Post on 23-Dec-2015
19-19-11
Chapter 19Enolates and Enamines
19-19-22
Formation of an Enolate AnionFormation of an Enolate Anion
Enolate anions are formed by treating an aldehyde, ketone, or ester, which has at least one -hydrogen, with base,
• Most of the negative charge in an enolate anion is on oxygen.
CH3-C-HO
NaOH H C C-HO
HH C C-H
O Na+
HH2O+ +
An enolate anion
oxygen
Reactive carbon
19-19-33
Enolate AnionsEnolate Anions
Enolate anions are nucleophiles in SN2 reactions and carbonyl addition reactions,
An enolateanion
nucleophilic addition
A ketone A tetrahedral carbonyl addition intermediate
R R
R
O
+–R' R'
OO
RR
R
OR'
R'
An enolateanion
nucleophilicsubstitution
A 1° haloalkaneor sulfonate
R R
R
O
+–
R' Br
O
RR
RSN2R' + Br
SN2
Carbonyl addition
19-19-44
The Aldol ReactionThe Aldol Reaction
The most important reaction of enolate anions is nucleophilic addition to the carbonyl group of another molecule of the same or different compound.• Catalysis: Base catalysis is most common although
acid also works. Enolate anions only exist in base.
19-19-55
The Aldol ReactionThe Aldol Reaction
The product of an aldol reaction is:• a -hydroxyaldehyde.
• or a -hydroxyketone.
OCH3-C-CH3CH3-C-CH3
OCH2-C-CH3
OH Ba(OH)2Ba(OH)2 OH
CH3
CH3-C-CH2-C-CH3
CH3
CH3-C-CH2-C-CH3
O
Acetone
+
4-Hydroxy-4-methyl-2-pentanone(a -hydroxyketone)
+
Acetone
CH3-C-HO
CH2-C-HH O NaOH
CH3-CH-CH2-C-H
OH O+
AcetaldehydeAcetaldehyde 3-Hydroxybutanal(a -hydroxyaldehyde;
racemic)
acid
acid
19-19-66
MechanismMechanism: the Aldol Reaction, Base: the Aldol Reaction, Base
Base-catalyzed aldol reaction (good nucleophile)Step 1: Formation of a resonance-stabilized enolate
anion.
Step 2: Carbonyl addition gives a TCAI.
Step 3: Proton transfer to O- completes the aldol reaction.
CH3-C-H
O
CH2-C-HO
CH3-CH-CH2-C-HOO -
A tetrahedal carbonyladdition intermediate
+
CH2=C-H
O
CH2-C-HO
H-O-H+H-CH2-C-HO
+H-O
An enolate anionpKa 20(weaker acid)
pKa 15.7(stronger acid)
19-19-77
MechanismMechanism: the Aldol Reaction: : the Aldol Reaction: Acid catalysisAcid catalysis
Before showing the mechanism think about what is needed.• On one molecule the beta carbon must have
nucleophilic capabilities to supply an electron pair.• On the second molecule the carbonyl group must
function as an electrophile.• One or the other molecules must be sufficiently
reactive.
19-19-88
MechanismMechanism: the Aldol Reaction: : the Aldol Reaction: Acid catalysisAcid catalysis
Acid-catalyzed aldol reaction (good electrophile)• Step 1: Acid-catalyzed equilibration of keto and enol
forms.
• Step 2: Proton transfer from HA to the carbonyl group of a second molecule of aldehyde or ketone.
O OH
CH3-C-H CH2=C-HHA
CH3-C-H
O
H A
O
CH3-C-H
H
A+ +
Nucleophilic carbon
Reactive carbonyl
19-19-99
Mechanism: the Aldol Reaction: Mechanism: the Aldol Reaction: Acid catalysisAcid catalysis
• Step 3: Attack of the enol of one molecule on the protonated carbonyl group of the other molecule.
• Step 4: Proton transfer to A- completes the reaction.
OCH3-C-H
H
CH2=C-H
HO
:A- CH3-CH-CH2-C-H
OH O
H-A+ ++
(racemic)
This may look a bit strange but compare to
19-19-1010
The Aldol Products: Dehydration to alkeneThe Aldol Products: Dehydration to alkene
• Aldol products are very easily dehydrated to ,-unsaturated aldehydes or ketones.
