THE CHEMISTRY OF THE CARBONYL GROUP - DOC

Document Sample
THE CHEMISTRY OF THE CARBONYL GROUP - DOC Powered By Docstoc
					    
    
    
    
    
    
    
    
    
    
    
    
Lecture 9
    
    
    
    
    
    
    
    
    
    
    
               -Alkylation of Carbonyl Compounds
-Alkylation of ketones - via the enolate anion - can be a useful
technique for extending or modifying the alkyl chain in aldehydes and
ketones at the -carbon:
                                                                    _
          O                            O                        O
                     LDA
          C                            C    _                   C
 C6 H5        CH3              C6 H5        CH2        C6 H5            CH2
   Acetophenone
                                            CH3

                                            I
                                                   O
    The reaction is most useful with
       1 alkyl halides - with 2                    C           CH3
    halides -elimination competes         C6 H5        C
                                                        H2
     significantly with alkylation.
                                             Propiophenone

As we saw earlier a problem here is that the intermediate enolate can be
a strong enough base to deprotonate the alkylated product at an -
carbon. This yields a new enolate which can then itself be alkylated -
hence mixtures which may be difficult to separate can be formed:
      O                         O                           O
                Base                      CH3I
                                    _                                CH3
H3C       CH3          H3 C         CH2          H3 C           C
                                                                H2
                                                        -
                                      CH3COCH2

                       O                                    O
                                          CH3I
           H3C                  CH3                _                 CH3
                  C        C                     H2C            C
                  H2       H2                                   H2
lkylation of -ketocarboxylic esters provides a clean alternative route
to direct -alkylation of ketones:
                                                           Na+
                                  1 Eq. NaOEt
            O           O                             O           O
                               [Quantitative]
            C           C                              C     _    C
     H3C         C          OEt                 H3C          C        OEt
                 H2                                          H
       Claisen condensation
          of ethyl acetate                   CH3CH2CH2Br

    N.B. Mono-alkylation only - the                   O           O
    mono-alkylated product is less
    acidic and more sterically                        C           C
                                                H3C          CH       OEt
    hindered than the -ketoester
    starting material - cannot be                            C3H7
    deprotonated by enolate.

                                        O             H3O+
           CH3CH2CH2Br
                                        C
                                  H3C        CH3
            O                                         O           O

            C                                          C          C
     H3C         CH2                           H3C          CH       OH
                                     - CO2
                 C3H7                                        C3H7

The activating effect of the ester group increases the acidity of the
'doubly -' CH, directing alkylation to that carbon but di-alkylation is
sterically inhibited.       Following removal of the ester group by
hydrolysis/decarboxylation the overall reaction is equivalent to - i.e.
yields the same product as - clean -monoalkylation of acetone.
The strategy of using a -ketoester as a synthetic 'stand-in' for a ketone
in alkylation reactions (in technical language, as a 'synthetic
equivalent' of a ketone) can also be applied to carry out effective
stepwise di-alkylation - to ketone carbonyl:
                                                            Na+
        O         O             1 Eq. NaOEt            O          O
                               [Quantitative]
        C         C                                 C _ C
 H3C         C       OEt             - H+       H3C   C               OEt
             H2                                       H
  Ethyl acetoacetate from                                         Mono-
  Claisen condensation of                    CH3CH2CH2Br
                                                                alkylation
  ethyl acetate.
        O        O                                     O          O
                               1 Eq. NaOEt
        C     _   C                                    C          C
 H3C          C       OEt            - H+       H3C         CH        OEt
              C3H7                                          C3H7
                                 O

       CH3I                      C                         (i) C3H7I, EtO-
                         H3C          CH3
                                                           (ii) CH3I, EtO-

        O         O                                    O
                                   H3O+
        C         C                                    C          H
 H3C          C       OEt        , - CO2       H3C         C
       H3C        C3H7                                H3C        C3H7

Although the reactions discussed above involve several steps, the ability
to exercise precise choice of mono- vs. di-alkylation and the ability to
attach two different alkyl groups to the -carbon makes them
significantly more useful than direct alkylation of the ketone enolate.
Revision: Indirect clean -monoalkylation of ketones via the Claisen
condensation:
                                                           Na+
                                  1 Eq. NaOEt
            O         O                               O           O
                              [Quantitative]
            C         C                                C     _    C
     H3C         C          OEt                 H3C          C        OEt
                 H2                                          H
       Claisen condensation
          of ethyl acetate                   CH3CH2CH2Br

    N.B. Mono-alkylation only - the                   O           O
    mono-alkylated product is less
    acidic and more sterically                        C           C
                                                H3C          CH       OEt
    hindered than the -ketoester
    starting material - cannot be                            C3H7
    deprotonated by enolate.

