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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 base to form a F-hydroxy carbonyl compound.

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Carbonyl Condensation Reactions
The Aldol Reaction ‡ The mechanism of the aldol reaction occurs in three steps.

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Carbonyl Condensation Reactions
The Aldol Reaction ‡ The aldol reaction is a reversible equilibrium, so the position of the equilibrium depends on the base and the carbonyl compound. ‡ ¯OH Is the base typically used in an aldol reaction. Although with ¯OH only a small amount of enolate is formed, this is appropriate because the starting aldehyde is needed to react with the enolate in the second step of the reaction. ‡ Aldol reactions can be carried out with either aldehydes or ketones. With aldehydes, the equilibrium usually favors products, but with ketones the equilibrium favors the starting materials. However, there are ways of driving the equilibrium to the right.
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Carbonyl Condensation Reactions
The Aldol Reaction ‡ Recall that the characteristic reaction of aldehydes and ketones is nucleophilic addition. An aldol reaction is a nucleophilic addition in which an enolate is the nucleophile.
Figure 24.1
The aldol reaction²An example of nucleophilic addition

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Carbonyl Condensation Reactions The Aldol Reaction ‡ A second example of an aldol reaction is shown with propanal as the starting material. 5 . The two molecules of the aldehyde that participate in the aldol reaction react in opposite ways.

6 .Carbonyl Condensation Reactions The Aldol Reaction ‡ These examples illustrate the general features of the aldol reaction. The E carbon of one carbonyl component becomes bonded to the carbonyl carbon of the other component.

7 .F-unsaturated carbonyl compound. it loses the elements of H2O from the E and F carbons to form an E. the initial aldol product is often not isolated. Instead.Carbonyl Condensation Reactions The Aldol Reaction²Dehydration of the Aldol Product ‡ Under the basic reaction conditions.

When the E. A condensation reaction is one in which a small molecule. ‡ It may or may not be possible to isolate the F-hydroxy carbonyl compound under the conditions of the aldol reaction.F-unsaturated carbonyl compound is further conjugated with a carbon-carbon double bond or a benzene ring (as is the case in reaction 2). in this case. H2O. elimination of H2O is spontaneous and the F-hydroxy carbonyl compound cannot be isolated. 8 .Carbonyl Condensation Reactions The Aldol Reaction ‡ An aldol reaction is often called an aldol condensation because the F-hydroxy carbonyl compound that is initially formed loses H2O by dehydration. is eliminated during the reaction.

9 .Carbonyl Condensation Reactions The Aldol Reaction ‡ The mechanism of dehydration consists of two steps: deprotonation followed by loss of ¯OH.

‡ E1cB stands for Elimination. thus favoring 10 product formation. ‡ Dehydration of the initial F-hydroxy carbonyl compound drives the equilibrium of an aldol reaction to the right. because hydroxide is a poor leaving group.Carbonyl Condensation Reactions The Aldol Reaction ‡ The elimination reaction that results in the dehydration proceeds via an E1cB mechanism. when the hydroxy group is F to a carbonyl. conjugate base. unimolecular. However. ‡ Regular alcohols dehydrate only in the presence of acid. ‡ Like the E1 elimination. . the intermediate in E1cB is a carbanion. not base. not a carbocation. E1cB requires two steps. ‡ The E1cB mechanism differs from the E1 and E2 mechanisms. and the stability of the conjugated system makes up for having such a poor leaving group. loss of H and OH from the E and F carbons forms a conjugated double bond. Unlike E1 though.

Such reactions are called crossed or mixed aldol reactions.Carbonyl Condensation Reactions Crossed Aldol Reactions ‡ Sometimes it is possible to carry out an aldol reaction between two different carbonyl compounds. 11 .

12 .Carbonyl Condensation Reactions Crossed Aldol Reactions Crossed aldols are synthetically useful in two different situations: [1] When only one carbonyl component has E hydrogens²such cases often lead to the formation of only one product.

the Fdicarbonyl compound always becomes the enolate component of the aldol reaction. As a result.Carbonyl Condensation Reactions Crossed Aldol Reactions [2] When one carbonyl component has especially acidic E hydrogens. these hydrogens are more readily removed than the other E H atoms. 13 .

