CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND...
Transcript of CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND...
! www.clutchprep.com
!
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
CONCEPT: ELECTROPHILIC α-HALOGENATIONS
Acid-Catalyzed α-halogenation: Always yields _________-halogenation
PRACTICE: Provide the major product for the following reaction.
CH3
OBr2
H+
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 2
CONCEPT: ELECTROPHILIC α-HALOGENATIONS
Base-Catalyzed α-halogenation: May yield _________-halogenation
PRACTICE: Provide the major product for the following reaction.
OBr2 excess
NaOH
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 3
CONCEPT: ELECTROPHILIC α-HALOGENATIONS
The Haloform Reaction: Base-Catalyzed α-halogenation of _______________ ______________
● The α-carbon is transformed into a good ________________________ through successive halogenations.
PRACTICE: Provide the major product for the following reaction.
OBr2 excess
NaOH
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 4
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 5
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 6
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 7
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 8
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 9
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 10
CONCEPT: ACETOACETIC ESTER SYNTHESIS — GENERAL REACTIONS
EXAMPLE: Predict the products of the following multi-step reactions
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 11
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
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 12
CONCEPT: MALONIC ESTER SYNTHESIS—GENERAL REACTIONS
EXAMPLE: Predict the products of the following multi-step reactions
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 13
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
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 14
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 15
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 16
PRACTICE: What product can be isolated from the following aldol condensation reaction?
O
OH –
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 17
PRACTICE: Provide the mechanism for the following transformation.
O OH
H
OH – O
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 18
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 19
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 20
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 21
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 22
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 23
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 24
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 25
PRACTICE: Consider the following reaction. Provide a stepwise mechanism to explain the given transformation.
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 26
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 27
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:
ORGANIC - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 28
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 29
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 30
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 - EGE 5E
CH. 17 - ENOLS AND ENOLATE ANIONS: ALKYLATION AND CONDENSATION
Page 31