Carbonyl Alpha-Substitution Reactions Capter-22 by jsk11664

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									              Carbonyl Alpha-
           Substitution Reactions

               Chem. 233 Fall 2004
                   Dr. Zand

9/3/2010             Farshid Zand    1
                     Sneak Peek:
• Keto-Enol Tautomerism

• Reactivity of Enols: Mech. of Alpha-Substitution Rxns.

• Alpha Halogenation of Aldehydes and Ketones

• Alpha Bromination of Carboxylic Acids:

       The Hell-Volhard-Zelinskii Rxn.

• Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation

• Reactivity of Enolate Ions

• Halogenatation of Enolate Ions: The Haloform Rxn.

• 9/3/2010
    Alkylation of Enolate ions
                             Farshid Zand                  2
            α-substitution Reaction


                             C               E+
           :O:                                           O
                         An enolate ion
           C     α   H                                   C       E
                 C           :                               C
       A carbonyl                            E+   An alpha-substituted
                             C                    carbonyl compound

                           An enol

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           Keto-Enol Tautomerism
A. Natures of tautomerism.

1.    Carbonyl compounds with hydrogens bonded to their α carbons equilibrate with
      their corresponding enols.
2.    This rapid equilibration is called tautomerism, and the individual isomers are
3.    Unlike resonance forms, tautomers are isomers.
4.    Despite the fact that very little of the enol isomer is present at room
      temperature, enols are very important because they are reactive.

B. Mechanism of tautomerism.

1.     In acid-catalyzed enoliztion, the carbonyl α carbon is protonated to form an
       intermediate that can lose a hydrogen from its carbon to yield a neutral enol.
2.     In base-catalyzed enol formation, an acid-0base reaction occurs between a
       base and an α hydrogen.
       a. The resultant enolate is potonated to yield an enol.
       b. Protonation can occur either on carbon or on oxygen.
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       c. Only hydrogen on the α positions of carbonyl compounds are acidic.
   Acid-catalyzed Enol Formation
                :O: H—A
                C       H
               Keto tautomer                       formation.
                                              enolProtonation of the carbonyl oxygen
                                                     atom by an acid catalyst HA yield a
                        The protonated intermediate can
                                           cation that can be represented by

       H         lose H+, either from the oxygen atom to
                            : H            two resonance structures.
                 regenerate keto tautomer or from the α
   C       H               C    H :A-
       C         carbon atom to yield an enol.
                                                     Loss of H+ from the α position by
                                                     reaction with a base A- then yields
                                                     the enol tautomer and regenerates
                                                     HA catalyst.

                               + HA
9/3/2010       Enol tautomer          Farshid Zand                                         5
 Base-catalyzed Enol Formation

                               : :

              C         H
                 C Base-catalyzed            enol formation.
             Keto tautomer            Base removes an acidic hydrogen
                                      from the α ion, a
                    The intermediate enolate position of the carbonyl
                                      forms, can bean enolate
              resonance hybrid of two compound,has two resonance
                                      anion that
              protonated either on carbon to
                               :      structures.
  :O:                          :O:-

                                          : :
              regenerate the starting keto tautomer or
   C                   C
              on oxygen to give an enol.

        C                 C
                                                     Protonation of the enolate anion on
                                                     the oxygen atom yields an enol and
                                                     regenerates the base catalyst.

             :O             + OH-
9/3/2010     Enol tautomer            Farshid Zand                                     6
             Reactivity of Enols:
       Mech. of Alpha-Substitution Rxns

1. The electron-rich double bonds of enols cause
   them to behave as nucleophiles.
   (The electron-donating enol -OH groups make
   enols more reactive then alkenes)

2. When an enol reacts with an electrophile, the initial
   adduct loses -H from oxygen to give a substituted
   carbonyl compound

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                H                             H

           :O                           +:O

           C                             C

                C                             C

                    Enol tautomer

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              Alpha Halogenation of
             Aldehydes and Ketones
 1.   Aldehydes and ketones can be halogenated at their α
      positions by reaction of X2 in acidic solution.