• Aldol reactions are reversible and often little aldol is present at equilibrium.
• Keq for dehydration is generally large.
• If reaction conditions bring about dehydration, good yields of product can be obtained.
An -unsaturatedaldehyde
+
OOH O
CH3CHCH2CH CH3CH=CHCH H2 O
warm in eitheracid or base
19-19-1111
Crossed Aldol ReactionsCrossed Aldol Reactions
In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group.
CH3CCH3
O
HCHO NaOH
CH3CCH2CH2OHO
4-Hydroxy-2-butanone+
acid Non-acidic, no alpha hydrogens
19-19-1212
Crossed Aldol ReactionsCrossed Aldol Reactions
Crossed aldol reactions are most successful if• one of the reactants has no -hydrogen and, therefore,
cannot form an enolate anion,•
• One reactant has a more acidic hydrogen than the other (next slide)
• One reactant is an aldehyde which has a more reactive carbonyl group.
HCH
OCHO
O CHO CHO
Formaldehyde Benzaldehyde Furfural 2,2-Dimethylpropanal
19-19-1313
Crossed Aldol Reactions, Nitro activationCrossed Aldol Reactions, Nitro activation
Nitro groups can be introduced by way of an aldol reaction using a nitroalkane.
• Nitro groups can be reduced to 1° amines.
HO H-CH2-NO
OH-O-H CH2-N
O
OCH2=N
O
O
Resonance-stabilized anion
+
NitromethanepKa 10.2
(stronger acid)
WaterpKa 15.7
(weaker acid)
+
O
CH3NO2NaOH
HO CH2NO2
H2, NiCH2NH2HO
1-(Aminomethyl)- cyclohexanol
1-(Nitromethyl)-cyclohexanol
Nitro-methane
Cyclohex-anone
(aldol)+
19-19-1414
Intramolecular Aldol ReactionsIntramolecular Aldol Reactions
• Intramolecular aldol reactions are most successful for formation of five- and six-membered rings.
• Consider 2,7-octadione, which has two -carbons.
O
O
O
O
KOH
KOH
O
HO
O
OH
-H2O
-H2O
O
O2,7-Octanedione
(not formed)
(formed)
19-19-1515
SynthesisSynthesis: Retrosyntheic Analysis: Retrosyntheic Analysis
Two Patterns to look for
19-19-1616
SynthesisSynthesis: Retrosyntheic Analysis: Retrosyntheic Analysis
Recognitionpattern
Analysis
19-19-1717
SynthesisSynthesis: Retrosyntheic Analysis: Retrosyntheic Analysis
Example
Mixed aldol
BenzaldehydeNo alpha hydrogens
19-19-1818
Claisen Condensation, Claisen Condensation, EsterEster Substitution Substitution
Esters also form enolate anions which participate in nucleophilic acyl substitution.
• The product of a Claisen condensation is a -ketoester.
O
2CH3COEt1. EtO
- Na
+
2. H2O, HCl
O O
CH3CCH2COEt EtOHEthanolEthyl 3-oxobutanoate
(Ethyl acetoacetate)Ethyl ethanoate(Ethyl acetate)
+
CC C C OR
O O
A -ketoester
Recognition Element
19-19-1919
Claisen CondensationClaisen Condensation
• Claisen condensation of ethyl propanoate
OEt
O
OEt
O1. EtO
- Na
+
2. H2O, HClOEt
OO
EtOH+
Ethyl propanoate
Ethyl 2-methyl-3-oxopentanoate
(racemic)
+
Ethyl propanoate
Here the enolate part of one ester molecule has replaced the alkoxy group of the other ester molecule.
19-19-2020
MechanismMechanism: : Claisen CondensationClaisen Condensation
Step 1: Formation of an enolate anion.
Step 2: Attack of the enolate anion on a carbonyl carbon gives a TCAI.
EtO - CH2-COEtHO
EtOH CH2-COEtO O -
CH2=COEtpKa = 22
(weaker acid)pKa 15.9(stronger
acid)
Resonance-stabilized enolate anion
-++
CH3-C-OEt
O OCH2-COEt
O - O
OEtCH3-C-CH2-C-OEt+
A tetrahedral carbonyladdition intermediate
19-19-2121
Mechanism: Mechanism: Claisen CondensationClaisen CondensationStep 3: Collapse of the TCAI gives a -ketoester and an
alkoxide ion.
