Chapter 19 Enolates and Enamines

19-1

Formation of an Enolate Anion

Enolate

anions are formed by treating an aldehyde, ketone, or ester, which has at least one a-hydrogen, with base,
O CH3 -C- H + N aOH O Na + O H C C-H + H2 O H C C-H H H An e nolate anion

Most of the negative charge in an enolate anion is on oxygen. oxygen Reactive carbon
19-2

Enolate Anions
Enolate

anions are nucleophiles in SN2 reactions and carbonyl addition reactions,

O R
R
+

SN2

R'

Br

nucleophilic substitution SN 2

O R R R R' + Br

R An enolate anion

A 1 haloalkane or sulfonate

Carbonyl addition
R

O
R +

O R'

nucleophilic addition

O R

R' R'

R'

R An enolate anion

R R A tetrahedral carbonyl addition intermediate

A ketone

19-3

The 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.

19-4

The Aldol Reaction

The

product of an aldol reaction is:

acid

a -hydroxyaldehyde.

OH O O H O a N aOH + CH2 - C-H CH3 - C-H CH3 - CH- CH 2 -C- H Acetaldehyde Acetaldehyde 3-Hydroxybutanal (a -h ydroxyaldehyde; racemic )

or a -hydroxyketone.
O H O CH3 -C-CH3 + CH2 -C-CH3 Acetone Acetone Ba(OH) 2

acid
OH O a CH3 -C-CH2 -C-CH3 CH3 4-Hydroxy-4-methyl-2-pentanone (a -hydroxyketone)
19-5

Mechanism: the Aldol Reaction, Base

Base-catalyzed

aldol reaction (good nucleophile)

O CH2 - C-H O CH2 = C- H

Step 1: Formation of a resonance-stabilized enolate anion.

H- O O + H- CH2 - C-H p Ka 20 (we ak er acid) H- O-H + pK a 15.7 (s tronger acid) An e nolate anion

Step 2: Carbonyl addition gives a TCAI.

O CH3 -C-H + O CH2 -C-H O OCH3 -CH-CH2 -C-H A tetrahedal carbonyl addition intermediate

Step 3: Proton transfer to O- completes the aldol reaction.

19-6

Mechanism: the Aldol Reaction: Acid 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.

19-7

Mechanism: the Aldol Reaction: Acid catalysis

Acid-catalyzed

aldol reaction (good electrophile)

Step 1: Acid-catalyzed equilibration of keto and enol forms. O OH Nucleophilic HA carbon CH 3 - C-H CH 2 = C- H Step 2: Proton transfer from HA to the carbonyl group of a second molecule of aldehyde or ketone.
O CH3 -C-H + H A O CH3 -C-H + A H

Reactive carbonyl

19-8

Mechanism: the Aldol Reaction: Acid 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.
O O CH3 -C-H + CH2 =C-H + :AH H O CH3 -CH-CH2 -C-H + H-A (racemic) OH

This may look a bit strange but compare to

19-9

The Aldol Products: Dehydration to alkene

Aldol products are very easily dehydrated to a,unsaturated aldehydes or ketones.
OH O CH3 CHCH 2 CH warm in either acid or bas e O a CH3 CH= CH CH + H2 O An a nsaturated -u aldehyde

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.

19-10

Crossed Aldol Reactions

In

a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group.
O O NaOH CH3 CCH3 + HCH O CH3 CCH2 CH2 OH 4-Hyd roxy-2-b utanone

acid

Nonacidic, no alpha hydrogens

19-11

Crossed Aldol Reactions

Crossed

aldol reactions are most successful if

one of the reactants has no a-hydrogen and, therefore, cannot form an enolate anion, O CHO CHO
HCH Formald ehyde Benzaldehyde CHO O Furfural 2,2-Dimethylprop anal

One reactant has a more acidic hydrogen than the other (next slide)
One reactant is an aldehyde which has a more reactive carbonyl group.

