Chapter 22. Carbonyl Alpha-Substitution Reactions 22. Carbonyl Alpha-Substitution Reactions O! !' #...

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Transcript of Chapter 22. Carbonyl Alpha-Substitution Reactions 22. Carbonyl Alpha-Substitution Reactions O! !' #...

  • 116

    228

    Chapter 22. Carbonyl Alpha-Substitution Reactions

    O

    !

    "

    #!'

    "'

    #'

    H

    O

    carbonylOH

    O

    Enol

    Enolate

    E

    O

    E+

    E+

    229

    Tautomers: isomers, usually related by a proton transfer,that are in equilibrium

    Keto-enol tautomeric equilibrium lies heavily in favor of theketo form.

    CC

    OH

    CC H

    O

    enol keto

    C=C H = 611 KJ/molC-O 380O-H 436

    C=O H = 735 KJ/molC-C 376C-H 420

    H = -104 KJ/mol

  • 117

    230

    Keto-enol tautomerism is catalyzed by both acid and base

    Acid-catalyzed mechanism (Figure 22.1):

    Base-catalyzed mechanism (Figure 22.2):

    The carbonyl significantly increases the acidity of the -protons C CC C

    O

    H H

    HH

    C

    H H

    HH

    231

    nucleophile

    22.2: Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions

    CC

    OH

    Enol

    CC

    OH

    General mechanism for acid-catalzyed -substitution of carbonyls (Figure 22.3)

  • 118

    232

    22.3: Alpha Halogenation of Aldehydes and Ketonesan -proton of aldehydes and ketones can be replacedwith a -Cl, -Br, or -I (-X) through the acid-catalyzed reaction with Cl2 , Br2 , or I2 , (X2) respectively.

    CC H

    OX2, H

    +

    CC X

    O

    X= Cl, Br, I

    Mechanism of the acid-catalyzed -halogenation (Fig. 22.4)

    Rate= k [ketone/aldehyde] [H+] rate dependent on enol formation

    233

    ,-unsaturated ketones and aldehydes: -bromination followed by elimination

    O

    Br2, CH3CO2H

    O

    Br

    O

    (H3C)3CO- K+

    E2

    CH3CH3

    CH3

    O

    CH3

    OH

    CH3

    OH

    CH3

    Why is one enol favored over the other?

    22.4: Alpha Bromination of Carboxylic Acids: The HellVolhardZelinskii (HVZ) Reaction

    -bromination of a carboxylic acid

    OHCCH

    O

    Br2, PBr3, AcOH

    then H2OOHC

    CBr

    O

  • 119

    234

    Mechanism (p. 828, please read)

    -bromo carboxylic acids, esters, and amidesBr2, PBr3, AcOH

    then H2OOH

    O

    Br

    O

    Br

    OCH2CH3

    O

    Br

    OH

    O

    Br

    NH

    O

    Br

    CH3

    H2O

    CH3CH2OH

    H3CNH

    2

    235

    ,-unsaturated ketones and aldehydes: -bromination followed by elimination

    O

    Br2, CH3CO2H

    O

    Br

    O

    (H3C)3CO- K+

    E2

    CH3CH3

    CH3

    O

    CH3

    OH

    CH3

    OH

    CH3

    Why is one enol favored over the other?

    22.4: Alpha Bromination of Carboxylic Acids: The HellVolhardZelinskii (HVZ) Reaction

    -bromination of a carboxylic acid

    OHCCH

    O

    Br2, PBr3, AcOH

    then H2OOHC

    CBr

    O

  • 120

    236

    22.5: Acidity of Alpha Hydrogen Atoms: Enolate Ion FormationBase induced enolate formation

    CC H

    OB

    CC

    O

    CC

    O

    Enolate anion

    The negative charge of the enolate ion (the conjugate baseof the aldehyde or ketone) is stabilized by delocalization onto the oxygen

    CCO

    H

    CCO

    CCO

    ethane acetone ethanolpKa= 60 pKa= 19 pKa= 16

    H3C CH3

    C

    O

    H3C CH3 H3CH2COH

    237

    Base induced enolate formation

    pKa= 19 pKa= 40(stronger acid) (stronger base) (weaker base) (weaker acid)

    H3CH2COHH3C CH3

    C

    O

    H3CH2CO+

    H3C CH2

    C

    O

    +

    Lithium diisopropylamide (LDA): a very strong base

    N Li N H

    diisopropylaminepKa= 40

    LDA is used to generate enolate ions from carbonyl by abstraction of -protons

    H3C CH3

    C

    O

    [(H3C)2CH]2N+

    H3C CH2

    C

    O

    + [(H3C)2CH]2NH

    acetone ethoxide enolate ethanol pKa= 19 pKa= 16(weaker acid) (weaker base) (stronger base) (stronger acid)

  • 121

    238

    N H + H3CH2CH2CH2C Li N Li+ H3CH2CH2CH3C

    pKa= 40 pKa= 60

    THF

    -deprotonation of a carbonyl compound by LDA occurs rapidly in THF at -78 C.

    Typical pKas of carbonyl compounds (-protons):aldehydes 17ketones 19esters 25amides 30nitriles 25

    H3C CH3C

    O

    H3C HC

    O

    H3C OCH3C

    O

    H3C N(CH3)2C

    O

    H3C C N

    239

    Acidity of 1,3-dicarbonyl compounds

    Why is Meldrums acid more acidic than other dicarbonylcompounds?