Step 4: An acid-base reaction drives the reaction to completion. This consumption of base must be anticipated.
EtOCH3-C-CH2-C-OEt
O OOCH3-C-CH2-C-OEt
O
OEt
+
EtO
H
CH3-C-CH-C-OEtO O
CH3-C-CH-C-OEt
OO
EtOH
pKa 15.9(weaker acid)
pKa 10.7(stronger acid)
++
19-19-2222
Intramolecular Claisen condensation: Intramolecular Claisen condensation: Dieckman CondensationDieckman Condensation
+
Diethyl hexanedioate(Diethyl adipate)
Ethyl 2-oxocyclo-pentanecarboxylate
1. EtO-
Na+
2. H2O, HCl
EtOH
OEt
OEtO
O
OEt
O O
Acidic
19-19-2323
Crossed Claisen CondsnsCrossed Claisen Condsns
Crossed Claisen condensations between two different esters, each with -hydrogens, give mixtures of products and are usually not useful.
But if one ester has no -hydrogens crossed Claisen is useful.
O
HCOEt EtOCOEtO
COEt
OO
EtOC-COEt
Diethyl ethanedioate (Diethyl oxalate)
Diethylcarbonate
Ethylformate
Ethyl benzoate
O
No -hydrogens
19-19-2424
Crossed Claisen CondsnsCrossed Claisen Condsns
• The ester with no -hydrogens is generally used in excess.
Ph OCH3
O
OCH3
O1. CH3O
- Na
+
2. H2O, HCl Ph OCH3
O O
Methylpropanoate
Methylbenzoate
+
Methyl 2-methyl-3-oxo-3-phenylpropanoate
(racemic)Used in excess
19-19-2525
Claisen condensations are a route to ketones via decarboxylation
OEt
O
OEt
OO
1. EtO-
Na+
2. H2O, HCl
3. NaOH, H2O, heat
OEt
OO
4. H2O, HCl
5. heatO
OH
O O
CO2
OH
OO
EtOH
EtOH
+
+
Reactions 1 & 2: Claisen condensation followed by acidification.
Reactions 3 & 4: Saponification and acidification
Reaction 5: Thermal decarboxylation.
+
Synthesis: Synthesis: Claisen CondensationClaisen Condensation
19-19-2626
Synthesis: Synthesis: Claisen CondensationClaisen Condensation
The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone.
R-CH2-COR'
O
R
O
CH2-C-OR' R-CH2-C-CH2-RO
2HOR' CO2++
severalsteps
+
from the esterfurnishing theenolate anion
from the esterfurnishing the carbonyl group
Note that in this Claisen (not crossed) the ketone is symmetric. Crossed Claisen can yield non symmetricketones.
19-19-2727
Synthesis: Synthesis: Retrosynthetic AnalysisRetrosynthetic Analysis
Site of acidic hydrogen, nucleophile
Site of substitution, electrophile
New bond
19-19-2828
Enamines (and imines, Schiff bases)Enamines (and imines, Schiff bases)
Recall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR2.
Primary amine
Secondary Amine
But secondary amines react to give enamines
19-19-2929
Formation of EnaminesFormation of Enamines
Again, enamines are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone.• The 2° amines most commonly used to prepare
enamines are pyrrolidine and morpholine.
Pyrrolidine Morpholine
N
O
N
HH
19-19-3030
Formation of EnaminesFormation of Enamines
• Examples:
+H
+
N
H
O
An enamine
-H2ON
OHN
+O
An enamine
N
O
OHN
O
N
O
H
H+
H+
-H2OH
+
19-19-3131
Enamines – Alkylation at Enamines – Alkylation at position. position.
The value of enamines is that the -carbon is nucleophilic.• Enamines undergo SN2 reactions with methyl and
1° haloalkanes, -haloketones, and -haloesters.• Treatment of the enamine with one equivalent of an
alkylating agent gives an iminium halide.
