ENOLATE ANIONS AND ENAMINES Chapter 22-23 ENOLATE ANIONS AND ENAMINES

Formation of an Enolate Anion Enolate anions are formed by deprotonation of an -hydrogen of an aldehyde, ketone, or ester. The majority of the negative charge in the hybrid is on oxygen.

Enolate Anions Enolate anions are nucleophiles in SN2 reactions and carbonyl addition reactions.

The Aldol Reaction Aldol Reaction: Addition of the enolate anion of an aldehyde or ketone to the carbonyl group of another molecule of the same or other aldehyde or ketone. They are catalyzed by either acid or base.

The Base-Catalyzed Aldol Reaction Step 1: Take a proton away. Removal of an -hydrogen gives a resonance-stabilized enolate anion. The position of this equilibrium lies toward the left.

The Base-Catalyzed Aldol Reaction Step 2: Make a new bond between a nucleophile and an electrophile. Nucleophilic addition of the enolate anion to the carbonyl carbon gives a tetrahedral carbonyl addition intermediate.

The Base-Catalyzed Aldol Reaction Step 3: Add a proton. Protonation of the intermediate gives the aldol product and generates a new base catalyst.

The Acid-Catalyzed Aldol Reaction Step 1: Keto-enol tautomerism. Step 2: Add a proton. Proton transfer to the carbonyl group of a second molecule of aldehyde or ketone gives an oxonium ion.

The Acid-Catalyzed Aldol Reaction Step 3: Make a new bond between a nucleophile and an electrophile. Attack by the enol of one molecule on the protonated carbonyl of another molecule forms the new carbon-carbon bond.

The Acid-Catalyzed Aldol Reaction Step 4: Take a proton away. Proton transfer to A- regenerates the acid catalyst and gives the racemic aldol product.

The Aldol Products: -H2O Aldol products are very easily dehydrated to ,-unsaturated aldehydes or ketones. Dehydration generates a resonance-stabilized conjugated system. Aldol reactions are reversible and often little aldol is present at equilibrium. Keq for dehydration is generally large. If reaction conditions bring about dehydration, good yields of product can be obtained.

Acid-Catalyzed Aldol Dehydration Step 1: Keto-enol tautomerism. Step 2: Add a proton. Proton transfer to -OH converts it to a better leaving group.

Acid-Catalyzed Aldol Dehydration Step 3: Break a bond to give stable molecules or ions. Loss of water from the oxonium ion gives the conjugate acid of the final product. Step 4: Take a proton away. Proton transfer to H2O completes the reaction.

Crossed Aldol Reactions In a crossed aldol reaction, one molecule provides the enolate anion and a different molecule provides the carbonyl group. Crossed aldol reactions are most successful if: one reactant has no -hydrogen and, therefore, cannot form an enolate anion, and the other reactant has a more reactive carbonyl group, namely an aldehyde.

Crossed Aldol Reactions Nitro groups can be introduced by way of an aldol reaction using a nitroalkane. Nitro groups can be reduced to 1° amines.

Aldol Reactions Intramolecular aldol reactions are most successful for formation of five- and six-membered rings. Consider 2,7-octadione, which has two a-carbons.

Claisen Condensation Esters also form enolate anions which participate in nucleophilic acyl substitution. The product of a Claisen condensation is a -ketoester.

Claisen Condensation Claisen condensation of ethyl propanoate gives this -ketoester.

Claisen Condensation Step 1: Take a proton away to form an enolate anion. Step 2: Make a new bond between a nucleophile and an electrophile. Attack of the enolate anion on a carbonyl carbon gives a tetrahedral carbonyl addition intermediate. E t O - C H 2 = p K a ( w e k r c i d ) 1 5 . 9 s o n g R b l z + C H 3 - O E t 2 + A e r a h d l c b o n y i m

Claisen Condensation Step 3: Break a bond to give stable molecules or ions. Collapse of the intermediate gives a -ketoester and an alkoxide ion. Step 4: Take a proton away. An acid-base reaction drives a Claisen condensation to completion.