2 below shows the steps for the crossed aldol reaction between diethylmalonate and benzaldehyde. Figure 24. In this type of crossed aldol reaction. the initial F-hydroxy compound always loses water to form the highly conjugated product.Carbonyl Condensation Reactions Crossed Aldol Reactions Figure 24.2 Crossed aldol reaction between benzaldehyde and CH2(COOEt)2 14 .

3Dinitriles and E-cyano carbonyl compounds are also active methylene compounds.Carbonyl Condensation Reactions Crossed Aldol Reactions F-Dicarbonyl compounds are sometimes called active methylene compounds because they are more reactive towards base than other carbonyl compounds. 1. 15 .

generating products with two functional groups.3 Conversion of a -hydroxy carbonyl compound into other compounds 16 .Carbonyl Condensation Reactions Useful Transformations of Aldol Products ‡ The aldol reaction is synthetically useful because it forms new carbon-carbon bonds. ‡ F-Hydroxy carbonyl compounds formed in aldol reactions are readily transformed into a variety of other compounds. Figure 24.

When an unsymmetrical ketone is used. Both carbonyl components can have E hydrogens because only one enolate is prepared with LDA.Carbonyl Condensation Reactions Directed Aldol Reactions A directed aldol reaction is one that clearly defines which carbonyl compound becomes the nucleophilic enolate and which reacts 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. Figure 24.4 A directed aldol reaction in the synthesis of periplanone B 17 . LDA selectively forms the less substituted kinetic enolate.

5-hexadienone with base forms a five-membered ring. and the carbonyl carbon of the other is the electrophile.Carbonyl Condensation Reactions Intramolecular Aldol Reactions ‡ Aldol reactions with dicarbonyl compounds can be used to make five-and six-membered rings²The enolate formed from one carbonyl group is the nucleophile. 1.4-dicarbonyl compound to emphasize the relative positions of its carbonyl groups. For example. treatment of 2. ‡ 2.4-Dicarbonyl compounds are starting materials for 18 synthesizing five-membered rings.5-Hexanedione is called a 1. .

followed by dehydration.Carbonyl Condensation Reactions Intramolecular Aldol Reactions The steps in this process are no different from the general mechanism of the aldol reaction. 19 .

Carbonyl Condensation Reactions Intramolecular Aldol Reactions ‡ When 2. 20 . intramolecular cyclization using enolate B would lead to a strained three-membered ring. ‡ Although enolate A goes on to form the five-membered ring. formed by removal of Ha and Hb respectively. two different enolates are possible²enolates A and B.5-hexanedione is treated with base in Step [1].

‡ In a similar fashion. six-membered rings can be formed from the intramolecular aldol reaction of 1. because all steps except dehydration are equilibria. enolate B is re-protonated to form 2.5-hexanedione. ‡ Under the reaction conditions. This equilibrium favors formation of the more stable five-membered ring over the much less stable three-membered ring.Carbonyl Condensation Reactions Intramolecular Aldol Reactions ‡ Because the three-membered ring is much higher in energy than the enolate starting material.5-dicarbonyl compounds. 21 . equilibrium greatly favors the starting materials and the three-membered ring does not form.

Carbonyl Condensation Reactions Intramolecular Aldol Reactions ‡ The synthesis of the female sex hormone progesterone involves an intramolecular aldol reaction. Figure 24.5 The synthesis of progesterone using an intramolecular aldol reaction 22 .

loss of the leaving group occurs to form the product of substitution. 23 . ‡ Unlike the aldol reaction which is base-catalyzed.Carbonyl Condensation Reactions The Claisen Reaction ‡ In the Claisen reaction. ‡ Note that because esters have a leaving group on the carbonyl carbon. not addition. two molecules of an ester react with each other in the presence of an alkoxide base to form a F-keto ester. a full equivalent of base is needed to deprotonate the F-keto ester formed in Step [3] of the Claisen reaction.

Carbonyl Condensation Reactions The Claisen Reaction 24 .

6 The Claisen reaction²An example of nucleophilic substitution 25 .Carbonyl Condensation Reactions The Claisen Reaction ‡ Keep in mind that the characteristic reaction of esters is nucleophilic substitution. A Claisen reaction is a nucleophilic substitution in which an enolate is the nucleophile. Figure 24.

