condensation revised
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organic chemistryTRANSCRIPT
© 2013 Pearson Education, Inc.
Condensations and Alpha
Substitutions of Carbonyl
Compounds
© 2013 Pearson Education, Inc.
© 2013 Pearson Education, Inc. Chapter 22 2
Alpha Substitution
Alpha substitution is the substitution of one of the hydrogens attached to the alpha-carbon for an electrophile.
The reaction occurs through an enolate ion intermediate.
© 2013 Pearson Education, Inc. Chapter 22 3
In drawing mechanisms, you can
show either resonance form of an
enolate attacking the electrophile.
© 2013 Pearson Education, Inc. Chapter 22 4
Condensation of an Enolate with
an Aldehyde or Ketone
The enolate ion attacks the carbonyl group to form an
alkoxide.
Protonation of the alkoxide gives the addition
product: a b-hydroxy carbonyl compound.
© 2013 Pearson Education, Inc. Chapter 22 5
Condensation with Esters
The enolate adds to the ester to form a tetrahedral
intermediate.
Elimination of the leaving group (alkoxide) gives the
substitution product (a b-carbonyl compound).
© 2013 Pearson Education, Inc. Chapter 22 6
Keto–Enol Tautomerism
Tautomerization is an interconversion of
isomers that occurs through the migration of
a proton and the movement of a double bond.
Tautomers are not resonance forms.
© 2013 Pearson Education, Inc. Chapter 22 7
Base-Catalyzed Tautomerism
A proton on the a carbon is abstracted to form a resonance-stabilized enolate ion with the negative charge spread over a carbon atom and an oxygen atom.
The equilibrium favors the keto form over the enolate ion.
© 2013 Pearson Education, Inc. Chapter 22 8
Acid-Catalyzed Tautomerism
In acid, the oxygen is first protonated, and
then a proton from the a carbon is removed.
© 2013 Pearson Education, Inc. Chapter 22 9
In acid, proton transfers usually occur by
adding a proton in the new position, then
deprotonating the old position.
In base, proton transfers usually occur by
deprotonating the old position, then
reprotonating at the new position.
© 2013 Pearson Education, Inc. Chapter 22 10
Racemization
For aldehydes and ketones, the keto form is greatly favored at equilibrium.
If a chiral a carbon has an enolizable hydrogen atom, a trace of acid or base allows that carbon to invert its configuration, with the enol serving as the intermediate. This is called racemization.
© 2013 Pearson Education, Inc. Chapter 22 11
Acidity of a Hydrogens
pKa for a H of aldehyde or ketone ~20.
Much more acidic than alkane or alkene
(pKa > 40) or alkyne (pKa = 25).
Less acidic than water (pKa = 15.7) or
alcohol (pKa = 16–19).
Only a small amount of enolate ion is
present at equilibrium.
© 2013 Pearson Education, Inc. Chapter 22 12
Formation and Stability of
Enolate Ions
The equilibrium mixture contains only a small
fraction of the deprotonated, enolate form.
© 2013 Pearson Education, Inc. Chapter 22 13
Energy Diagram of Enolate
Reaction
Even though the keto–enol tautomerism equilibrium
favors the keto form, addition of an electrophile shifts
the equilibrium toward the formation of more enol.
© 2013 Pearson Education, Inc. Chapter 22 14
Synthesis of Lithium
Diisopropylamine (LDA)
LDA is made by using an alkyllithium reagent
to deprotonate diisopropylamine.
LDA can convert a carbonyl compound
completely to its enolate.
© 2013 Pearson Education, Inc. Chapter 22 15
Enolate of Cyclohexanone
When LDA reacts with a ketone, it abstracts
the a proton to form the lithium salt of the
enolate.
© 2013 Pearson Education, Inc. Chapter 22 16
The a Halogenation of Ketones
When a ketone is treated with a halogen and a base, an ahalogenation reaction occurs.
The reaction is called base-promoted, rather than base-catalyzed, because a full equivalent of the base is consumed in the reaction.
© 2013 Pearson Education, Inc. Chapter 22 17
Base-Promoted Halogenation
Mechanism
The base-promoted halogenation takes place by a nucleophilic attack of an enolate ion on the electrophilic halogen molecule.
