University:
Rutgers University Newark
Course:
CHEM 335 | Organic Chemistry
Academic year:

2024
Views:

54

Pages:

105
Author:

Mahitab S.

CHAPTER 19 ENOLATE ANIONS AND ENAMINES ©2018 Cengage Learning. All Rights Reserved. Chapter Outline • (19.1) • (19.2) • (19.3) • (19.4) • • • • (19.5) (19.6) (19.7) (19.8) • (19.9) Formation and reactions of enolate anions: An overview Aldol reaction Claisen and Dieckmann condensations Claisen and aldol condensations in the biological world Enamines Acetoacetic ester synthesis Malonic ester synthesis Conjugate addition to α,β-unsaturated carbonyl compounds Crossed enolate reactions using LDA ©2018 Cengage Learning. All Rights Reserved. Notes d R j YER YER E R e Rik r It Tet Reactivity R or note É A don'tworkonsnareaction someelectrophilesthat oh In Decarboxylation iftar a l b r my r fferenceoli fine us Michalacceptort Arn nudiophise Is electrophile out b RA th Formation of an Enolate Anion • Enolate anions are formed by treating aliphatic carbonyl derivatives (e.g. acetaldehyde) with base Base • The majority of the negative charge in the hybrid is on oxygen ©2018 Cengage Learning. All Rights Reserved. Enolate Anions • Function as nucleophiles in (1) SN2 reactions; and (2) carbonyl addition reactions ©2018 Cengage Learning. All Rights Reserved. Enolate Anions • React primarily at carbon for the following reasons: • Counterions such as the Li+ or Na+ ion are always associated with the enolate anion, and they are more tightly associated with the oxygen atom than the alpha carbon • These counterions block the approaching electrophiles to some degree and reduce the likelihood of a productive collision with the oxygen • Form new carbon-carbon bonds ©2018 Cengage Learning. All Rights Reserved. Aldol Reaction • Nucleophilic addition of the enolate anion derived from an aldehyde or ketone to the carbonyl group of another molecule of the same or different compound • Catalyzed by either acid or base ©2018 Cengage Learning. All Rights Reserved. Base-Catalyzed Aldol Reaction • Step 1: Take a proton away (deprotonation) (key step) • Removal of an α-hydrogen gives a resonance-stabilized enolate anion • Position of this equilibrium lies toward the left ©2018 Cengage Learning. All Rights Reserved. Base-Catalyzed Aldol Reaction • Step 2: Make a new bond between a nucleophile and an electrophile (key step 2) • Nucleophilic addition of the enolate anion to the carbonyl carbon gives a tetrahedral carbonyl addition intermediate ©2018 Cengage Learning. All Rights Reserved. AldolReactions jIr m Nadiophile ÉmÉ R it nuedophia kTr electrophile Is ÉÉÉr rigger t.tt hr Base-Catalyzed Aldol Reaction • Step 3: Add a proton (protonation) • Protonation of the tetrahedral carbonyl addition intermediate gives the aldol product as a racemic mixture and regenerates a new base catalyst ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Aldol Reaction • Step 1: Keto-enol tautomerism (key step) • Step 2: Add a proton (protonation) • Proton transfer to the carbonyl oxygen of a second molecule of aldehyde or ketone gives an oxonium ion ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Aldol Reaction • Step 3: Make a new bond between a nucleophile and an electrophile (key step) • Attack by the enol of one molecule on the protonated carbonyl group of another molecule forms the new carboncarbon bond ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Aldol Reaction • Step 4: Take a proton away (proton transfer) • Proton transfer to A− regenerates the acid catalyst and gives the racemic aldol product ©2018 Cengage Learning. All Rights Reserved. Example 19.1 - Aldol Reaction • Draw the product of the base-catalyzed aldol reaction of each compound a. Butanal b. Cyclohexanone • Solution • The aldol product is formed by nucleophilic addition of the αcarbon of one molecule to the carbonyl carbon of another ©2018 Cengage Learning. All Rights Reserved. Example (Ch.16, α-carbons) x 00 x • Which of the above carbonyl compounds is most acidic? 