ALPHA HYDROGEN
OBJECTIVES
1. 2.
3.
4.
5.
Decsribe the acidity of -hydrogen of carbonyl compounds in the form of enolate anions (page : 832) Predict the products from alkylation and halogenation (bromination and haloform) reaction of -hydrogen of ketone (page : 837, 842) Predict the product from the aldol condensation reaction and be able to propose synthetic routes to get the target products. (page : 876-889) Predict the product from the Claisen condensation reaction (Claisen ester condensation and Dieckmann condensation). (page : 870-874) Predict the product from the addition to , unsaturated carbonyl compounds and Michael addition. (page : 889, 892)
OBJECTIVES
6 7
Predict the products from the Robinson annulation (ring forming) (page : 893) Able to write the synthesis of acetoacetic ester and malonic ester by following basic steps via alkylation, hydrolysis and decarboxylation. (page : 845-849, 850-853)
1. Decsribe the acidity of -hydrogen of carbonyl compounds in the form of enolate anions (page : 832)
The Acidity of the a Hydrogens of Carbonyl Compounds: Enolate Anions
Hydrogens on carbons a to carbonyls are unusually acidic
The resulting anion is stabilized by resonance to the carbonyl
Chapter 17
The enolate anion can be protonated at the carbon or the oxygen
The resultant enol and keto forms of the carbonyl are formed reversibly and are interconvertible
Chapter 17
REACTION OF -HYDROGEN
2. Predict the products from alkylation and halogenation (-bromination and haloform) reaction of -hydrogen of ketone (page : 837, 842)
Direct Alkylation of Ketones via Lithium Enolates
Enolates can also be alkylated with primary alkyl halides via an SN2 reaction
Unsymmetrical ketones can be alkylated at the least substituted position if LDA is used to form the kinetic enolate
Chapter 17
17
a-Selenation: A Synthesis of a,b-Unsaturated
Carbonyl Compounds
A lithium enolate can be selenated with benzeneselenyl bromide
Chapter 17
18
The a-selenyl ketone is converted to the a,b-unsaturated carbonyl compound by reaction with hydrogen peroxide
Elimination of the selenoxide produces the unsaturated carbonyl
Chapter 17
19
Halogenation of Ketones
Ketones can be halogenated at the a position in the presence of acid or base and X2
Base-promoted halogenation occurs via an enolate
Chapter 17
20
Acid-catalyzed halogenation proceeds via the enol
Chapter 17
21
Haloform Reaction
Reaction of methyl ketones with X2 in the presence of base results in multiple halogenation at the methyl carbon
Insert mechanism page 777
Chapter 17
22
When methyl ketones react with X2 in aqueous hydroxide the reaction gives a carboxylate anion and a haloform (CX3H)
The trihalomethyl anion is a relatively good leaving group because the negative charge is stabilized by the three halogen atoms
Chapter 17
23
3. Predict the product from the aldol condensation reaction and be able to propose synthetic routes to get the target products. (page : 876-889)
The Aldol Reaction: The Addition of Enolate Anions to Aldehydes and Ketones
Acetaldehyde dimerizes in the presence of dilute sodium hydroxide at room temperature The product is called an aldol because it is both an aldehyde and an alcohol
Chapter 17
29
The mechanism proceeds through the enolate anion
Chapter 17
30
Dehydration of the Aldol Product
If the aldol reaction mixture is heated, dehydration to an a,bunsaturated carbonyl compound takes place
Dehydration is favorable because the product is stabilized by conjugation of the alkene with the carbonyl group
In some aldol reactions, the aldol product cannot be isolated because it is rapidly dehydrated to the a,b-unsaturated compound
Synthetic Applications
The aldol reaction links two smaller molecules and creates a new carbon-carbon bond
Example
O CH 3 C H + O NaOH CH 3 C H OH CH 3 C H "Aldol" O CH 2 C H
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Another Example
O CH3 CH2 C H + O NaOH CH3 CH2 C H OH CH3 CH2 C H CH CH3 O C H
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One More:
O CH3 C CH3 + O NaOH CH3 C CH3 OH CH3 C CH3 "Diacetone alcohol" O CH2 C CH3
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Synthesis Problem
OH CH3 CH2 CH CH CH3 O C H
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Preparation via Aldol Condensation
