19 19-3 Enolate Anions Enolate anions are nucleophiles in S N 2 reactions and carbonyl addition reactions
19 19-4 The Aldol Reaction The most important reaction of an enolate anion is nucleophilic addition to the carbonyl group of another molecule of the same or different compound Although these reactions may be catalyzed by either acid or base, base catalysis is more common
19 19-5 The Aldol Reaction The product of an aldol reaction is a -hydroxyaldehyde or a -hydroxyketone
19 19-6 The Aldol Reaction: base A three-step mechanism Step 1: formation of a resonance-stabilized enolate anion Step 2: the enolate anion adds to the carbonyl group of another carbonyl-containing molecule to give a TCAI Step 3: proton transfer to O - completes the aldol reaction
19 19-7 The Aldol Reaction: acid Step 1: acid-catalyzed equilibration of keto and enol forms Step 2: proton transfer from HA to the carbonyl group of a second molecule of aldehyde or ketone
19 19-8 The Aldol Reaction: acid Step 3: attack of the enol of one molecule on the protonated carbonyl group of another molecule Step 4: proton transfer to A - completes the reaction
19 19-9 The Aldol Products: -H 2 O Aldol products are very easily dehydrated to an , - unsaturated aldehyde or ketone aldol reactions are reversible and often little aldol present at equilibrium K eq for dehydration is generally large if reaction conditions bring about dehydration, good yields of product can be obtained
19 19-10 Crossed Aldol Reactions In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group
19 19-11 Crossed Aldol Reactions Crossed aldol reactions are most successful if one of the reactants has no -hydrogen and, therefore, cannot form an enolate anion and the other reactant has a more reactive carbonyl group, namely an aldehyde
19 19-12 Aldol Reactions Intramolecular aldol reactions are most successful for formation of five- and six- membered rings
19 19-13 Aldol Reactions in this example, a six-membered ring forms in preference to a four-membered ring
19 19-14 Aldol Reactions The -hydrogens of nitroalkanes are removed by strong bases such as KOH and NaOH
19 19-15 The Aldol Reaction Reduction of a nitro group gives a 1° amine
19 19-16 Directed Aldol Reactions Kinetic vs thermodynamic control when alkali metal hydroxides or alkoxides are used as bases, the position of equilibrium for formation of enolate anions favors reactants
19 19-17 Directed Aldol Reactions With stronger bases, however, the formation of enolate anion can be driven to the right One of the most widely used bases for this purpose is lithium diisopropylamide, LDA LDA is a very strong base but, because of crowding around nitrogen, is a poor nucleophile
19 19-18 Directed Aldol Reactions With 1 mole of LDA, an aldehyde, ketone, or ester is converted completely to its enolate anion
19 19-19 Lithium Enolate Anions For a ketone with two different sets of - hydrogens, is formation of the enolate anion regioselective? The answer depends on experimental conditions when a slight excess of LDA, a ketone is converted to its lithium enolate anion, which consists almost entirely of the less substituted enolate anion kinetic controlthis reaction is said to be under kinetic control for a reaction under kinetic control, the composition of the product mixture is determined by the relative rates of formation of each product
19 19-20 Kinetic Control with slight excess of LDA for formation of lithium enolates, kinetic control refers to the rates of removal of alternative -hydrogens
19 19-21 Thermodynamic Control thermodynamic control In a reaction under thermodynamic control: reaction conditions permit equilibration of alternative products under equilibrium conditions, the composition of the product mixture is determined by their relative stabilities with the ketone in slight excess, the lithium enolate is richer in the more substituted enolate anion
19 19-22 Directed Aldol Reactions Consider the crossed aldol reaction between phenylacetaldehyde and acetone each reactant has -hydrogens and a mixture of four aldol products is possible
19 19-23 Directed Aldol Reactions the desired reaction can be carried out by preforming the lithium enolate anion of acetone and treating it with benzaldehyde
19 19-24 Claisen Condensation Esters also form enolate anions which participate in nucleophilic acyl substitution the product of a Claisen condensation is a -ketoester