1. 2. 3. 4. A B C D ©2018 Cengage Learning. All Rights Reserved. Example (Ch.16, α-carbons) 2esters most acidic • Rank the above from the least to the most acidic 1. 2. 3. 4. 5. ©2018 Cengage Learning. All Rights Reserved. compound Example (decarboxylation Ch.17) • Predict the major product of the following reaction 1. 2. 4. 3. 5. ©2018 Cengage Learning. All Rights Reserved. Example (decarboxylation Ch.17) • Predict the product of the following reaction 1. 2. 4. 3. 5. ©2018 Cengage Learning. All Rights Reserved. Example (alkylation/decarboxylation) of • Predict the product of the following sequence of reactions 1. 2. 4. 3. 5. None of these ©2018 Cengage Learning. All Rights Reserved. Dehydration of Aldol Products • β-Hydroxyaldehydes and β-hydroxyketones are very easily dehydrated to α,β-unsaturated aldehydes or ketones • Major product is one in which the carbon-carbon double bond is conjugated with the carbonyl group • Aldol reactions are reversible, and little aldol product is present at equilibrium • Keq for dehydration is generally large • If reaction conditions are sufficiently vigorous to bring about dehydration, good yields of product can be obtained ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Dehydration of an Adol Product • Step 1: Keto-enol tautomerism (key step) • Step 2: Add a proton (protonation) • Proton transfer converts —OH to a better leaving group, —OH2 ©2018 Cengage Learning. All Rights Reserved. Acid-Catalyzed Dehydration of an Adol Product • Step 3: Break a bond to give stable molecules or ions • Loss of water from the oxonium ion intermediate gives the conjugate acid of the final product (key step 2) • Step 4: Take a proton away (proton transfer) • Proton transfer to H2O completes the reaction ©2018 Cengage Learning. All Rights Reserved. Crossed Aldol Reactions • In a crossed aldol reaction, one molecule provides the enolate anion and a different molecule provides the carbonyl group • Is successful when one of the two reactants has NO α-hydrogens and cannot form an enolate anion • It also helps if the same reactant has the more reactive carbonyl group, for example, an aldehyde ©2018 Cengage Learning. All Rights Reserved. Example 19.3 - Crossed Aldol Reactions • Draw a structural formula for the product of the base-catalyzed crossed aldol reaction between furfural and cyclohexanone and for the product formed by its dehydration • Solution ©2018 Cengage Learning. All Rights Reserved. Crossed Aldol Reactions • Nitro groups can be introduced into aliphatic compounds by way of an aldol type reaction between the anion of a nitroalkane and an aldehyde or a ketone Note Nitrates canform Enolate • Reduction of the nitro group in the aldol product formed is a convenient synthetic route to β-aminoalcohols ©2018 Cengage Learning. All Rights Reserved. Intramolecular Aldol Reactions • Useful for the formation of five- and six-membered rings • Example: 2,7-octanedione, which has two α-carbons (5 vs. 7) ©2018 Cengage Learning. All Rights Reserved. Intramolecular Aldol Reactions • A six-membered ring is formed exclusively in the following intramolecular aldol reaction because of its greater stability in comparison to a four-membered ring (6 vs. 4) ©2018 Cengage Learning. All Rights Reserved. Retrosynthetic Analysis of Aldol Products • Aldol products can be dissected into the proper reactants using retrosynthetic analysis ©2018 Cengage Learning. All Rights Reserved. Claisen Condensation (Esters) • Esters form enolate anions, which participate in nucleophilic acyl substitution • Product of a Claisen condensation is a β-ketoester ©2018 Cengage Learning. All Rights Reserved. Claisen Condensation (Esters) • Requires