An iminiumbromide(racemic)
The morpholineenamine of
cyclohexanone
+
Br••N
O
BrSN2 N
O
3-Bromopropene(Allyl bromide)
19-19-3232
Compare mechanisms of acid catalyzed aldol and enamineCompare mechanisms of acid catalyzed aldol and enamine
OCH3-C-H
H
CH2=C-H
HO
:A- CH3-CH-CH2-C-H
OH O
H-A+ ++
(racemic)
An iminiumbromide(racemic)
The morpholineenamine of
cyclohexanone
+
Br••N
O
BrSN2 N
O
3-Bromopropene(Allyl bromide)
19-19-3333
Enamines - AlkylationEnamines - Alkylation
• Hydrolysis of the iminium halide gives an alkylated aldehyde or ketone.
Morpholinium chloride
2-Allylcyclo-hexanone
+HCl/ H2O
+Br-N
OO
+Cl-N
O
H H
Overall process is to render the alpha carbonss of ketone nucleophilic enough so that substitution reactions can occur.
19-19-3434
Enamines – Acylation at Enamines – Acylation at position position
• Enamines undergo acylation when treated with acid chlorides and acid anhydrides.
N
CH3CClO
Cl- N OHCl
O O
NH H
Cl-
+
Acetyl chloride
An iminiumchloride(racemic)
2-Acetylcyclo-hexanone(racemic)
++
+
H2O
O
Could this be made via a crossed Claisen followed by decarboxylation.
19-19-3535
Overall, Acetoacetic Ester SynthesisOverall, Acetoacetic Ester Synthesis
The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types:
CH3CCH2COEtO O
R'
CH3CCHRO
CH3CCH2RO
A disubstitutedacetone
A monosubstituted acetone
Ethyl acetoacetate(Acetoacetic ester)
Main points1.Acidic hydrogen providing a nucleophilic center.2.Carboxyl to be removed thermally3.Derived from a halide
RX
19-19-3636
Overall, Malonic Ester SynthesisOverall, Malonic Ester Synthesis
The strategy of a malonic ester (ME) synthesis is identical to that of an acetoacetic ester synthesis, except that the starting material is a -diester rather than a -ketoester.
O
EtOCCH2COEt
O
OR
RCHCOH
RCH2COHO
A disubstitutedacetic acid
A monosubstitutedacetic acid
Diethyl malonate(Malonic ester)
Main points1.Acidic hydrogen providing a nucleophilic center2.Carboxyl group removed by decarboxylation3.Introduced from alkyl halide
RX
19-19-3737
Malonic Ester SynthesisMalonic Ester Synthesis
Consider the synthesis of this target molecule:
MeO OH
O
5-Methoxypentanoic acid
These two carbonsare from diethyl malonate
Recognize as substituted acetic acid. Malonic Ester Synthesis
19-19-3838
Malonic Ester Synthesis StepsMalonic Ester Synthesis Steps
1. Treat malonic ester with an alkali metal alkoxide.
2. Alkylate with an alkyl halide.
COOEt
COOEtEtO- Na++
Na+
COOEt
COOEtEtOH
EthanolpKa 15.9
(weaker acid)
Sodium ethoxide
Sodium salt of diethyl malonate
+
Diethyl malonatepKa 13.3
(stronger acid)