19-12

Crossed Aldol Reactions, Nitro activation

Nitro

groups can be introduced by way of an aldol reaction using a nitroalkane.

O HO + H-CH2 -N O N itromethane pK a 10.2 (stronger acid) Water p Ka 15.7 (w eaker acid) H-O-H + CH2 -N O O CH2 =N O O

Resonance-stabilized an ion

Nitro groups can be reduced to 1 amines.

O + CH3 NO2 Cyclohexan on e N itrometh ane NaOH
( aldol)

HO

CH2 NO2 H2 , Ni

HO

CH2 NH2

1-(N itromethyl)cyclohexanol

1-(A min omethyl)cycloh exanol

19-13

Intramolecular Aldol Reactions

Intramolecular aldol reactions are most successful for formation of five- and six-membered rings. Consider 2,7-octadione, which has two a-carbons.
a O a O KOH HO O a O KOH OH (n ot formed)
19-14

O -H2 O (formed) O -H2 O

O 2,7-Octanedione O a

Synthesis: Retrosyntheic Analysis

Two Patterns to look for

19-15

Synthesis: Retrosyntheic Analysis

Recognition pattern

Analysis

19-16

Synthesis: Retrosyntheic Analysis

Example

Mixed aldol

Benzaldehyde No alpha hydrogens

19-17

Claisen Condensation, Ester Substitution

Esters

also form enolate anions which participate in nucleophilic acyl substitution.

O 2 CH3 COEt Ethyl ethan oate (Ethyl acetate) 1 . EtO Na
+

+ EtOH CH3 CCH2 COEt 2 . H2 O, HCl Eth yl 3-oxobutanoate Ethanol (Ethyl acetoacetate)

The product of a Claisen condensation is a ketoester. O O a Recognition C C C C OR Element

A -ketoest er
19-18

Claisen Condensation
Claisen condensation of ethyl propanoate
O OEt Ethyl propan oate
+

O OEt Ethyl propan oate

1 . Et O Na

O OEt + EtOH

2 . H2 O, HCl

Eth yl 2-methyl-3oxopen tan oate (racemic)

Here the enolate part of one ester molecule has replaced the alkoxy group of the other ester molecule.

19-19

Mechanism: Claisen Condensation

Step 1: Formation of an enolate anion.
Et O O + H CH -COEt 2 pK a = 22 (w eaker acid) OO EtOH + CH2 -COEt CH2 =COEt pK a 15.9 Res on ance-s tab ilized enolate anion (stronger acid )

Step 2: Attack of the enolate anion on a carbonyl carbon gives a TCAI.

O CH 3 -C-OEt + O CH2 -COEt O
-

CH3 -C-CH2 -C-OEt OEt A tetrahedral carbonyl add ition in termediate

19-20

Mechanism: Claisen Condensation

Step 3: Collapse of the TCAI gives a -ketoester and an alkoxide ion.
O O CH3 -C-CH2 -C-OEt OEt O O CH3 -C-CH2 -C-OEt + Et O

Step 4: An acid-base reaction drives the reaction to completion. This consumption of base must be anticipated.
O O Et O + CH3 -C-CH-C-OEt H pK a 10.7 (stron ger acid) O O CH3 -C-CH-C-OEt + Et OH p Ka 15.9 (w eaker acid)
19-21

Intramolecular Claisen condensation: Dieckman Condensation

O Et O OEt O Die thyl h exanedioate (Dieth yl adipate)

1 . Et O Na

2 . H2 O, HCl O O OEt Ethyl 2-oxocyclopentanecarboxylate

+

Et OH

Acidic

19-22

Crossed Claisen Condsns

Crossed

Claisen condensations between two different esters, each with a-hydrogens, give mixtures of products and are usually not useful. But if one ester has no a-hydrogens crossed Claisen is useful.
O HCOEt Eth yl formate O EtOCOEt Dieth yl carbonate OO EtOC-COEt Diethyl ethanedioate (Diethyl oxalate) O COEt Ethyl ben zoate

