chapter 15 enols and enolates (烯醇与烯醇负离子) 15.1 the acidity of the αhydrogens of...
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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