26 . ‡ A crossed Claisen is synthetically useful in two different instances: [1] Between two different esters when only one has E hydrogens. it is sometimes possible to carry out a Claisen reaction with two different carbonyl components as starting materials. ‡ A Claisen reaction between two different carbonyl compounds is called a crossed Claisen reaction.Carbonyl Condensation Reactions The Crossed Claisen and Related Reactions ‡ Like the aldol reaction. one product is usually formed.

Carbonyl Condensation Reactions The Crossed Claisen and Related Reactions [2] Between a ketone and an ester²the enolate is always formed from the ketone component. and the reaction works best when the ester has no E hydrogens. 27 . The product of this crossed Claisen reaction is a Fdicarbonyl compound. not a F-keto ester.

Carbonyl Condensation Reactions The Crossed Claisen and Related Reactions F-Dicarbonyl compounds are also prepared by reacting an enolate with ethyl chloroformate or diethyl carbonate. 28 .

as shown in the following steps. Cl¯ is eliminated rather than ¯OEt in Step [3] because Cl¯ is a better leaving group. which are useful starting materials in the acetoacetic ester synthesis. In this reaction. 29 .Carbonyl Condensation Reactions The Crossed Claisen and Related Reactions Reaction [2] is noteworthy because it provides easy access to F-ketoesters.

30 .Carbonyl Condensation Reactions The Dieckmann Reaction An intramolecular Claisen reaction is called a Dieckmann reaction. Two types of diesters give good yields of cyclic products.

Carbonyl Condensation Reactions The Dieckmann Reaction 31 .

Recall that E. 32 .F-unsaturated carbonyl compound.F-unsaturated carbonyl compounds are resonance stabilized and have two electrophilic sites² the carbonyl carbon and the F carbon.Carbonyl Condensation Reactions The Michael Reaction The Michael reaction involves two carbonyl components²the enolate of one carbonyl compound and an E.

Carbonyl Condensation Reactions The Michael Reaction The E.F-unsaturated carbonyl component is often called a Michael acceptor. 33 .

Carbonyl Condensation Reactions The Michael Reaction 34 .

This forms a 1.5-dicarbonyl compound.5-dicarbonyl compounds are starting materials for intramolecular aldol reactions.Carbonyl Condensation Reactions The Michael Reaction ‡ When the product of a Michael reaction is also a F-keto ester. ‡ Recall that 1. it can be hydrolyzed and decarboxylated by heating in aqueous acid. 35 .

Figure 24.7 shows a Michael reaction that was a key step in the synthesis of estrone. a female sex hormone.Carbonyl Condensation Reactions The Michael Reaction Figure 24.7 Using a Michael reaction in the synthesis of the steroid estrone 36 .

37 .F-unsaturated carbonyl compound and an enolate.Carbonyl Condensation Reactions The Robinson Annulation ‡ The Robinson annulation is a ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction. ‡ The starting materials for a Robinson annulation are an E.

Carbonyl Condensation Reactions The Robinson Annulation ‡ The Robinson annulation forms a six-membered ring and three new C²C bonds²two W bonds and one T bond. ‡ The product contains an E. ‡ To generate the enolate component of the Robinson annulation.F-unsaturated ketone in a cyclohexane ring²that is. ¯OH in H2O or ¯OEt in EtOH are typically used. 38 . a 2-cyclohexenone.

Carbonyl Condensation Reactions The Robinson Annulation ‡ The mechanism of the Robinson annulation consists of two parts: a Michael addition to the E. followed by an intramolecular aldol condensation. 39 .F-unsaturated carbonyl compound.

an intramolecular aldol reaction is followed by dehydration to form a six-membered ring. 40 .Carbonyl Condensation Reactions The Robinson Annulation ‡ In part two of the mechanism.

F-unsaturated carbonyl compound. the double bond in the product always ends up in the same position of the sixmembered ring. [2] Join the appropriate carbons together as shown. 41 .Carbonyl Condensation Reactions The Robinson Annulation ‡ To draw the product of Robinson annulation without writing out the entire mechanism each time: [1] Place the E carbon of the carbonyl compound that becomes the enolate next to the F carbon of the E. If you follow this method of drawing the starting materials.