Condensation Revised

© 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.


In drawing mechanisms, you can

show either resonance form of an

enolate attacking the electrophile.


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.


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).


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.


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.


Acid-Catalyzed Tautomerism

In acid, the oxygen is first protonated, and

then a proton from the a carbon is removed.


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.


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.


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.


Formation and Stability of

Enolate Ions

The equilibrium mixture contains only a small

fraction of the deprotonated, enolate form.


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.


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.


Enolate of Cyclohexanone

When LDA reacts with a ketone, it abstracts

the a proton to form the lithium salt of the

enolate.


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.


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.


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.


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.


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.


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.


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


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.


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.


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


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.


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.


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.


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.


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.


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.


Mechanism of Enolate Formation

An enamine results from the reaction of a

ketone or aldehyde with a secondary amine.


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.


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.


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.


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.


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.




The enolate attacks the carbonyl carbon of a

second molecule of carbonyl compound.




Protonation of the alkoxide gives the aldol

product.


Acid-Catalyzed Aldol


Formation of the enol, by protonation on

O followed by deprotonation on C




Addition of the enol to the protonated

carbonyl




Deprotonation to give the aldol product


Driving an Aldol Condensation to

Completion


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.


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.


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.


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


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.


Retrosynthesis of Aldol

Condensation


Claisen Ester Condensation

The Claisen condensation results when an

ester molecule undergoes nucleophilic acyl

substitution by an enolate.


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).


Dieckman Condensation

An internal Claisen cyclization is called a Dieckmann

condensation or a Dieckmann cyclization.


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.


Crossed Claisen Condensation

In a crossed Claisen condensation, an ester

without a hydrogens serves as the

electrophilic component.


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.


Crossed Claisen Mechanism

The ketone enolate attacks the ester, which

undergoes nucleophilic acyl substitution and,

thereby, acylates the ketone.


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


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)


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


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)



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.


Decarboxylation of the

Alkylmalonic Acid

Decarboxylation takes place through a cyclic

transition state, initially giving an enol form

that quickly tautomerizes to the product.


Example of the Malonic

Synthesis


Dialkylation of Malonic Ester


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.


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


Acetoacetic Ester Synthesis

The acetoacetic ester synthesis is similar to

the malonic ester synthesis, but the final

products are ketones.


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.


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.


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.


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


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)


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.


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.


Donors and Acceptors


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).


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


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.


Robinson Mechanism


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.

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Condensation Revised

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