    H3C OCH3

    C

    O

    H3C CH3

    C

    O

    C CH3

    C

    O

    CH3C

    O

    H H

    ketone

    pKa= 19

    1,3-diketone

    pKa= 9

    C OCH3

    C

    O

    CH3CO

    O

    H H

    ester

    pKa= 25

    1,3-diester

    pKa= 13

    C OCH3

    C

    O

    CH3C

    O

    H H

    1,3-keto ester

    pKa= 11

    C

    OC

    O

    CC OO

    HH

    H3C CH3

    Meldrum's acid

    pKa= 5

  • 122

    240

    C OCH3

    C

    O

    CH3C

    O

    H H

    acetoacetic ester

    pKa= 11

    + H3CO

    C OCH3

    C

    O

    CH3C

    O

    H

    + H3COH

    pKa= 16

    Delocalization of the negative charge over two carbonyl groupsdramatically increases the acidity of the -protons

    C OCH3

    C

    O

    CH3C

    O

    H

    C OCH3

    C

    O

    CH3C

    O

    H

    C OCH3

    C

    O

    CH3C

    O

    H

    C CH3

    C

    O

    CH3C

    O

    H

    C CH3

    C

    O

    CH3C

    O

    H

    C CH3

    C

    O

    CH3C

    O

    H

    C OCH3

    C

    O

    CH3CO

    O

    H

    C OCH3

    C

    O

    CH3CO

    O

    H

    C OCH3

    C

    O

    CH3CO

    O

    H

    Enolate formation for a 1,3-dicarbonyl is very favorable

    pKa= 9

    pKa= 11

    pKa= 13

    241

    22.6: Reactivity of enolate ionsBy treating carbonyl compounds with a strong base such

    as LDA, quantitative -deprotonation occurs to give an enolate ion.

    Enolate ions are much more reactive toward electrophiles than enols.

    CC H

    OB

    CC

    O

    CC

    O

    E E

    CC

    O

    CC E

    OE

    Enolates can react with electrophiles at two potential sites

  • 123

    242

    22.7 Halogenation of Enolate Ions: The Haloform ReactionCarbonyls undergo -halogenation through base

    promoted enolate formation

    CC H

    OOH

    CC

    OBrBr

    CC Br

    ONaOH, H2O

    + NaBr

    Base promoted -halogenation carbonyls is difficult to controlbecause the product is more acidic than the starting material; mono-, di- and tri-halogenated products are often produced

    CC Br

    O

    H H

    CC

    O

    Br

    BrBrNaOH, H2O

    CC Br

    O

    H Br

    NaOH, H2O

    CC

    O

    Br

    Br

    Br2

    CC Br

    O

    Br Br

    243

    Haloform reaction:

    Iodoform reaction: chemical tests for a methyl ketone

    CC X

    O

    X X

    CH3C

    O NaOH, H2O

    X2

    OH

    CC X

    X X

    OHO

    OHC

    O

    + CX3

    OC

    O+ HCX3

    Haloform

    R CH3C

    O NaOH, H2O

    I2 R OC

    O

    + HCI3

    Iodoform

    Iodoform: bright yellow precipitate

  • 124

    244

    22.8 Alkylation of Enolate IonsEnolates react with alkyl halides (and tosylates) to form

    a new C-C bond (alkylation reaction)

    Reactivity of alkyl halides toward SN2 alkylation:

    Tertiary, vinyl and aryl halides and tosylates do not participate in SN2 reactions

    XC

    H H

    ~_X

    C

    H H

    XC

    H

    H H

    > >

    XC

    R

    H H>

    XC

    R

    R H

    benzylic allylic methyl primary secondary

    >

    tosylate -I > -Br > -Cl~_

    CC H

    OB

    CC

    O

    CC

    O

    CC

    O

    C

    SN2XC

    245

    Malonic Ester Synthesisoverall reaction

    C OEtC

    O

    CEtO

    O

    H H

    diethyl malonate

    pKa= 13

    + EtO

    C OEtC

    O

    CEtO

    O

    H

    + EtOH

    pKa= 16

    CO2Et

    CO2Et

    Et= ethyl

    diethyl malonate

    + RH2C-X

    alkylhalide

    EtO Na+, EtOHRH2C-CH2-CO2H

    carboxylicacid

    then HCl, !

    C OEtC

    O

    H

    H H

    ethyl acetate

    pKa= 25

    + EtOC OEt

    C

    O

    H

    + EtOH

    pKa= 16H

  • 125

    246

    A malonic ester can undergo one or two alkylations to give an-substituted or -disubstituted malonic ester

    Decarboxylation: Treatment of a malonic ester with acid andheat results in hydrolysis to the malonic acid (-di-acid).An acid group that is to a carbonyl will lose CO2 uponheating.

    C OEtC

    O

    CEtO

    O

    H CH2R

    HCl, !

    C OHC

    O

    CHO

    O

    H CH2R

    - CO2

    C OHC

    O

    RH2C

    H H

    247

    Mechanism of decarboxylation:-dicarboxylic acid (malonic acid synthesis)

    -keto carboxylic acid (acetoacetic ester synthesis)

  • 126

    248

    C

    CO2Et

    CO2Et EtO Na+, EtOH HCl, !H

    HH3CH2CH2CH2C-Br+ C

    CO2Et

    CO2EtH3CH2CH2CH2C

    H

    H3CH2CH2CH2C-H2CCO2H

    C

    CO2Et

    CO2Et EtO Na+, EtOHH

    HH3CH2CH2CH2C-Br+ C

    CO2Et

    CO2EtH3CH2CH2CH2C

    H

    EtO Na+, EtOH

    H3CH2C-Br

    C

    CO2Et

    CO2EtH3CH2CH2CH2C