No a-hydrogens
19-23

Crossed Claisen Condsns

The ester with no a-hydrogens is generally used in excess.
O Ph OCH3 + O 1 . CH3 O Na OCH3 2 . H2 O, HCl
+

O Ph

O OCH3

Meth yl benzoate

Meth yl p ropan oate

Methyl 2-meth yl-3-oxo3-ph enylprop anoate (racemic)

Used in excess

19-24

Synthesis: Claisen Condensation

Claisen

condensations are a route to ketones via decarboxylation

Reactions 1 & 2: Claise n condens ation followed by acidification. O O O + 1 . Et O Na OEt 2 . H O, HCl OEt + Et OH
2

Reactions 3 & 4: Saponification and acidification O O OEt 3 . Na OH, H2 O, he a t 4 . H2 O, HCl O O OH + Et OH

Reaction 5: Thermal de carboxylation. O O OH 5 . he at O

+ CO 2

19-25

Synthesis: Claisen Condensation

The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone.
from the ester furnish ing the carbonyl group s everal O O steps + CH2 -C-OR' R-CH2 -C OR' R from the ester furnish ing the enolate anion

O R-CH2 -C-CH2 -R + 2 HOR' + CO2

Note that in this Claisen (not crossed) the ketone is symmetric. Crossed Claisen can yield non symmetric ketones.
19-26

Synthesis: Retrosynthetic Analysis

Site of acidic Site of hydrogen, substitution, nucleophile electrophile

New bond

19-27

Enamines (and imines, Schiff bases)

Recall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR2. Primary amine

But secondary amines react to give enamines

Secondary Amine

19-28

Formation 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.
O N H Pyrrolidine N H Morpholine

19-29

Formation of Enamines
Examples:
O + N H O O + N H O H
+ + +

OH

H -H2 O

N An enamine O

OH

H -H2 O

An en amin e
19-30

Enamines Alkylation at a position.

The

value of enamines is that the -carbon is nucleophilic.

Enamines undergo SN2 reactions with methyl and 1 haloalkanes, a-haloketones, and a-haloesters. Treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide.
O

O SN2 N Br

N
+

Br

The morph olin e en amin e of cyclohexan on e

3-Bromopropene (Allyl bromide)

An iminiu m bromid e (racemic)

19-31

Compare mechanisms of acid catalyzed aldol and enamine

O O CH3 -C-H + CH2 =C-H + :A-

O CH3 -CH-CH2 -C-H + H-A (racemic)

O SN2 N Br

OH

N
+

Br

The morph olin e en amin e of cyclohexan on e

3-Bromopropene (Allyl bromide)

An iminiu m bromid e (racemic)

19-32

Enamines - Alkylation
Hydrolysis of the iminium halide gives an alkylated aldehyde or ketone.
O N Br+

O HCl/ H 2 O 2-Allylcyclohexanone
+

O N ClH H Morpholinium chloride

+

Overall process is to render the alpha carbonss of ketone nucleophilic enough so that substitution reactions can occur.

19-33

Enamines Acylation at a position

Enamines undergo acylation when treated with acid chlorides and acid anhydrides.
N O + CH3 CCl Acetyl ch loride
+

Could this be made via a crossed Claisen followed by decarboxylation.

Cl N
-

O HCl H2 O

O
+ +

N ClH H

A n iminium chlorid e (racemic)

2-Acetylcyclohexan on e (racemic)
19-34

Overall, Acetoacetic Ester Synthesis

The

acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types:
O O RX CH3 CCH2 COEt Ethyl acetoacetate (Acetoacetic ester) O CH3 CCH2 R A mon os ubs tituted acetone O CH3 CCHR R'

A dis ubs tituted acetone

Main points 1. Acidic hydrogen providing a nucleophilic center. 2. Carboxyl to be removed thermally 3. Derived from a halide
19-35

Overall, 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 O

RX

O RCH2 COH A mon os ubs tituted acetic acid R O RCHCOH A dis ubs tituted acetic acid