MeO Br
Na+
COOEt
COOEt
COOEt
COOEtMeO Na+ Br-++
SN2
19-19-3939
Malonic Ester SynthesisMalonic Ester Synthesis
3. Saponify and acidify.
4. Decarboxylation.
2EtOH+COOEt
COOEtMeO
3. NaOH, H2O
4. HCl, H2OCOOH
COOHMeO
COOH
COOHMeO
heatMeO
COOH CO2+
5-Methoxypentanoic acid
19-19-4040
Michael Reaction, addition to Michael Reaction, addition to ,,-unsaturated carbonyl -unsaturated carbonyl
Michael reaction:Michael reaction: the nucleophilic addition of an enolate anion to an ,-unsaturated carbonyl compound.• Example:
COOEt
EtOOCO
EtO- Na
+
EtOHCOOEt
EtOOCO
+
3-Buten-2-one(Methyl vinyl
ketone)
Diethylpropanedioate
(Diethyl malonate)
Recognition Pattern: Nucleophile – C – C – CO (nitrile or nitro)
19-19-4141
CH2=CHCCH3
O
CH2=CHCOEtO
CH2=CHCNR2
O
CH3CCH2CCH3
O O
CH2=CHNO2
CH2=CHC N
CH2=CHCHO
CH3CCH2COEtO O
O
EtOCCH2COEtO
NCH3C=CH2
CH3CCH2CNO
NH3, RNH2, R2NH
These Types of -Unsaturated Compounds are Nucleophile Acceptors in Michael Reactions
These Types of CompoundsProvide Effective Nucleophilesfor Michael Reactions
-Ketoester
-Diketone
-Diester
Enamine
-Ketonitrile
Aldehyde
Ketone
Ester
Amide
Nitrile
Nitro compound
Amine
Michael ReactionMichael Reaction
19-19-4242
Michael Reaction in baseMichael Reaction in base
Example:
• The double bond of an ,-unsaturated carbonyl compound is activated for attack by nucleophile.
COOEt
OO
EtO- Na
+
EtOH
O
COOEt
O
2-CyclohexenoneEthyl 3-oxobutanoate(Ethyl acetoacetate)
+
O O
+
O+
More positive carbon
19-19-4343
Mechanism: Mechanism: Michael ReactionMichael Reaction
Mechanism1: Set up of nucleophile; Proton transfer to the base.
2: Addition of Nu:- to the carbon of the ,-unsaturated carbonyl compound.
Base+ +Nu-H :B- Nu:- H-B
+ C C C
O
CCNu C
O
CCNu C
O
Resonance-stabilized enolate anion
Nu
19-19-4444
Michael ReactionMichael Reaction
Step 3: Proton transfer to HB gives an enol.
Step 4: Tautomerism of the less stable enol form to the more stable keto form.
CCNu CO
H-B+ CCNu C
O-H
BB
An enol(a product of 1,4-addition)
1
4 3 2+
CCNuO-H
C CCNu CH O
More stable keto formLess stable enol form
19-19-4545
Michael Reaction, Cautions 1,4 vs 1,2Michael Reaction, Cautions 1,4 vs 1,2
• Resonance-stabilized enolate anions and enamines are weak bases, react slowly with ,-unsaturated carbonyl compounds, and give 1,4-addition products.
• Organolithium and Grignard reagents, on the other hand, are strong bases, add rapidly to carbonyl groups, and given primarily 1,2-addition.
PhLi
O O-Li
+Ph
H2OHCl
OHPh
4-Methyl-2-phenyl-3-penten-2-ol
4-Methyl-3-penten-2-one
+
Phenyl-lithium
19-19-4646
Michael Reaction: Thermodynamic vs KineticMichael Reaction: Thermodynamic vs Kinetic
Addition of the nucleophile is irrevesible for strongly basic carbon nucleophiles (kinetic product)
COCC
Nu
ROHC C C
OH
Nu
Nu:
RO-
C C CO
ROHCCNu C
OC C
H
Nu CO
RO-
-
- +
-
+
+
fast
slow
1,2-Addition(less stable product)
1,4-Addition(more stable product)
19-19-4747
Micheal-Aldol CombinationMicheal-Aldol Combination
+
Ethyl 2-oxocyclohex- anecarboxylate
3-Buten-2-one(Methyl vinyl
ketone)
1. NaOEt, EtOH
(Michael reaction)
2. NaOEt, EtOH
(Aldol reaction)
COOEt
O O
COOEt
OO O
COOEt
Carbanion siteunsaturated
Dieckman
19-19-4848
Retrosynthesis of 2,6-HeptadioneRetrosynthesis of 2,6-Heptadione
O O O O
COOH
O
COOEt
O
this carbonlost by decarboxylation
this bond formedin a Michael reaction
Ethyl acetoacetate
Methyl vinyl ketone
these three carbons fromacetoacetic ester
+
Recognize as substituted acetone, aae synthesis
Recognize as Nucleophile – C – C – COMichael
19-19-4949
Michael ReactionsMichael Reactions
• Enamines also participate in Michael reactions.