Dieckmann Condensation Dieckmann condensation: An intramolecular Claisen condensation

Crossed Claisen Condensations Crossed Claisen condensations between two different esters, each with -hydrogens, give mixtures of products and are not useful. Useful crossed Claisen condensations are possible, however, if there is an appreciable difference in reactivity between the two esters; that is, when one of them has no -hydrogens.

Crossed Claisen Condensations The ester with no -hydrogens is generally used in excess.

Claisen Condensation Claisen condensations are a route to ketones.

Claisen Condensation The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone.

Carbonyl Condensations Carbonyl condensations are among the most widely used reactions in the biological world for the formation of new carbon-carbon bonds in such biomolecules as: fatty acids. cholesterol, bile acids, and steroid hormones. terpenes. One source of carbon atoms for the synthesis of these biomolecules is acetyl coenzyme A (acetyl-CoA). Coenzyme A is a carrier of the two-carbon acetyl group, CH3-CO-

Acetyl-CoA Claisen condensation of acetyl-CoA is catalyzed by the enzyme thiolase.

Acetyl-CoA This is followed by an aldol reaction with a second molecule of acetyl-CoA. Note that this reaction is stereoselective and gives only the S enantiomer.

Acetyl-CoA Enzyme-catalyzed reduction by NADPH of the thioester group. Phosphorylation by ATP followed by -elimination.

Acetyl-CoA Isopentenyl pyrophosphate has the carbon skeleton of isoprene and is a key intermediate in the synthesis of these classes of biomolecules.

Enamines Enamines (Section 16.8A) are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone. The 2° amines most commonly used to prepare enamines are pyrrolidine and morpholine.

Enamines Examples:

Enamines - Alkylation The value of enamines is that the -carbon is nucleophilic. Enamines undergo SN2 reactions with methyl and 1° haloalkanes, -haloketones, and -haloesters. Treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide. A n i m u b r o d e ( a c ) T h p l f y x + B • N O S 2 3 -

Enamines - Alkylation Hydrolysis of the iminium halide gives an alkylated aldehyde or ketone.

Enamines - Alkylation Enamines undergo acylation when treated with acid chlorides and acid anhydrides.

Acetoacetic Ester Synthesis The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types:

Acetoacetic Ester Synthesis Consider the acetoacetic ester synthesis of this target molecule, which is a monosubstituted acetone.

Acetoacetic Ester Synthesis Step 1: Formation of the enolate anion of AAE. Step 2: Alkylation with allyl bromide. C O E t - N a + H S o d i u m s l f e h y c x n p K 1 5 . 9 ( w k r ) 7 g O C E t N a + B r 3 - o m p e n ( A l y b i d ) S 2 c

Acetoacetic Ester Synthesis Steps 3 & 4 Saponification followed by acidification. Step 5: Thermal decarboxylation.

Acetoacetic Ester Synthesis To prepare a disubstituted acetone, treat the monoalkylated AAE with a second mole of base, etc. C O E t - N a + H ( r c e m i ) N a + C O E t H 3 I - S 2 ( r c e m i ) O C E t 3 . N a H , 2 4 l + - M e h y 5 x n o ( r c m i )

Malonic Ester Synthesis The strategy of a malonic ester (ME) synthesis is identical to that of an acetoacetic ester synthesis, except that the starting material is a -diester rather than a -ketoester.

Malonic Ester Synthesis Consider the synthesis of this target molecule:

Malonic Ester Synthesis Treat malonic ester with an alkali metal alkoxide. Alkylate with an alkyl halide. C O E t - N a + H h n o l p K 1 5 . 9 ( w e k r c i d ) S u m x s f y D 3 g M e O B r N a + C E t - S 2

Malonic Ester Synthesis Saponification and acidification. Decarboxylation.

Michael Reaction Michael reaction: the nucleophilic addition of an enolate anion to an ,-unsaturated carbonyl compound.

Michael Reaction Recall that nucleophiles do not add to ordinary  bonds.  bonds generally react only with strong electrophiles (Section 6.3). What activates a carbon-carbon double bond for nucleophilic attack in a Michael reaction is the presence of the adjacent carbonyl group.