CH3 CH
CH
CH2 OH
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Preparation via Aldol Condensation
CH3 CH2 CH2 CH2 CH CH2 CH3 CH2 OH
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Synthesis Problem
OH CH 2 CH 2 CH CH CH 2 O C H
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Chalcone Formation
OH C H O "spontaneous" CH 2 C
(formed from an aldol condensation)
CH CH
O C
a chalcone
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Crossed Aldol Reactions
Crossed aldol reactions (aldol reactions involving two different aldehydes) are of little use when they lead to a mixture of products
Crossed Aldol Condensations
O C H
acceptor
OH NaOH O CH2 C H
+ O CH3 C H
C H
donor
- H2O (spontaneously)
O CH CH C H
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Practical Crossed Aldol Reactions Crossed aldol reactions give one predictable product when one of the reaction partners has no a hydrogens The carbonyl compound without any a hydrogens is put in basic solution, and the carbonyl with one or two a hydrogens is added slowly Dehydration usually occurs immediately, especially if an extended conjugated system results
Claisen-Schmidt Reactions
Crossed-aldol reactions in which one partner is a ketone are called Claisen-Schmidt reactions
The
product of ketone self-condensation is not obtained because the equilibrium is not favorable
From Experiment 35
O C CH 3 OH NaOH + O C H NO 2 - H2O (spontaneous) NO 2 O CH CH C CH O CH 2 C
NO 2 3-Nitrochalcone
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Do the synthesis of:
O CH C CH3 C H
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Cyclization via Aldol Condensations
Intramolecular reaction of dicarbonyl compounds proceeds to form five- and six-membered rings preferentially In the following reaction the aldehyde carbonyl carbon is attacked preferentially because an aldehyde is less sterically hindered and more electrophilic than a ketone
Also:
O C CH 2 CH 2 C O a CH 3 CH 3 O
NaOH C2H5OH 25
CH 3
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Synthesis of:
O C H
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Crossed Aldol Condensations
O C H
acceptor
OH NaOH O CH2 C H
+ O CH3 C H
C H
donor
- H2O (spontaneously)
O CH CH C H
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From Experiment 35
O C CH 3 OH NaOH + O C H NO 2 - H2O (spontaneous) NO 2 O CH CH C CH O CH 2 C
NO 2 3-Nitrochalcone
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Do the synthesis of:
O CH C CH3 C H
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Synthesis of an Insect Repellent
O CH3 CH2 CH2 C H NaOH O CH3 CH2 CH2 C a H OH CH3 CH2 CH2 C CH3 CH2 CH ALDOL CONDENSATION H C O 2-Ethyl-3-hydroxyhexanal OH H C O H H2 Ni HYDROGENATION CH3 CH2 CH2 C H CH3 CH2 CH H C O H H H
OH CH3 CH2 CH2 C CH3 CH2 CH
2-Ethyl-1,3-hexanediol --used in "6-12" repellent WWUinsect -- Chemistry
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Synthesis of a Compound used in Perfumery
O C CH2 CH2 C CH3 ALDOL CONDENSATION cis a CH2 CH2 CH CH O O CH2 CH3 KOH C CH2 CH2 C CH3 OH CH CH2 CH cis CH CH2 CH3
O CH2 C H CH3 cis-Jasmone --- used for the scent of jasmine in perfumes C H CH2 CH3
- H2O DEHYDRATION
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Biological Synthesis of Fructose
O CH2 CH O O P OH O enzyme C H + O a CH2 C OH CH2 O O P O Dihydroxyacetone phosphate ALDOL CONDENSATION O CH OH C CH2 O O P O OH OH
OH Glyceraldehyde-3-phosphate
OH CH2 CH O O P OH OH O C H
Fructose-1,6-diphosphate
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The Aldol Condensation Reaction: Mechanism
1) :O: CH3 C 2) :O: CH3 C _ .. CH2 3) .. : O: CH3 C H H :O: C H : O: fast CH2 C + H2O H CH3 C H CH2 C H _ .. + :OH .. donor H _ .. + :O .. fast H H .. O .. .. :O : CH3 C H :O : CH2 C .. :O H H + H .. CH2 _ :O: C H .. _ :O : CH2 C H
an enolate ion
acceptor slow
: O:
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The Heart of the Mechanism
H H3C + C .. CH2 C H O donor _ acceptor _ O H H3C C CH2 C H
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_ O
4. Predict the product from the Claisen condensation reaction (Claisen ester condensation and Dieckmann condensation). (page : 870-874)
b-Dicarbonyl compounds can be synthesized by the Claisen condensation
