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 tautomers15.3 αHalogenation of aldehydes and ketones15.4 The Haloform Reaction15.5 The Aldol Condensation （羟醛缩合）15.5.1 Mechanism for the aldol addition15.5.2 The features of aldol addition15.5.3 Mixed aldol condensation Claisen-Schmidt condensation

15.6 Nucleophlic addiotion to αβ-unsaturate aldehydes and ketones15.6.1 1,2 addition and 1,4 addition15.6.2 The Micheal reaction15.6.3 Conjugate addition of organocopper reagents15.7 Alkylation of enolate ions

αHydrogens are acidic:

βhydrogen

When a carbonyl compoundloses an αproton, the anion called enolate is produced:

The acidity of the αhydrogens of carbonyl compounds: enolate ions

R C

O

C C

H Hαhydrogen

R C

O

C

H

> HC C H

Pka: 19-20 25

R C

O

C

HB

CO

RC C C

O

RA B

Enolates ( 烯醇负离子）Enolate is stabilizedby resonance

P358P358

H --

C CO

:BC C

OC C O

p-πconjugationp-πconjugation

Lithium diisopropylamide( 二异丙基氨基锂 )

(LDA)

Sodium hydride( 氢化钠 )

Li N Na+H -

OLi NTHF

O Li

+ NH

Cyclohexanone CyclohexanoneEnolate ion(100%)

Compound pKa

CH3COOHCH2(COCH3)2

CH3COCH2CO2CH3

CH2(CO2CH3)2

H2OCH3CH2OHCH3COClCH3CHO

CH3COCH3

CH3CNCH3CON(CH3)2

NH3

59

1113

15.7416161719253035

Table 15.1 Acidity Constants for Some Organic Compounds

P361P361

Keto and enol form are called tautomers

R2CCR'

H

OR2C CR'

OH

Aldehydes and ketones containing α-hydrogen are in equilibrium with their enol isomers

Tautomerization（互变异构）

Keto and Enol tautomerism ( 酮式与烯醇式互变异构）

CH3CH

OCH2 CH

OHKeto form Enol form

Acetaldehyde(~100) (Extremely small)

Acetone(>99%) (1.5×10-4)

O OHCyclohexanone Keto Enol

(98.8%) (1.2%)

CH3CCH3

OCH2 CCH3

OH

The bond of C=Ois stronger than C=C

The bond of C=Ois stronger than C=C

P353 P353

In β-dicarbonyl compounds, two carbonylgroups are separated by one － CH2 － group

CH3CCH2CCH3

O OCH3C CHCCH3

OH O

2,4-Pentanedinone（ 2,4- 戊二酮）

(24%)

Enol form(76%)

CCH

C

O OH

H3C CH3

hydrogen bond

CCH

C

O OH

H3C CH3

Resonance stabilization of the enol form

αHalogenation of aldehydes and ketones Aldehydes and ketones react with halogens by substitution of one of the αhydrogen

C

O

C

H

H

H

Br2, AlCl3Et2O, 0¡æ

C

O

C

H

H + HBr

BrFeatures of the reaction:Acid –catalyzedRegiospecificAldehydic hydrogen isn’t affected

CO

HH

+ Br2

CO

BrH

+ HBrCHCl3

(80%)

H3CC

O

CC

O

CH3

HH3C

C

O

CC

O

CH3

H

H3CC

CC

O

CH3

H

O

P35611.3P35611.3

Mechanism of αhalogenation of aldehydes and ketones

Step 1 Acid-catalyzed formation of an enol

C C

O

H

+ H:Bfast C C

OH

HB

slow C C

OH+ H:B

Step 2 Reaction of the enol with halogen

Br Br+ C C

O Hfast

C C

O

Br

+ HBr

Ch.P349Ch.P349The Haloform ( 卤仿 )Reaction

PhCCH3

O

+ X2NaOH PhCCH2X

ONaOH

X2PhCCHX2

ONaOH

X2PhCCX3

O

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

PhC

O

OH+ PhCCX3

O

O + HCX3

CHI3 is yellowPrecipitate

( 沉淀）

CHI3 is yellowPrecipitate

( 沉淀）

The haloform reaction using I2

Indentification CH3CO

CH3 CH

OH

CH3 CH

OH

15.5 The Aldol Condensation( 羟醛缩合 )2 Molecules of aldehydes

Dilute sodium hydroxideTo form hydroxy aldehyde

2 CH3CH

O10% NaOH, H2O

5 ¡æ

CH3CHCH2CH

OH O

Acetaldehyde 3-hydroxybutanalaldehyde + 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 ionHO + H CH2CH

O

HOH + CH2 CH

O

CH2 CH

O

P36611.8

P36611.8

Step 2 The nucleophilic addition of enolate to carbonyl group:

CH2 CH

O

CH3CH

O

+

CH3CH

O

CH2CH

O

CH3CH

O

CH

O

CH2

Step 3 The alkoxide ion abstracts a proton from water to form aldol:

CH3CH

O

CH2CH

O

HOH

CH3CHCH2CH

OH O

OH

π-πconjugation

π-πconjugation

15.5.2 The features of aldol additions:1. Carbon-carbon bond formation between theα-carbon atom of one aldehyde and the carbonyl group of another.

