Báo cáo Enolates Enamines

Enolate Anions◆ Enolate anions are nucleophiles in S N 2 reactions and carbonyl addition reactions , nucleophilic addition An enolate anion nucleophilic substitution... The Aldol Reacti

Chapter 19 Enolates and Enamines

Formation of an Enolate Anion

◆ Enolate anions are formed by treating an aldehyde,

ketone, or ester, which has at least one α-hydrogen, with base,

• Most of the negative charge in an enolate

H C C-H

O Na + H

Enolate Anions

◆ Enolate anions are nucleophiles in S N 2 reactions and

carbonyl addition reactions ,

nucleophilic    addition

An enolate anion

nucleophilic substitution

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.

The Aldol Reaction

◆ The product of an aldol reaction is:

(a β­hydroxyaldehyde; 

racemic)

acid

acid

Mechanism: 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.

CH 2 =C-H

O

CH 2 -C-H

O H-O-H+

H-CH 2 -C-H

O +

H-O

An enolate anion

pKa  20 (weaker acid) (stronger acid)pKa  15.7

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.

Mechanism: the Aldol Reaction: Acid 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

Reactive carbonyl

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

The Aldol Products: Dehydration to alkene

• Aldol products are very easily dehydrated to

α , β -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,

Crossed Aldol Reactions

◆ In a crossed aldol reaction, one kind of molecule

provides the enolate anion and another kind provides the carbonyl group.

+

Non-acidic, no alpha

hydrogens

Crossed Aldol Reactions

◆ Crossed aldol reactions are most successful if

• one of the reactants has no α -hydrogen and, therefore, cannot form an enolate anion,

Crossed 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.

+

Nitromethane

pKa  10.2 (stronger acid)

Water

pKa  15.7 (weaker acid) +

+

Intramolecular Aldol Reactions

• Intramolecular aldol reactions are most

successful for formation of five- and

(not formed)

(formed)

Synthesis: Retrosyntheic Analysis

Two Patterns to look for

Synthesis: Retrosyntheic Analysis

Recognition

pattern

Analysis

Synthesis: Retrosyntheic Analysis

Example

Mixed aldol

Benzaldehyde

No alpha hydrogens

Claisen Condensation, Ester Substitution

◆ Esters also form enolate anions which participate in

nucleophilic acyl substitution

• The product of a Claisen condensation is a β ketoester.

-O 2CH 3 COEt 1 EtO

Here the enolate part of one ester molecule has

replaced the alkoxy group of the other ester molecule.

Mechanism: Claisen Condensation

Step 1: Formation of an enolate anion.

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

acid)

Resonance­stabilized enolate anion

+ +

Mechanism: Claisen Condensation

Step 3: Collapse of the TCAI gives a β -ketoester and an alkoxide ion.

Step 4: An acid-base reaction drives the reaction

to completion This consumption of base must

Intramolecular Claisen condensation: Dieckman Condensation

+

Diethyl hexanedioate (Diethyl adipate)

O

OEt

Acidic

Crossed Claisen Condsns

◆ Crossed Claisen condensations between two different

esters, each with α-hydrogens, give mixtures of products and are usually not useful.

◆ But if one ester has no α-hydrogens crossed Claisen is useful.

O

Crossed Claisen Condsns

• The ester with no α -hydrogens is generally

Methyl

benzoate

+

Methyl 2­methyl­3­oxo­ 3­phenylpropanoate

(racemic)

Used in

excess

◆ Claisen condensations are a route to ketones via

decarboxylation

OEt O

OEt

O O

O O

EtOH

EtOH +

Synthesis: Claisen Condensation

The result of Claisen condensation,

saponification, acidification, and

+

from the ester furnishing the enolate anion

from the ester furnishing the  carbonyl group

Note that in this Claisen (not crossed) the ketone is

symmetric Crossed Claisen can yield non symmetric

Synthesis: Retrosynthetic Analysis

Site of acidic hydrogen, nucleophile

Site of substitution, electrophile

New bond

Enamines (and imines, Schiff bases)

Recall primary amines react with carbonyl

compounds to give Schiff bases (imines), RN=CR 2

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

Enamines – Alkylation at α position.

◆ The value of enamines is that the β-carbon is

nucleophilic.

• Enamines undergo SN2 reactions with methyl and 1° haloalkanes, α -haloketones, and α -

haloesters.

• Treatment of the enamine with one equivalent

of an alkylating agent gives an iminium halide.

