Problems Chapter 18 861 Cuprate additions followed by enolate alkylations O B ⌷ C 1. R2CuLi, THF Ј 2. R X N CPC COCOC A A R RЈ 15. Michael Addition (Section 18-11) O B O H O ϪO C B A B D RЈ Hϩ P ϩ P RCOCOCOCOCRЈ DC C C C R 16. Robinson Annulation (Section 18-11) CH HOϪ ϩ A KC O CH2 O O Important Concepts 1. Hydrogens next to the carbonyl group (A-hydrogens) are acidic because of the electron-withdrawing nature of the functional group and because the resulting enolate ion is resonance stabilized. 2. Electrophilic attack on enolates can occur at both the a-carbon and the oxygen. Haloalkanes usu- ally prefer the a-carbon. Protonation of the oxygen leads to enols. 3. Enamines are neutral analogs of enolates. Resonance donation of the nitrogen lone pair imparts nucleophilic character on the remote double bond carbon, which can be alkylated to give iminium cations that hydrolyze to aldehydes and ketones on aqueous work-up. 4. Aldehydes and ketones are in equilibrium with their tautomeric enol forms; the enol – keto conversion is catalyzed by acid or base. This equilibrium allows for facile a-deuteration and stereochemical equilibration. 5. A-Halogenation of carbonyl compounds may be acid or base catalyzed. With acid, the enol is halogenated by attack at the double bond; subsequent renewed enolization is slowed down by the halogen substituent. With base, the enolate is attacked at carbon, and subsequent enolate forma- tion is accelerated by the halogens introduced. 6. Enolates are nucleophilic and reversibly attack the carbonyl carbon of an aldehyde or a ketone in the aldol condensation. They also attack the b-carbon of an a,b-unsaturated carbonyl com- pound in the Michael addition. 7. a,b-Unsaturated aldehydes and ketones show the normal chemistry of each individual double bond, but the conjugated system may react as a whole, as revealed by the ability of these com- pounds to undergo acid- and base-mediated 1,4-additions. Cuprates add in 1,4-manner, whereas alkyllithiums normally attack the carbonyl function. Problems 32. Underline the a-carbons and circle the a-hydrogens in each of the following structures. O O O B B H3C[ CH[ 3 (a) CH3CH2CCH2CH3 (b) CH3CCH(CH3)2 (c) O O CH3 H3C≈ CH[ 3 CHO CH (d) (e) 3 (f ) 862 Chapter 18 Enols, Enolates, and the Aldol Condensation O O B B (g) (CH3)3CCH (h) (CH3)3CCH2CH 33. Write the structures of every enol and enolate ion that can arise from each of the carbonyl com- pounds illustrated in Problem 32. 34. What product(s) would form if each carbonyl compound in Problem 32 were treated with (a) alkaline D2O; (b) 1 equivalent of Br2 in acetic acid; (c) excess Cl2 in aqueous base? 35. Describe the experimental conditions that would be best suited for the effi cient synthesis of each of the following compounds from the corresponding nonhalogenated ketone. Br O Cl Cl Cl Cl O A B Cl (a) C6H5CHCCH3 (b) (c) O 36. Propose a mechanism for the following reaction. (Hint: Take note of all of the products that are formed and base your answer on the mechanism for acid-catalyzed bromination of acetone shown in Section 18-3.) O O Cl Catalytic HCl, CCl ϩ 4 ϩ ϩ SO2Cl2 SO2 HCl 37. Give the product(s) that would be expected on reaction of 3-pentanone with 1 equivalent of LDA, followed by addition of 1 equivalent of O B (a) CH CH Br (b) (CH ) CHCl (c) (CH ) CHCH OS CH (d) (CH ) CCl 3 2 3 2 3 2 2 B 3 3 3 O 38. Give the product(s) of the following reaction sequences. N 1. H, Hϩ N ϩ 1. H, H 2. CH2Br 2. (CH3)2CPCHCH2Cl ϩ ϩ 3. H , H2O 3. H , H2O (a) CH3CHO (b) CH2CHO 39. The problem of double compared with single alkylation of ketones by iodomethane and base is mentioned in Section 18-4. Write a detailed mechanism showing how some double alkylation occurs even when only one equivalent each of the iodide and base is used. Suggest a reason why N the enamine alkylation procedure solves this problem. 