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

Two major types of rxns of carbonyl compounds occur under basic conditions: 1) Substitution at the α-carbon (focus of Ch. 22) (halogenation & alkylations) 2) Condensation by reaction at the α-carbon (focus of Ch. 23) Key factor in reactions: The nearby C=O 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 Resonance-stability of the conjugate

base (enolate)

Major feature of all α-C 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

CH2

YX

O

Mechanism of acid-catalyzed substitution (enol form):

RR

O H+

RR

OH

RR

OH

E+

RR

OH

E

RR

OH

E

RR

O

E

HA-

RR

OH

H

H

H Key acid-catalyzed alpha-C substitution reactions: A. Acid-catalyzed alpha-halogenation (22.3)

Br2, Cl2 or I2 can substitute at the α-carbon of an aldehyde or ketone Main uses: 1. Allows the α-carbon to be functionalized by SN2 substitutions 2. Provides route to α, β unsaturated ketones by elimination B. Hell-Volhard-Zelinski (HVZ) reaction: Carboxylic acids normally don’t enolize, so this reaction forms an acyl bromide that does enolize and then undergoes α-bromination. Hydrolysis gives back the carboxylic acid:

CH2

H3CCH3

OBr2

HOAcCH

H3CCH3

O

Br

CH2

H3COH

O1. Br2, PBr3

2. H2OCH

H3COH

O

Br

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:

Two nucleophilic sites are produced : the α-carbon and the oxygen.

Some strong bases: Lithium diisopropyl amide (LDA) Sodium ethoxide (Na+ -OEt)

NaOH, NaNH2 Formation of an enolate by LDA: In a based-catalyzed α-substitution:

• The nucleophile is a carbanion generated by deprotonation at α-C

• The electrophile can be varied for each reaction, to give variety of products. Substitution reactions involving the enolate intermediate result in replacement of acidic H by halogen or alkyl group A) Halogenations: 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

RR

O

RR

O

RR

O

H

-:B

H HH

Steric hindrance can determine what the major product will be

A) Base-catalyzed halogenation: Iodoform reaction: Classification test to identify a methyl ketone 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 SN2 reaction with alkyl halides:

H3C CH3

OI2, NaOH

H3C CI3

O-OH

H3C O

O+ CHI3

CCH2

CH3

OLDA, THF

CCH

CH3

O

CCH CH3

O

H3C H3C H3CCH3CH2I

CH2

H3C

CCH

CH3

O

H3C

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 R groups

Amobarbital Pentobarbital Phenobarbital R = ethyl R = ethyl R = ethyl R’ = isoamyl R = 2-pentyl R = phenyl

Part 1 of the synthesis is α-alkylation of diethyl malonate: Part 2: Repeat with bromoethane to put the ethyl group on Part 3: Condensation reaction with urea and strong base to complete ring

CCH2

OEt

O

CCH

OEt

O

CCH OEt

O

C C C

CH2

CH

O O O

EtO EtO EtO

CH3

CH3H2C

NaOEtor K2CO3 Br(CH2)2CH(CH3)2

HN NH

O

O OR R'

HN NH

O

O O

Et C5H11

CC OEt

O

C

O

EtO

C5H11Et

H2N NH2

O

+NaOEtEtOH

B3) Malonic ester synthesis: Base-catalyzed alkylation followed by hydrolysis and decarboxylation is used to prepare longer carboxylic acids from alkyl halides Overall reaction: 1. Base

CH2(CO2Et)2 2. R-X RCH2COOH + CO2 + EtOH 3. H3O+ Example:

How can you prepare these using malonic ester synthesis?

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

How would you prepare:

How 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:

Fill in the reagents needed to accomplish the transformation shown:

LDA/THF

CH3CH2IC CH2

H3C

H3CCH3

O

CH3

Reactions at the alpha-carbon, Part II: Additions and condensations (Chapter 23)

1. Common and biologically relevant additions/condensations: Formation of new C – C bonds with loss of water A) Aldol Reactions: Aldol Addition 23.1 (preparation of β-hydroxy aldehydes or ketones) Aldol Condensation to form enones 23.3 – 23.4 (α, β unsaturated ketones) Mixed Aldol 23.5 Intramolecular (cyclic) aldol 23.6 (yields primarily 5 or 6 membered rings) B) Claisen Reactions: Claisen Condensation & Mixed Claisen Condensation (preparation of β-keto esters or β-diketones) 23.7 - 23.8 Dieckmann cyclization (forms cyclic β-keto esters) 23.9 2. Special addition & elimination reactions with synthetic utility A) Michael Addition: Conjugate addition of enolates to 23.10

α,β-unsaturated carbonyls ->1,5-dicarbonyls B) Stork Enamine reaction: Conjugate addition of enamines to 23.11

α,β-unsaturated carbonyls followed by hydrolysis (forms 1,5-diketones)

1. Additions and condensations between aldehydes, ketones & esters Review concepts:

• Carbonyl compounds have acidic H 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 • Condensations only require a catalytic amount of base

1A: Aldol addition: produces β-hydroxy aldehydes & ketones (“aldols”): 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 • One serves as nucleophile, the other as electrophile • The dehydration step produces α,β-unsaturated product

CH

O

+H3C

CCH3

O

CH

HC C

CH3

ONaOH

heator acid

+ H2O

H3CC

H

O

2 NaOH

CH2

CH

O

CH

OH

H3C

1B: Claisen condensation: β-keto esters and β-diketones

Ester + ester produces β-keto esters (precursor of acetoacetic acid synthesis):

Ketone + ester produces β-diketones:

The main difference between the aldol and Claisen reactions: Claisen reaction involves elimination of a leaving group, regenerating C=O! Intramolecular condensations: Treating dicarbonyl compounds with base can promote cyclizations by aldol or Claisen. Products form in a way that maximizes ring stability (favoring 5 or 6 membered rings). Some examples: Dieckmann cyclizations Claisen, works well with 1,6- or 1,7-diesters:

H3CC

CH3

O 1. NaOCH3

2. H3O+ + CH3OH+CH2

CH3C

O

C

O

O CH3

C

O

1. NaOCH2CH3

2. H3O+ CH2

CH3C

O

H3CC

O

O

H2C C

O

CH3 OH2C CH3

2

Aldol & Claisen reactions are very common in nature! Some biological examples: A. Aldol addition of two 3-carbon units B. Cross-linking of collagen protein to make a 6-carbon unit occurs during as animals age: an aldol condensation: gluconeogenesis:

C. Claisen condensation of thioesters (malonyl-CoA and acetyl-CoA) occurs in fatty acid chain-building (biosynthesis)

2. Special Additions/Eliminations 2A. Michael Additions of α, β−unsaturated carbonyl compounds Recall 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 Robinson annulation

2B. Stork Reaction: 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: 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 2o amine 2. Michael addition of enamine to α, β-unsaturated carbonyl compound 3. Hydrolysis of the enamine regenerates the ketone group.

R2N R2N

1,5-diketones prepared in this way may undergo intramolecular aldol condensation (annulation) forming a new 6-membered ring

O O OH

O ONaOH

heat

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?

How 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

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