a base • Nonaqueous bases such as sodium ethoxide (NaOEt) in ethanol and sodium methoxide (NaOMe) in methanol are most commonly used • Example: Claisen condensation of two molecules of ethyl propanoate gives the following β-ketoester ©2018 Cengage Learning. All Rights Reserved. Claisen Condensation (Esters) • Step 1: Take a proton away (deprotonation) (key step) • Removal of an α-hydrogen gives a resonance-stabilized enolate anion • Step 2: Make a new bond between a nucleophile and an electrophile (key step 2) (next slide) • Attack of the enolate anion of one ester on the carbonyl carbon of another ester gives a tetrahedral carbonyl addition intermediate ©2018 Cengage Learning. All Rights Reserved. Claisen Condensation (Esters) • Step 3: Break a bond to give stable molecules or ions • Collapse of the tetrahedral carbonyl addition intermediate and ejection of ethoxide ion gives a β-ketoester ©2018 Cengage Learning. All Rights Reserved. Claisen Condensation (Esters) • Step 4: Take a proton away (deprotonation) • An acid-base reaction between the β-ketoester and the ethoxide ion drives the condensation to completion • Step 5: Add a proton (protonation) • Mild acid is added to protonate the enolate anion giving the βketoester ©2018 Cengage Learning. All Rights Reserved. Example 19.4 - Claisen Condensation • Show the product of the Claisen condensation of ethyl butanoate in the presence of sodium ethoxide followed by acidification with aqueous HCl • Solution: The new bond formed in a Claisen condensation is between the carbonyl group of one ester molecule and the αcarbon of another ©2018 Cengage Learning. All Rights Reserved. Dieckmann Condensation • Intramolecular Claisen condensation of a dicarboxylic ester to give a five- or six-membered ring • Mechanism is identical to the mechanism of Claisen condensation ©2018 Cengage Learning. All Rights Reserved. Crossed Claisen Condensations • Crossed Claisen condensations between two different esters • (1) Each ester with two α-hydrogens, give mixtures of four βketoesters: reactions are not synthetically useful • (2) Useful if there are appreciable differences in reactivity between the two esters, that is, when one of them has no αhydrogens and can function only as an enolate anion acceptor Examples of esters without α-hydrogens ©2018 Cengage Learning. All Rights Reserved. Crossed Claisen Condensations • Example: following crossed Claisen condensation is carried out by using the ester with no α-hydrogens in excess ©2018 Cengage Learning. All Rights Reserved. Claisen and Dieckmann Condensations Retrosynthetic Analysis • Functional group pattern created by (1) Claisen, (2) mixed Claisen, or (3) Dieckmann condensation is a β-ketoester ©2018 Cengage Learning. All Rights Reserved. Example (Ch.20) • What is the product of Claisen rearrangement of the 2-butenyl phenyl ether shown below? 1. 2. 4. 3. 5. ©2018 Cengage Learning. All Rights Reserved. Hydrolysis and Decarboxylation of β-Ketoesters • Both the Claisen and Dieckmann condensations yield esters of β-ketoacids ©2018 Cengage Learning. All Rights Reserved. Hydrolysis and Decarboxylation of β-Ketoesters • A Claisen condensation followed by (1) hydrolysis of the ester, (2) acidification, and (3) decarboxylation is a symmetrical ketone ©2018 Cengage Learning. All Rights Reserved. Example 19.6 - Claisen, Hydrolysis, and Decarboxylation • Each compound or set of compounds undergoes a Claisen or Dieckmann condensation followed by acidification, saponification, acidification, and thermal decarboxylation • Draw a structural formula of the product isolated after completion of this reaction sequence ©2018 Cengage Learning. All Rights Reserved. Example 19.6 - Claisen, Hydrolysis, and Decarboxylation • Steps 1 and 2 bring about a crossed Claisen or Dieckmann condensation to give a β-ketoester • Steps 3 