Chapter 23 Carbonyl Condensation Reactions SHORT ANSWER Exhibit 23-1 Draw the structure of the aldol self-condensation product for each of the following compounds. If a compound does not undergo aldol self-condensation, explain why it does not. 1. 2. Benzophenone does not undergo aldol self-condensation because it has no α-hydrogens. 3. 1
Carbonyl Condensation Reactions 4. 2,2-Dimethylpropanal does not undergo aldol self-condensation because it has no α-hydrogens. Exhibit 23-2 Consider the reaction below to answer the following question(s): 5. Refer to Exhibit 23-2. Write the complete stepwise mechanism for the reaction above. Show all intermediate structures and all electron flow with arrows. 6. Refer to Exhibit 23-2. This reaction is an example of: a. an intramolecular Claisen condensation b. an intramolecular aldol condensation c. a Robinson annulation d. a Michael reaction b 2
Chapter 23 7. Refer to Exhibit 23-2. The product of this reaction is: a. a β, γ-unsaturated aldehyde b. an α, β-unsaturated ketone c. an α, β-unsaturated aldehyde d. an enol c Exhibit 23-3 Consider the data below to answer the following question(s): The Friedlander Quinoline Synthesis, first reported in 1882, is the base-catalyzed condensation of 2-aminobenzaldehydes with ketones to form quinoline derivatives. 8. Refer to Exhibit 23-3. The first step of the Friedlander Quinoline Synthesis is a mixed aldol condensation. Write the complete stepwise mechanism for this reaction. 3
Carbonyl Condensation Reactions 9. Refer to Exhibit 23-3. The second step of the Friedlander Quinoline Synthesis is a nucleophilic addition of a primary amine to a ketone yielding an imine. Write the complete stepwise mechanism for this imine forming reaction. Show all electron flow with arrows and show all intermediate structures. 10. In the alkylation of cyclohexanone, better yields are obtained by first reacting cyclohexanone with an equivalent of lithium diisopropylamide in THF and then adding the alkyl halide, rather than mixing cyclohexanone, alkyl halide, and a catalytic amount of sodium ethoxide in ethanol. Explain this observation by pointing out what the problems with the second reaction conditions might be and how the first set of reaction conditions help alleviate the problems. When cyclohexanone is placed in a solution of sodium ethoxide in ethanol, the enolate is generated in small amounts in the presence of large amounts of ketone-ideal conditions for an aldol self-condensation. Consequently, aldol self-condensation competes with alkylation of the enolate, and product mixtures result. 4
Chapter 23 Conversely, when cyclohexanone is treated first with an equivalent of LDA, the enolate is rapidly generated and no ketone remains. Addition of alkyl halide then yields the desired alkylated product. Exhibit 23-4 Each of the following compounds can be prepared by a mixed aldol condensation reaction. Give the structures of the aldehyde and/or ketone precursors for each aldol product and formulate the reaction. 11. 12. 5
Carbonyl Condensation Reactions 13. Exhibit 23-5 Consider the reaction below to answer the following question(s). 14. Refer to Exhibit 23-5. Which carbonyl compound functions as the electrophile in this reaction? A 15. Refer to Exhibit 23-5. Draw the structure of the enolate ion that is generated during the course of this reaction. 16. Refer to Exhibit 23-5. This reaction is an example of: a. a mixed Claisen condensation. b. a Dieckman condensation. c. a Michael reaction. d. a mixed aldol reaction. 6
Chapter 23 d Exhibit 23-6 Draw the structure of the product you would expect to obtain by Claisen condensation of each of the following esters. If an ester does not undergo Claisen condensation, explain why it does not. 17. This ester does not undergo Claisen condensation, because it has no α-hydrogens and cannot undergo enolization. 18. 19. 7
Carbonyl Condensation Reactions Exhibit 23-7 Consider the reaction below to answer the following question(s): Acetoacetic ester can be prepared by the Claisen self-condensation reaction of ethyl acetate. 20. Refer to Exhibit 23-7. Write the complete stepwise mechanism for this reaction. Show all electron flow with arrows and draw all intermediate structures. 21. Ethyl acetate can be prepared from ethanol as the only organic starting material. Show all reagents and structures for all intermediates in this preparation. 8
Chapter 23 22. Give the structures of the ester precursors for the following Claisen condensation product and formulate the reaction. Exhibit 23-8 Consider the compound 2-methyl-2-carboethoxycyclopentanone, whose structure is shown below, to answer the following question(s). 23. Refer to Exhibit 23-8. Formulate a synthesis of 2-methyl-2-carboethoxycyclopentanone starting with acyclic precursors using a Dieckmann cyclization as a key carbon-carbon bond forming step. Show all reagents and all intermediate structures. 24. Refer to Exhibit 23-8. When 2-methyl-2-carboethoxycyclopentanone is treated with sodium ethoxide in ethanol solution followed by a mild aqueous acid work-up, 5-methyl-2- carboethoxycyclopentanone is isolated as the major product. This reaction proceeds by a reverse Claisen condensation mechanism followed by a recyclization. On the structures provided below, show electron flow with arrows in this interesting reaction. 9
Carbonyl Condensation Reactions 25. Oxaloacetic acid is an important intermediate in the biosynthesis of citric acid. Synthesize oxaloacetic acid using a mixed Claisen condensation as a key carbon-carbon bond forming reaction. 10