N 1. CH2=CHCN
2. H2O, HCl
OCN
NHHCl-
+ +
Pyrrolidine enamineof cyclohexanone
(racemic)
19-19-5050
Gilman Reagents vs other organometallicsGilman Reagents vs other organometallics
Gilman reagents undergo conjugate addition to ,-unsaturated aldehydes and ketones in a reaction closely related to the Michael reaction.
• Gilman reagents are unique among organometallic compounds in that they give almost exclusively 1,4-addition.
• Other organometallic compounds, including Grignard reagents, add to the carbonyl carbon by 1,2-addition.
O
1. (CH3)2CuLi, ether, -78°C
2. H2O, HCl
O
3-Methyl-2-cyclohexenone
3,3-Dimethyl-cyclohexanone
CH3 CH3
CH3
19-19-5151
Crossed Enolate Reactions using LDACrossed Enolate Reactions using LDA
With a strong enough base, enolate anion formation can be driven to completion.
The base most commonly used for this purpose is lithium diisopropylamide , LDA.
LDA is prepared by dissolving diisopropylamine in THF and treating the solution with butyl lithium.
[(CH3)2CH]2N-Li+
Lithium diisopropylamde(weaker base)
[(CH3)2CH]2NH + CH3(CH2)3Li + CH3(CH2)2CH3
ButanepKa 50
(weaker acid)
Butyllithium(stronger base)
Diisopropylamine(pKa 40
(stronger acid)
LDA
19-19-5252
Crossed Enolate Reactions using LDACrossed Enolate Reactions using LDA
The crossed aldol reaction between acetone and an aldehyde can be carried out successfully by adding acetone to one equivalent of LDA to completely preform its enolate anion, which is then treated with the aldehyde.
O LDA
-78°C
O-Li+ C6H5CH2CHO
1.
2. H2O
OOHC6H5
4-Hydroxy-5-phenyl-2-pentanone(racemic)
Acetone Lithiumenolate
19-19-5353
Examples using LDAExamples using LDA
Crossed aldol
Michael
Alkylation
Acylation
19-19-5454
Crossed Enolate Reactions using LDACrossed Enolate Reactions using LDA
Question: For ketones with nonequivalent -hydrogens, can we selectively utilize the nonequivalent sites?
Answer: A high degree of regioselectivity exists and it depends on experimental conditions.
19-19-5555
Crossed Enolate Reactions using LDACrossed Enolate Reactions using LDA
• When 2-methylcyclohexanone is treated with a slight excess of LDA, the enolate is almost entirely the less substituted enolate anion.
• When 2-methylcyclohexanone is treated with LDA where the ketone is in slight excess, the product is richer in the more substituted enolate.
O
+ LDA0°C
O-Li+ O-Li+
[(CH3)2CH]2NH
(racemic) 10% 90%
++
slight excess of the ketone
O
+ LDA0°C
O-Li+ O-Li+
[(CH3)2CH]2NH
(racemic) 99% 1%
++
slight excess of base
19-19-5656
Crossed Enolate Reactions using LDACrossed Enolate Reactions using LDA
The most important factor determining the composition of the enolate anion mixture is whether the reaction is under kinetic (rate) or thermodynamic (equilibrium) control.
Thermodynamic Control: Experimental conditions that permit establishment of equilibrium between two or more products of a reaction.The composition of the mixture is determined by the relative stabilities of the products.
19-19-5757
Crossed Enolate Reactions using LDACrossed Enolate Reactions using LDA
• Equilibrium among enolate anions is established when the ketone is in slight excess, a condition under which it is possible for proton-transfer reactions to occur between an enolate and an -hydrogen of an unreacted ketone. Thus, equilibrium is established between alternative enolate anions.
OH
+CH3
O Li+ O-Li+ O
+
(racemic)More stableenolate anion
(racemic) Less stableenolate anion
(racemic)
19-19-5858
Crossed Enolate Reactions using LDACrossed Enolate Reactions using LDA
Kinetic control: Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each product. First formed dominates.• In the case of enolate anion formation, kinetic control
refers to the relative rate of removal of alternative -hydrogens.
• With the use of a bulky base, the less hindered hydrogen is removed more rapidly, and the major product is the less substituted enolate anion.
• No equilibrium among alternative structures is set up.
19-19-5959
ExampleExample
1. 1.01 mol LDA, kinetic control
1. 0.99 mol LDA, thermodynamic control