The products are the halogenated ketone and a halide ion.
© 2013 Pearson Education, Inc. Chapter 22 18
Multiple Halogenations
The a-haloketone produced is more reactive than ketone because the enolate ion is stabilized by the electron-withdrawing halogen.
The second halogenation occurs faster than the first.
Because of the tendency for multiple halogenations this base-promoted halogenation is not widely used to prepare monohalogenated ketones.
© 2013 Pearson Education, Inc. Chapter 22 19
Haloform Reaction
A methyl ketone reacts with a halogen under
strongly basic conditions to give a
carboxylate ion and a molecule of haloform.
The trihalomethyl intermediate is not isolated.
© 2013 Pearson Education, Inc. Chapter 22 20
Final Steps of the Haloform
Reaction
The trihalomethyl ketone reacts with hydroxide ion to give a carboxylic acid.
A fast proton exchange gives a carboxylate ion and a haloform.
When Cl2 is used, chloroform is formed; Br2 forms bromoform; and I2 forms iodoform.
© 2013 Pearson Education, Inc. Chapter 22 21
Positive Iodoform Test
for Alcohols
Iodoform test is used to identify methyl
ketones.
Alcohols can give a positive iodoform test.
Iodoform (CHI3) is a yellow solid that will
precipitate out of solution.
© 2013 Pearson Education, Inc. Chapter 22 22
Propose a mechanism for the reaction of 3-pentanone with sodium hydroxide and bromine to give
2-bromo-3-pentanone.
In the presence of sodium hydroxide, a small amount of 3-pentanone is present as its enolate.
The enolate reacts with bromine to give the observed product.
Solved Problem 1
Solution
© 2013 Pearson Education, Inc. Chapter 22 23
Acid-Catalyzed α Halogenation
Ketones also undergo acid-catalyzed a halogenation.
Acidic halogenation may replace one or more alpha hydrogens depending on how much halogen is used.
© 2013 Pearson Education, Inc. Chapter 22 24
Mechanism of Acid-Catalyzed
α Halogenation
The mechanism of acid-catalyzed halogenation involves attack of the enol form of the ketone on the electrophile halogen molecule.
Loss of a proton gives the haloketone and the hydrogen halide.
© 2013 Pearson Education, Inc. Chapter 22 25
Propose a mechanism for the acid-catalyzed conversion of cyclohexanone to 2-chlorocyclohexanone.
Under acid catalysis, the ketone is in equilibrium with its enol form.
The enol acts as a weak nucleophile, attacking chlorine to give a resonance-stabilized intermediate.
Loss of a proton gives the product.
Solved Problem 2
Solution
© 2013 Pearson Education, Inc. Chapter 22 26
Hell–Volhard–Zelinsky (HVZ)
Reaction
The HVZ reaction replaces a hydrogen atom with a
bromine atom on the alpha carbon of a carboxylic acid
(a-bromoacid).
The acid is treated with bromine and phosphorus
tribromide, followed by hydrolysis.
© 2013 Pearson Education, Inc. Chapter 22 27
Hell–Volhard–Zelinski Reaction:
Step 1
The enol form of the acyl bromide serves as a
nucleophilic intermediate.
The first step is the formation of acyl bromide, which
enolizes more easily than does the acid.
© 2013 Pearson Education, Inc. Chapter 22 28
Hell–Volhard–Zelinski Reaction:
Step 2
The enol is nucleophilic, so it attacks bromine to give the alpha-brominated acyl bromide.
In the last step of the reaction, the acyl bromide is hydrolyzed by water to the carboxylic acid.
© 2013 Pearson Education, Inc. Chapter 22 29
Alkylation of Enolate Ions
Because the enolate has two nucleophilic sites (the oxygen and the a carbon), it can react at either of these sites.
The reaction usually takes place primarily at the acarbon, forming a new C—C bond.
© 2013 Pearson Education, Inc. Chapter 22 30
a Alkylation of Enolate Ions
LDA forms the enolate.
The enolate acts as the nucleophile and attacks the
partially positive carbon of the alkyl halide, displacing
the halide and forming a C—C bond.
