organic - brown 8e ch. 19 - enolate anions and...
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ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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:
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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.
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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PRACTICE: What product can be isolated from the following aldol condensation reaction?
O
OH –
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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PRACTICE: Provide the mechanism for the following transformation.
O OH
H
OH – O
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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:
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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.
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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:
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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.
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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PRACTICE: Consider the following reaction. Provide a stepwise mechanism to explain the given transformation.
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CH. 19 - ENOLATE ANIONS AND ENAMINES
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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.
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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!)
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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.
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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CONCEPT: ACETOACETIC ESTER SYNTHESIS — GENERAL REACTIONS
EXAMPLE: Predict the products of the following multi-step reactions
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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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CH. 19 - ENOLATE ANIONS AND ENAMINES
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CONCEPT: MALONIC ESTER SYNTHESIS—GENERAL REACTIONS
EXAMPLE: Predict the products of the following multi-step reactions
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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PRACTICE: Provide the major product for the following reaction
O O
O OCH3 CH3
1. 2 moles NaOEt, EtOH2. BrCH2CH2CH2Br
3. NaOH, H2O, H3O+
4. LiAlH4
PRACTICE: Provide the major product for the following reaction
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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CH. 19 - ENOLATE ANIONS AND ENAMINES
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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
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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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CH. 19 - ENOLATE ANIONS AND ENAMINES
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PRACTICE: Determine the product in the following conjugated addition reaction.
PRACTICE: Determine the product in the following conjugated addition reaction.
PRACTICE: Determine the product in the following conjugated addition reaction.
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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.
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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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.
ORGANIC - BROWN 8E
CH. 19 - ENOLATE ANIONS AND ENAMINES
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