Chapter 15 Enols and Enolates （烯醇与烯醇负离子） 15.1 The acidity of the αhydrogens of carbonyl compounds: enolate ions 15.2 Keto and Enol tautomers 15.3 αHalogenation of aldehydes and ketones 15.4 The Haloform Reaction 15.5 The Aldol Condensation（羟醛缩合） 15.5.1 Mechanism for the aldol addition 15.5.2 The features of aldol addition 15.5.3 Mixed aldol condensation Claisen-Schmidt condensation

15.6 Nucleophlic addiotion to αβ-unsaturate aldehydes and ketones 15.6.1 1,2 addition and 1,4 addition 15.6.2 The Micheal reaction 15.6.3 Conjugate addition of organocopper reagents 15.7 Alkylation of enolate ions

The acidity of the αhydrogens of carbonyl compounds: enolate ions αHydrogens are acidic: βhydrogen αhydrogen Pka: 19-20 25 When a carbonyl compound loses an αproton, the anion called enolate is produced: A B Enolate is stabilized by resonance Enolates (烯醇负离子）

Lithium diisopropylamide p-πconjugation H - Na+H - Sodium hydride (氢化钠) Lithium diisopropylamide (二异丙基氨基锂) (LDA) Cyclohexanone Enolate ion(100%)

Table 15.1 Acidity Constants for Some Organic Compounds Compound pKa CH3COOH CH2(COCH3)2 CH3COCH2CO2CH3 CH2(CO2CH3)2 H2O CH3CH2OH CH3COCl CH3CHO CH3COCH3 CH3CN CH3CON(CH3)2 NH3 5 9 11 13 15.74 16 17 19 25 30 35 Table 15.1 Acidity Constants for Some Organic Compounds P361

Keto and Enol tautomerism (酮式与烯醇式互变异构） P353 Aldehydes and ketones containing α- hydrogen are in equilibrium with their enol isomers Tautomerization （互变异构） Keto and enol form are called tautomers Keto form Enol form Acetaldehyde (~100) (Extremely small) Acetone (>99%) (1.5×10-4) Cyclohexanone Keto Enol (98.8%) (1.2%) The bond of C=O is stronger than C=C

In β-dicarbonyl compounds, two carbonyl groups are separated by one－CH2－group 2,4-Pentanedinone （2,4-戊二酮） (24%) Enol form (76%) Resonance stabilization of the enol form

αHalogenation of aldehydes and ketones Aldehydes and ketones react with halogens by substitution of one of the αhydrogen P356 11.3 Features of the reaction: Acid –catalyzed Regiospecific Aldehydic hydrogen isn’t affected

Mechanism of αhalogenation of aldehydes and ketones Step 1 Acid-catalyzed formation of an enol Step 2 Reaction of the enol with halogen

The Haloform (卤仿)Reaction Ch.P349 A methyl ketone react with a halogen in the present of base, multiple halogenations occur at the carbon of -CH3 The dissociation of the trihalomethylketone in aqueous base, to produce carboxylate （羧酸盐）and the haloform CHI3 is yellow Precipitate (沉淀） The haloform reaction using I2 Indentification

15.5 The Aldol Condensation(羟醛缩合) 2 Molecules of aldehydes To form hydroxy aldehyde Dilute sodium hydroxide P366 11.8 Acetaldehyde 3-hydroxybutanal aldehyde + alcohol = aldol Aldol addition , aldol reaction or aldol condensetion 15.5.1 Mechanism for the aldol addition: Step 1 Base-catalyzed formation of enolate ion: Enolate ion

Step 2 The nucleophilic addition of enolate to carbonyl group: Step 3 The alkoxide ion abstracts a proton from water to form aldol:

15.5.2 The features of aldol additions: Carbon-carbon bond formation between theα-carbon atom of one aldehyde and the carbonyl group of another. 2. Dehydration of addition product The addition product ( aldol + OH－）is heated,hydration occurs to form α,β- unsaturated aldehyde: π-π conjugation

3. Reversible reaction. the equilibrium of aldol reation for ketones is unfavorable. Intra-molecular aldol condensation: Bicyclo[5.3.0]dec-1(7)- en-2-one(96%) （二环[5.3.0]-1-癸烯-2-酮） 1.6-Cyclodecanedione （1,6-环癸二酮）

15.5.3 Mixed aldol condensation 4. The product with two functional groups: Insect repellent 15.5.3 Mixed aldol condensation Only one of the reactant can form an enolate. One of the reactant is more reactive toward nuelophilic addition than other.