                                        O             H3O+
           CH3CH2CH2Br
                                        C
                                  H3C        CH3
            O                                         O           O

            C                                          C          C
     H3C         CH2                           H3C          CH       OH
                                     - CO2
                 C3H7                                        C3H7

The activating effect of the ester group, increases the acidity of the
'doubly -' CH, directing alkylation to that carbon but sterically
inhibiting di-alkylation.    Following removal of the ester group by
hydrolysis/decarboxylation the overall reaction is equivalent to - i.e.
yields the same product as - clean -monoalkylation of acetone.
Some further examples of indirect ketone monoalkylation:
     O                                                      O
               CO2Et                                              _    CO2Et
                                   NaOEt
                                   - H+


     O                                                      O
         _     CO2Et                                                   CO2Et


             Br
          3-Bromopropene
           Allyl bromide                                        H3O+
     O                                                      O
                                                                       CO2H
                                    , - CO2

              [Equivalent to -allylation of
              cyclohexanone]
         O             O                                    O          O
         C             C           (i) NaOEt                C    H     C
   H3C            C        OEt                        H3C        C           OEt
                  H2             (ii) BrCH2CO2Et
                                                                 CH2CO2Et
                                 Ethyl Bromoacetate
                                                                      H3O+

         O                                                  O          O
                                      , - CO2
         C                                                 C H         C
   H3C           CH2CH2CO2H                          H3C  C             OH
[Equivalent to alkylation of acetone by BrCH2CO2H] CH2CO2H
Malonic Ester Synthesis - A synthesis of -substituted carboxylic
acids - equivalent to clean indirect mono- or di- -alkylation of acetic
acid:
        CO2H                   CO2Et                                      H
                                            (i) Base, RX      R
  H2C                  H2C                            1
                                                                      C
                                        (ii) Base, R X            1
                                                              R
        CO2H                   CO2Et                                      CO2H
                                            (iii) H3O+, 
 Malonic Acid        Diethylmalonate
                    aka Malonic Ester                        RR1CHCO 2H

        CO2Et               CO2Et                                         CO2Et
                EtO-                          MeBr
  H2C                    HC _                                Me       CH
        CO2Et                   CO2Et                                   CO2Et
        -2                                                            EtO-
        CH CO2H

         (i) MeBr; (ii) EtBr
  Me                             Me         CO2Et                         CO2Et
                     (i) H3O+                         EtBr
                                                                          _
        C CO2H                          C                    Me       C
        H             (ii) ,
   Et                 - CO2       Et        CO2Et                         CO2Et
The CH2 hydrogens in diethylmalonate are 'doubly -' to the two ester
carbonyl groups and therefore have enhanced acidity.              One or two
deprotonation/alkylation steps leads cleanly to monoalkylated or
dialkylated products (compare the -ketoester chemistry just studied)
Hydrolysis of both ester groups gives a -dicarboxylic acid which - like
a -keto carboxylic acid - undergoes rapid decarbonylation to a
monocarboxylic acid. The overall reaction is equivalent (i.e. gives the
same product as) the clean indirect di--alkylation of acetic acid. 

The Knoevenagel Condensation - The 'doubly -' enolate anion of
diethyl malonate behaves as the nucleophile in an aldol-like reaction
with an aldehyde or ketone forming an ,-unsaturated diester.
Following hydrolysis and decarboxylation, the final product is an ,-
unsaturated carboxylic acid.         Here diethyl malonate acts as a
synthetic equivalent of the enolate anion of acetic acid.
                                         Mild base
 H2C(CO2Et)2 + PhCHO                                       PhCH        C(CO2 Et)2

                                                          (i) H3 O+ (ii) , - CO2

                                                           PhCH        CHCO2H
                         Piperidine       Š
   H2C(CO2 Et)2                        HC(CO2 Et)2        Piperidine =
                                                                           N
                                                                           H
                                                             _
                          CO2Et                             O      CO2Et
      H           O
          C            HC _                           H     C     CH
          Ph                  CO2Et                         Ph    CO2Et
                                                             H2 O

                  OH        CO2Et                           OH     CO2Et
                       _
                                          Base
          H       C    C                              H     C     CH

                  Ph        CO2Et                           Ph     CO2Et
                              -
                       - OH

              H             CO2Et
                                       (i) H3 O+
                  C     C                             PhHC        CHCO2H
                                      (ii) , - CO2
          Ph                CO2Et
Tutorial Question:
In the base-catalysed Aldol-Claisen Condensation of a ketone and an
ester the ketone behaves as the nucleophile and the ester behaves as the
electrophile:
         O                 O                                      O_
                                              O
         C    _            C                       C CH2 C               CH
                                                                         3
 H3C          CH2 H3C          OEt         H3 C
                                                                  OEt
                                                         -
                                                  - OEt
                                              O                     O
                                                   C CH2 C
                                           H3C                      CH3
                                                          Etc.