CH3CH2CH2C

H

O H CHCHO

CH2CH3

baseCH3CH2CH2CH CHCHO

CH2CH3OH2-Ethyl-3-hydroxy-hexanal

2. Dehydration of addition product The addition product ( aldol + OH －） isheated,hydration occurs to form α,β-unsaturated aldehyde:

HO + CH3CH CH C

OH

H

O

H-H2O CH3CH CH C

OH O

HCH3CH

OH

CH3CH-OH-

CH C

O

H

3. Reversible reaction. the equilibrium of aldol reation for ketones is unfavorable.

2 CH3CCH3

O

CH3C

OH

CH3

CH2CCH3

OBa(OH)2/ Soxhlet apparatusBa(OH)2/

80£¥

Intra-molecular aldol condensation:

K2CO3, H2O

reflux

OH

OO

O

O

1.6-Cyclodecanedione （ 1,6- 环癸二酮）

Bicyclo[5.3.0]dec-1(7)-en-2-one(96%)

（二环 [5.3.0]-1- 癸烯 -2- 酮）

CH3CH2CH2C H

O aldolreaction CH3CH2CH2CH CHC

CH2CH3

OH

2-Ethyl-3-hydroxy-hexanal

OH

H2Ni

CH3CH2CH2CHCHCH2OH

OH

CH2CH3

CH3CH2CH2CH2CHCH2OH

CH2CH32-Ethylhexanol

¡÷ CH3CH2CH2CH CCHO2-Ethyl-2-hexenal CH2CH3

H2,Ni

2-Ethyl-1,3-hexanediol

4. The product with two functional groups:

InsectrepellentInsectrepellent

15.5.3 Mixed aldol condensation

CH3CHO + CH3CH2CH2CHOTwo products of self-addition

+Two products of mixed addition

1. Only one of the reactant can form an enolate.2. One of the reactant is more reactive toward nuelophilic addition than other.

HCH

O

+ (CH3)2CHCH2CH

OK2CO3

H2O-Et2O

(CH3)2CHCHCH

O

CH2OH

Claisen-Schmidt condensation Ketones react with aromatic aldehyde in the presence of base, to give mixed aldol condensation product:

C6H5CH

O

CH3CCH3

OOH100¡æ

C6H5CH CHCCH3

O

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, LudwigBorn: Köln (Germany), 1851 Died: Godesberg near Bonn

(Germany), 1930http://www.chemsoc.org/networks/enc/fecs/Claisen.htm

15.6 Conjugation addition to α,β- unsaturated aldehydes and ketones

The nucleophilic addition of α,β- unsaturated aldehydes or ketones may be in two way:

CH2 CH C CH3

O

(a)

(a)

Nu:

+ H+

+ H+

CH2 CH C CH3

OH

Nu

(b)(b)CH2 CH2 C CH3

OH

Nu

CH2 CH2 C CH3

O

Nu

1,2-additionDirect addition

（直接加成）

1,4-additionConjugate addition （共轭加成）

The resonance structure:

H

C C C

O

C C C

O

C C C

O

C C C

O¦Ä

¦Ä ¦ÄC C C

O¦Ä

¦Ä ¦Ä

15.6.1 1,2 addition and 1,4 addition

General roles:1. When the nucleophile is stronger base, 1,2 addition is often observed: RMgX, RLi, LiAlH4.

CH3CH CHCCH3 + CH3MgX

O

CH3CH CHCCH3

OH

CH3

(2) H3O72%

(1) THF

2. When the nucleophile is weaker base, conjugate addition is observed:

C6H5CH CH CC6H5

O

KCN+EtOH-AcOH C6H5CH CH CC6H5

O

CN

C N , RNH2

EtOH-AcOH C6H5CH CH CC6H5

OHC6H5CHCH2CC6H5

CN

O

CN (95%)

3. 1,2 addition － Kinetic control 1,4 addtion － Thermodynamic control1,2 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 bonds15.6.2 The Micheal Reaction Conjugate additions of enolate ions (or carbanions)to α,β-unsaturate carbonylcompounds － Micheal addition( 迈克尔加成 )or Micheal reaction.

Enolate ions or carbanions: derived from β- dicarbonyl compounds.

Ch.P413Ch.P413

Micheal addition + Intromecular aldol

addition

Robinson annulation

Robinson annulation

O

O

CH3 + CH2 CHCCH3

OKOH

CH3OH, refluxO

O

OCH3

1)

2) H3O+ O

OCH3NaOH / ¡÷

OCH3

OHO

-H2O

2-Methyl-1,3-Cyclohexanedione

（ 2- 甲基 -1,3- 环己二酮）

Methylvinyl 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%)

IntramolecularAldol addition

product

Micheal addition of stabilized anionsO

+ CH2(COOC2H5)2C2H5ONaC2H5OH

O

CH(COOC2H5)2

1. KOH, EtOH-H2O

2. H+ 3. Heat

O

CH2COOH

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:Problem:CH3COCH2COCH3 + H2C CHCN

:B ?CH3COCH2COCH3 + H2C CHCN:B ?

http://books.nap.edu/books/0309022401/html/331.html#pagetop

Arthur Micheal(1853-1942) wasborn to a wealthy family in Buffalo,New York. Although he received no formal university degree,he studiedin Heidelberg,Berlin,and the Écolede 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

Sir Robert Robinson United Kingdom University of Oxford

Oxford, United Kingdom b. 1886 d. 1975

http://www.nobel.se/chemistry/laureates/1947/robinson-bio.html

 

The Nobel Prize in Chemistry 1947

Robinson received the 1947 Nobel Prize in Chemistry for his workon 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 papersand 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 reagentsOrganocopper reagents (CuLiR2) undergo conjugate addition toα,β-unsaturated carbonyl compounds:

98% 2%

O

CH3

(1) Ether

(2) H2O

O

CH3

CH3

O

CH3

CH3++ (CH3)2CuLi

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 ionsEnolate ions derived from β- dicarbonyl compounds react with alkyl halide by SN2 mechanism :

CH3CCH2CCH3

O O

+ CH3IK2CO3 CH3CCHCCH3

O O

CH32,4-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.

CCH

C

O OC

CHC

O O p-π conjugation2. Alkyl halide: CH3X, RCH2X,

P36211.6

P36211.6