© 2013 Pearson Education, Inc. Chapter 22 31
Enamine Formation
Ketones or aldehydes react with a secondary amine to form enamines.
The enamine has a nucleophilic a carbon, which can be used to attack electrophiles.
© 2013 Pearson Education, Inc. Chapter 22 32
Mechanism of Enolate Formation
An enamine results from the reaction of a
ketone or aldehyde with a secondary amine.
© 2013 Pearson Education, Inc. Chapter 22 33
Alkylation of an Enamine
Enamines displace halides from reactive alkyl
halides, giving alkylated iminium salts.
The alkylated iminium salt can be hydrolyzed
to the ketone under acidic conditions.
© 2013 Pearson Education, Inc. Chapter 22 34
Acylation of Enamines
The enamine attacks the acyl halide, forming an acyl iminium salt.
Hydrolysis of the iminium salt produces the b-diketone as the final product.
© 2013 Pearson Education, Inc. Chapter 22 35
Condensation of Ketones and
Aldehydes
Condensations combine two or more
molecules, often with the loss of a small
molecule such as water or an alcohol.
The aldol condensation is the addition
of an enolate ion to another carbonyl
group. It occurs under basic conditions.
© 2013 Pearson Education, Inc. Chapter 22 36
Aldol Condensation
Under basic conditions, the aldol condensation involves the nucleophilic addition of an enolate ion to another carbonyl group.
When the reaction is carried out at low temperatures, the b-hydroxy carbonyl compound can be isolated.
Heating will dehydrate the aldol product to the a,b-unsaturated compound.
© 2013 Pearson Education, Inc. Chapter 22 37
Base-Catalyzed Aldol
Condensation: Step 1
During step 1, the base removes the a proton, forming the enolate ion.
The enolate ion has a nucleophilic a carbon.
© 2013 Pearson Education, Inc. Chapter 22 38
Base-Catalyzed Aldol
Condensation: Step 2
The enolate attacks the carbonyl carbon of a
second molecule of carbonyl compound.
© 2013 Pearson Education, Inc. Chapter 22 39
Base-Catalyzed Aldol
Condensation: Step 3
Protonation of the alkoxide gives the aldol
product.
© 2013 Pearson Education, Inc. Chapter 22 40
Acid-Catalyzed Aldol
Condensation: Step 1
Formation of the enol, by protonation on
O followed by deprotonation on C
© 2013 Pearson Education, Inc. Chapter 22 41
Acid-Catalyzed Aldol
Condensation: Step 2
Addition of the enol to the protonated
carbonyl
© 2013 Pearson Education, Inc. Chapter 22 42
Acid-Catalyzed Aldol
Condensation: Step 3
Deprotonation to give the aldol product
© 2013 Pearson Education, Inc. Chapter 22 43
Driving an Aldol Condensation to
Completion
© 2013 Pearson Education, Inc. Chapter 22 44
Dehydration of Aldol Products
Heating a basic or acidic aldol dehydration of
the alcohol functional group.
The product is a a,b-unsaturated conjugated
aldehyde or ketone.
© 2013 Pearson Education, Inc. Chapter 22 45
Crossed Aldol Condensations
When the enolate of one aldehyde (or ketone) adds to the
carbonyl group of a different aldehyde or ketone, the result is
called a crossed aldol condensation.
© 2013 Pearson Education, Inc. Chapter 22 46
Successful Crossed Aldol
Condensations
A crossed aldol condensation can be effective if it is
planned so that only one of the reactants can form an
enolate ion.
© 2013 Pearson Education, Inc. Chapter 22 47
Propose a mechanism for the base-catalyzed aldol condensation of acetone (Figure 22-2).
The first step is formation of the enolate to serve as a nucleophile.
The second step is a nucleophilic attack by the enolate on another molecule of acetone. Protonation
gives the aldol product.
Solved Problem 3
Solution
© 2013 Pearson Education, Inc. Chapter 22 48
Aldol Cyclization
Intramolecular aldol reactions of diketones are often used for making five- and six-membered rings.
Rings smaller or larger than five or six members are not favored due to ring strain or entropy.
