C C C C C O C C C C C C C C C C C C O O O Keys to the Chapter • 325 1559T_ch18_323-343 11/3/05 11:12 Page 325
1559T_ch18_323-34311/3/0511:12Page326 ⊕ EQA 326 Chapter 18 ENOLS,ENOLATES,AND THE ALDOL CONDENSATION:B-UNSATURATED ALDEHYDES AND KETONES The first step is michael addition to give a 15-dicarbonyl comr 3 of a cyclohexenone.which may be converted toa wide range of new compounds using the reactions of thes Solutions to Problems 0 HC、 28.(a)CHC①Sc①CH bc①cc①cHhd@j@ CHO (e) ((CH3)CCH (h)(CH3).CCCH OH 29.(a)(i)CHCH=CCH-CH, 0 0- mCH,CHCCH,CH,←一CH,CH=CCH,CH For the rest,only one of the enolate resonance forms will be writter OH OH (b)(i)CH2-CCH(CH3)2.CH;C-C(CHs)z 0 CH.CCH(CHCH.CE(CH CH (d)Same as(c).Stereochemistry will be lost as a-carbon becomes sp OH e)(i) Gi)
The first step is Michael addition to give a 1,5-dicarbonyl compound. This, in principle, can be done in either of two ways (formation of either bond 1 or bond 2). Then intramolecular aldol condensation forms bond 3 of a cyclohexenone, which may be converted to a wide range of new compounds using the reactions of these sections. Solutions to Problems 28. (a) (b) (c) (d) (e) (f) (g) (h) OH A 29. (a) (i) CH3CHPCCH2CH3 (ii) For the rest, only one of the enolate resonance forms will be written. OH OH A A (b) (i) CH2PCCH(CH3)2, CH3CPC(CH3)2 (ii) (c) (i) (ii) (d) Same as (c). Stereochemistry will be lost as -carbon becomes sp2 . (e) (i) (ii) (f) (i) (ii) O CH OH CH H CH3 CH3 OH O H CH3 CH3 CH3 CH3 O OH CH3 CH3 CH2CCH(CH3)2, CH3CC(CH3)2 O O CH3CHCCH2CH3 CH3CH CCH2CH3 O O (CH3)3CC H2CH O (CH3)3CCH O CHO H O H CH3 CH3 H H3C CH3 O H H H3C CH3 O H H C H3CC H (CH3)2 O CH3C H2CC H2CH3 O 326 • Chapter 18 ENOLS, ENOLATES, AND THE ALDOL CONDENSATION: , -UNSATURATED ALDEHYDES AND KETONES 1559T_ch18_323-343 11/3/05 11:12 Page 326
1559r.ch10323-34311/3/0s11:12Page327 EQA Solutions to Problems37 (g)None possible(noa-hydrogens!) OH (h)()(CH)CCH-CH ((CH)CCHCH 30.(a)Replace all a-hydrogens with D:for instance. 0 CH.CH.CCH-CH,gives CH.CD.CCD.CH 品品 D 0 (CHa)CCH.CH gives (CHJCCD,CH. (Note how the aldehyde hydrogen is not replaced-it is not acidic.) (b)Conditions for introduction of a single a-halogen.In order,the products are 1(a)CH:CHBrCCH-CH, 1(b)A mixture of CH,CCBr(CH)and BrCH,CCH(CH) 0 (Mixture of stereoisomers from either cis or trans starting ketone) B Br 1(g)No reaction 1(h)(CH.CCHBrCH (c)All o-hydrogens are replaced by Cl under these conditions 31.(a)An equivalent of Bra in acetic acid (CHCO,H)solvent (b)Excess Cl2 in aqueous base (e)One equivalent of Clin acetic acid
