organic - carey 10e ch. 21 - enols and...

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ORGANIC - CAREY 10E

CH. 21 - ENOLS AND ENOLATES

CONCEPT: ALPHA CARBONS AND TAUTOMERIZATION

We have discussed the high reactivity of the carbonyl carbon.

However, carbonyls contain another highly reactive component.

● What is the acidity of the β-carbon? ____________

● What is the acidity of the α-carbon? ____________

● Which phenomenon is responsible for this difference?

Tautomerization General Reaction:

Acid-Catalyzed Mechanism:

Base-Catalyzed Mechanism:

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PRACTICE: Draw the enol tautomer for the following compound.

Cyclopentanone

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CONCEPT: ENOLATES

Upon deprotonation, the α-carbon forms a resonance-stabilized intermediate structure called an _________________

● Both notations can be used to represent an enolate

● Note that the negative charge now rests on the _____________________

● This makes the α-carbon of the enolate a good __________________________

General Reactions of Enolates:

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CONCEPT: OVERVIEW OF α-CARBON ALKYLATIONS AND ACYLATIONS

Adding –R groups to α-carbons of carbonyl compounds is synthetically important.

●There are _______ main synthetic pathways that we use to accomplish this.

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CONCEPT: ENOLATE ALKYLATION AND ACYLATION

We can expose enolates to alkyl halides to produce α-alkyations

● Using acid chlorides results in α-acylations.

Directed Reactions:

When we run α-alkyations with asymmetrical ketones, two enolates are possible.

● This leads to a mixture of products. We can use different bases to direct the direction of deprotonation

□ The thermodynamic product is the product with the lowest overall energy _____________

□ The kinetic product is the product with the lowest activation energy _____________

Enolates of Esters:

LDA can also be used in the alkylation of esters

● Use of alkoxide bases may yield transesterification (stay away!)

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PRACTICE: The following molecule forms two products. Determine the products and determine if they follow thermodynamic control or kinetic control.

O

1) TBuOK, TBuOH

2) CH3Br

1) LiH

2) CH3Br

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CONCEPT: ENAMINE ALKYLATION AND ACYLATION

Carbonyls easily react with acid-catalyzed amine solvents to form imines and enamines.

Secondary Amine Addition: Enamines

Enamines have the ability to alkylate or acylate via the formation of an iminium salt

EXAMPLE: Predict the products of the following reactions

1.

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PRACTICE: Provide the major product after each step for the following reaction.

OHN

H+

Br

Acetone

H3O+

PRACTICE: Which of the following can NOT be formed through the stork enamine reaction with 2-butanone?

a) 3-pentanone

b) 3-methyl-2-butanone

c) 2-octanone

d) 3-octanone

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CONCEPT: TAUTOMERS OF DICARBONYL COMPOUNDS

● Most carbonyl compounds favor the ______________ tautomer

● β-dicarbonyl compounds favor the _____________ tautomer due to _________________ and _____________________

● β-dicarbonyl compounds are exceptionally acidic due to the high stability of the conjugate base

● If the α-carbon exists as a chiral center, that carbon will ALWAYS BE ____________________

EXAMPLE: Which of the following ketones is the most acidic?

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CONCEPT: β-DICARBONYL ESTER SYNTHESIS—PATHWAY

β-dicarbonyl compounds are unusually acidic due to the incredible stability of the enolate.

We can take advantage of this acidity to easily alkylate the central α-carbon through a predictable multi-step synthesis.

β-dicarbonyl Ester Synthetic Pathway

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CONCEPT: ACETOACETIC ESTER SYNTHESIS — GENERAL REACTIONS

EXAMPLE: Predict the products of the following multi-step reactions

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PRACTICE: Provide the major product for the following reaction

O

CH3

O

O CH3

1. NaOEt2. PhCH2Br

3. H3O+

4. Δ

PRACTICE: Beginning from ethyl acetoacetate, and using any other necessary reagents, show the necessary compounds needed to form the following compound.

O

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CONCEPT: MALONIC ESTER SYNTHESIS—GENERAL REACTIONS

EXAMPLE: Predict the products of the following multi-step reactions

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O O

O OCH3 CH3

1. 2 moles NaOEt, EtOH2. BrCH2CH2CH2Br

3. NaOH, H2O, H3O+

4. LiAlH4


O O

O OCH3 CH3

1. NaOEt, EtOH2. CH3CH2CH2Br

3. NaOH, H2O, H3O+

4. Heat

PRACTICE: Beginning from diethyl malonate, and using any other necessary reagents, show the necessary compounds needed to form the following compound.

O

OH

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CONCEPT: ELECTROPHILIC α-HALOGENATIONS

Acid-Catalyzed α-halogenation: Always yields _________-halogenation

PRACTICE: Provide the major product for the following reaction.

CH3

OBr2

H+

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Base-Catalyzed α-halogenation: May yield _________-halogenation


OBr2 excess

NaOH

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The Haloform Reaction: Base-Catalyzed α-halogenation of _______________ ______________

● The α-carbon is transformed into a good ________________________ through successive halogenations.


