Resumo reações enol e enolatos

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Review of Reactions 1091
Aldol Reactions
Aldol Addition and Condensation
H
O
H
O OH
H
O
H
O
H2O+ +
b-Hydroxy aldehyde a,b-Unsaturated aldehyde
Aldol addition
Aldol condensation
NaOH
H2O
Heat
REVIEW OF REACTIONS
Alpha Halogenation
Of Ketones
O O
Br + HBr
Br2
[H3O
+]
Of Carboxylic Acids (Hell-Volhard-Zelinsky Reaction)
OH
O
OH
O
Br
1) Br2, PBr3
2) H2O
Haloform Reaction
O
OH
O
1) NaOH, Br2
2) H3O
+
Crossed Aldol Condensation
H H
O
+
H
O
H
OH
H
NaOH
heat
Intramolecular Aldol Condensation
O
O O
NaOH, heat
Claisen Condensation
Claisen Condensation
EtO
O
EtO
O O
1) NaOEt
2) H3O
+ 
Crossed Claisen Condensations
OEt
O
OEt
O
O
OEt
O
+
1) NaOEt
2) H3O
+ 
Intramolecular Claisen Condensation (Dieckmann Cyclization)
OEt
EtO
O
O
O
OEt
O
1) NaOEt
2) H3O
+ 
1092 CHAPTER 22 Alpha Carbon Chemistry: Enols and Enolates
Alkylation
Via Enolate Ions
O
R
O
RR
O
R
R
1) LDA, –78°C 
2) RX 
1) NaH, 25°C 
2) RX 
The Malonic Ester Synthesis
EtO OEt
O O
R
OH
O
1) NaOEt, EtOH
2) RBr
3) H3O
+, heat 
The Acetoacetic Ester Synthesis
EtO
O O
R
O
1) NaOEt/EtOH
2) RBr
3) H3O
+, heat 
Stabilized Carbon Nucleophiles
H
O
H
OR
1) R2CuLi
2) H3O
+
O
O
O
O
H
O
H
O
1) KOH
2)
3) H3O
+
The Stork Enamine Synthesis
O O O
O
1) R2NH, [H
+], (–H2O)
2)
3) H3O
+ 
The Robinson Annulation
O
O O
O
O
+
NaOH, heat
REVIEW OF CONCEPTS AND VOCABULARY
SECTION 22.1
• Greek letters are used to describe the proximity of each car-
bon atom to the carbonyl group. Alpha (a) protons are the 
protons connected to the a carbon.
• In the presence of catalytic acid or base, a ketone will exist 
in equilibrium with an enol. In general, the equilibrium will 
significantly favor the ketone.
• The a position of an enol can function as a nucleophile.
• When treated with a strong base, the a position of a ketone 
is deprotonated to give an enolate.
• Sodium hydride or LDA will irreversibly and completely con-
vert an aldehyde or ketone into an enolate.
SECTION 22.2
• Ketones and aldehydes will undergo alpha halogenation in 
acidic or basic conditions.
• The acid-catalyzed process produces HBr and is therefore 
autocatalytic.
• In the Hell-Volhard-Zelinsky reaction, a carboxylic acid under-
goes alpha halogenation when treated with bromine in the 
presence of PBr3.
• In the haloform reaction, a methyl ketone is converted into a 
carboxylic acid upon treatment with excess base and excess 
halogen followed by acid workup.
SECTION 22.3
• When an aldehyde is treated with sodium hydroxide, an aldol 
addition reaction occurs, and the product is a b-hydroxy 
aldehyde or ketone.
• For most simple aldehydes, the position of equilibrium favors 
the aldol product.
• For most ketones, the reverse process, called a retro-aldol 
reaction, is favored.
• When an aldehyde is heated in aqueous sodium hydroxide, 
an aldol condensation reaction occurs, and the product is 
an a,b-unsaturated aldehyde or ketone. Elimination of water 
occurs via an E1cb mechanism.
Michael Additions
• Crossed aldol, or mixed aldol, reactions are aldol reactions 
that occur between different partners and are only efficient if 
one partner lacks a protons or if a directed aldol addition is 
performed.