In the base-catalysed Knoevenagel Condensation of malonic ester and a
ketone the ester behaves as the nucleophile and the ketone behaves as
the electrophile:
                                                    _
     CH3          O      CO2 Et                    O             CO2Et
             C        HC _                   H     C         CH
             Ph          CO2 Et                     Ph           CO2Et

                                                     H2O

                                                   OH            CO2Et
                                             H     C         CH
                                                    Ph     CO2Et
                                                      Etc.
How do you explain the difference?
Enamines - nitrogen analogues of enols:
               OH                                          O
      C    C                              H       C   C

       Enol                                   Carbonyl
               NH 2                                        NH
      C    C                              H       C   C


      Enamine                                      Imine
               NR 2
      C    C          Isolable because tautomerism is now impossible


Preparation of 3° enamines - acid-catalysed addition of a secondary
amine to an enolisable ketone:
                                    +                                +
       O                            OH                          HO   NHMe2

                 H3O+                             Me2NH

                 TsOH

                       Methylene imminium cation

                                              H       H
 Me        Me                 Me + Me
      N                          N                               +
                                                  O            H2O   NMe2
                                              H

                                                  - H2O

Reactivity of enamines:
                                                             +
                         NR 2                    _           NR 2
                C    C                           C    C


                                            Nucleophilic
                                              carbon

-Alkylation of enamines - another synthetic equivalent of clean -
monoalkylation of ketones:
                        +                                   +
  Me2N             Me2N                                  Me2N

                                _                                         CH
                                                                          3
                                    CH3     I                                 -
                                                                          I



    The neutral enamine - unlike the anionic
                                                           H2 O
    enolate - is a weak base and does not de-
    protonate the mono-alkylated product.
    Hence no di-alkylation occurs.                       O
                                                                    CH3
            O                       Me2NH +


                                Base/CH3I
                    Poor control - mono & di-alkylation

Although a multi-step process, ketone alkylation via enamines may be
more efficient than direct alkylation via the enolate.
Special properties of conjugated carbonyl compounds:
Carbonyl compounds in which other multiple bonds are conjugated with
the C-O double bond are significantly more stable than their non-
conjugated isomers.           For this reason ,-unsaturated carbonyl
compounds readily isomerise to the more stable conjugated ,-
unsaturated isomers via enol (acidic conditions) or enolate (basic
conditions) intermediates:

                   O                                                          O
                                 Catalysis by
 H2 C    C        C C                      -         H3 C       C       C       C
         H        H2             H+ or OH                       H       H
                      H                                                             H


Acid catalysis:




                                                                                :
                          O                                                     :OH
                                     H+
  H2C    C        C C                            H2C        C       C       C
         H        H2                                        H       H
                          H                                                     H

                          +                                                     +
                          OH                    H+   _                          OH
 H3C     C        C   C                          H2C        C       C       C
         H        H                                         H       H
                          H                                                     H
              - H+
                          O
 H3C     C        C   C
         H        H
                          H
-Unsaturated carbonyl compounds have two electrophilic carbon
sites - the carbonyl carbon and the -carbon:
                                                                                  _
                           O -                                                   O
                                                             +        
  H3 C    C     C       C +                        H3C       C       C C
          H     H                                             H       H
                           H                                                      H

                Electrophilic                           Electrophilic
                   carbon                                  carbon



Addition reactions tto the C=C or C=O double bond alone are called
'normal' or 1,2 additions:
                                                                                  Y
         O                                          O                     2   O
                                            1
C        C    + X           Y               C   2   C       or    C       1   C
     C        C                         X       C       C             C           C
                                                                              X
                                                Y

Addition reactions that involve the conjugated system as a whole are
called 'conjugate additions' or 1,4 additions:
                                                                      1       Y
              O                                                       O
                                                             4
     C        C         +       X   Y                       C         C
          C         C                                   X         C   2       C
                                                                  3


Note that here '1,2' and '1,4', do not refer to the numbering system for
identifying carbon atoms in the systematic naming of the molecules.
Examples of 1,4 (i.e. conjugate) addition:
              O                                            O

  H2 C    C    C     CH3 + HCl               ClH2C     CH C     CH3
          H                                            H

This reaction looks like a 'normal' or 1,2 - although anti-Markownikov -
addition of HCl to the C-C double bond. However the mechanism
involves acid-catalysed 1,4-addition:

                                                           +
                O                                          OH

   H2 C    C    C    CH3 + H3O+               H2 C    C    C    CH3
           H                                          H




                      OH                                   OH
                                                +
      ClH2 C     C    C    CH3                H2C     C    C    CH3
                 H                                    H
                                                 -
                                               Cl


                     O
                 H
      ClH2C      C    C    CH3
                 H

This apparent contradiction arises because 1,4-addition of HZ to the
C=C-C=O structure yields an enol which then tautomerises to the
corresponding keto form which has the same structure as would be
produced by anti-Markovnikov 1,2-addition to the C=C bond.

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:20
posted:2/25/2012
language:
pages:16