and 4 bring about hydrolysis of the β-ketoester to give a β- ketoacid • Step 5 brings about decarboxylation to give a ketone ©2018 Cengage Learning. All Rights Reserved. Acetyl-CoA • Aldol reactions are among the most widely used reactions in the biological world for the formation of new carbon-carbon bonds • One source of carbon atoms for the synthesis of biomolecules is acetyl coenzyme A (acetyl-CoA) • Coenzyme A is a carrier of the two-carbon acetyl group, —CH3CO− ©2018 Cengage Learning. All Rights Reserved. Acetyl-CoA • (1) Claisen condensation of acetyl-CoA is catalyzed by the enzyme thiolase • Followed by an enzyme-catalyzed (2) aldol reaction with a third molecule of acetyl-CoA on the ketone carbonyl of acetoacetylCoA and (3) thioester hydrolysis: Reaction is enantioselective and gives only the S enantiomer. Carboxyl group is ionized at pH 7.4, the approximate pH of blood plasma and many cellular fluids • ©2018 Cengage Learning. All Rights Reserved. Acetyl-CoA • (4) Enzyme-catalyzed reduction by NADPH of the thioester group of 3-hydroxy-3-methylglutaryl-CoA to a 1° alcohol gives mevalonic acid • Change occurs in the designation of configuration from S to R because priorities 2 and 3 become reversed as a result of the reduction ©2018 Cengage Learning. All Rights Reserved. Acetyl-CoA • (5) Phosphorylation by adenosine triphosphate (ATP) followed by (6) β-elimination • Isopentenyl pyrophosphate has the carbon skeleton of isoprene and is a key intermediate in the synthesis of terpenes, cholesterol, and steroid hormones ©2018 Cengage Learning. All Rights Reserved. Enamines • Formed by the reaction of a 2° amine with an aldehyde or ketone (Section 16.8A) • 2° amines most commonly used to prepare enamines are pyrrolidine and morpholine pepraline II • Value of enamines in synthetic organic chemistry • β-carbon is a nucleophile by virtue of the conjugation of the C=C bond with the electron pair on nitrogen • Resemble enols and enolate anions in their reactions ©2018 Cengage Learning. All Rights Reserved. Example 19.7 - Enamines • Draw structural formulas for the aminoalcohol and enamine formed in the following reactions • Solution ©2018 Cengage Learning. All Rights Reserved. Alkylation of Enamines • Enamines undergo SN2 reactions with methyl and 1° haloalkanes, α-haloketones, and α-haloesters • Superior to enolate anions for these reactions as they are less basic and consequently give (1) higher ratios of substitution to elimination products and (2) more alkylation on carbon • Step 1: Make a new bond between a nucleophile and an electrophile: Treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide (key step) ©2018 Cengage Learning. All Rights Reserved. Alkylation of Enamines • Step 2: Hydrolysis of the iminium salt gives an alkylated ketone and regenerates morpholine as its hydrochloride salt ©2018 Cengage Learning. All Rights Reserved. Acylation of Enamines • Process of introducing an acyl group, RCO- or ArCO-, onto an organic molecule • Enamines undergo acylation when treated with acid chlorides or acid anhydrides ©2018 Cengage Learning. All Rights Reserved. Example 19.9 - Enamines • Show how to use an enamine to bring about this synthesis • Solution: (1) Treating cyclopentanone with pyrrolidine gives an enamine; (2) Treating the enamine with hexanoyl chloride, and (3) hydrolysis in aq HCl gives the desired β-diketone ©2018 Cengage Learning. All Rights Reserved. meine Em Alkylation and Acylation Reactions - Retrosynthetic Analysis • Characteristic functional group created by alkylation • Carbonyl compound with an α-carbon possessing a group that can be derived from an SN2 reaction • Characteristic functional group created by acylation • β-dicarbonyl (aldehyde or ketone) ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following reagents will not form an enolate upon reaction with a ketone? Not a base 1. 