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Chapter 23

Carbonyl Condensation

Reactions

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Condensation Reactions

Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions

Combines both nucleophilic and –substitution steps

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Why this Chapter?

Carbonyl condensation reactions also occur

often in metabolic pathw ays.

Also, one of the general methods used to form

new C-C bonds.

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Carbonyl Condensation: The Aldol Reaction

Acetaldehy de reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldehy de

The b-hy droxy aldehy de product is aldol (aldehy de + alcohol)

This is a general reaction of aldehy des and ketones

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The Equilibrium of the Aldol

The aldol reaction is reversible, favoring the

condensation product only for aldehydes w ith no

substituent

Steric factors are increased in the aldol product

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Aldehydes and Ketones and the Aldol Equilibrium

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Mechanism of Aldol Reactions

Aldol reactions, like all carbony l condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbony l group of the

acceptor molecule

The addition intermediate is protonated to giv e an

alcohol product

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Carbonyl Condensation versus Alpha-Substitution

Carbonyl condensations and -substitutions both involve f ormation of the enolate ion intermediates

Alpha-substitution reactions are accomplished by converting all of the carbonyl compound to enolate form so it is not an electrophile

Immediate addition of an alkyl halide completes the alkylation reaction

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Conditions for Condensations

A small amount (cataly tic amount) of base is used to generate a small amount of enolate in the presence of unreacted carbony l compound

Af ter the condensation, the basic cataly st is regenerated

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Dehydration of Aldol Products: Synthesis of Enones

The b-hy droxy carbony l products dehy drate to y ield conjugated enones

The term “condensation” ref ers to the net loss of water and combination of 2 molecules

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Dehydration of β-Hydroxy Ketones and

Aldehydes

The hy drogen is remov ed by a base, y ielding an enolate ion that expels the –OH leav ing group

Under acidic conditions the –OH group is protonated and water is expelled

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Driving the Equilibrium

Remov al of water f rom the aldol reaction mixture can be used to driv e the reaction toward products

Ev en if the initial aldol f av ors reactants, the subsequent dehy dration step pushes the reaction to completion

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Using Aldol Reactions in Synthesis

If a desired molecule contains either a b-hydroxy carbonyl or a conjugated enone, it might come from an aldol reaction

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Extending the Synthesis

Subsequent transformations can be carried out on the aldol products

A saturated ketone might be prepared by catalytic hy drogenation of the enone product

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Mixed Aldol Reactions

A mixed aldol reaction betw een tw o similar aldehyde or ketone partners leads to a mixture of four possible products

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Mixed Aldol Condensations

Single Mixed Aldol Product

If one of the carbonyl partners contains no hydrogens and the carbonyl is unhindered (such as benzaldehyde and f ormaldehyde) it is a good electrophile and can react with enolates, then a mixed aldol reaction is likely to be successful

2-methylcyclohexanone gives the mixed aldol product on reaction with benzaldehyde

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Single Mixed Aldol Condensations

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Mixed Aldols With Acidic Carbonyl Compounds

Ethy l acetoacetate is completely conv erted into its enolate ion under less basic conditions than monocarbony l partners

Aldol condensations with ethy l acetoacetate occur pref erentially to giv e the mixed product

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Retrosynthesis of Aldol

Condensation

Practice I:21

(1) Which of the following compounds can be prepared as a single product in a mixed aldol reaction?

(2) Show the reactants that will combine to give each compound.

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Intramolecular Aldol Reactions

Treatment of certain dicarbony l compounds with base produces cy clic products by intramolecular reaction

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Mechanism of IntramolecularAldolReactions

Both the nucleophilic carbony l anion donor and the electrophilic carbony l acceptor are now in the same molecule.

The least strained product is f ormed because the reaction is rev ersible

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Intramolecular Cyclization

Reaction

Intramolecular aldol reactions of diketones are of ten used f or making f iv e- and six-membered ringed compounds

Rings smaller or larger than f iv e or six members are not f av ored due to ring strain or entropy

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Practice II:

What product w ould you expect from the base

treatment of 1,6-cyclodecanedione

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The Claisen Condensation Reaction

Reaction of an ester having an hydrogen w ith 1 equivalent of a base to yield a b-keto ester

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Synthesis of acetoacetic ester

Mechanism of the Claisen

Condensation

Similar to aldol condensation: nucleophilic acy l substitution of an ester enolate ion on the carbony l group of a second ester

molecule

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Features of the Claisen Condensation

If the starting ester has more than one acidic

hydrogen, the product b-keto ester has a doubly

activated proton that can be abstracted by base

Requires a full equivalent of base rather than a

catalytic amount

The deprotonation drives the reaction to the

product

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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 I

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 I (Continued)

Solution (Continued)

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Show what ester would undergo a self-claisen condensation to give the following b-keto ester.