Claisen-Schmidt condensation Ketones react with aromatic aldehyde in the presence of base, to give mixed aldol condensation product: benzaldehyde acetone 4-Phenyl-3-buten-2-one （4-苯基-3-丁烯-2-酮）(70%) The enolate of ketone as a nucleophile attacks the carbonyl group of aromatic aldeyhyde. 2-Hydroxymethyl- 3-methylbutanal (3-甲基-2-羟甲基丁醛)

Claisen, Ludwig Born: Köln (Germany), 1851 Died: Godesberg near Bonn http://www.chemsoc.org/networks/ enc/fecs/Claisen.htm

Conjugate addition（共轭加成） 15.6 Conjugation addition to α,β- unsaturated aldehydes and ketones 15.6.1 1,2 addition and 1,4 addition The nucleophilic addition of α,β- unsaturated aldehydes or ketones may be in two way: 1,2-addition Direct addition （直接加成） The resonance structure: 1,4-addition Conjugate addition（共轭加成）

When the nucleophile is stronger base, General roles: When the nucleophile is stronger base, 1,2 addition is often observed: RMgX, RLi, LiAlH4. 2. When the nucleophile is weaker base, conjugate addition is observed: (95%)

15.6.2 The Micheal Reaction 3. 1,2 addition－Kinetic control 1,4 addtion－Thermodynamic control 1,2 addition product retains C=C bond, 1,4 addition product retains C=O bond. carbon-oxygen double bonds are more stable than carbon-carbon double bonds 15.6.2 The Micheal Reaction Ch.P413 Conjugate additions of enolate ions (or carbanions)to α,β-unsaturate carbonyl compounds－Micheal addition(迈克尔加成) or Micheal reaction. Enolate ions or carbanions: derived from β- dicarbonyl compounds.

Robinson annulation Intromecular aldol addition 2-Methyl-1,3- Cyclohexanedione （2-甲基-1,3-环己二酮） Methyl vinyl ketone （甲基乙烯基甲酮） 2-Methyl-2- (3’-oxobutyl)- 1,3-cyclohexanediol) [2-甲基2-(3’-氧代丁基)- 1,3-环己二酮](85%) (65%) Robinson annulation Intramolecular Aldol addition product Micheal addition + Intromecular aldol addition

Micheal addition of stabilized anions 3-oxocyclohexylacetic acid 2-Cyclohexenone （2－环己烯酮） Diethyl,3-oxocyclohexyl- malonate (3-氧代环己基丙二酸二乙酯) (90%) 3-oxocyclohexylacetic acid (3-氧代环己基乙酸) Problem:

Arthur Micheal Arthur Micheal(1853-1942) was http://books.nap.edu/books/0309022401/html/331.html#pagetop Arthur Micheal(1853-1942) was born to a wealthy family in Buffalo, New York. Although he received no formal university degree,he studied in Heidelberg,Berlin,and the École de Médecine,Paris.Returning to the United State, he became Professor of Chemistry at Tufts University and then at Harvard University (1912-1936).Perhaps his most impor- tant contribution to science was his instrumental role in bring the European model of gradual education to the United State. Arthur Micheal

United Kingdom University of Oxford Oxford, United Kingdom   Sir Robert Robinson United Kingdom University of Oxford Oxford, United Kingdom b. 1886 d. 1975 The Nobel Prize in Chemistry 1947 http://www.nobel.se/chemistry/laureates/1947/robinson-bio.html

Robinson received the 1947 Nobel Prize in Chemistry for his work on the synthesis of natural products, especially the alkaloids. His 1917 landmark one-step synthesis of tropinone from three simple precursors at room temperature in dilute aqueous solution was the forerunner of modern biomimetic syntheses. He did structural and synthetic work on other alkaloids (strychnine, morphine, brucine), on steroids (cholesterol), on wood dyes (brazilin, haematoxylin), and on the coloring matter of flowers (anthocyanins). In connection with steroid synthesis, he developed a general method for constructing a six-membered ring onto a ketone with an enolizable hydrogen (Robinson annulation). In the mid-1920s, Robinson introduced his electronic theory of organic reactions, and used it to rationalize orientation in electrophilic aromatic substitution. The curved arrow used by chemists to represent electron displacements was first used in this way by Robinson (1924). Robinson wrote over 500 papers and several books on natural products but in addition he was an avid chess player who wrote "The Art and Science of Chess: A Step-by-Step Approach". http://poohbah.cem.msu.edu/Portraits/PortraitsHH_Detail.asp? HH_LName=Robinson

15.6.3 Conjugate addition of organo- copper reagents Organocopper reagents (CuLiR2) undergo conjugate addition toα,β-unsaturated carbonyl compounds: 98% 2% Lithium dialkylcuprates adds predominantly in the less-hindered way to give the product with the alkyl groups trans to each other.

15.7 Alkylation of enolate ions Enolate ions derived from β- dicarbonyl compounds react with alkyl halide by SN2 mechanism : P362 11.6 2,4-Pentanedione （2,4-戊二酮） Iodo- methane 3-Methyl- 2,4-pentanedione Enolate ions of β- dicarbonyl compounds are more stables than aldehydes or ketones. p-π conjugation 2. Alkyl halide: CH3X, RCH2X,