carbonyl condensation reactions

8/3/2019 Carbonyl Condensation Reactions

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Carbonyl Condensation Reactions

The Aldol Reaction

In the aldol reaction, two molecules of an aldehyde or ketone react with each other in the presence of a baseto form a F-hydroxy carbonyl compound.



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The Aldol Reaction

The mechanism of the aldol reaction occurs in threesteps.




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The Aldol Reaction

The aldol reaction is a reversible equilibrium, so theposition of the equilibrium depends on the base and thecarbonyl compound.

¯ OH Is the base typically used in an aldol reaction.

Although with ¯ OH only a small amount of enolate isformed, this is appropriate because the startingaldehyde is needed to react with the enolate in thesecond step of the reaction.

Aldol reactions can be carried out with either aldehydesor ketones. With aldehydes, the equilibrium usuallyfavors products, but with ketones the equilibrium favorsthe starting materials. However, there are ways of driving the equilibrium to the right.




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The Aldol Reaction

Recall that the characteristic reaction of aldehydes andketones is nucleophilic addition. An aldol reaction is anucleophilic addition in which an enolate is thenucleophile.


Figure 24.1The aldol reaction²An example

of nucleophilic addition



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The Aldol Reaction

A second example of an aldol reaction is shown withpropanal as the starting material. The two molecules of the aldehyde that participate in the aldol reaction reactin opposite ways.




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The Aldol Reaction

These examples illustrate the general features of thealdol reaction. The E carbon of one carbonyl componentbecomes bonded to the carbonyl carbon of the other component.




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The Aldol Reaction²Dehydration of the Aldol Product

Under the basic reaction conditions, the initial aldolproduct is often not isolated. Instead, it loses theelements of H2O from the E and F carbons to form anE, F-unsaturated carbonyl compound.




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The Aldol Reaction

An aldol reaction is often called an aldol condensationbecause the F-hydroxy carbonyl compound that isinitially formed loses H2O by dehydration. Acondensation reaction is one in which a small molecule,

in this case, H2O, is eliminated during the reaction. It may or may not be possible to isolate the F-hydroxy

carbonyl compound under the conditions of the aldolreaction. When the E, F-unsaturated carbonyl compoundis further conjugated with a carbon-carbon double bond

or a benzene ring (as is the case in reaction 2),elimination of H2O is spontaneous and the F-hydroxycarbonyl compound cannot be isolated.




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The Aldol Reaction

The mechanism of dehydration consists of two steps:deprotonation followed by loss of ¯ OH.




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The Aldol Reaction

The elimination reaction that results in the dehydrationproceeds via an E1cB mechanism.

The E1cB mechanism differs from the E1 and E2 mechanisms.

Like the E1 elimination, E1cB requires two steps. Unlike E1though, the intermediate in E1cB is a carbanion, not a

carbocation. E1cB stands for Elimination, unimolecular, conjugate base.

Regular alcohols dehydrate only in the presence of acid, notbase, because hydroxide is a poor leaving group. However,when the hydroxy group is F to a carbonyl, loss of H and OH

from the E and F carbons forms a conjugated double bond, andthe stability of the conjugated system makes up for having sucha poor leaving group.

Dehydration of the initial F-hydroxy carbonyl compound drivesthe equilibrium of an aldol reaction to the right, thus favoring

product formation.




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Crossed Aldol Reactions

Sometimes it is possible to carry out an aldol reaction betweentwo different carbonyl compounds. Such reactions are calledcrossed or mixed aldol reactions.




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Crossed aldols are synthetically useful in two differentsituations:

[1] When only one carbonyl component has E

hydrogens²such cases often lead to the formation

of only one product.




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[2] When one carbonyl component has especially acidicE hydrogens, these hydrogens are more readilyremoved than the other E H atoms. As a result, the F-

dicarbonyl compound always becomes the enolatecomponent of the aldol reaction.




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Figure 24.2 below shows the steps for the crossed aldolreaction between diethylmalonate and benzaldehyde. Inthis type of crossed aldol reaction, the initial F-hydroxycompound always loses water to form the highlyconjugated product.


Figure 24.2Crossed aldol reaction

between benzaldehyde and

CH2(COOEt)2



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F-Dicarbonyl compounds are sometimes called activemethylene compounds because they are more reactivetowards base than other carbonyl compounds. 1,3-Dinitriles and E-cyano carbonyl compounds are also

active methylene compounds.




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Useful Transformations of Aldol Products

The aldol reaction is synthetically useful because it forms newcarbon-carbon bonds, generating products with two functionalgroups.

F-Hydroxy carbonyl compounds formed in aldol reactions arereadily transformed into a variety of other compounds.


Figure 24.3Conversion of a -hydroxy

carbonyl compound into other

compounds



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Directed Aldol Reactions

A directed aldol reaction is one that clearly defines whichcarbonyl compound becomes the nucleophilic enolate and whichreacts at the electrophilic carbonyl carbon:

[1] The enolate of one carbonyl component is prepared with LDA.

[2] The second carbonyl compound (the electrophile) is added to

this enolate.Both carbonyl components can have E hydrogens because onlyone enolate is prepared with LDA.

When an unsymmetrical ketone is used, LDA selectively forms theless substituted kinetic enolate.


Figure 24.4 A directed aldol reaction

in the synthesis of

periplanone B



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Intramolecular Aldol Reactions

Aldol reactions with dicarbonyl compounds can be usedto make five-and six-membered rings²The enolateformed from one carbonyl group is the nucleophile, andthe carbonyl carbon of the other is the electrophile.

