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A library of the enol and enolate mediated carbonyl compound reactions:
Intermolecular -alkylationand acetoacetic and malonic ester
synthesisvia enolate anions
Chapters 22 and 23
Intermolecular -halogenationand haloform reaction
via enols and enolate anionsChapters 22
O
O
CH3X
Intramolecular -alkylationFavorskii rearrangement
via enolate anionsextra
O
O
XX2
O
X
OH-
CH3O-
CO2H
CO2CH3
A library of the enol and enolate mediated carbonyl compound reactions:
Self-condensationSelf and mixed Aldol and Claisen
via enols and enolate anionsChapter 23
H
O
OH-OH
H
O
H
O
OH-
H
O
H
O
+
OCH3
O
OH-O
OCH3
O
OCH2CH3
O
OH-
H3CH2CO
O
OCH2CH3
O
H3CH2CO OCH2CH3
O
+
A library of the enol and enolate mediated carbonyl compound reactions:
Intramolecular condensationDieckmann
via enolate anionsChapter 23
OH-
OO
O
O
O
CO2Et
The α Position The carbon next to the carbonyl group is designated
as being in the α position Electrophilic substitution occurs at this position
through either an enol or enolate ion
Enols and enolate anions behave as nucleophiles and react with electrophiles because the double bonds are electron-rich compared to alkenes
Part A: Keto–Enol Tautomerism A carbonyl compound with a hydrogen atom on its a carbon rapidly
equilibrates with its corresponding enol Compounds that differ only by the position of a moveable proton are
called tautomers The enol tautomer is usually present to a very small extent and cannot
be isolated, but is formed rapidly, and serves as a reaction intermediate
1H-NMR spectrum of neat 2,4-pentanedione
O O O OH
2.22 ppm3.61 ppm 5.52 ppm 2.05 ppm
Acid Catalysis of Enolization Brønsted acids catalyze keto-enol tautomerization by
protonating the carbonyl and activating the α protons
Base Catalysis of Enolization Brønsted bases
catalyze keto-enol tautomerization
The hydrogens on the α carbon are weakly acidic and transfer to water is slow
In the reverse direction there is also a barrier to the addition of the proton from water to enolate carbon
General Mechanism of Addition to Enols
When an enol reacts with an electrophile the intermediate cation immediately loses the -OH proton to give an -substituted carbonyl compound.
O
H
O
O
O
-Halogenation of Aldehydes and Ketones
Aldehydes and ketones can be halogenated at their α positions by reaction with Cl2, Br2, or I2 in either the acidic or basic solutions.
Mechanism of Acid-Catalyzed Electrophilic
Substitution
O
CF3CO2H
O
Br
O
+ HO2CCF3
O
H
+ CF3CO2-
1.
2.
C
O
H
H
HH
+ CF3CO2-
fast
fastC
O
H
H
H
+ CF3CO2H
enol
Mechanism of Acid-Catalyzed Electrophilic Substitution
OH
+ Br Br
slowCH2Br
OH
+ Br
3.
CH2Br
O
H
+ Brfast
Br
O
+ HBr
4.
α-Bromoketones Undergo Facile Elimination Reaction to Yield α,-unsaturated Carbonyl Compounds for 1,4-addition Reactions.
-Bromination of Carboxylic Acids:The Hell–Volhard–Zelinskii Reaction
Carboxylic acids do not react with Br2.
Unlike aldehydes and ketones, they are brominated by a mixture of Br2 and PBr3
Mechanism of the Hell–Volhard–Zelinskii Reaction
PBr3 converts -CO2H to –COBr, which can enolize and add Br2
Part B: Enolate Ion Formation
Carbonyl compounds can act as weak acids (pKa of acetone = 19.3; pKa of ethane = 60)
The conjugate base of a ketone or aldehyde is an enolate ion - the negative charge is delocalized onto oxygen
Two Reactions Sites on Enolates Reaction on oxygen yields an enol derivative Reaction on carbon yields an -substituted carbonyl
compound
Reagents for Enolate Formation Ketones are weaker acids than the OH of alcohols but can be deprotonated
to a small extent by an alkoxide anion (RO-) to form the enolate. This is sufficient in reactions with strong electrophiles such as Br2.
Sodium hydride (NaH) or lithium diisopropylamide [LiN(i-C3H7)2] are strong enough to form large amounts of the enolates required for -alkylation reactions.
LDA is generated from butyllithium (BuLi) and diisopropylamine (pKa = 40) and is soluble in organic solvents.