19 19-25 Claisen Condensation Claisen condensation of ethyl propanoate gives this -ketoester
19 19-26 Claisen Condensation Step 1: formation of an enolate anion
19 19-27 Claisen Condensation Step 2: attack of the enolate anion on a carbonyl carbon gives a TCAI Step 3: collapse of the TCAI gives a -ketoester and an alkoxide ion
19 19-28 Claisen Condensation Step 4: formation of the enolate anion of the -ketoester drives the Claisen condensation to the right
19 19-29 Dieckman Condensation An intramolecular Claisen condensation
19 19-30 Crossed Claisen Condsns 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, e.g., when one of them has no -hydrogens
19 19-31 Crossed Claisen Condsns the ester with no -hydrogens is generally used in excess
19 19-33 Claisen Condensation The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone
19 19-34 From Acetyl Coenzyme A Carbonyl condensations are among the most widely used reactions in the biological world for 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)
19 19-35 Acetyl-CoA Claisen condensation of acetyl-CoA is catalyzed by the enzyme thiolase
19 19-36 Acetyl-CoA this is followed by an aldol reaction with a second molecule of acetyl-CoA
19 19-37 Acetyl-CoA enzyme-catalyzed reduction of the thioester group phosphorylation by ATP followed by -elimination
19 19-38 Acetyl-CoA isopentenyl pyrophosphate has the carbon skeleton of isoprene and is a key intermediate in the synthesis of these classes of biomolecules
19 19-39 Enamines Enamines 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
19 19-41 Enamines the value of enamines is that the -carbon is nucleophilic and resembles enols and enolate anions in its reactions
19 19-42 Enamines - Alkylation Enamines undergo S N 2 reactions with methyl and 1° alkyl halides, -haloketones, and -haloesters Step 1: treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide
19 19-43 Enamines - Alkylation Step 2: hydrolysis of the iminium halide gives an alkylated aldehyde or ketone
19 19-44 Enamines - Acylation Enamines undergo acylation when treated with acid chlorides and acid anhydrides the reaction is an example of nucleophilic acyl substitution
19 19-45 Acetoacetic Ester Synth. The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types
19 19-46 Acetoacetic Ester Synth. consider the AAE synthesis of this target molecule, which is a monosubstituted acetone
19 19-47 Acetoacetic Ester Synth. Step 1: formation of the enolate anion of AAE Step 2: alkylation with allyl bromide
19 19-48 Acetoacetic Ester Synth. saponification, acidification, and decarboxylation gives the target molecule
19 19-49 Acetoacetic Ester Synth. to prepare a disubstituted acetone, treat the monoalkylated AAE with a second mole of base
19 19-50 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
19 19-51 Malonic Ester Synthesis Consider the synthesis of this target molecule
19 19-52 Malonic Ester Synthesis treat malonic ester with an alkali metal alkoxide alkylation with benzyl chloride saponification, acidification, and decarboxylation
19 19-53 Michael Reaction Michael reaction: Michael reaction: the nucleophilic addition of an enolate anion to an , -unsaturated carbonyl compound Example:
19 19-55 Michael Reaction We can write the following 4 step mechanism for a Michael reaction Step 1: proton transfer to the base Step 2: addition of Nu: - to the carbon of the , - unsaturated carbonyl compound
19 19-56 Michael Reaction Step 3: proton transfer to HB gives an enol Step 4: tautomerism of the less stable enol to the more stable keto (not shown) form gives the observed product
19 19-59 Michael Reactions Enamines also participate in Michael reactions
19 19-60 Gilman Reagents Gilman reagents undergo conjugate addition to , -unsaturated aldehydes and ketones in a reaction closely related to the Michael reaction
19 19-61 Gilman Reagents Gilman reagents are unique among organometallic compounds in that they give almost exclusively 1,4-addition Other organometallic compounds, including Grignard reagents, add to the carbonyl carbon by 1,2-addition The mechanism of conjugate addition of Gilman reagents is not fully understood
19 19-62 Prob 19.18 Draw the structural formula for the product of the aldol reaction of each compound followed by dehydration.
19 19-63 Prob 19.19 Draw the structural formula for the product of each crossed aldol reaction followed by its dehydration.