 2.   The reaction proceeds by acid-catalyzed formation of an
      enol intermediate.

 3.   Halogen isn’t involved in the rate-limiting step: the rate
      doesn’t depend on the identity of the halogen, but only on
      [ketone] and [H+].

 4.      α-Bromo ketones are useful in synthesis because they
         can be dehydrobrominated by base treatment to from α,β-
         unsaturated ketones. Farshid Zand                       9
      Carbonyl α-substitution Rxn.
Acid-catalyzed enol formation
occurs by the usual mechanism.

                                         :O                     E+
           C         H                       C
                 C       Acid catalyst           C

                            Carbonyl α–substitution Rxn.
An electron pair from the enol
oxygen attacks an electrophile initial formed cation loses H+
(E+), forming a new bond and                       :Base
                 to regenerate a carbonyl compound.
leaving a cation intermediate
that is stabilized by resonance
between two forms.              + H              H
                                                            :O             Loss of a proton from oxygen
                                   C             E
                                                                C        E yields the neutral α-substitution
                                         C                                 product as a new C=O bond is
                                                                +    C
9/3/2010                                         Farshid Zand
                                                                                               C       10

Aldehydes and ketones can be halogenated at their α positions by reaction
with Cl2, Br2, or I2 in acidic solution.
Bromine in acetic acid solvent is often used.

                O                                     O
                C                                     C
                    CH3 + Br2                              CH2Br + HBr

            Acetophnone                         α- Bromoacetophenone (72%)

            O                                     O
                                                           + HCl
                                H2O, HCl

            Cyclohexanone                       2- Chlorocyclohexanone (66%)

 9/3/2010                        Farshid Zand                             11
     Acid-catalyzed bromination of acetone
                                          H                              ..      H
        :O:         H—Br             :O             :Base               :O                 Br—Br
        C                            C         H                         C            H
 H 3C         CH3              H3C        C         + Br-        H 3C           C
                                      H        H                                H         Enol
The carbonyl oxygen atom is
protpnated by acid catalyst.                                                                       :Base
                                                             H                       ..    H
Loss of an acidic proton from the alpha                 +
                                                        :O                           :O
carbon takes place in the normal way to
yield an enol intermediate                              C        Br                  C           Br
                                                 H 3C        C                H 3C    +   C
An electron pair from the enol attacks                   H       H                    H        H
bromine, giving an intermediate cation
that is stabilized by resonance between
two forms.
Loss of the –OH proton then gives the
                                                                        C                 + HBr
alpha-halongenated product and                                   H 3C         CH2Br
generates more acid catalyst.
   9/3/2010                                   Farshid Zand                                            12
Alpha Bromination of Carboxylic Acids:
    The Hell-Volhard-Zelinskii Rxn

 1. In the Hell-Volhard-Zelinskii (HVZ) reaction, a
    mixture of Br2 and PBr3 can be used to
    brominate carboxylic acids in the α position.

 2. The initially formed acid bromide reacts with Br2
    to form an α–bromo acid bromide, which is
    hydrolyzed by water to give the α–bromo
    carboxylic acid.

 3. The reaction proceeds through an acid bromide
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    The Hell-Volhard-Zelinskii Rxn
H        1st step takes place between PBr3
  C   OH and a carboxylic acid to yield an
 R R     intermediate acid bromide plus HBr.
                       The Hell-Volhard-Zelinskii Rxn.
                        The overall result of the reaction is
         O the transformation of an acid into an α-
  H                                       R     C
         C bromo acid. Note, though, that the key Br         Br2
     C                                       C    Br                   C
           Br                                                        C
    R R      step involves α substitution of an acid
                                           R                             Br
                                                                    R R
             bromide enol rather than enol
  Acid bromide                       Acid bromide   a carboxylic
             acid enol.
The HBr catalyzes enolization of the acid bromide and the resultant
enol reacts rapidly with Br2 in an α-substitution rxn.                        H2O