+

Br

••

N O

Br S N 2

N O

Compare mechanisms of acid catalyzed aldol and enamine

The morpholine enamine of

+

Br

••

N O

Br S N 2

N O

3­Bromopropene (Allyl bromide)

Enamines - Alkylation

• Hydrolysis of the iminium halide gives an

alkylated aldehyde or ketone.

Morpholinium       chloride     

-O

O

+

Cl N

-O

Overall process is to render the alpha carbonss of

ketone nucleophilic enough so that substitution

reactions can occur.

Enamines – Acylation at α position

• Enamines undergo acylation when treated with

acid chlorides and acid anhydrides.

Overall, Acetoacetic Ester Synthesis

◆ The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types:

A monosubstituted  acetone

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 β-diester rather than a β-ketoester.

O EtOC CH 2 COEt

A monosubstituted acetic acid

Malonic Ester Synthesis

◆ Consider the synthesis of this target molecule:

O

5­Methoxypentanoic acid

These two carbons are from diethyl malonate

Recognize as substituted acetic acid

Malonic Ester Synthesis

Malonic Ester Synthesis Steps

1 Treat malonic ester with an alkali metal

Sodium  ethoxide diethyl malonate Sodium salt of 

+

Diethyl malonate

pKa  13.3 (stronger acid)

Na +

COOEt COOEt

COOEt COOEt MeO + Na + Br -

Malonic Ester Synthesis

3 Saponify and acidify.

4 Decarboxylation.

2EtOH

+ COOEt

COOH

COOH

5­Methoxypentanoic acid

Michael Reaction, addition to α,β-unsaturated carbonyl

◆ Michael reaction: the nucleophilic addition of an enolate anion to an α,β-unsaturated carbonyl compound.

3­Buten­2­one (Methyl vinyl ketone)

Diethyl propanedioate

(Diethyl malonate)

Recognition Pattern:

β­Diketone

β­Diester Enamine

β­Ketonitrile

Aldehyde Ketone Ester

Amide Nitrile Nitro compoundMichael Reaction

Michael Reaction in base

Example:

• The double bond of an α , β -unsaturated

carbonyl compound is activated for attack by nucleophile.

COOEt

EtO - Na + EtOH

Mechanism: Michael Reaction

◆ Mechanism

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

2: Addition of Nu:- to the β carbon of the α , β

-unsaturated carbonyl compound.

O

C C

O Nu

Michael 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.

C C

1

4 3 2

+

C C

Nu

O-H

H O More stable keto form Less stable enol form

Michael Reaction, Cautions 1,4 vs 1,2

• Resonance-stabilized enolate anions and

enamines are weak bases, react slowly with

α , β -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 Ph O - Li +

H 2 O Ph OH +

Michael Reaction: Thermodynamic vs Kinetic

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

C

O C

RO

-C -C -C

O

ROH C

+

-+

+ fast

slow

1,2­Addition (less stable product)

1,4­Addition (more stable product)

2 NaOEt, EtOH (Aldol reaction)

Retrosynthesis of 2,6-Heptadione

COOH

O COOEt

O

this carbon lost by 

decarboxylation

this bond formed

in a Michael reaction

      Ethyl  acetoacetate Methyl vinyl     ketone

Cl + +

-Pyrrolidine enamine

of cyclohexanone

(racemic)

Gilman Reagents vs other organometallics

◆ Gilman reagents undergo conjugate addition to α,β

-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

Crossed Enolate Reactions using LDA

◆ With a strong enough base, enolate anion formation can

(weaker base)

[( CH 3 ) 2 CH] 2 NH + CH 3 (CH 2 ) 3 Li + CH 3 (CH 2 ) 2 CH 3

Butane

pK a  50 (weaker acid)

Butyllithium (stronger base)

Diisopropylamine

(pK a  40

(stronger acid)

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.

Examples using LDA

Crossed aldol

Michael

Alkylation

Crossed Enolate Reactions using LDA

Question: For ketones with nonequivalent α-hydrogens , can we selectively utilize the nonequivalent sites?

Answer: A high degree of regioselectivity exists and it

depends on experimental conditions.

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.

• When 2-methylcyclohexanone is treated with

LDA where the ketone is in slight excess, the product is richer in the more substituted slight excess 

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.

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.

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 α -hydrogen of an unreacted ketone Thus, equilibrium is established

between alternative enolate anions.O H

enolate anion

Crossed Enolate Reactions using LDA

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

• 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.