2. 3. 4. 5. ©2018 Cengage Learning. All Rights Reserved. Acetoacetic Ester Synthesis • Useful for the preparation of mono-substituted and disubstituted acetones of the following types: • Example 1: Consider the acetoacetic ester synthesis of this target molecule, which is a mono-substituted acetone ©2018 Cengage Learning. All Rights Reserved. Acetoacetic Ester Synthesis - Five Reactions • Step 1: Conversion of ethyl acetoacetate to its anion by sodium ethoxide or other alkali metal alkoxides (deprotonation) • Step 2: Alkylation with allyl bromide ©2018 Cengage Learning. All Rights Reserved. Acetoacetic Ester Synthesis - Five Reactions • Steps 3 and 4: Hydrolysis of the alkylated acetoacetic ester followed by acidification • Step 5: Thermal decarboxylation ©2018 Cengage Learning. All Rights Reserved. Acetoacetic Ester Synthesis - Five Reactions • Example 2: Preparation of a di-substituted acetone from ethyl acetoacetate (MeCOCH2CO2Et) • The sequence is interrupted after Step 2 (alkylation) • The monosubstituted acetoacetic ester is treated with a second equivalent of base, carrying out a second alkylation, then Steps 3–5 are carried out ©2018 Cengage Learning. All Rights Reserved. Acetoacetic Ester Synthesis - Retrosynthetic Analysis • Helps derive a desired ketone from the appropriate β-ketoester and alkylating agent (R-Lv, R-LG, Lv or LG = leaving group) ©2018 Cengage Learning. All Rights Reserved. Acetoacetic Ester Synthesis - Variants • Synthetic strategy of acetoacetic ester synthesis is applicable to any β-ketoester • Example: β-ketoesters available from Dieckmann and Claisen condensations that can be made to undergo formation of (1) enolate anion, (2) alkylation or acylation, (3) hydrolysis, which is followed by (4) acidification, and (5) decarboxylation ©2018 Cengage Learning. All Rights Reserved. Example 19.11 - Acetoacetic Ester Synthesis - Variants • Show how to convert racemic ethyl 2oxocyclopentanecarboxylate to racemic 2-allylcyclopentanone • Solution: (1) Treat this β-ketoester with one equivalent of sodium ethoxide to form an anion followed by (2) alkylation of the anion with one equivalent of an allyl halide. Subsequent (3) hydrolysis of the ester in aqueous base followed by (4) acidification and thermal (5) decarboxylation gives the desired product ©2018 Cengage Learning. All Rights Reserved. Example • An acetoacetic ester synthesis can be used to make the following compound a B 1. 2. True False ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following cannot be prepared by the acetoacetic ester synthesis sequence? isnotagoodsNzcompound 1. 2. 3. 4. 5. ©2018 Cengage Learning. All Rights Reserved. Malonic Ester Synthesis • Strategy of a malonic ester (ME) synthesis is identical to that of an acetoacetic ester synthesis • Exception: Starting material is a β-diester rather than a βketoester (diester instead of keto-ester) • Useful for the preparation of mono-substituted and disubstituted acetic acids of the following types: ©2018 Cengage Learning. All Rights Reserved. Malonic Ester Synthesis - Sequential Reactions • Example 1: Consider the synthesis of this target molecule • Step 1: Conversion of diethyl malonate to its anion by sodium ethoxide or some other metal alkoxide (deprotonation) ©2018 Cengage Learning. All Rights Reserved. Malonic Ester Synthesis - Sequential Reactions • Step 2: Alkylation of the anion of diethyl malonate with 1bromo-3-methoxypropane • Steps 3 and 4: Hydrolysis of the alkylated malonic ester and acidification ©2018 Cengage Learning. All Rights Reserved. Malonic Ester Synthesis - Sequential Reactions • Step 5: Decarboxylation • Example 2: Preparation of di-substituted acetic acid from malonic ester • Sequence is interrupted after Step 2 (alkylation) • The monosubstituted diethyl malonate is treated