EtOCCH2 COEt Diethyl malonate (Malonic ester)

Main points 1. Acidic hydrogen providing a nucleophilic center 2. Carboxyl group removed by decarboxylation 3. Introduced from alkyl halide
19-36

Malonic Ester Synthesis

Consider

the synthesis of this target molecule:

O These tw o carbons are from diethyl malon ate

MeO OH 5-Methoxyp entanoic acid

Recognize as substituted acetic acid. Malonic Ester Synthesis

19-37

Malonic Ester Synthesis Steps

1. Treat malonic ester with an alkali metal alkoxide.
COOEt
+

Na EtO Na
+

COOEt
+

COOEt D ieth yl malon ate Sodiu m ethoxide pK a 13.3 (s tronger acid)

COOEt Sodiu m s alt of dieth yl malonate

EtOH

Eth anol p Ka 15.9 (w eaker acid)

2. Alkylate with an alkyl halide.

Na MeO Br
+
+

COOEt

SN2

MeO

COOEt

COOEt + + Na Br COOEt

19-38

Malonic Ester Synthesis

3. Saponify and acidify.
MeO COOEt 3 . NaOH, H2 O 4 . HCl, H2 O COOEt MeO COOH + 2 EtOH COOH

4. Decarboxylation.
MeO COOH heat COOH MeO 5-Methoxypentanoic acid COOH + CO2

19-39

Michael Reaction, addition to a,-unsaturated carbonyl

Michael

reaction: the nucleophilic addition of an enolate anion to an a,-unsaturated carbonyl compound.

Example:
EtOOC O + Et O Na EtOH
+

O EtOOC COOEt

COOEt Dieth yl 3-Buten-2-one prop anedioate (Methyl vinyl (D iethyl malonate) k eton e)

Recognition Pattern: Nucleophile C C CO (nitrile or nitro)

19-40

Michael Reaction
Thes e Types of a -Uns aturate d Compounds are Nu cle ophile Acce ptors in Michael Reactions O CH2 = CHCH O CH2 = CHCCH 3 O CH2 = CHCOEt O CH2 = CHCNR 2 CH 2 = CHC N CH2 = CHN O2 Aldehyde Ketone Ester Amide Nitrile Nitro compou nd N CH3 C= CH2 Enamine Thes e Types of Compounds Provide Effective Nucle ophiles for Michael Re actions O O CH3 CCH 2 CCH 3 O O CH3 CCH 2 COEt O CH3 CCH 2 CN O O Et OCCH2 COEt -Dik etone -Ketoes ter -Ketonitrile -Diester

N H3 , RNH2 , R2 NH Amine

19-41

Michael Reaction in base

Example: O
+ COOEt Eth yl 3-oxobutanoate (Ethyl acetoacetate) O EtO Na EtOH 2-Cyclohexen on e COOEt
+

O O

The double bond of an a,-unsaturated carbonyl compound is activated for attack by nucleophile.
O O + + O

More positive carbon

19-42

Mechanism: Michael Reaction

Mechanism

1: Set up of nucleophile; Proton transfer to the base.

Nu-H + :BBase Nu:- + H- B

2: Addition of Nu:- to the carbon of the a,-unsaturated carbonyl compound.

O Nu
+

O Nu C C C Nu C C

O C

C C C

Resonance-stabilized enolate anion

19-43

Michael Reaction
Step 3: Proton transfer to HB gives an enol.
1

O Nu C C C

O-H
+
4 3

H-B

Nu C C C

A n enol (a p rodu ct of 1,4-ad dition)

Step 4: Tautomerism of the less stable enol form to the more stable keto form. H O O-H Nu C C C Nu C C C
Less stable en ol form More stab le keto form
19-44

Michael Reaction, Cautions 1,4 vs 1,2

Resonance-stabilized enolate anions and enamines are weak bases, react slowly with a,-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 1,2addition.
O PhLi + Phenyl4-Methyl-3lithiu m pen ten-2-one Ph O Li
+