(g) None possible (no -hydrogens!) OH A (h) (i) (CH3)3CCHPCH (ii) 30. (a) Replace all -hydrogens with D; for instance, O O B B CH3CH2CCH2CH3 gives CH3CD2CCD2CH3, and O O B B (CH3)3CCH2CH gives (CH3)CCD2CH. (Note how the aldehyde hydrogen is not replaced—it is not acidic.) (b) Conditions for introduction of a single -halogen. In order, the products are O B 1(a) CH3CHBrCCH2CH3 O O B B 1(b) A mixture of CH3CCBr(CH3)2 and BrCH2CCH(CH3)2 1(c), (d) (Mixture of stereoisomers from either cis or trans starting ketone) 1(e) 1(f) 1(g) No reaction O B 1(h) (CH3)3CCHBrCH (c) All -hydrogens are replaced by Cl under these conditions. 31. (a) An equivalent of Br2 in acetic acid (CH3CO2H) solvent (b) Excess Cl2 in aqueous base (c) One equivalent of Cl2 in acetic acid CHO Br CH3 O Br CH3 CH3 CH3 O Br O CH3 CH3 gives CH3 CH3, O D D O (CH3)3CCHCH Solutions to Problems • 327 1559T_ch18_323-343 11/3/05 11:12 Page 327
1559T_ch18_323-34311/3/0511:12Page328 EQA 328.Chapter 18 ENOLS,ENOLATES,AND THE ALDOL CONDENSATION:B-UNSATURATED ALDEHYDES AND KETONES 32 33.a (b)3-Pentanone H2C=CHCH3 (d)3-Pentanone +H2C-C(CHa) CH.CH(CHz akylation sequences.The new carbon carbon bond is marked with (a)(CHaC-CHCHCHCHO ac=H-○ u te and iodomethan
32. 35. Illustrated with cyclohexanone: Before the reaction between cyclohexanone enolate and iodomethane has gone to completion, a mixture is present containing CH3 O CH3I, , and O SO2 Cl O O Cl O H O H H H O H O S O Cl Cl H Cl H H H H 328 • Chapter 18 ENOLS, ENOLATES, AND THE ALDOL CONDENSATION: , -UNSATURATED ALDEHYDES AND KETONES 33. (a) (b) 3-Pentanone H2CPCHCH3 (c) (d) 3-Pentanone H2CPC(CH3)2 (b) and (d) show the results of E2 elimination: Alkylation requires an SN2 process and you already know that these are poor with secondary and impossible with tertiary haloalkanes. CH2CH(CH3)2 O CH2CH3 O 34. Both are aldehyde n enamine n alkylation sequences. The new carbon–carbon bond is marked with an arrow. (a) (b) CH2 CHCHO (via CH2 Br CH CH N SN2 reaction) (CH3)2C CHCH2 CH2CHO via CH2 CH N 1559T_ch18_323-343 11/3/05 11:12 Page 328
1559r_eh18_323-34311/3/0511:12Page329 EQA one can take place unde &8m-8m 36.Yes.Enamines (neutral)are much less basic than enolates (anionic)and show much less tendency to cause E2 elimination reactions. 37.Use the catalyst!Then it's straightforward 号号牙子 风 -心9 (E and Z E and
An acid-base reaction between cyclohexanone enolate and 2-methylcyclohexanone can take place under these conditions, leading to either possible enolate of the latter. Reaction of the new enolates with CH3I leads to double alkylation products. Enamines reduce this problem. They are less reactive and more selective than enolate ions. 36. Yes. Enamines (neutral) are much less basic than enolates (anionic) and show much less tendency to cause E2 elimination reactions. 37. Use the catalyst! Then it’s straightforward: 38. The direction of nucleophilic attack is shown, and the new bond is marked in the product with an arrow. Both the initial hydroxycarbonyl compound and the enone that forms upon dehydration are shown. (a) (b) OH CHO CHO and (E and Z) O H O H OH CHO CHO and (E and Z) O H O H N H H H N OH N H O H (Section 17-8) O N N N O N H H2O H H O O O H H H O H H CH3 CH3 O CH3 or Solutions to Problems • 329 1559T_ch18_323-343 11/3/05 11:12 Page 329
