Substitution at the α-carbon of carbonyl compounds: Chapter 22 or "How to functionalize a C next to a C=O"

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1 Substitution at the α-carbon of carbonyl compounds: hapter 22 or "ow to functionalize a next to a =" Two major types of rxns of carbonyl compounds occur under basic conditions: 1) Substitution at the α-carbon (focus of h. 22) (halogenation & alkylations) 2) ondensation by reaction at the α-carbon (focus of h. 23) X 2 Y Key factor in reactions: The nearby = of ketones, aldehydes, esters and amides makes the α-hydrogens acidic and easy to remove (see Table 22.1) Two reasons: Electron-withdrawing nature of the carbonyl group esonance-stability of the conjugate base (enolate) Major feature of all α- reactions and mechanisms: Keto-enol tautomerism Section 22.1 Most compounds are far more stable in the keto form When the enol forms, it s reactive Phenols have more stable enol tautomers because they are aromatic

3 Mechanism of acid-catalyzed substitution (enol form): + A- E + E E E Key acid-catalyzed alpha- substitution reactions: A. Acid-catalyzed alpha-halogenation (22.3) Br 2, l 2 or I 2 can substitute at the α-carbon of an aldehyde or ketone Main uses: 1. Allows the α-carbon to be functionalized by S N 2 substitutions 2. Provides route to α, β unsaturated ketones by elimination Br 2 Ac 3 Br 3 B. ell-volhard-zelinski (VZ) reaction: arboxylic acids normally don t enolize, so this reaction forms an acyl bromide that does enolize and then undergoes α-bromination. ydrolysis gives back the carboxylic acid: Br 2, PBr Br

4 Enolates In the presence of strong base, an α-hydrogen can be removed to create a carbanion that is resonance-stabilized through formation of an enolate species: -:B Two nucleophilic sites are produced : the α-carbon and the oxygen. Some strong bases: Lithium diisopropyl amide (LDA) Sodium ethoxide (Na + -Et) Na, NaN 2 Formation of an enolate by LDA: In a based-catalyzed α-substitution: The nucleophile is a carbanion generated by deprotonation at α- The electrophile can be varied for each reaction, to give variety of products. Substitution reactions involving the enolate intermediate result in replacement of acidic by halogen or alkyl group A) alogenations: Iodoform reaction (base-catalyzed) 22.6 B) Alkylations: Direct α-alkylation of ketones, esters & nitriles 22.7 Malonic Ester Synthesis of substituted esters or carboxylic acids Acetoacetic Acid synthesis of methyl ketones

5 A) Base-catalyzed halogenation: Iodoform reaction: lassification test to identify a methyl ketone I 2, Na I I 3 B) Alkylation: Base-catalyzed substitution of alkyl groups at the α-position B1) Strong base (LDA) deprotonates the α-carbon of a ketone, ester or nitrile. Enolate species is a good nucleophile, undergoes S N 2 reaction with alkyl halides: LDA, TF 3 2 I Steric hindrance can determine what the major product will be

6 B2) Base-catalyzed diester alkylation: Activation of the sandwiched α-carbon of diethyl malonate A practical example: Synthesis of active barbiturates Barbituric acid and its active derivatives are heterocyclic rings that can be synthesized in 2 parts by condensation. The bottom half comes from a diester, diethyl malonate; the top half from urea The substituted barbiturates have sedative, hypnotic and anaesthetic properties that vary with the chain length and structure of groups Amobarbital Pentobarbital Phenobarbital = ethyl = ethyl = ethyl = isoamyl = 2-pentyl = phenyl N N ' Part 1 of the synthesis is α-alkylation of diethyl malonate: Part 2: NaEt or K 2 3 Br( 2 ) 2 ( 3 ) 2 Et Et Et Et Et Et epeat with bromoethane to put the ethyl group on Part 3: ondensation reaction with urea and strong base to complete ring 2 N N 2 + Et Et Et 5 11 NaEt Et N N Et 5 11

7 B3) Malonic ester synthesis: Base-catalyzed alkylation followed by hydrolysis and decarboxylation is used to prepare longer carboxylic acids from alkyl halides verall reaction: 1. Base 2 ( 2 Et) X Et Example: ow can you prepare these using malonic ester synthesis?