40. Would the use of an enamine instead of an enolate improve the likelihood of successful alkylation ϩ of a ketone by a secondary haloalkane? H2O 41. Formulate a mechanism for the acid-catalyzed hydrolysis of the pyrrolidine enamine of cyclo- hexanone (shown in the margin). Hϩ 42. Write the structures of the aldol condensation products of (a) pentanal; (b) 3-methylbutanal; (c) cyclopentanone. O 43. Write the structures of the expected major products of crossed aldol condensation at elevated tem- perature between excess benzaldehyde and (a) 1-phenylethanone (acetophenone — see Section 17-1 ϩ for structure); (b) acetone; (c) 2,2-dimethylcyclopentanone. N H 44. Formulate a detailed mechanism for the reaction that you wrote in (c) of Problem 43. Problems Chapter 18 863 45. Give the likely products for each of the following aldol addition reactions. NaOH, H2O (a) 2 CH2CHO NaOH, H O ϩ 2 (b) CHO (CH3)2CHCHO CHO O NaOH, H2O CH3 NaOH, H2O (c) H (d) H CCH O 3 3 O CHO 46. Rotundone (margin) is the natural product responsible for the peppery aroma in peppers, many herbs, and red wines (p. 846). What cyclic diketone will give rotundone upon intramolecular aldol condensation? 47. Write all possible products of the base-catalyzed crossed aldol reactions between each pair of reaction partners given below. (Hint: Multiple products are possible in every case; be sure to Rotundone include thermodynamically unfavorable as well as favorable ones.) (a) Butanal and acetaldehyde (b) 2,2-Dimethylpropanal and acetophenone (c) Benzaldehyde and 2-butanone 48. For each of the three crossed aldol reactions described in Problem 47, indicate which, if any, of the multiple possible products should predominate in the reaction mixture and explain why. 1 49. Aldol condensations may be catalyzed by acids. Suggest a role for H in the acid-catalyzed version. (Hint: Consider what kind of nucleophile might exist in acidic solution, where enolate ions are unlikely to be present.) 50. Reaction review. Without consulting the Reaction Road Maps on pp. 818 – 819, suggest reagents to convert butanal into each of the following compounds. O O O (a) (b) (c) H H H Cl Br Br O H O O O (d) (e) H (f) H (g) H OH 51. Reaction review II. Without consulting the Reaction Road Maps on pp. 818 – 819, suggest reagents to convert acetophenone into each of the following compounds. O O OOH (a) C6H5 (b) C6H5 CCl3 (c) C6H5 O O O (d) C6H5 (e) C6H5 (f) C6H5 CH2Br 52. Reaction review III. Without consulting the Reaction Road Maps on pp. 818 – 819, suggest reagents to convert 3-buten-2-one into each of the following compounds. O O O O (a) (b) (c) (d) C6H5 864 Chapter 18 Enols, Enolates, and the Aldol Condensation O O OH O OH O (e) (f) (g) (h) OH 53. A number of highly conjugated organic compounds have found use as sunscreens. One of the more widely used is 4-methylbenzylidene camphor (4-MBC), whose structure is shown in the margin. This compound is effective in absorbing so-called UV-B radiation (with wavelengths between 280 and 320 nm, responsible for most sunburns). Suggest a simple synthesis of this compound using a crossed aldol condensation. 4-MBC 54. The distillate from sandalwood is one of the oldest and most highly valued fra- grances in perfumery. The natural oil is in short supply and, until recently, synthetic substitutes have been diffi cult to prepare. Polysantol® (margin) is the most successful of these substitutes. Its synthesis in 1984 involved the aldol condensation shown below. OH O O Polysantol® O KOH, H2O, H CH3OH (a) This synthetic step, although usable, had a signifi cant drawback that was responsible for its modest yield (60%). Identify this problem in detail. (b) A solution that avoids conventional aldol condensation was published in 2004. A bromo- ketone is prepared and, upon reaction with Mg metal, gives a magnesium enolate. This enolate then reacts with the aldehyde selectively to give a hydroxyketone that may be dehydrated to the desired product. Discuss how this approach solves the problem outlined in part (a). O O OϪ ϩMgBr Br2, CH3CO2H, CCl4 Mg, ether Br O O H HO 55. Write the expected major product of reaction of each of the carbonyl compounds (i) – (iii) with each of the reagents (a) – (h). O O DCH2CH2CH3 P (i) (ii) CH3CH CG (iii) CH B O (a) H2, Pd, CH3CH2OH (b) LiAlH4, (CH3CH2)2O 1 (c) Cl2, CCl4 (d) KCN, H , H2O (e) CH3Li, (CH3CH2)2O (f) (CH3CH2CH2CH2)2CuLi, THF (g) NH2NHCNH2, CH3CH2OH (h) (CH3CH2CH2CH2)2CuLi, followed B P by treatment with CH2 CHCH2Cl in THF O 56. Give the expected product(s) of each of the following reactions. 1. LDA, THF H O 2. BrCH2COCH3 B 1. LDA, THF B 2. CH3CH2Br, HMPA O (a) C6H5CCH2CH2CH3 (b) O H Problems Chapter 18 865 H3C CH3 O 1. (CH3)2CuLi, THF CH3 2. C6H5CH2Cl LDA, THF (c) (d) O (CH2)4Br 57. Write the products of each of the following reactions after aqueous work-up. O O O O B B B LDA, THF NaOH, H O ϩ P ϩ P 2 (a) C6H5CCH3 CH2 CHCC6H5 (b) (CH3)2C CHCH P O 1. (CH2 CH)2CuLi, THF 1. (CH3)2CuLi, THF O CH3 O B B 2. CH PCHCCH 2.