1559T_ch18_323-34311/3/0511:12Page330 ⊕ EQA 330.Chapter 18 ENOLS,ENOLATES,AND THE ALDOL CONDENSATION:B-UNSATURATED ALDEHYDES AND KETONES 0d- rrow.Bo l hydroxycarbonyl compound
(c) 39. The direction of nucleophilic attack is shown, and the new bond is marked in the product with an arrow. Both the initial hydroxycarbonyl compound and the enone that forms upon dehydration are shown. (a) (b) (c) OH and (E and Z) O O O H O O O OH and (E and Z) O H CH3 O H2C O O OH and (E and Z) O H O H2C O O O O and OH 330 • Chapter 18 ENOLS, ENOLATES, AND THE ALDOL CONDENSATION: , -UNSATURATED ALDEHYDES AND KETONES 1559T_ch18_323-343 11/3/05 11:12 Page 330
1559reh18323-34311/3/0511:12Pag0331 EQA Solutions to Problems331 uamaa-a 0 CH: CHO 42 and 43.(a)CH,CHO CH,CHCH.CHO OH OH CH;-CH-CH2-CHO CH:CH2CH2-CH-CH-CHO CH-CH OH OH CH3-CH-CH-CHO CH;CH2CH2-CH-CH2-CHO CH.CH3
40. 41. Aldol condensations. The direction of nucleophilic attack is shown, and the new bond is marked in the product with an arrow. (a) (b) (c) (d) 42 and 43. (a) CH3CHO CH3CH2 CH2CHO None of these compounds will be a “major” product, but the first one may form in somewhat higher yield than the others because it is the least sterically crowded. OH CH3 CH CH2 CHO CH2 CHO OH CH3 CH CH2CH3 CH3CH2CH2 CH CHO OH CH CH CH2CH3 CHO CH3CH2CH2 OH CH H O H OH C CHO CHO HCC(CH3)2CH2CH2CHCCH3 CH3 CH3 CH3 O O OH O H (CH3)2CCHO CH3CH3 C H C O CH CHO OH CH2 C H CHCHO CHCHO O CH2CH OH OH O O H O HOOH O OH O H H OH O H O Solutions to Problems • 331 1559T_ch18_323-343 11/3/05 11:12 Page 331
1559T_ch18_323-34311/3/0511:12Page332 EQA 332.Chapter 18 ENOLS,ENOLATES,AND THE ALDOL CONDENSATION:B-UNSATURATED ALDEHYDES AND KETONES wSae+a8○ No a hydrogens in-inC o a hydroge Major product OH O OH O :-CH2-C-CHCHa CH:CH2-C-CH-C-CH acetaldehyde for illustration). :OH :OH CH CH-CH-CH-C product
(b) (c) 44. Because enolates are not feasible intermediates, consider an alternative—a neutral enol, which should be a nucleophile somewhat similar to an enamine. Compare with How can acid play a role? You already know (Section 17-5) that acid can catalyze carbonyl addition reactions by attachment to the carbonyl oxygen, thereby generating a better electrophile. So (using acetaldehyde for illustration), OH CH3 CH CH2 OH C H H product O OH CH3 C H CH2 CH OH CH3 C H H NR2 NR2 C C C C OH C C OH C C , O CH2 C CH2CH3 O CH3 C CH2CH3 CH3 CH OH Very little of these (ketone ketone) Major product O C H No hydrogens O C CH3 CH CH OH O CH2 C CH2CH3 CH3 C OH CH3CH2 CH3 C OH CH3CH2 CH3 O CH C CH3 C O CH3 C CH2 OH C O (CH3)3C CH CH2 OH Very minor (ketone ketone) Major product C O (CH3)3CCHO CH3 No hydrogens 332 • Chapter 18 ENOLS, ENOLATES, AND THE ALDOL CONDENSATION: , -UNSATURATED ALDEHYDES AND KETONES 1559T_ch18_323-343 11/3/05 11:12 Page 332