                                          Addition of H2O results in          O
                                          hydrolysis of the α-bromo acid Br   C
                                          bromide and gives the α-bromo     C   OH
                                          carboxylic acid product.
                                          Farshid Zand
                                                                        R R          14
      Acidity of Alpha Hydrogen Atoms:
            Enolate Ion Formation
1.   Hydrogens α to a carbonyl group are weakly acidic.
     a. This stability is due to overlap of a vacant ρ orbital with the carbonyl group
        ρ orbitals, allowing the carbonyl group to stabilize the negative charge by
     b. The two resonance forms aren’t equivalent; the form with the negative
        charge on oxygen is of lower energy.

2.   Strong bases are needed for enolate ion formation.
     a. Alkoxide ions are too weak to use in enolate formation.
     b. Lithium diisopropylamide (LDA) is used for forming enolates because it is
     a very strong base, it is soluble in THF, it is hindered and it can be used at
         low temperatures.
     c. LDA can be used to form the enolate of many different carbonyl

3.     When a hydrogen is flanked by two carbonyl groups, it is much more acidic.
       (Both carbonyl groups can stabilize the negative charge.)
9/3/2010                            Farshid Zand                                  15
   Acidity Constants for Some Organic Compounds
           Compound type     Compound           Pka
           Carboxylic acid   CH3CO2H            5
           1,3-Diketone      CH2(COCH3)2        9
           1,3-Keto ester    CH3COCH2CO2C2H5    11
           1,3-Dinitrile     CH2(CN)2           11
           1,3-Diester       CH2(CO2C2H5)2      13
           Alcohol           CH3CH2OH           16
           Acid chloride     CH3COCl            16
           Aldehyde          CH3CHO             17
           Ketone            CH3COCH3           19
           Ester             CH3CO2C2H5         25
           Nitrile           CH3CN              25
           Dialkylamine      CH3CON(CH3)2       30
           Ammonia           NH3                36
           Dialkylamine      HN(ι-C3H7)2        40
           Alkyne            HC≡CH              25
           Alkene            CH2=CH2            44
9/3/2010   Alkane            CH3CH3
                                 Farshid Zand   60    16
           Reactivity of Enolate Ions
1. Enolates are more useful than enols for two
   a. Unlike enols, stable solutions of enlolates are
      easily prepared.
   b. Enolates are more reactive then enols because
      they are more neucleophilic.

2. Enolates can react either at carbon or at oxygen.
   a. Reaction at carbon yields an α-substituted
      carbonyl compound.
   b. Reaction at oxygen yields an enol derivative.
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           Reactivity of Enolate Ions
                Reaction here             or        Reaction here

                        :O:                         :O:-
                      Relativity of Enolate Ions.

                        C                    C
                                C                          C
                   Two modes of reaction of an
                 Α-Keto canbanion     Vinylic alkoxide
            enolate ion with an electrophile, E+.
            ReactionEon carbon to yield an α-
                        +                     E            +

            substituted carbonyl product is more                    E
              O                                      O
              C        E
                  C                                             C

           An α-substituted                             An enol derivative
           carbonyl compound
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      Halogenatation of Enolate Ions:
            The Haloform Rxn
 1.   Base-promoted halogenation of aldehydes and
      ketones proceeds readily because each halogen
      added makes the carbonyl compound more

 2.   Consequently, polyhalogenated compounds are
      usually produced.

 3.      This reaction is only useful with methyl ketones,
         which form HCX3 when reacted with halogens.
         a. The HCX3 is a solid that can be identified.
         b. The last step of the reaction involves a carbanion
9/3/2010    leaving group.     Farshid Zand                      19
                      The Haloform Rxn
           C                    The Haloform Rxn.
    R          CH3

A methyl ketone   If excess base and halogen are
          used, a methyl ketone is triply
     X NaOH
          halogenate and then cleaved by a base.
          The products are a carboxylic acid plus a

      O so-called haloform. OH
                -:OH      -:O:
                                 Note, that the 2ndO

      C step of the rxn is a nucleophillic acyl C
                               C                                   + -CX3
    R   CX3                                     R
          substitution of RCX3CX3 –OH. That is, a OH
                            –    by
          carbanion acts as a leaving grp.