For example, treatment of 2,5-hexadienone with base

forms a five-membered ring.

2,5-Hexanedione is called a 1,4-dicarbonyl compound toemphasize the relative positions of its carbonyl groups.1,4-Dicarbonyl compounds are starting materials for

synthesizing five-membered rings.




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Intramolecular Aldol ReactionsThe steps in this process are no different from the generalmechanism of the aldol reaction, followed by dehydration.




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When 2,5-hexanedione is treated with base in Step [1],two different enolates are possible²enolates A and B,formed by removal of Ha and Hb respectively.

Although enolate A goes on to form the five-memberedring, intramolecular cyclization using enolate B wouldlead to a strained three-membered ring.




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Because the three-membered ring is much higher in energythan the enolate starting material, equilibrium greatly favors thestarting materials and the three-membered ring does not form.

Under the reaction conditions, enolate B is re-protonated toform 2,5-hexanedione, because all steps except dehydration are

equilibria. This equilibrium favors formation of the more stablefive-membered ring over the much less stable three-memberedring.

In a similar fashion, six-membered rings can be formed from theintramolecular aldol reaction of 1,5-dicarbonyl compounds.




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The synthesis of the female sex hormone progesteroneinvolves an intramolecular aldol reaction.


Figure 24.5The synthesis of progesterone

using an intramolecular

aldol reaction



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The Claisen Reaction

In the Claisen reaction, two molecules of an ester reactwith each other in the presence of an alkoxide base toform a F-keto ester.

Unlike the aldol reaction which is base-catalyzed, a full

equivalent of base is needed to deprotonate the F-ketoester formed in Step [3] of the Claisen reaction.

Note that because esters have a leaving group on thecarbonyl carbon, loss of the leaving group occurs to

form the product of substitution, not addition.




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Keep in mind that the characteristic reaction of esters isnucleophilic substitution. A Claisen reaction is anucleophilic substitution in which an enolate is thenucleophile.


Figure 24.6The Claisen reaction²An

example of nucleophilic

substitution



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The Crossed Claisen and Related Reactions

Like the aldol reaction, it is sometimes possible to carry outa Claisen reaction with two different carbonyl componentsas starting materials.

A Claisen reaction between two different carbonylcompounds is called a crossed Claisen reaction.

A crossed Claisen is synthetically useful in two differentinstances:

[1] Between two different esters when only one has E

hydrogens, one product is usually formed.




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[2] Between a ketone and an ester²the enolate is alwaysformed from the ketone component, and the reactionworks best when the ester has no E hydrogens.

The product of this crossed Claisen reaction is a F-

dicarbonyl compound, not a F-keto ester.




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F-Dicarbonyl compounds are also prepared by reactingan enolate with ethyl chloroformate or diethyl carbonate.




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Reaction [2] is noteworthy because it provides easyaccess to F-ketoesters, which are useful startingmaterials in the acetoacetic ester synthesis.

In this reaction, Cl ¯ is eliminated rather than ¯ OEt in Step

[3] because Cl ¯ is a better leaving group, as shown in thefollowing steps.




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The Dieckmann Reaction

An intramolecular Claisen reaction is called a Dieckmannreaction. Two types of diesters give good yields of cyclicproducts.




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The Dieckmann Reaction




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The Michael Reaction

The Michael reaction involves two carbonylcomponents²the enolate of one carbonyl compound andan E, F-unsaturated carbonyl compound.

Recall that E, F-unsaturated carbonyl compounds areresonance stabilized and have two electrophilic sites²the carbonyl carbon and the F carbon.




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The E, F-unsaturated carbonyl component is often called aMichael acceptor.




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When the product of a Michael reaction is also a F-ketoester, it can be hydrolyzed and decarboxylated byheating in aqueous acid. This forms a 1,5-dicarbonylcompound.

Recall that 1,5-

dicarbonyl compounds are startingmaterials for intramolecular aldol reactions.




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Figure 24.7 shows a Michael reaction that was a key stepin the synthesis of estrone, a female sex hormone.


Figure 24.7Using a Michael reaction in the

synthesis of the steroid estrone



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The Robinson Annulation

The Robinson annulation is a ring-forming reaction thatcombines a Michael reaction with an intramolecular aldol reaction.

The starting materials for a Robinson annulation are an

E, F-

unsaturated carbonyl compound and an enolate.




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The Robinson annulation forms a six-membered ringand three new C²C bonds²two W bonds and one T

bond.

The product contains an E, F-unsaturated ketone in acyclohexane ring²that is, a 2-cyclohexenone.

To generate the enolate component of the Robinsonannulation, ¯ OH in H2O or ¯ OEt in EtOH are typicallyused.




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The mechanism of the Robinson annulation consists of twoparts: a Michael addition to the E, F-unsaturated carbonylcompound, followed by an intramolecular aldol condensation.




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In part two of the mechanism, an intramolecular aldol reactionis followed by dehydration to form a six-membered ring.




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To draw the product of Robinson annulation without writingout the entire mechanism each time:

[1] Place the E carbon of the carbonyl compound that becomesthe enolate next to the F carbon of the E, F-unsaturated carbonylcompound.

[2] Join the appropriate carbons together as shown. If you followthis method of drawing the starting materials, the double bondin the product always ends up in the same position of the six-membered ring.


carbonyl condensation reactions

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