The acetoacetic ester and malonic acid syntheses use bdicarbonyl compounds for carbon-carbon bond forming reactions
The acetoacetic ester and malonic ester syntheses usually conclude with decarboxylation of a b-keto acid
Chapter 19
69
The Claisen Condensation: Synthesis of b-Keto Esters
Ethyl acetate undergoes a Claisen condensation when treated with sodium ethoxide
The product is commonly called an acetoacetic ester
Ethyl pentanoate undergoes an analogous reaction
Chapter 19
70
The overall reaction involves loss of an a hydrogen from one ester and loss of ethoxide from another
The mechanism is an example of the general process of nucleophilic addition-elimination at an ester carbonyl
Chapter 19
71
Chapter 19
72
The alkoxide base must have the same alkyl group as the alkoxyl group of the ester
The use of a different alkoxide would result in formation of some transesterification products Esters with only one a hydrogen do not undergo Claisen condensation A second hydrogen on the a carbon is necessary so that it can be deprotonated in Step 3 This deprotonation drives the reaction to completion
Chapter 19
73
Crossed Claisen Condensations
Crossed Claisen condensations can lead to one major product when one of the two esters has no a hydrogen
Chapter 19
74
The Dieckmann condensation is an intramolecular Claisen condensation
Only 5- and 6-membered rings may be prepared in this way
Chapter 19
75
5. Predict the product from the addition to , unsaturated carbonyl compounds and Michael addition. (page : 889, 892)
Additions to a,b-Unsaturated Aldehydes and Ketones
a,b-Unsaturated aldehydes and ketones can react by simple (1,2) or
conjugate (1,4) addition
Both
the carbonyl carbon and the b carbon are electrophilic and can react with nucleophiles
Stronger nucleophiles such as Grignard reagents favor 1,2 addition whereas weaker nucleophiles such as cyanide or amines favor 1,4 addition
Michael Additions
Addition of an enolate to an a,b-unsaturated carbonyl compound usually occurs by conjugate addition This reaction is called a Michael addition
6 Predict the products from the Robinson annulation (ring forming) (page : 893)
A Robinson annulation can be used to build a new six-membered ring on an existing ring
Robinson
annulation involves a Michael addition followed by an aldol condensation to close the ring
7. Able to write the synthesis of acetoacetic ester and malonic ester by following basic steps via alkylation, hydrolysis and decarboxylation. (page : 845-849, 850-853)
The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones (Substituted Acetones)
Alkylation
Alkylation of the enolate derived from acetoacetic ester is called the acetoacetic ester synthesis
This is an SN2 reaction with the ethyl acetoacetate enolate acting as the nucleophile
Chapter 19
84
A second alkylation can be performed A stronger base such as potassium tert-butoxide must be use to deprotonate the monoalkyl ester
Chapter 19
85
Hydrolysis of the ester and heating of the resultant bketoacid causes decarboxylation
The product is a substituted acetone derivative
Chapter 19
86
Example:
Chapter 19
87
Ethylacetoacetate serves as a synthetic equivalent of the acetone enolate
It is possible to use acetone enolate directly, but this would require a much stronger base and special reaction conditions
If a-halo esters are used to alkylate the enolate, g-keto acids are obtained
Chapter 19
88
Acetoacetic Ester Dianion: Alkylation at the Terminal Carbon
Treating acetoacetic ester with two equivalents of a very strong base produces the dianion
Alkylation of the dianion occurs first at the terminal carbon
The terminal carbanion is more nucleophilic and more basic because it is stabilized by only one carbonyl group
Chapter 19
89
The Malonic Ester Synthesis: Synthesis of Substituted Acetic Acids
Alkylation of diethylmalonate, hydrolysis of the diester to the b-dicarboxylic acid, and decarboxylation can be used to synthesize mono- and disubstituted acetic acids
The mechanism is analogous to that for the acetoacetic ester synthesis
In step 1 the stabilized anion is formed
Chapter 19
90
In step 2 the anion is mono- or dialkylated using SN2 reactions
Chapter 19
91
In step 3 the mono- or dialkylated product is hydrolyzed and decarboxylated
Chapter 19
92
Examples
Chapter 19
93
