Enols and Enolate Anions as Nucleophiles
Enols and Enolate Anions as Nucleophiles. α-Substitution and Condensation Reactions I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds I.4.1 Aldol Condensation I.4.2 Claisen Condensation I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds 1- Aldol Condensation a) Self Aldol Condensation • In the aldol reaction, two molecules of an aldehyde or ketone with an a hydrogen atom undergo a base-catalyzed carbonyl condensation reaction to form a -hydroxy carbonyl compound. 3 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds ❖Recall that the characteristic reaction of aldehydes and ketones is nucleophilic addition. An aldol reaction is an example of nucleophilic addition in which an enolate is the nucleophile. 4 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds • The mechanism of the aldol reaction occurs in three steps . 5 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds ❖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. 6 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds Position of the aldol equilibrium depends both on reaction conditions and substrate structure ❖ Equilibrium favors condensation product in the case of aldehydes with no a substituent (RCH2CHO) I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds ❖ Equilibrium favors reactant for disubstituted aldehydes (R2CHCHO) and most ketones Worked Example.1 Predicting the Product of an Aldol Reaction What is the structure of the aldol product from propanal? Strategy • . The two molecules of the aldehyde that participate in the aldol reaction react in opposite ways. Solution:In the general features of the aldol reaction, the a carbon of one carbonyl component becomes bonded to the carbonyl carbon of the other component. 10 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds Carbonyl Condensations versus a-Substitutions Carbonyl condensation reactions and a substitutions take place under basic conditions and involve enolate-ion intermediates ❖ a-substitution reactions require a full equivalent of strong base and are carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at low temperature before addition of the electrophile I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds ❖ Carbonyl condensation reactions require only a catalytic amount of a relatively weak base ❖ Enolate ion is generated in the presence of unreacted carbonyl compound I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds Dehydration of Aldol Products • Under the basic reaction conditions, the initial aldol product is often not isolated. Instead, it loses the elements of H2O from the a and carbons to form an a,unsaturated carbonyl compound. 13 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds • An aldol reaction is often called an aldol condensation because the -hydroxy carbonyl compound that is initially formed loses H2O by dehydration. A condensation 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 -hydroxy carbonyl compound under the conditions of the aldol reaction. When the a,-unsaturated carbonyl compound is 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 hydroxy carbonyl compound cannot be isolated. I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds The mechanism of dehydration of Aldol Product Aldol products dehydrate easily because of carbonyl group • Under basic conditions, an acidic a hydrogen is removed, yielding an enolate ion that expels the –OH leaving group in an E1cB reaction • Under acidic conditions an enol is formed, the –OH group is protonated, and water is expelled in an E1 or E2 reaction I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds • The elimination reaction that results in the dehydration proceeds via an E1cB mechanism. • The E1cB mechanism differs from the E1 and E2 mechanisms. • Like the E1 elimination, E1cB requires two steps. Unlike E1 though, 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, not base, because hydroxide is a poor leaving group. However, when the hydroxy group is to a carbonyl, loss of H and OH from the a and carbons forms a conjugated double bond, and the stability of the conjugated system makes up for having such a poor leaving group. • Dehydration of the initial -hydroxy carbonyl compound drives the equilibrium of an aldol reaction to the right, thus favoring product formation. I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds Reaction conditions needed for aldol dehydration are often only slightly more vigorous than conditions for aldol formation • Conjugated enones are often obtained directly from aldol reactions without isolating the intermediate -hydroxy carbonyl compounds • Conjugated enones are more stable than nonconjugated enones • The p bonding molecular orbitals of a conjugated enone like propenal are spread over the entire p system,similar to the p bonding molecular orbitals of a conjugated diene I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds Removal of water from reaction mixture drives the aldol equilibrium toward product Worked Example .2 Predicting the Product of an Aldol Reaction Q: What is the structure of the enone obtained from aldol condensation of acetaldehyde? Strategy • In the aldol reaction, H2O is eliminated and a double bond is formed by removing two hydrogens from the acidic a position of one partner and the carbonyl oxygen from the second partner. Solution I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds b) Crossed Aldol Condensation • Sometimes it is possible to carry out an aldol reaction between two different carbonyl compounds. Such reactions are called crossed or mixed aldol reactions. 20 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds Crossed aldols are synthetically useful in two different situations: [1] When only one carbonyl component has a hydrogens—such cases often lead to the formation of only one product. 21 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds [2] When one carbonyl component has especially acidic a hydrogens, these hydrogens are more readily removed than the other a H atoms. As a result, the -dicarbonyl compound always becomes the enolate component of the aldol reaction. 