• Intramolecular aldol reactions show a preference for formation 
of five- and six-membered rings.
SECTION 22.4
• When an ester is treated with an alkoxide base, a Claisen con-
densation reaction occurs, and the product is a b-keto ester.
• A Claisen condensation between two different partners is 
called a crossed Claisen condensation.
• An intramolecular Claisen condensation, called a Dieckmann 
cyclization, produces a cyclic, b-keto ester.
SECTION 22.5
• The a position of a ketone can be alkylated by forming an 
enolate and treating it with an alkyl halide.
• For unsymmetrical ketones, reactions with LDA at low 
temperature favor formation of the kinetic enolate, 
while reactions with NaH at room temperature favor the 
 thermodynamic enolate.
• When LDA is used with an unsymmetrical ketone, alkylation 
occurs at the less hindered position.
• The malonic ester synthesis enables the conversion of an 
alkyl halide into a carboxylic acid with the introduction of two 
new carbon atoms. The acetoacetic ester synthesis enables 
the conversion of an alkyl halide into a methyl ketone with the 
introduction of three new carbon atoms.
• Decarboxylation occurs upon heating a carboxylic acid with 
a b-carbonyl group.
SECTION 22.6
• Aldehydes and ketones that possess a,b unsaturation are 
susceptible to nucleophilic attack at the b position. This 
 reaction is called a conjugate addition, or 1,4-addition, or 
a Michael reaction.
• The nucleophile is called a Michael donor, and the electro-
phile is called a Michael acceptor.
• Regular enolates do not serve as Michael donors, but the 
desired Michael reaction can be achieved with a Stork 
enamine synthesis.
• A Robinson annulation is a Michael addition followed by an 
intramolecular aldol and can be used to make cyclic compounds.
SECTION 22.7
• The Stork enamine synthesis produces 1,5-difunctionalized 
compounds.
• Aldol addition reactions and Claisen condensation reactions 
both produce 1,3-difunctionalized compounds.
• The initial product of a Michael addition is an enolate ion, 
which can be treated with an alkyl halide, thereby alkylating 
both the a and b positions in one reaction flask.
 SkillBuilder Review 1093
SKILLBUILDER REVIEW
22.1 DRAWING ENOLATES
STEP 1 Identify 
all a protons. 
O
H
STEP 2 Using two curved arrows, remove the proton,
and then draw the enolate with a lone pair and a
negative charge at the a position. 
Base
O
H
O
STEP 3 Draw the other resonance structure of the enolate.
OO
@ @@
@
Try Problems 22.4, 22.5, 22.59
22.2 PREDICTING THE PRODUCTS OF AN ALDOL ADDITION REACTION
STEP 1 Draw all three steps of the mechanism as a guide for predicting the product. STEP 2 Double-check 
your answer to ensure 
that the product has a 
hydroxyl group at the b 
position. 
H
H
O OH
H
H
O
H
O
H H
O
OH
H
O
H
H
O O
ProtonateDeprotonate
Nucleophilic
attack
The a position
is deprotonated to
form an enolate
The enolate serves
as a nucleophile and
attacks an aldehyde
The resulting alkoxide
ion is protonated to
give the product
H
O OH
b
a
@
@
@
Try Problems 22.15–22.19, 22.72
1094 CHAPTER 22 Alpha Carbon Chemistry: Enols and Enolates
22.3 DRAWING THE PRODUCT OF AN ALDOL CONDENSATION
STEP 3 Remove two a protons and
the oxygen atom, forming a double
bond in place of those groups.
O
H
H2O+
STEP 2 Draw two molecules of the ketone,
oriented such that two a protons of one
molecule are directly facing the carbonyl 
group of the other molecule. 
O
O
H
H
H
STEP 1 Identify 
the a protons.
O
H
H
H
STEP 4 Make sure to draw
the product with fewer steric 
interactions.