Michael Reaction Combinations

Michael Reaction Step 1: Take a proton away. Treating H-Nu with base gives the nucleophile, Nu:-. Step 2: Make a new bond between a nucleophile and an electrophile.

Michael Reaction Step 3: Add a proton. Proton transfer from H-A gives the enol of the final product. Step 4: Keto-enol tautomerism. Conversion of the less stable enol form to the more stable keto form gives the final product.

Michael Reaction A final word about nucleophilic addition to a,b-unsaturated carbonyl compounds. Resonance-stabilized enolate anions and enamines are weak bases, react slowly with a,b-unsaturated carbonyl compounds, and give 1,4-addition products. Organolithium and Grignard reagents, on the other hand, are strong bases, add rapidly to carbonyl groups, and given primarily 1,2-addition.

Michael Reaction Thermodynamic versus kinetic control. Addition of the nucleophile is irreversible for strongly basic carbon nucleophiles.

Robinson Annulations Robinson Annulation: A Michael reaction of -unsaturated ketone followed by an intramolecular aldol reaction that results in the synthesis of a substituted 2-cyclohexenone.

Retrosynthesis of 2,6-Heptanedione

Michael Reactions Enamines also participate in Michael reactions.

Gilman Reagents Gilman reagents undergo conjugate addition to ,-unsaturated aldehydes and ketones in a reaction closely related to the Michael reaction. Gilman reagents are unique among organometallic compounds; They give almost exclusively 1,4-addition. Other organometallic compounds, including Grignard reagents, add to carbonyl carbons by 1,2-addition.

Crossed Enolate Reactions using LDA With a strong enough base, enolate anion formation can be driven to completion. The base most commonly used for this purpose is lithium diisopropylamide , LDA. LDA is prepared by dissolving diisopropylamine in THF and treating the solution with butyllithium.

Crossed Enolate Reactions using LDA Using a molar equivalent of LDA converts an aldehyde, ketone, or ester completely to its corresponding enolate anion.

Crossed Enolate Reactions using LDA The crossed aldol reaction between acetone and an aldehyde can be carried out successfully by adding acetone to one equivalent of LDA to preform its enolate anion, which is then treated with the aldehyde.

Crossed Enolate Reactions using LDA For ketones with two sets of nonequivalent a-hydrogens, is formation of the enolate anion regioselective? The answer is that a high degree of regioselectivity exists and that it depends on experimental conditions.

Crossed Enolate Reactions using LDA When 2-methylcyclohexanone is treated with a slight excess of LDA, the enolate is almost entirely the less substituted enolate anion.

Crossed Enolate Reactions using LDA When 2-methylcyclohexanone is treated with LDA under conditions in which the ketone is in slight excess, the product is richer in the more substituted enolate.

Crossed Enolate Reactions using LDA The most important factor determining the composition of the enolate anion mixture is whether the reaction is under kinetic (rate) or thermodynamic (equilibrium) control. Thermodynamic Control: Experimental conditions that permit establishment of equilibrium between two or more products of a reaction. The composition of the mixture is determined by the relative stabilities of the products.

Crossed Enolate Reactions using LDA Equilibrium among enolate anions is established when the ketone is in slight excess, a condition under which it is possible for proton-transfer reactions to occur between an enolate anion and an a-hydrogen of an unreacted ketone. Thus, equilibrium is established between alternative enolate anions.

Crossed Enolate Reactions using LDA Kinetic control: Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each product. In the case of enolate anion formation, kinetic control refers to the relative rate of removal of alternative a-hydrogens. With the use of a bulky base, the less hindered hydrogen is removed more rapidly, and the major product is the less substituted enolate anion. No equilibrium among alternative structures is set up.

Problem 19.59 The widely used anticoagulant Warfarin is synthesized from 4-hydroxycoumarin, benzaldehyde, and acetone as shown in this retrosynthesis. Show how warfarin is synthesized from these reagents.

Problem 19.59 The synthesis starts with a crossed aldol reaction with dehydration between benzaldehyde and acetone.

Problem 19.59 Next is a Michael reaction followed by proton transfer and keto-enol tautomerism.