22 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds Figure 2 below shows the steps for the crossed aldol reaction between diethylmalonate and benzaldehyde. In this type of crossed aldol reaction, the initial -hydroxy compound always loses water to form the highly conjugated product. Figure2 Crossed aldol reaction between benzaldehyde and CH2(COOEt)2 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds -Dicarbonyl compounds are sometimes called active methylene compounds because they are more reactive towards base than other carbonyl compounds. 1,3Dinitriles and a-cyano carbonyl compounds are also active methylene compounds. I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds 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. Both carbonyl components can have a hydrogens because only one enolate is prepared with LDA. When an unsymmetrical ketone is used, LDA selectively forms the less substituted kinetic enolate. I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds c)Intramolecular Aldol Reactions • Some dicarbonyl (dione) compounds react when treated with base in an intramolecular aldol reaction leads to formation of cyclic product –five or sixmembered rings. For example, treatment of 2,5-hexadienone with base forms a fivemembered ring. • 2,5-Hexanedione is called a 1,4-dicarbonyl compound to emphasize the relative positions of its carbonyl groups. 1,4-Dicarbonyl compounds are starting materials for synthesizing five-membered rings. 26 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds Dione contains both electrophile and nucleophile. The enolate formed from one carbonyl group is the nucleophile, and the carbonyl carbon of the other is the electrophile. The steps in this process are no different from the general mechanism of the aldol reaction, followed by dehydration. 27 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds • When 2,5-hexanedione is treated with base in Step [1], two different enolates are possible—enolates A and B, formed by removal of Ha and Hb respectively. • Although enolate A goes on to form the five-membered ring, intramolecular cyclization using enolate B would lead to a strained three-membered ring. I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds • Because the three-membered ring is much higher in energy than the enolate starting material, equilibrium greatly favors the starting materials and the three-membered ring does not form. • Under the reaction conditions, enolate B is re-protonated to form 2,5hexanedione, because all steps except dehydration are equilibria. This equilibrium favors formation of the more stable five-membered ring over the much less stable three-membered ring. • In a similar fashion, six-membered rings can be formed from the intramolecular aldol reaction of 1,5-dicarbonyl compounds. 29 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds • The synthesis of the female sex hormone progesterone involves an intramolecular aldol reaction. 30 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds Useful Transformations of Aldol Products • The aldol reaction is synthetically useful because it forms new carboncarbon bonds, generating products with two functional groups. • -Hydroxy carbonyl compounds formed in aldol reactions are readily transformed into a variety of other compounds. 31 I.4 Condensation Reactions: Reactions of Enolate anions with Carbonyl compounds I.4.2 The Claisen Condensation Reaction Esters have weakly acidic a hydrogens. Reversible condensation reaction between two esters with an a hydrogen in the presence of an alkoxide base to form a -keto ester. is called the Claisen condensation reaction • Unlike the aldol reaction which is base-catalyzed, a full equivalent of base is needed to deprotonate the -keto ester formed in Step [3] of the Claisen reaction. • Note that because esters have a leaving group on the carbonyl carbon, loss of the leaving group occurs to form the product of substitution, not addition. 2-Claisen Condensation Reaction Claisen condensation mechanism proceeds through a tetrahedral intermediate The tetrahedral intermediate expels an alkoxide leaving group to yield an acyl substitution product 35 2-Claisen Condensation 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. Crossed Claisen Condensation Reaction • Like the aldol reaction, 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. • A crossed Claisen is synthetically useful in two different instances: [1] Between two different esters when only one has a hydrogens, one product is usually formed. 37 Crossed Claisen Condensation Reaction [2] Between a ketone and an ester—the enolate is always formed from the ketone component, and the reaction works best when the ester has no a hydrogens. The product of this crossed Claisen reaction is a -dicarbonyl compound, not a -keto ester. Crossed Claisen Condensation Reaction -Dicarbonyl compounds are also prepared by reacting an enolate with ethyl chloroformate or diethyl carbonate. 39 Crossed Claisen Condensation Reaction Reaction [2] is noteworthy because it provides easy access to -ketoesters, which are useful starting materials 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 the following steps. 40 Worked Example. Predicting the Product of a Claisen Condensation Reaction Q: What product would you obtain from Claisen condensation of ethyl propanoate? Strategy • The Claisen condensation of an ester results in loss of one molecule of alcohol and formation of a product in which an acyl group of one reactant bonds to the a carbon of the second reactant. Solution 3-Dieckmann Cyclizations An intramolecular Claisen reaction is called a Dieckmann reaction. Two types of diesters give good yields of cyclic products. 42 3-Dieckmann Cyclizations 43 3-Dieckmann Cyclizations The cyclic -keto ester produced in an intramolecular Claisen cyclization can be further alkylated and decarboxylated • 2-substituted cyclohexanones and cyclopentanones are prepared by the following sequence: 1. Intramolecular Claisen cyclization 2. -Keto ester alkylation 3. Decarboxylation
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