Chapter 13 α-Substitution and Condensations of Enols and Enolate

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1 Chapter 13 α-Substitution and Condensations of Enols and Enolate
Text 1: Chapter 22, p Text 2: 11,13章

2 13.1 Enols and enolate ions （烯醇和烯醇负离子）
Resonance-stabilized anion Keto form (酮式，Stable) Enol form (烯醇式，unstable) 烯醇阴离子，Enolate ion Keto form (酮式， Stable) Resonance-stabilized cation Enol form (烯醇式， unstable) Keto and enol tautomers (酮和烯醇互变异构体）

3 Keto and enol tautomers (酮和烯醇互变异构体）
Racemization ( 外消旋作用)

4 α-Substitution (α-取代)
α-halogenation α-alkylation

5 13.2 α-Halogenation of ketones and aldehydes
Base-promoted α-halogenation In many cases, base-promoted halogenation does not stop with replacement of just one hydrogen. The product (α-haloketone) is more reactive toward further halogenation than is the starting material. 碱促进的卤代很难停止在单取代产物。卤代酮更容易发生进一步卤代。

6 Reactivity of α-H under basic condition:
Why ? Less stable More stable

7 The haloform reaction 卤仿反应 The iodoform test (碘仿试验)
bromoform（溴仿） iodoform（碘仿） yellow precipitate (黄色沉淀) The haloform reaction 卤仿反应 The iodoform test (碘仿试验)

8 The mechanism of the haloform reaction

9 Iodoform can test the stuctures of –COCH3 or–CHOHCH3
碘仿反应可以用来检验分子中是否存在甲基酮或乙醇结构。

10 Acid-catalyzed α-halogenation
Acidic halogenation can selectively replace just one hydrongen or more than one if appropreate amounts of the halogen are used.ition. 酸性条件下的卤代反应可以控制在一取代，或通过加卤素的量而控制得多取代产物。

11 Reactivity of α-H under acidic condition:
More stable Less stable 解释：取代基的超共轭效应

12 How about aldehydes?

13 13.3 α-Bromogenation of carboxylic acids
The Hell-Volhard-Zelinsky (HVZ) reaction 赫尔-乌尔哈-泽林斯基反应

14 13.4 α-alkylation （α烷基化） 1. Alkylation of enolate ions (烯醇负离子的烷基化)
C- alkylation O- alkylation more common less common

15 Base: Strong base, but weak nucleophile
LDA (lithium diisopropylamide, 二异丙基氨基锂) C4H (i-C3H7)2NH -CHCO- ROH HOH pKa: > ~

16 LDA优先与位阻小的H反应。

17 2. Formation and alkylation of enamine :
The Stork reaction δ- δ- δ-

18 Alkylation烷基化 β-diketone, useful intermediate β-二酮，重要的合成中间体 Acylation酰基化

19 1,4-dicarbonyl compound 1，4-二羰基化合物 Problem: synthesis with two methods. Hint: LDA The Stork reaction

20 Condensation (缩合) The Aldol reaction (羟醛缩合反应)
The Perkin reaction (珀金反应) The ester condenstion (酯缩合反应) Synthesis using β-dicarboyl compounds Conjugate additions (共轭加成): the Michael reaction The Robinson annulation (罗宾逊增环反应)

21 13.5 The aldol condensation
羟醛缩合反应；醛醇缩合反应 1. Base-catalyzed aldol condensation base: NaOH, NaOR

22 Mechanism of the base-catalyzed aldol reaction
aldol product β-hydroxy aldehyde β-羟基醛

23 Base-catalyzed dehydration of aldol product
α,β-unsaturated aldehyde α, β-不饱和醛

24 2. Acid-catalyzed aldol condensation
How about the mechanism of the acid-catalyzed hydration of the aldol product?

25 Problems: Synthetic applications
1. CH3CH=CHCH2OH 2. CH3CH2CH2CH2OH

26 3. Crossed Aldol condensations 交错羟醛缩合反应

27

28 Aldol Cyclizations （经羟醛缩合环化作用）
To make 5- and 6-membered rings. Less hindered carbonyl group is attacked prefered. 位阻小的羰基优先被进攻。

29 Problems: predict products.

30 Problem: Show how each compound can be dissected into reagents joined by an aldol condensation, then decide wether the necessary alsol condensation is feasible.

31 Problem: Show how to accomplish the following syntheses.

32 13.6 The Claisen ester condensation (克莱森酯缩合)
pKa : ~24, less acidic than ketones and aldehydes (pKa~20)

33 Mechanism of ester condensation 酯缩合机理
β-keto ester（ β-酮酸酯） Base: NaOC2H5, not NaOCH3，or NaOH, Why?

34 乙酰乙酸乙酯 Self-condensation, 自缩合

35 The Dieckmann condensation
——a Claisen cyclization

36 Crossed Claisen condensations 交叉克莱森缩合

37 Crossed Claisen condensation between ketones and esters
β-diketone（ β-二酮） β-keto ester（ β-酮酸酯） diketo ester（ 二酮酸酯）

38 13.7 Synthesis using β-carbonyl compounds (β-二羰基化合物在合成中的应用)
丙二酸二乙酯 乙酰乙酸乙酯 pKa1: 15.7(H2O ) (EtOH)

39 The Malonic ester synthesis: ----- Synthesis of substituted acetic acids
mono- substituted acetic acids 单取代乙酸 Decarboxylation (脱羧)

40 Decarboxylation (脱羧)

41 di- substituted acetic acids
二取代乙酸

42 Temporary ester group Problem: target molecule:

43 The acetoacetic ester synthesis:
-----Synthesis of substituted acetones Temporary ester group

44 For example: The target molecule:

45

46 酮式分解 酸式分解

47

48

49 Why?

50 Problem: target molecule:

51 Problem: target molecule:

52 Summary Temporary ester group

53 13.8 Michael Addition: conjugate addition (麦克尔加成, 共轭加成）
Michael acceptor 麦克尔受体 Michael donor 麦克尔给体 1,2-addition 1,4-addition Michael addition

54 Michael donor 麦克尔给体 Michael acceptor 麦克尔受体

55 Products: 1,4-dicarbonyl compounds

56 Michael addition Aldol condensation

57 Problem: How to synthesize:

58 13.9 The Robinson annulations
罗宾逊增环反应 热力学控制产物 Mechanism ?? Michael ----aldol----dehydration 引入角甲基，在天然产物的合成中非常有用。 若以LDA为碱，则得到 动力学控制产物

59 The Knoevenagel condensation（克诺温格缩合）
cinnamic acid肉桂酸

60 The perkin reaction (珀金反应)
cinnamic acid肉桂酸

61 The benzoic condensation (安息香缩合，苯偶因缩合)

62 Assignment Text-1: , 64, 65, 66, 69, 70, 71, 75, 77 Text-2: 8, 9, 15