Mechanism of Base-Promoted Electrophilic Halogenation
1. The base abstracts the -H from the keto tautomer.
2. The resulting enolate anion reacts with an electrophile.O
O
XBr2
CH3O-Na+
Mechanism
C
O O
H
CH3O-
H
HH H
+ CH3OHfast
O
H
H
+Br Br
slow
O
Br
+ Br-
The Haloform Reaction
Base-promoted reaction occurs through an enolate anion intermediate. Monohalogenated products are themselves rapidly turned into enolate
anions and further halogenated until the trihalo compound is formed from a methyl ketone.
The product is cleaved by hydroxide with -CX3 as a leaving group.
-Alkylation of Enolate Ions via Lithium Enolate Salts
Even unreactive ketones will be easily deprotonated with LDA to give stable, isolable lithium enolate salts.
-Alkylation of Enolate Ions Alkylation occurs when the nucleophilic enolate ion reacts with the
electrophilic alkyl halide or tosylate and displaces the leaving group
SN2 reaction:, the leaving group X can be chloride, bromide, iodide, or tosylate R should be primary or methyl and preferably should be allylic or benzylic Secondary halides react poorly, and tertiary halides don't react at all because of
competing elimination
Mechanism of Base-Promoted Electrophilic Alkylation
2. CH3OTs
1. THF / [(CH3)2CH]2N-Li+
Mechanism
O O
HH
H+
fast
+H3C OTs
slow
+ OTs-Li+
O O
Li+
[(CH3)2CH]2NH[(CH3)2CH]2N-
O
H
Li+ O
O
+ BrCH2CH CH2LDA
THF
O
1.
CH2
O
H + N fast
O
+ NH
2.O
Br CH2
C
H
C
H
H
O
++ Br
allylic
allylic bromide
Intramolecular -alkylation reaction: Favorskii rearrangement.
Intramolecular -alkylation in the Favorskii rearrangement proceeds via enolate anion generated within the molecule. The molecule must contain a leaving group, usually a halide. The purpose of the reaction is two fold: 1. Molecular rearrangements of ketones to carboxylic acids and 2. Ring contraction reaction to make high energy small size and/or fused rings.
O
X
OH-
CH3O-
CO2H
CO2CH3
12 3 4
5
5
4
3
21
O
BrOH-
CO2H
H H
+
O
Br
H
O
Br
H
O
Br-+
O
OH-+
OHO
OHOH2O
CO2H
OH-+
Mechanism
Intramolecular -alkylation reaction: Favorskii rearrangement resulting in ring contractions.
O
Br
OH-
CO2H
1
2 3 4
55
4
3
21
6 6
O
Br
CH3O-CO2CH3
O
BrH
HCH3O
fastCH3OH +
O
Br
O
Brslow
O
+ Br
O
+ CH3Oslow
OCH3O
OCH3O
fast
OCH3
O+ CH3OH
fast
COCH3O
1.
2.
3.
4. 5.
β-Dicarbonyls Are More Acidic
When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced (Table 22.1)
Negative charge of enolate delocalizes over both carbonyl groups
Relative acidities are dictated by the substituents on the carbonyl group.
H
O
O
OCH3
O
O
OCH3
O
H3CH2CO
O
OCH2CH3
O
O O
OCH3
O
17 19 25pKa
acidity reduced due to theinductive effect of the alkyl group
acidity reduced due to theresonance effect of the alkoxy group
pKa 19 9 19 11 13
Ethyl Acetoacetate Ester
O
OCH2CH3
O
H3CH2CO
O
OCH2CH3
O
pKa 19 11 13
Diethyl Malonate Ester
Acetoacetic and malonic esters are easily converted into the corresponding enolate anions by reaction with sodium ethoxide in ethanol. The enolates are good nucleophiles that react rapidly with alkyl halides to give an -substituted derivatives. The product has an acidic α-hydrogen, allowing the alkylation process to be repeated.
Formation of Enolate and Alkylation
Formation of Enolate and Alkylation
2. The Malonic Ester Synthesis
For preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms
3. The Acetoacetic Ester Synthesis
Overall: converts an alkyl halide into a methyl ketone
Synthesis of ketones using acetoacetic ester via the decarboxylation of acetoacetic acid
-Ketoacid from hydrolysis of ester undergoes decarboxylation to yield a ketone via the enol
The malonic ester synthesis converts an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms
Synthesis of carboxylic acids using malonic ester via the decarboxylation of malonic acid
Decarboxylation of -Ketoacids
Decarboxylation requires a carbonyl group two atoms away from the β CO2H
The second carbonyl permit delocalization of the resulting enol The reaction can be rationalized by an internal acid-base reaction
Generalization: -Keto Esters The sequence: enolate ion formation, alkylation,
hydrolysis/decarboxylation is applicable to -keto esters in general
Cyclic -keto esters give 2-substituted cyclohexanones
Preparation Cycloalkane Carboxylic Acids
1,4-dibromobutane reacts twice, giving a cyclic product Three-, four-, five-, and six-membered rings can be prepared
in this way