H2 O HCl 4-Methyl-2-phen yl3-penten -2-ol

Ph OH

19-45

Michael Reaction: Thermodynamic vs Kinetic

O C C C fast O Nu: + C C C s low O Nu C C C
-

ROH

OH
-

Nu

+ RO C C C Nu 1,2-Add ition (les s stab le prod uct)

ROH

O Nu C C C

RO

1,4-Add ition (more stable p rodu ct)

Addition of the nucleophile is irrevesible for strongly basic carbon nucleophiles (kinetic product)

19-46

Micheal-Aldol Combination
a unsaturated Carbanion site
O + COOEt Ethyl 2-oxocyclohexanecarboxylate (Michael reaction) 3-Buten-2-one (Methyl vinyl k etone) O COOEt O 2 . Na OEt , Et OH (Aldol reaction) COOEt O O 1 . Na OEt , Et OH

Dieckman
19-47

Retrosynthesis of 2,6-Heptadione
thes e three carbons from acetoacetic ester O O this b on d formed in a Mich ael reaction O COOH O O + this carb on los t by decarboxylation COOEt Eth yl acetoacetate Meth yl vinyl k eton e O

Recognize as substituted acetone, aae synthesis Recognize as Nucleophile C C CO Michael

19-48

Michael Reactions
Enamines also participate in Michael reactions.
O N 1 . CH2 =CHCN 2 . H2 O, HCl Pyrrolidin e enamine of cycloh exanone (racemic) CN + H + N ClH

19-49

Gilman Reagents vs other organometallics

Gilman

reagents undergo conjugate addition to a,-unsaturated aldehydes and ketones in a reaction closely related to the Michael reaction.
O 1 . ( CH3 ) 2 CuLi, eth er, -78C CH3 3-Methyl-2cyclohexenone 2 . H2 O, HCl O CH3 CH3 3,3-D imethylcyclohexanone

Gilman reagents are unique among organometallic compounds in that they give almost exclusively 1,4addition. Other organometallic compounds, including Grignard reagents, add to the carbonyl carbon by 1,2-addition.
19-50

Crossed 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 ) 2 CH] 2 N H + CH3 ( CH2 ) 3 Li Diisopropylamine (pK a 40 (s tronger acid) Butyllithium (s tronger bas e) [ ( CH3 ) 2 CH] 2 N - Li + + CH3 ( CH2 ) 2 CH 3 Lithium diisopropylamde (we ak er bas e) Butane pK a 50 (we ak er acid)

LDA
19-51

Crossed 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 Acetone LDA -78C Lithium enolate O O Li 1.C H CH CH 6 5 2
+

OH O C6 H5

2. H2O 4-Hydroxy-5-phen yl-2-pentan one (racemic)

19-52

Examples using LDA

Crossed aldol

Michael

Alkylation

Acylation
19-53

Crossed Enolate Reactions using LDA

Question: For ketones with nonequivalent ahydrogens, can we selectively utilize the nonequivalent sites? Answer: A high degree of regioselectivity exists and it depends on experimental conditions.

19-54

Crossed 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. slight excess
O of base + LDA 0C (racemic) 99% O - Li + + O - Li + + [ ( CH3 ) 2 CH] 2 N H

When 2-methylcyclohexanone is treated with LDA where the ketone is in slight excess, the product is richer in the more substituted enolate.
slight excess of the ketone O + LDA 0C (racemic) 10% O - Li + + O - Li + + [ ( CH3 ) 2 CH] 2 N H

1%

90%

19-55

Crossed 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.

19-56

Crossed 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 a-hydrogen of an unreacted ketone. Thus, equilibrium is established between alternative enolate anions.
O H CH3 + (racemic) Less s table enolate anion (racemic) O Li+ O - Li + + More stable enolate anion (racemic) O

19-57

Crossed 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 a-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.

19-58

Example
1. 1.01 mol LDA, kinetic control

1. 0.99 mol LDA, thermodynamic control

19-59