8 B4) Acetoacetic ester synthesis is used to prepare methyl ketones from alkyl halides Using acetoacetic acid synthesis to prepare 2-pentanone: ow would you prepare:

9 ow could you prepare the substituted ester shown? Show the step-by-step mechanism, including resonance forms, and the final product(s) of this base-catalyzed alkylation reaction: LDA/TF 3 2 I Fill in the reagents needed to accomplish the transformation shown:

10 eactions at the alpha-carbon, Part II: Additions and condensations (hapter 23) 1. ommon and biologically relevant additions/condensations: Formation of new bonds with loss of water A) Aldol eactions: Aldol Addition 23.1 (preparation of β-hydroxy aldehydes or ketones) Aldol ondensation to form enones (α, β unsaturated ketones) Mixed Aldol 23.5 Intramolecular (cyclic) aldol 23.6 (yields primarily 5 or 6 membered rings) B) laisen eactions: laisen ondensation & Mixed laisen ondensation (preparation of β-keto esters or β-diketones) Dieckmann cyclization (forms cyclic β-keto esters) Special addition & elimination reactions with synthetic utility A) Michael Addition: onjugate addition of enolates to α,β-unsaturated carbonyls ->1,5-dicarbonyls B) Stork Enamine reaction: onjugate addition of enamines to α,β-unsaturated carbonyls followed by hydrolysis (forms 1,5-diketones)

11 1. Additions and condensations between aldehydes, ketones & esters eview concepts: arbonyl compounds have acidic at the α-position Deprotonation at this position produces a resonance-stabilized carbanion/enolate This reacts readily with electrophilic site of another molecule Synthesis considerations: Focus on the functional groups that form in each reaction Keep track of which reagents supply which carbons and how they connect ondensations only require a catalytic amount of base 1A: Aldol addition: produces β-hydroxy aldehydes & ketones ( aldols ): 2 3 Na 3 2 Mechanism: The ensuing condensation (dehydration) of the aldol produces α, β- unsaturated ketones Example: The mixed aldol condensation of benzaldehyde and acetone Mixed aldols best when one reagent has no α-carbons ne serves as nucleophile, the other as electrophile The dehydration step produces α,β-unsaturated product Na heat or acid 3 + 2

12 1B: laisen condensation: β-keto esters and β-diketones Ester + ester produces β-keto esters (precursor of acetoacetic acid synthesis): 1. Na Ketone + ester produces β-diketones: Na The main difference between the aldol and laisen reactions: laisen reaction involves elimination of a leaving group, regenerating =! Intramolecular condensations: Treating dicarbonyl compounds with base can promote cyclizations by aldol or laisen. Products form in a way that maximizes ring stability (favoring 5 or 6 membered rings). Some examples: Dieckmann cyclizations laisen, works well with 1,6- or 1,7-diesters:

13 Aldol & laisen reactions are very common in nature! Some biological examples: A. Aldol addition of two 3-carbon units B. ross-linking of collagen protein to make a 6-carbon unit occurs during as animals age: an aldol condensation: gluconeogenesis:. laisen condensation of thioesters (malonyl-oa and acetyl-oa) occurs in fatty acid chain-building (biosynthesis)

14 2. Special Additions/Eliminations 2A. Michael Additions of α, β unsaturated carbonyl compounds ecall that there are 2 positively charged sites in these species; they can undergo both direct addition and conjugate addition: In the Michael reaction, the nucleophile is an enolate species and conjugate addition to the unsaturated structure produces a multifunctionalized carbonyl compound: The products have the new group attached at the β-carbon The enolate can come from a β-diketone, β-diester or β-keto ester When the reactant is an ester, the base must have the same alkyl group to avoid any change in the molecule if substitution occurs. The resulting 1,5-diketone can undergo a obinson annulation

15 2B. Stork eaction: Addition of enamines to α, β-unsaturated carbonyls to produce 1,5-diketones Ketones can be converted to enamines and used to alkylate α,β-unsaturated carbonyl compounds because enamines have a carbanion resonance form: 2 N 2 N The 3-step process results in formation of 1,5-diketones (which are synthetically useful in cyclizations): 1. Enamine formation by reaction of ketone with a 2 o amine 2. Michael addition of enamine to α, β-unsaturated carbonyl compound 3. ydrolysis of the enamine regenerates the ketone group. 1,5-diketones prepared in this way may undergo intramolecular aldol condensation (annulation) forming a new 6-membered ring Na heat

16 Problems: What enone product would form from aldol condensation in each of these molecules? What aldol condensation product would form from treatment of this compound with base?

17 ow might each compound be prepared using a Michael reaction? Show which nucleophilic donor and electrophilic acceptor you would use (Table 23.1) Fill in the missing reagents

18 Predict the products formed from a Michael addition, followed by intramolecular aldol condensation (obinson annulation): 1) 2,4-pentanedione + 2-cyclohexenone 2)

Chapter 22 Carbonyl Alpha-Substitution Reactions

John E. McMurry www.cengage.com/chemistry/mcmurry Chapter 22 Carbonyl Alpha-Substitution Reactions The α Position The carbon next to the carbonyl group is designated as being in the α position Electrophilic