© 2013 Pearson Education, Inc. Chapter 22 49
Retrosynthesis of Aldol
Condensation
© 2013 Pearson Education, Inc. Chapter 22 50
Claisen Ester Condensation
The Claisen condensation results when an
ester molecule undergoes nucleophilic acyl
substitution by an enolate.
© 2013 Pearson Education, Inc. Chapter 22 51
The Claisen condensation occurs
by a nucleophilic acyl substitution,
with different forms of the ester
acting as both the nucleophile
(the enolate) and the electrophile
(the ester carbonyl).
© 2013 Pearson Education, Inc. Chapter 22 52
Dieckman Condensation
An internal Claisen cyclization is called a Dieckmann
condensation or a Dieckmann cyclization.
© 2013 Pearson Education, Inc. Chapter 22 53
Crossed Claisen
Two different esters can be used, but one
ester should have no a hydrogens.
Useful esters are benzoates, formates,
carbonates, and oxalates.
Ketones (pKa = 20) may also react with an
ester to form a b-diketone.
© 2013 Pearson Education, Inc. Chapter 22 54
Crossed Claisen Condensation
In a crossed Claisen condensation, an ester
without a hydrogens serves as the
electrophilic component.
© 2013 Pearson Education, Inc. Chapter 22 55
Crossed Claisen Condensation
with Ketones and Esters
Crossed Claisen condensation between ketones and esters are also possible.
Ketones are more acidic than esters, and the ketone component is more likely to deprotonate and serve as the enolate component in the condensation.
© 2013 Pearson Education, Inc. Chapter 22 56
Crossed Claisen Mechanism
The ketone enolate attacks the ester, which
undergoes nucleophilic acyl substitution and,
thereby, acylates the ketone.
© 2013 Pearson Education, Inc. Chapter 22 57
Propose a mechanism for the self-condensation of ethyl acetate to give ethyl acetoacetate.
The first step is formation of the ester enolate. The equilibrium for this step lies far to the
left; ethoxide deprotonates only a small fraction of the ester.
The enolate ion attacks another molecule of the ester; expulsion of ethoxide ion gives ethyl
acetoacetate.
Solved Problem 4
Solution
© 2013 Pearson Education, Inc. Chapter 22 58
In the presence of ethoxide ion, ethyl acetoacetate is deprotonated to give its enolate. This exothermic
deprotonation helps to drive the reaction to completion.
When the reaction is complete, the enolate ion is reprotonated to give ethyl acetoacetate.
Solved Problem 4 (Continued)
Solution (Continued)
© 2013 Pearson Education, Inc. Chapter 22 59
Show what ester would undergo Claisen condensation to give the following b-keto ester.
First, break the structure apart at the a,b bond (a,b to the ester carbonyl). This is the bond formed in
the Claisen condensation.
Solved Problem 5
Solution
© 2013 Pearson Education, Inc. Chapter 22 60
Next, replace the a proton that was lost, and replace the alkoxy group that was lost from the carbonyl.
Two molecules of methyl 3-phenylpropionate result.
Now draw out the reaction. Sodium methoxide is used as the base because the reactants are methyl
esters.
Solved Problem 5 (Continued)
Solution (Continued)
© 2013 Pearson Education, Inc. Chapter 22 61
© 2013 Pearson Education, Inc. Chapter 22 62
Malonic Ester Synthesis
The malonic ester synthesis makes substituted derivatives of acetic acids.
Malonic ester is alkylated or acylated on the carbon that is alpha to both carbonyl groups.
The resulting derivative is hydrolyzed and allowed to decarboxylate.
© 2013 Pearson Education, Inc. Chapter 22 63
Decarboxylation of the
Alkylmalonic Acid
Decarboxylation takes place through a cyclic
transition state, initially giving an enol form
that quickly tautomerizes to the product.
© 2013 Pearson Education, Inc. Chapter 22 64
Example of the Malonic
Synthesis
© 2013 Pearson Education, Inc. Chapter 22 65
Dialkylation of Malonic Ester
© 2013 Pearson Education, Inc. Chapter 22 66
A malonic ester synthesis goes through
alkylation of the enolate, hydrolysis, and
decarboxylation. To design a synthesis,
look at the product and see what groups
are added to acetic acid. Use those
groups to alkylate malonic ester, then
hydrolyze and decarboxylate.