                                                                   + CHX3
                                                      R       O-
9/3/2010    X = Cl, Br, I              Farshid Zand                     20
           Alkylation of Enolate ions

1.   General features.
     a. Alkylatons are useful because they form a new C—C bond.
     b. Alkylations have the same limitations as SN2 reactions; the alkyl groups
        must be methyl, primary, allylic or benzylic.

2.   The malonic ester synthesis.
     a. The malonic ester synthesis is used for preparing a carboxylic acid from a
        halide while lengthening the chain by two atoms.
     b. Diethyl malonate is useful because its enolate is easily prepared by
     reaction     with sodium ethoxide.
     c. Since diethyl malonate has two acidic hydrogens, two alkylations can take
     d. Heating in aqueous HCL causes hydrolysis and decarboxylation of the
        alkylated malonate.
        (Decarboxylations are common only to β–keto acids and malonic acids.)
     e. Cycloalkanecarboxylic acids can also be prepared.
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      The Malonic Ester Synthesis
       CO2Et                            CO2Et                             CO2Et
                   Na+ -OEt                               RX
 H     C   CO2Et                  Na+- :C     CO2Et                   R   C    CO2Et

      H                              H                                     H
Diethyl propanedioate          Sodio malonic ester                    An alkylated
   (malonic ester)                                                    malonic ester
                              —X: Tosylate > — I > — Br > — Cl
                   R—X {
                              R—: Allylic ≈ Benzylic > H3C— > RCH2—

       CO2Et                            H
 R     C   CO2Et                  R     C     CO2Et + CO2 + 2 EtOH

       H                                H

9/3/2010                              Farshid Zand                                    22
     Alkylation of Enolate ions cont...

3.    The acetoacetic ester synthesis.
      a. The acetoacetic ester synthesis is used for converting an alkyl halide to a
         methyl ketone, while lengthening the the carbon chain by 3 atoms.
      b. As with malonic ester, acetoacetic ester has two acidic hydrogens which
         are flanked by a ketone and an ester, and two alkylations can take place.
      c. Heating in aqueous HCL hydrolyzes the ester and decarboxylate the acid
      to yield the ketone.
      d. All β–keto esters can undergo this type of reaction.

4.    Direct alkylation of ketones, esters, and nitriles.
      a. LDA in a nonprotic solvent can be used to convert the above compounds
      to their enolates.
      b. Alkylation of an unsymmetrical ketone leads to a mixture of products, but
          the major product is alkylated at the less hindered position.

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     The Acetoacetic Ester Synthesis
      H     O                                  O                            H     O
                          Na+ -OEt                             RX

H                                    H                                 R    C     C      CH3
      C     C       CH3                  C     C     CH3

      CO2Et                              CO2Et                              CO2Et

    Acetoacetic ester                                                A monoalkylated
                                                                     acetoacetic ester

       H        O                               O                            R’   O
                          Na+ -OEt                             R’X

R                                    R                                  R    C    C        CH3
       C        C   CH3                   C     C        CH3

       CO2Et                              CO2Et                              CO2Et

    A monoalkylated                                                   A dialkylatedn
    acetoacetic ester                                                 acetoacetic ester

     9/3/2010                             Farshid Zand                                24
               Alkylation of ketones

    O                         O                       O
               H   LDA                      R’X               R’
    C                                                 C

           C       THF        C                           C
R                        R          C             R

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                    Alkylation of esters

     O                          O                        O
                H   LDA                       R’X                R’
     C                                                   C

            C       THF         C                            C
RO                        RO          C             RO

 9/3/2010                      Farshid Zand                      26
                   Alkylation of nitriles

               N                      N                     N
                   LDA                    RX
H          C                    C              R       C

    C                     C                        C

9/3/2010                   Farshid Zand                    27

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