Chapter 23 Exhibit 23-9 Draw the structures of the precursors to each of the following Michael reaction products. Label the Michael donor and the Michael acceptor in each case and formulate the reaction. 26. 27. 11
Carbonyl Condensation Reactions 28. 29. 30. 12
Chapter 23 Exhibit 23-10 Consider the reaction below to answer the following question(s). The Stork enamine reaction is a variation on the Michael reaction which utilizes an enamine nucleophile. 31. Refer to Exhibit 23-10. On the structures above, draw arrows indicating electron flow in each step of this reaction. 13
Carbonyl Condensation Reactions 32. Refer to Exhibit 23-10. Draw the structures of the Ketone + Amine products of this reaction. 33. Refer to Exhibit 23-10. Show how you might use a Stork enamine reaction to prepare the following compound. 34. Provide the indicated starting material and intermediate in the synthetic sequence below involving a Dieckmann cyclization, followed by a Robinson annulation. 14
Chapter 23 15
Carbonyl Condensation Reactions 35. Show how you might use a Robinson annulation reaction to synthesize the following compound. Draw the structures of both reactants and the structure of the intermediate Michael addition product. Exhibit 23-11 Give the major organic product(s) for each of the following reactions or reaction sequences. 36. 16
Chapter 23 37. This question was omitted on the printed copy. This placeholder question is here to maintain the numbering system integrity between the printed copy and ExamView. Therefore, it has been marked "do not use on test" in ExamView's question information dialog. As a result, this placeholder question is automatically prevented from being chosen as a test question. Answer not provided. 38. 39. 17
Carbonyl Condensation Reactions 40. 41. 18
Chapter 23 42. A multistep synthesis can be used to prepare 3,3-dimethylindanone. From the list provided below, choose the best reagent(s) for each step in this sequence. Place the letter in the box over the reaction arrow. a. Cl 2, HOAc e. I 2, NaOH, H 2O b. 0.05 equiv. NaOEt, ethanol, heat f. H 2 SO 4, Δ c. 1. PhMgBr, ether g. 1. (Ph) 2 CuLi, ether 2. H 3 O + 2. H 3 O + d. 1. Mg, ether h. 1. LDA, THF 2. CO 2 2. (CH 3 ) 2 CHBr 3. H 3 O + i. SOCl 2, CHCl 3 step 1 = b; step 2 = g; step 3 = e; step 4 = i 19
Carbonyl Condensation Reactions 43. Consider the following molecular model. Atoms other than carbon and hydrogen are labeled. A synthesis is set-up based upon treatment of this compound with NaOH in ethanol. This synthesis aims to produce the following substance. What is wrong with this synthesis? Benzaldehyde and its derivatives, such as p-bromobenzaldehye shown, will not undergo Aldol reactions because they do not possess α-hydrogens. 44. Draw the products of the Claisen condensation of the following substance. Atoms other than carbon and hydrogen are labeled. 20
Chapter 23 MULTIPLE CHOICE 1. In carbonyl condensation reactions, a. the carbonyl acts as an electrophile. b. the carbonyl acts as a nucleophile. c. the carbonyl acts as both an electrophile and a nucleophile. d. the carbonyl acts as neither an electrophile nor a nucleophile. C 2. Which of the following does not characterize carbonyl condensation reactions? a. rare in biological systems b. form new carbon-to-carbon bonds c. enolate ion can act as a nucleophile d. an α-hydrogen required for an aldol condensation e. All of these characterize carbonyl condensation reactions. A 3. The product of an aldol condensation reaction is generally favored if a. an aldehyde is disubstituted. b. a ketone is disubstituted c. an aldehyde has no alpha substituents. d. substituents near the carbonyl are large. C 4. Which of the following will not undergo an aldol condensation reaction? a. butanal b. 2-methylbutanal c. 2, 2-dimethylbutanal d. 3, 3-dimethyl-2-butanone e. neither c nor d f. All will undergo an aldol condensation. C 5. For which of the following will the aldol reaction go the furthest toward completion? a. c. 21
Carbonyl Condensation Reactions b. d. D 6. Which of the following when reacted with butanal would be the most likely to produce a single aldol product? a. b. c. d. D 7. Experimentally to produce 2-ethylpentanal from pentanal, how should the reaction conditions be adjusted to ensure the alpha substitution product rather than the aldol product result or a mixture of the two products? a. use a catalytic amount of a relatively weak base b. add a full equivalent of a strong base c. add the base and alklylation agent simultaneously d. add the alkylating agent after the addition of the base e. warm the reaction mixture f. a and c g. b and d h. b, d, and e 22
Chapter 23 G 8. Which of the following constitutes a difference between a aldol and a Claisen condensation? a. basic conditions c. enolate ion formation b. tetrahedral intermediate d. protonation of the intermediate D 9. Which of the following will produce a five-membered ring via a Dieckmann cyclization? a. 1,6-diester b. 1,6-diketone c. 1,7-diester d. 1,7-diketone e. a and c f. b and d A 10. Which of the following would be classified as a Michael donor? a. propenamide c. 3-buten-2-one b. 1-nitropentane d. propylpropenoate B 11. What is the structure of the enamine produced in the reaction of cyclohexanone with piperidine? See structure below. a. c. b. d. D 12. Which of the following is the ester analog of an aldol condensation? a. Robinson annulation reaction b. Michael reaction c. Claisen condensation d. Dieckmann cyclization e. c and d f. All are analogs of an aldol condensation. E 23
Carbonyl Condensation Reactions 13. Which of the following can result in cyclization? a. aldol condensation b. Claisen condensation c. Robinson annulation d. All can result in cyclization. D 24