with a second equivalent of base, carrying out a second alkylation, and then Steps 3–5 are carried out ©2018 Cengage Learning. All Rights Reserved. Malonic Ester Synthesis - Retrosynthetic Analysis • Characteristic functional group produced by the malonic acid synthesis: Carboxylic acid in which the α-carbon has one or two methyl, primary, or secondary alkyl groups (SN2 reaction) ©2018 Cengage Learning. All Rights Reserved. Example 19.12 - Malonic Ester Synthesis • Show how the malonic ester synthesis can be used to prepare 3phenylpropanoic acid • Solution: (1) Determine which two carbons of the product originate from diethyl malonate, (2) the location on the carbon chain of the COOH lost in decarboxylation, and (3) the bond formed in the alkylation step. On the basis of this analysis, determine that the starting materials are diethyl malonate and a benzyl halide (retrosynthetic analysis) ©2018 Cengage Learning. All Rights Reserved. Example 19.12 – Malonic Ester Synthesis • Combine the reagents in the following way to get the desired product (Show how the malonic ester synthesis can be used to prepare 3-phenylpropanoic acid) ©2018 Cengage Learning. All Rights Reserved. Conjugate Addition - Michael Reaction • Conjugate addition: Addition of a nucleophile to the β-carbon of an α,β-unsaturated carbonyl compound • Examples of Michael reactions ©2018 Cengage Learning. All Rights Reserved. Conjugate Addition - Michael Reaction • Recall that nucleophiles do not add to ordinary π bonds: π bonds are considered weak nucleophiles that are capable of reacting with strong electrophiles (Section 6.3) • Presence of the adjacent carbonyl group activates a C=C bond for nucleophilic attack in a Michael reaction • Michael reaction with enolate anions gives products with oxygens in a 1,5 relationship: Relationships are a consequence of the polarization of the reagents ©2018 Cengage Learning. All Rights Reserved. Conjugate Addition - Michael Reaction • Aldol (1,3-relationship) vs. Michael reaction (1,5-relationship) prediophile geofrophic • Michael reaction takes place with a wide variety of α,βunsaturated carbonyl compounds and with α,β-unsaturated nitriles and nitro compounds ©2018 Cengage Learning. All Rights Reserved. Table 19.1 - Combinations of Reagents for Effective Michael Reactions (important!) ©2018 Cengage Learning. All Rights Reserved. Michael Reaction - Conjugate Addition of Enolate Anions (Mechanism) • Step 1: Take a proton away (deprotonation) • Treating H—Nu with base gives the nucleophile, Nu:− • Step 2: Make a new bond between a nucleophile and an electrophile (key step) ©2018 Cengage Learning. All Rights Reserved. Michael Reaction - Conjugate Addition of Enolate Anions (Mechanism) • Step 3: Add a proton • Proton transfer from H—B gives the ketone ©2018 Cengage Learning. All Rights Reserved. Michael Reaction - Conjugate Addition of Enamines • Enamines participate as nucleophiles in Michael reactions. • For example, addition of the enamine of cyclohexanone to acrylonitrile, CH2=CHCN deprotarite thdouble bond • Resonance-stabilized enolate anions and enamines are weak bases: react slowly with α,β-unsaturated carbonyl compounds and give 1,4-addition products ©2018 Cengage Learning. All Rights Reserved. Michael Reaction - Organolithium and Grignard Exceptions • Organolithium and Grignard reagents are strong bases: react rapidly with α,β-unsaturated carbonyl compounds and give primarily 1,2-addition products ©2018 Cengage Learning. All Rights Reserved. Michael Reaction - Thermodynamic vs. kinetic • Thermodynamic versus kinetic control of product formation • Conditions of thermodynamic (equilibrium) control lead to the formation of the more stable 1,4-addition product • Provides an answer to why nucleophiles react with conjugated carbonyl compounds by 1,4-addition rather than 1,2-addition ©2018 Cengage Learning. All Rights Reserved. Michael Reaction - Retrosynthetic Analysis ©2018 Cengage Learning. All Rights Reserved. Example 19.13 - Michael Addition • Draw a structural formula for the product formed by treating each set of reactants with sodium ethoxide in ethanol under conditions of the Michael reaction • Solution ©2018 Cengage Learning. All Rights Reserved. Example 19.14 - Michael Addition • Show how the series of reactions in Example 19.13 can be used to prepare 2,6-heptanedione: (1) Michael addition, (2) hydrolysis, (3) acidification, (4) decarboxylation • Retrosynthesis: ©2018 Cengage Learning. All Rights Reserved. Conjugate Addition - Robinson Annulation • Treatment of a cyclic β-ketoester or β-diketone with an α,βunsaturated ketone in the presence of a base catalyst forms a cyclohexenone ring fused to the original ring pard Micro ©2018 Cengage Learning. All Rights Reserved. M Example 19.15 - Robinson Annulation • Draw structural formulas for the lettered compounds (A) and (B) in the following synthetic sequence adiprotonate micahedddition • Solution: Product is the result of (1) Michael addition to an α,βunsaturated ketone followed by (2) base-catalyzed aldol reaction and (3) dehydration I product ofmichaladditi ©2018 Cengage Learning. All Rights Reserved. Robinson Annulation - Retrosynthetic Analysis • Functional group present in the product of a Robinson annulation is a six-membered ring containing an α,β-unsaturated ketone ©2018 Cengage Learning. All Rights Reserved. Conjugate Addition - Lithium Diorganocopper Reagents • Lithium diorganocopper reagents undergo 1,4-addition to α,βunsaturated aldehydes and ketones in a reaction closely related to the Michael reaction • Yields are highest with 1° alkyl, allylic, vinyl, and aryl organocopper reagents • Give almost exclusively 1,4-addition • Other organometallic compounds, including Grignard reagents, add to carbonyl carbons by 1,2-addition ©2018 Cengage Learning. All Rights Reserved. Crossed Enolate Reactions - Acid-Base Considerations • Using a molar equivalent of LDA (lithium diisopropylamide) converts (1) an aldehyde, (2) a ketone, or (3) an ester to its corresponding lithium enolate ©2018 Cengage Learning. All Rights Reserved. Crossed Enolate Reactions - Acid-Base Considerations • With a strong enough base, enolate anion formation can be driven to completion • Lithium diisopropylamide (LDA) - Most commonly used base for enolate anion formation • Prepared by dissolving diisopropylamine in tetrahydrofuran (THF) and treating the solution with butyllithium ©2018 Cengage Learning. All Rights Reserved. Lithium Enolate Reactions - Base Stoichiometry • Proper amount of LDA to use in an aldol reaction is 0.5 equivalents • Quantity is enough to generate 50% enolate, which then reacts with the remaining 50% aldehyde for an efficient and rapid aldol reaction • If one full equivalent of LDA is used, all the aldehyde would be deprotonated and exist as the enolate, leaving no further aldehyde in solution to react and no aldol product would form • This is correct ONLY for self-aldol (1 carbonyl compound) ©2018 Cengage Learning. All Rights Reserved. Crossed Enolate Reactions - LDA • 2 different carbonyl compounds: • crossed aldol reaction between ketone and an aldehyde can be carried out successfully by (1) adding ketone to one equivalent of LDA to convert it completely to its enolate anion, (2) preformed enolate is treated with the aldehyde, (3) followed by workup in water to give the crossed aldol condensation product Goy • Using LDA allows one to direct crossed aldol and crossed Claisen reactions ©2018 Cengage Learning. All Rights Reserved. IDA ex Ling RF f R la RYER Cohere i ey i river I l Metrefates fl.ba R I R Cher pheltzdto.ME Example 19.17 - LDA • Show how to prepare 5-hydroxy-4-methyl-3-hexanone using