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    Alkylation of Enolate Ions

    Uploaded by

    Gabriel Pekárek
    This document summarizes methods for alkylating enolate ions through various reactions. Some key points covered include: 1. The malonic ester and acetoacetic ester syntheses for introducing alkyl groups to b-dicarbonyl compounds using bases like sodium ethoxide followed by alkyl halides. 2. Hydrolysis and decarboxylation of the resulting products yields substituted malonic esters or acetoacetic esters which can be further transformed. 3. Direct alkylation of ketones, esters, and nitriles can be achieved using strong, non-nucleophilic bases like lithium diisopropylamide followed by alkyl halides.

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    Alkylation of Enolate Ions

    Uploaded by

    Gabriel Pekárek
    150 views13 pages
    This document summarizes methods for alkylating enolate ions through various reactions. Some key points covered include: 1. The malonic ester and acetoacetic ester syntheses for introducing alkyl groups to b-dicarbonyl compounds using bases like sodium ethoxide followed by alkyl halides. 2. Hydrolysis and decarboxylation of the resulting products yields substituted malonic esters or acetoacetic esters which can be further transformed. 3. Direct alkylation of ketones, esters, and nitriles can be achieved using strong, non-nucleophilic bases like lithium diisopropylamide followed by alkyl halides.

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    This document summarizes methods for alkylating enolate ions through various reactions. Some key points covered include: 1. The malonic ester and acetoacetic ester syntheses for introducing alkyl groups to b-dicarbonyl compounds using bases like sodium ethoxide followed by alkyl halides. 2. Hydrolysis and decarboxylation of the resulting products yields substituted malonic esters or acetoacetic esters which can be further transformed. 3. Direct alkylation of ketones, esters, and nitriles can be achieved using strong, non-nucleophilic bases like lithium diisopropylamide followed by alkyl halides.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    150 views13 pages

    Alkylation of Enolate Ions

    Uploaded by

    Gabriel Pekárek
    This document summarizes methods for alkylating enolate ions through various reactions. Some key points covered include: 1. The malonic ester and acetoacetic ester syntheses for introducing alkyl groups to b-dicarbonyl compounds using bases like sodium ethoxide followed by alkyl halides. 2. Hydrolysis and decarboxylation of the resulting products yields substituted malonic esters or acetoacetic esters which can be further transformed. 3. Direct alkylation of ketones, esters, and nitriles can be achieved using strong, non-nucleophilic bases like lithium diisopropylamide followed by alkyl halides.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    of 13

    Alkylation of Enolate Ions

    1. 2.

    3.

    The malonic ester synthesis The acetoacetic ester synthesis Direct alkylation of ketones, esters and nitriles

    Relative acidity of selected organics


    Structure
    O CH3C OH O O

    pKa
    5 9 11

    CH3CCH2CCH3
    O O

    CH3CCH2COCH3
    O O

    CH3OCCH2COCH3

    13

    These compounds are MORE ACIDIC than CH3CH2OH (pKa = 16); NaOCH2CH3 can deprotonate them.

    Relative acidity of selected organics


    Structure
    O CH3CCl

    pKa
    16 17 19

    O CH3CH
    O CH3CCH3

    These compounds are SLIGHTLY LESS ACIDIC than CH3CH2OH; NaOCH2CH3 would result in only a small amount of deprotonation.

    Relative acidity of selected organics


    Structure
    O CH3COCH3

    pKa
    25 25 35

    CH3C N

    N H3

    R2NH

    40

    These compounds are MUCH LESS ACIDIC than CH3CH2OH; to deprotonate the top two, a base such as the R2N anion must be used.

    Acidity of b-dicarbonyl compounds


    A base removes a proton a to both carbonyl groups:
    O C H C O C H OCH2CH3 O C C O C H + C H3CH2OH

    Resonance stabilizes the resulting anion:


    O C C O C H O C C H O C O C C H O C

    General mechanism for alkylation


    The anion attacks the carbon bearing a leaving group:
    O C C O C H R X RX O C R C O C H + X

    A second equivalent of base can remove the second proton :


    O C R C O C H OCH2CH3 O C R C O C + C H3CH2OH

    Introduction of a second alkyl group:


    This anion can be alkylated by a second alkyl halide
    O C R R' X C O C R'X O C R C O C R' + X

    Hydrolysis and Decarboxylation


    O CH3CH2O C R C O C H OCH2CH3 OH, heat followed by H3O or, H3O, heat O HO C R C O C H OH

    a substituted malonic ester


    O HO C R C O C H H C R H HO OH HO O C R H C O C H H3O, heat O HO H + C R O C H C R H H O C O

    O C

    O HO C

    a substituted acetic acid

    Hydrolysis and Decarboxylation


    O CH3 C R C O C H OCH2CH3 OH, heat followed by H3O or, H3O, heat O CH3 C R C O C H OH

    a substituted acetoacetic ester


    O CH3 C R C O C H H C R H CH3 OH CH3 O C R H C O C H H3O, heat O CH3 H + C R O C H C R H H O C O

    O C

    O CH3 C

    a substituted acetone

    Overall Process, single substitution, using abbreviations


    O O 1. Na OEt 2. RBr 3. H3O, 1. Na OEt 2. RBr 3. H3O,
    + +

    O RCH2COH

    EtOCCH2COEt

    O R CH2CCH3

    CH3CCH2COEt

    Overall Process, double substitution, using abbreviations


    O O 1. Na OEt 2. RBr 3. Na OEt 4. R'Br 5. H3O,
    +

    O RCHCOH R'

    EtOCCH2COEt

    1. Na OEt 2. RBr 3. Na OEt 4. R'Br 5. H3O,


    +

    O RCHCCH3 R'

    CH3CCH2COEt

    Forming a ring that includes the a-carbon


    O O 1. Na OEt 2. BrCH2CH2CH2CH2Br 3. Na OEt 4. H3O,
    +

    CH3CCH2COEt

    CH2

    CH2

    CHCCH3

    CH2 CH 2

    Substituted acetic acids having a ring that includes the a-carbon can be synthesized similarly using diethyl malonate:
    O O 1. Na OEt 2. BrCH2CH2CH2CH2CH2Br 3. Na OEt 4. H3O,
    +

    CH2 CH2 CH2

    O CHCOH CH2

    EtOCCH2COEt

    CH2

    5- or 6-membered rings can be made using a 4- or 5-carbon alkyl dihalide

    Direct alkylation of ketones, esters, and nitriles (but NOT aldehydes)


    O C CH3 1. Li N(CH(CH3)2)2 (lithium diisopropylamide, LDA) 2. CH3I 1. Li N(CH(CH3)2)2 (lithium diisopropylamide, LDA) 2. CH3CH2I 1. Li N(CH(CH3)2)2 (lithium diisopropylamide, LDA) CH3CH2CH2C N 2. CH3I O C CH2CH3

    O CH3CH2COCH3

    O CH3CHCOCH3 CH2CH3

    CH3 CH3CH2CHC N

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