OBr2 excess

NaOH

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The HVZ Reaction

PRACTICE: Provide the major product after each step for the following reaction.

O

OH

Br2 , PBr3

H2O

NH3

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CONCEPT: CONDENSATION REACTIONS

A condensation reaction spontaneously combines two or more molecules with the loss of a smaller molecule.

● Instead of just reacting with electophiles, enolates are able to react with themselves to self-condensate

● Obviously, ___________________________ are required for this type of reaction to take place

Example Reactions:

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CONCEPT: ALDOL CONDENSATION

Via enolates, ketones and aldehydes will react with ___________________ to condensate into ______________

● The final products are called “aldols” because they are part ________________ and part __________________

Mechanism:

1. Form the enolate

2. Nucleophilic attack the other carbonyl (which we will call the electrophile)

3. Protonate the tetrahedral intermediate:

β-hydroxy carbonyls are ______________ to dehydrate than typical alcohols due to __________________________

Many times, we will simply assume that the condensation product dehydrated on its own, without requiring an explanation.

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PRACTICE: What product can be isolated from the following aldol condensation reaction?

O

OH –

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PRACTICE: Provide the mechanism for the following transformation.

O OH

H

OH – O

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CONCEPT: DIRECTED CONDENSATIONS

When we run condensation reactions with asymmetrical ketones, two enolates may be possible.

● We can use different bases to direct the direction of deprotonation

□ The thermodynamic enolate is the ___ substituted one. Favored by ___________ bases.

□ The kinetic enolate is the ___ substituted one. Favored by ___________ bases.

EXAMPLE: Predict the products of the following self-condensation.

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CONCEPT: CROSSED ALDOL

When we run condensation reactions on two different ketones or aldehydes, mixed products are difficult to avoid.

In general, condensation reactions with two different carbonyls work best when one carbonyl is nonenolizable.

Nonenolizable Carbonyls:

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PRACTICE: Give the structure of the aldehydes or ketones used to create the product prepared by a crossed aldol condensation reaction.

PRACTICE: Give the structure of the aldehydes or ketones used to create the product prepared by a crossed aldol reaction.

O OH

PRACTICE: What product can be isolated from the following aldol condensation reaction?

OH –O O O

H

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CONCEPT: CLAISEN-SCHMIDT REACTION

When a crossed aldol contains an enolizable aldehyde and a ketone, one product does predominate.

● Aldehydes are more susceptible toward nucleophilic addition than ketones, favoring a single enolate.

EXAMPLE: Predict the major product of the following condensation.

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CONCEPT: CLAISEN CONDENSATION

Via enolates, esters will react with _________________ to condensate into ________________________

Mechanism:

1. Form the enolate

2. Nucleophilic attack the other carbonyl (which we will call the electrophile)

3. Kick out the good leaving group:

Example Application:

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PRACTICE: Draw the structure of the Claisen condensation product for each of the following compounds.

O

OEt

O

OEt

NaOEt

EtOH

PRACTICE: Draw the structure of the Claisen condensation product for each of the following compounds.

O

O

O

O

NaOMe

MeOH

PRACTICE: Give the structure of the ester precursor for the following Claisen condensation product.

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CONCEPT: INTRAMOLECULAR CONDENSATION

Dicarbonyl compounds have the ability to self-condensate through cyclization if it will generate a ___ or ___-membered ring.

● When a diketone or dialdehyde self-condensate, the resulting product is called a cyclic enone

● When a diester self-condensates, the resulting product is called a cyclic β-ketoester

□ This is known as a Dieckmann Condensation

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PRACTICE: Consider the following reaction. Provide a stepwise mechanism to explain the given transformation.

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CONCEPT: CONJUGATE ADDITION OF ENONES

Once an aldol condensation is completed, an electrophilic carbonyl still remains.

● Enones remain susceptible to nucleophilic attack, however they now have two electrophilic regions:

● Also known as 1,2 vs. 1,4 addition of enones, or nucleophilic addition vs. conjugate addition of carbonyls.

Nucleophilic Addition vs. Conjugate Addition

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CONCEPT: THE MICHAEL REACTION

The Michael Reaction is a 1,4-conjugate addition of an enone with an enolate.

● Basically _____________________

● Always forms 1,5-dicarbonyls

Mechanism:

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PRACTICE: Determine the product in the following conjugated addition reaction.



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CONCEPT: ROBINSON ANNULATION

1,5-dicarbonyl compounds have the ability to undergo intramolecular self-condensation into 6-membered enones.

● When the 1,5-dicarbonyl is generated via Michael Reaction (enone + enolate), it is called a Robinson Annulation

` ●Basically _____________________

EXAMPLE: Predict the major product of the following Robinson Annulation.

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PRACTICE: Provide the product for the following Robinson Annulation Reaction.

O OO

PRACTICE: How would you prepare the following compound using a Robinson annulation reaction between a di-ketone and an alpha, beta unsaturated ketone?

O

O

PRACTICE: How would you prepare the following compound using a Robinson annulation reaction between a ketone and an alpha, beta unsaturated ketone?

O

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organic - carey 10e ch. 21 - enols and...

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