a crossed aldol reaction • Solution: First, recognize that the two carbonyl-containing compounds to be joined in the aldol reaction are 3-pentanone and acetaldehyde. (1) Treat the symmetrical ketone with LDA to form its lithium enolate. (2) Treat this enolate anion with acetaldehyde , (3) followed by aqueous workup gives the desired aldol product. ©2018 Cengage Learning. All Rights Reserved. Crossed Enolate Reactions - Kinetic vs. Thermodynamic Enolates • For ketones with two sets of nonequivalent α-hydrogens, is formation of an enolate anion regioselective? • It has been determined experimentally that a high degree of regioselectivity exists, and its occurrence depends on experimental conditions • Example: When 2-methylcyclohexanone is treated with a slight excess of LDA, the lithium enolate is almost entirely of the salt of the less substituted enolate anion, but when the ketone is used in a slight excess, the more substituted enolate anion is formed ©2018 Cengage Learning. All Rights Reserved. Crossed Enolate Reactions - Kinetic vs. Thermodynamic Enolates • 2-methylcyclohexanone, excess of LDA (kinetic product) • 2-methylcyclohexanone, excess of ketone (thermodynamic prduct) ©2018 Cengage Learning. All Rights Reserved. Crossed Enolate Reactions - Kinetic vs. Thermodynamic Enolates • 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 the establishment of equilibrium between two or more products of a reaction: Composition of the mixture is determined by the relative stabilities of the products • Kinetic control: Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each product ©2018 Cengage Learning. All Rights Reserved. Crossed Enolate Reactions - Kinetic vs. Thermodynamic Enolates (Mechanism) • Equilibrium among enolate anions is established when the ketone is in slight excess • Mechanism: Proton-transfer reactions can occur between an enolate anion and an α-hydrogen of an unreacted ketone, and equilibrium is established between alternative enolate anions ©2018 Cengage Learning. All Rights Reserved. Crossed Enolate Reactions - Kinetic vs. Thermodynamic Enolates • In the case of enolate anion formation, kinetic control refers to the relative rate of removal of alternative α-hydrogens • With the use of a bulky base, the less hindered α-hydrogen is removed more rapidly, and the major product is the less substituted enolate anion • No equilibrium among alternative structures is set up ©2018 Cengage Learning. All Rights Reserved. Example • Which of the following explains why protons α to a carbonyl group show enhanced acidity? 1. 2. 3. 4. 5. An inductive effect from the adjacent carbonyl weakens the C—H bond The conjugate base is stabilized by resonance The charge that results after deprotonation is delocalized An inductive effect from the adjacent carbonyl weakens the C—H bond, and the conjugate base is stabilized by resonance All of these ©2018 Cengage Learning. All Rights Reserved. Example • How many protons with a pKa < 22 exist in the following molecule? 1. 2. 3. 4. 5. 0 1 2 3 4 ©2018 Cengage Learning. All Rights Reserved. Example (phenols, Ch.21) • The equilibrium will favor the products in the following reaction 1. 2. True False ©2018 Cengage Learning. All Rights Reserved. Problem 19.59 - Michael Addition • The widely used anticoagulant warfarin is synthesized from 4hydroxycoumarin, benzaldehyde, and acetone as shown in this retrosynthesis • Show how warfarin is synthesized from these reagents ©2018 Cengage Learning. All Rights Reserved. Problem 19.59 - Michael Addition • The synthesis starts with a crossed aldol reaction and dehydration between benzaldehyde and acetone ©2018 Cengage Learning. All Rights Reserved. Problem 19.59 - Michael Addition • Next is a Michael reaction followed by proton transfer and ketoenol tautomerism ©2018 Cengage Learning. All Rights Reserved.