19 19-64 Prob 19.21 Show how to prepare each -unsaturated ketone by an aldol reaction followed by dehydration.
19 19-65 Prob 19.22 Show how to prepare each -unsaturated ketone by an aldol reaction followed by dehydration.
19 19-66 Prob 19.23 Propose a structural formula for the product of this aldol/dehydration reaction.
19 19-67 Prob 19.24 Propose a structural formula for the intermediate compound C 6 H 10 O 2 in this conversion.
19 19-68 Prob 19.25 Propose a structural formula for each lettered compound.
19 19-69 Prob 19.26 Show how to bring about this conversion.
19 19-70 Prob 19.27 Propose a mechanism for the steam hydrolysis of pulegone. Assign an R or S configuration to pulegone, and to the 3-methylcyclohexanone formed in the reaction.
19 19-71 Prob 19.28 Propose a mechanism for this acid-catalyzed aldol reaction and for its acid-catalyzed dehydration.
19 19-72 Prob 19.35 Propose structural formulas for A, B, and the ketone formed in this reaction sequence.
19 19-73 Prob 19.36 Propose a synthesis for each ketone, using as one step in the sequence a Claisen condensation followed by hydrolysis and decarboxylation.
19 19-74 Prob 19.37 Propose a mechanism for this conversion.
19 19-75 Prob 19.38 Propose structural formulas for A, B, and the diketone, C 9 H 6 O 2.
19 19-76 Prob 19.39 Show how a Reformatsky reaction can be used to prepare each compound from an -haloester and an aldehyde or ketone.
19 19-77 Prob 19.40(a) Propose a mechanism for the Perkins condensation; the condensation of an aromatic aldehyde with a carboxylic anhydride.
19 19-78 Prob 19.40(b) Propose a mechanism for the Darzen’s glycidic ester condensation; the condensation of an -haloester with a ketone or aldehyde.
19 19-79 Prob 19.41 Why is enamine A with the less substituted double bond the thermodynamically favored product?
19 19-80 Prob 19.42 Enamines can undergo C-alkylation and N-alkylation. Explain why heating the C- and N-alkylated isomers gives only the C-alkylated product.
19 19-81 Prob 19.43 Propose a mechanism for this conversion.
19 19-82 Prob 19.44 Propose a synthesis for this target molecule from compound A.
19 19-83 Prob 19.45 Propose a mechanism for this reaction.
19 19-84 Prob 19.46 Propose a synthesis for each compound from diethyl malonate.
19 19-85 Prob 19.49 Propose a mechanism for the formation of each named compound in this sequence.
19 19-86 Prob 19.50 Show how to prepare each lactone using the scheme from the previous problem.
19 19-87 Prob 19.51 Draw structural formulas for intermediates A-D in this synthesis.
19 19-88 Prob 19.52 Propose a mechanism for the formation of the bracketed intermediate and the bicyclic ketone.
19 19-89 Prob 19.53 Show reagents and experimental conditions to bring about this synthesis.
19 19-90 Prob 19.54 Show how nifedipine can be synthesized from 2- nitrobenzaldehyde, methyl acetoacetate, and ammonia.
19 19-91 Prob 19.55 Show reagents and experimental conditions to bring about this synthesis.
19 19-92 Prob 19.56 Propose a mechanism for the formation of the bracketed intermediate and for its conversion to compound A.
19 19-93 Prob 19.57 Show how this -diketone can be synthesized from the given starting materials using an enamine reaction.
19 19-94 Prob 19.58 Propose a synthesis for the two needed compounds starting from diethyl malonate, 1,5-dibromopentane, and 1,3-dibromopropane.
19 19-95 Prob 19.59 Show reagents and experimental conditions for the synthesis of oxanamide from butanal.
19 19-96 Prob 19.60 Show how warfarin can be synthesized from the three named starting materials.
19 19-97 Prob 19.61 Propose a synthesis of this vitamin A precursor from isoprene and ethyl acetoacetate.
19 19-98 Prob 11.62 Propose reagents for Steps 1-8 and a mechanism for cyclization of 8 to give frontalin.