© 2013 Pearson Education, Inc. Chapter 22 67
Show how the malonic ester synthesis is used to prepare 2-benzylbutanoic acid.
2-Benzylbutanoic acid is a substituted acetic acid having the substituents Ph–CH2– and CH3CH2–.
Adding these substituents to the enolate of malonic ester eventually gives the correct
product.
Solved Problem 6
Solution
© 2013 Pearson Education, Inc. Chapter 22 68
Acetoacetic Ester Synthesis
The acetoacetic ester synthesis is similar to
the malonic ester synthesis, but the final
products are ketones.
© 2013 Pearson Education, Inc. Chapter 22 69
Alkylation of Acetoacetic Ester
Ethoxide ion completely deprotonates acetoacetic ester.
The resulting enolate is alkylated by an unhindered alkyl halide or tosylate to give an alkylacetoacetic ester.
© 2013 Pearson Education, Inc. Chapter 22 70
Hydrolysis of Alkylacetoacetic
Ester
Acidic hydrolysis of the alkylacetoacetic ester initially gives an alkylacetoacetic acid, which is a b-keto acid.
The keto group in the b position promotes decarboxylation to form a substituted version of acetone.
© 2013 Pearson Education, Inc. Chapter 22 71
An acetoacetic ester synthesis goes
through alkylation of the enolate,
hydrolysis, and decarboxylation. To
design a synthesis, look at the product
and see what groups are added to
acetone. Use those groups to alkylate
acetoacetic ester, then hydrolyze and
decarboxylate.
© 2013 Pearson Education, Inc. Chapter 22 72
Show how the acetoacetic ester synthesis is used to make 3-propylhex-5-en-2-one.
The target compound is acetone with an n-propyl group and an allyl group as substituents.
Solved Problem 7
Solution
© 2013 Pearson Education, Inc. Chapter 22 73
Hydrolysis proceeds with decarboxylation to give the disubstituted acetone product.
With an n-propyl halide and an allyl halide as the alkylating agents, the acetoacetic ester synthesis
should produce 3-propyl-5-hexen-2-one. Two alkylation steps give the required substitution.
Solved Problem 7 (Continued) Solution (Continued)
© 2013 Pearson Education, Inc. Chapter 22 74
Conjugate Additions: The
Michael Reaction
a,b-Unsaturated carbonyl compounds have unusually electrophilic double bonds.
The b carbon is electrophilic because it shares the partial positive charge of the carbonyl carbon through resonance.
© 2013 Pearson Education, Inc. Chapter 22 75
1,2-Addition and 1,4-Addition When attack occurs at the carbonyl group, protonation
of the oxygen leads to a 1,2-addition.
When attack occurs at the b position, the oxygen atom is the fourth atom counting from the nucleophile, and the addition is called a 1,4-addition.
© 2013 Pearson Education, Inc. Chapter 22 76
Donors and Acceptors
© 2013 Pearson Education, Inc. Chapter 22 77
1,4-Addition of an Enolate to
Methyl Vinyl Ketone (MVK)
An enolate will do a 1,4-attack on the
a,b-unsaturated ketone (MVK).
© 2013 Pearson Education, Inc. Chapter 22 78
Show how the following diketone might be synthesized using a Michael addition.
A Michael addition would have formed a new bond at the b carbon of the acceptor. Therefore,
we break this molecule apart at the b,gbond.
Solved Problem 8
Solution
© 2013 Pearson Education, Inc. Chapter 22 79
Robinson Annulation
With enough base, the product of the Michael
reaction undergoes a spontaneous intramolecular
aldol condensation, usually with dehydration, to give
a six-membered ring—a conjugated cyclohexenone.
© 2013 Pearson Education, Inc. Chapter 22 80
Robinson Mechanism
© 2013 Pearson Education, Inc. Chapter 22 81
You can usually spot a product of
Robinson annulation because it has
a new cyclohexenone ring. The
mechanism is not difficult if you
remember “Michael goes first,”
followed by an aldol with dehydration.