O
H
Try Problems 22.20–22.22, 22.71, 22.84c
22.4 IDENTIFYING THE REAGENTS NECESSARY FOR A CROSSED ALDOL REACTION
STEP 2 Using a retrosynthetic analysis, break
apart the bond between the a and b positions, 
placing a carbonyl group in place of the 
hydroxyl group.
O
H
O
+
STEP 1 Identify 
the a and b positions. 
O OH
b
a
STEP 3 Determine which base should be used. A crossed
aldol will require the use of LDA.
O OHO
1) LDA
2)
H
O
3) H2O 
Try Problems 22.23, 22.24, 22.67, 22.68
22.5 USING THE MALONIC ESTER SYNTHESIS
STEP 2 Identify the alkyl 
halides necessary and ensure 
that both will readily undergo 
an SN2 process. 
Br
Br
STEP 1 Identify the alkyl groups that
are connected to the a position
of the carboxylic acid.
CO2H
a
STEP 3 Identify the reagents. Begin with diethyl malonate 
as the starting material. Perform each alkylation and then heat 
with aqueous acid. 
EtO OEt
O O
Target
compound4)
Br
1) NaOEt
2) PhCH2Br
3) NaOEt
5) H3O
+, heat 
Try Problems 22.35–22.38, 22.78
22.6 USING THE ACETOACETIC ESTER SYNTHESISSTEP 2 Identify the alkyl 
halides necessary and ensure 
that both will readily undergo 
an SN2 process.
I I
STEP 1 Identify the alkyl groups 
that are connected to the a 
position of the methyl ketone.
H3C
O
a
STEP 3 Identify the reagents. Begin with ethyl acetoacetate 
as the starting material. Perform each alkylation and then heat
with aqueous acid.
OEt
O O O
2) EtI
1) NaOEt
3) NaOEt
5) H3O
+, heat 
4) I
Try Problems 22.39–22.43, 22.79
 Practice Problems 1095
22.7 DETERMINING WHEN TO USE A STORK ENAMINE SYNTHESIS
STEP 2 If the Michael donor must be an enolate, then a 
Stork enamine synthesis is required. 
O
H
OO
H
O
2)
3) H3O
+ 
1) R2NH, [H
+], (–H2O)
STEP 1 Using a retrosynthetic analysis, identify whether it is possible to
prepare the target compound with a Michael addition. 
O
H
O
H
OO
+
Michael
@
Try Problems 22.47, 22.48, 22.87d
22.8 DETERMINING WHICH ADDITION OR CONDENSATION REACTION TO USE
For compounds with two functional groups, the relative positioning of the groups, as well as their
oxidation states, will dictate which addition or condensation reaction to use. 
1,5-DIFUNCTIONALIZED COMPOUNDS
Stork enamine synthesis
O
1
2
5
O O
3
4
O
1) R2NH, [H
+], (–H2O)
2)
3) H2O 
1,3-DIFUNCTIONALIZED COMPOUNDS
Aldol addition
Claisen condensation
EtO
O
1
2
3EtO
O O
1) NaOEt
2) H3O
+ 
H
O
H
O OH
1
2
3
NaOH
H2O
Try Problems 22.51–22.53, 22.87d
22.9 ALKYLATING THE a AND b POSITIONS
A strategy for installing two neighboring alkyl groups at the a and b positions.
O
R2CuLi
Enolate
O
R
R
O
R
R X
@
Try Problems 22.54–22.56, 22.82, 22.89
Note: Most of the Problems are available within , 
an online teaching and learning solution.
22.57 Identify which of the following compounds are expected to 
have pKa < 20. For each compound with pKa < 20, identify the most 
acidic proton in the compound.
O
H
O O
OH
O O
22.58 One of the compounds from the previous problem has 
pKa < 10. Identify that compound and explain why it is so much more 
acidic than all of the other compounds.
22.59 Draw resonance structures for the conjugate base that is pro-
duced when each of the following compounds is treated with sodium 
ethoxide:
(a) OEt
O O
 (b)
OEt
O O
 (c)
CN
O
22.60 Rank the following compounds in terms of increasing acidity:
O O O O
O
O
O
OH
PRACTICE PROBLEMS