First, break the structure apart at the , b bond (, b to the ester carbonyl). This is the bond formed in

the Claisen condensation.

Solved Problem II

Solution

Next, replace the 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 II(Continued)

Solution (Continued)

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Mixed Claisen Condensation

Tw o different esters can be used, but one

ester should have no hydrogens.

Useful esters are benzoates, formates,

carbonates, and oxalates.

Ketones (pKa = 20) may also react w ith an

ester to form a b-diketone.

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Mixed Claisen Condensations

Successful w hen one of the tw o esters acts as the electrophilic acceptor in reactions w ith other ester anions to give mixed b-keto esters

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Mixed Claisen Condensation with

Ketones and Esters

Mixed 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 serv e as the enolate component in the condensation.

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Ketones and Esters

The ketone enolate attacks the ester, w hich

undergoes nucleophilic acyl substitution, and

thereby, acylates the ketone.

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Ketones and Esters

Reactions betw een ketones and esters results in the formation of b-diketones

Best w hen the ester component has no hydrogens and can't act as the nucleophilic donor

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Intramolecular Claisen Condensations: The Dieckmann Cyclization

Intramolecular Claisen condensation

Best with 1,6-diesters (product: 5-memberedb-ketoester) and 1,7-diesters (product: 6-membered b-ketoester)

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Mechanism of the Dieckmann Cyclization

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Alkylation of Dieckmann Product

The cyclic b-keto ester can be further alkylated and decarboxylated as studied in the acetoacetic ester synthesis

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Conjugate Carbonyl Additions:

The Michael Reaction

,b-unsaturated carbony l compounds hav e unusually electrophilic double bonds.

The b-carbon is electrophilic because it shares the partial positiv e charge of the carbony l carbon through resonance.

Conjugate Carbonyl Additions: The Michael Reaction

Enolates can add as nucleophiles to ,b-unsaturated aldehydes and ketones to give the conjugate addition product

More like Aldol products reacting w ith the product from the claisen condensation/Dieckmann reaction

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Best Conditions for the Michael Reaction

Enolate from a b-keto ester or other 1,3-dicarbonyl compound adding to an unhindered ,b-unsaturated ketone

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Mechanism of the Michael

Reaction Nucleophilic

addition of an enolate ion donor to the b carbon of an ,b-unsaturated carbony l acceptor

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Generality of the Michael Reaction Occurs with a variety of ,b-unsaturated carbonyl compounds

(aldehy des, esters, amides), ,b-unsaturated nitriles and nitro compounds

Donors include b-diketones, b-keto esters, malonic esters, b-keto nitriles, and nitro compounds

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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,g bond.

Solved Problem

Solution

Carbonyl Condensations with Enamines:

The Stork Reaction

Enamines are equiv alent to enolates in that their reactions and can be used to accomplish the transf ormations under milder conditions

Enamines are prepared f rom a ketone and a secondary amine

(recall: chapter 19)

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Enamines Are Nucleophilic

Ov erlap of the nitrogen lone-pair orbital with the double-bond π orbitals increases electron density on the carbon atom

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Enamine Addition and

Hydrolysis Enamine adds to an ,b-unsaturated carbonyl

acceptor

The product is hydrolyzed to a 1,5-dicarbonyl compound

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The Robinson Annulation Reaction

A tw o-step process: combines a Michael reaction w ith an intramolecular aldol reaction

The product is a substituted 2-cyclohexenone

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Robinson: Mechanism

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Robinson: Mechanism

Some Biological Carbonyl Condensation Reactions

Malony l ACP is decarboxy lated and enolate is f ormed

Enolate is added to the carbony l group of another acy l group through a thioester linkage to a sy nthase

Tetrahedral intermediate giv es acetoacety l ACP

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Problem

In a mixed Claisen reaction of cyclopentanone

w ith ethyl formate, a much higher yield of the

desired product is obtained by f irst mixing the

tw o carbonyl components and then adding base,

rather than by f irst mixing base w ith

cyclopentanone and then adding ethyl formate.

Explain.

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Answer

If cyclopentanone and base are mixed f irst, aldol

self-condensation of cyclopentanone (Aldol

product) can occur before ethyl formate is

added. If both carbonyl components are mixed

together before adding base, the more favorable

mixed Claisen condensation occurs w ith less

competition from the aldol self -condensation

reaction.

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