Chapter 13 α-Substitution and Condensations of Enols and Enolate Text 1: Chapter 22, p 1003-1056 Text 2: 11,13章

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）

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

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

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。

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

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)

The mechanism of the haloform reaction

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。

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。

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

How about aldehydes?

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

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

Base: Strong base, but weak nucleophile LDA (lithium diisopropylamide, 二异丙基氨基锂) C4H10 (i-C3H7)2NH -CHCO- ROH HOH pKa: >40 40 20 16~18 15

LDA优先与位阻小的H反应。

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

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

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

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)

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

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

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

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

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

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

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。

Problems: predict products.

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

Problem: Show how to accomplish the following syntheses.

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

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

乙酰乙酸乙酯 Self-condensation, 自缩合

The Dieckmann condensation ——a Claisen cyclization

Crossed Claisen condensations 交叉克莱森缩合

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）

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: 13 11 15.7(H2O ) 16(EtOH)

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

Decarboxylation (脱羧)

di- substituted acetic acids 二取代乙酸

Temporary ester group Problem: target molecule:

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

For example: The target molecule:

酮式分解 酸式分解

Why?

Problem: target molecule:

Problem: target molecule:

Summary Temporary ester group

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

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

Products: 1,4-dicarbonyl compounds

Michael addition Aldol condensation

Problem: How to synthesize:

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

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

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

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

Assignment Text-1: 22-62, 64, 65, 66, 69, 70, 71, 75, 77 Text-2: 8, 9, 15