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					                                Chapter 19: Carbonyl Compounds III

Learning Objectives:

1.     Write the mechanism for keto-enol tautomerization and explain the consequence of such
       tautomerizarion in the optical chiral of compound.
2.     Remember the approximate pKa value for the -hydrogen of a carbonyl group.
3.     Provide appropriate bases for the formation of enolate and use such enolate for halogenation and
       alkylation.
4.     Be able to write the general electron-pushing (arrow-pushing) mechanisms of Aldol reaction,
       Michael reaction, Claisen condensation, and Dieckmann condensation.
5.     Be able to write the general electron-pushing (arrow-pushing) mechanisms for decarboxylation
       of 3-oxocarboxylic acids
6.     Be able to employ the above-mentioned reaction for the formation of new carbon-carbon bond

Sections:

19.1       Acidity of -hydrogens*
19.2       Keto-Enol Tautomerism*
19.3       How Enols and Enolate Ions React*
19.4       Halogenation of the -Carbon of Aldehydes and Ketones*
19.5       Halogenation of the -Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ)
           Reaction
19.6       -Halogenated Carbonyl Compounds in Synthesis*
19.7       Using LDA to form an Enolate*
19.8       Alkylation of the -Carbon of Carbonyl Compounds*
19.9       Alkylation and Acylation of the -Carbon via an Enamine Intermediate
19.10      Alkylation of the  -Carbon: the Michael Reaction*
19.11      The Aldol Reaction*
19.12      Dehydration of Aldol Addition Products: Formation of  -Unsaturated Aldehydes and
           Ketones*
19.13      The Mixed Aldol Reaction
19.14      The Claisen Condensation*
19.15      The Mixed Claisen Condensation
19.16      Intramolecular Condensation and Addition Reactions*
19.17      Decarboxylation of 3-Oxocarboxylic Acids*
19.18      The Malonic Ester Synthesis: Synthesis of Carboxylic Acids
19.19      The Acetoacetic Ester Synthesis: Synthesis of Methyl Ketones
19.20      Designing a Synthesis VI: Making New Carbon-Carbon Bonds
19.21      Reactions at the -carbon in Biological Systems#

* Sections that will be focused
#
  Sections that will be skipped

Recommended additional problems

19.44 – 19.52, 19.54 – 19.64, 19.66 – 19.80



                                                    1
Class Note

19.1       Acidity of -hydrogens

       A. pKa of -hydrogen of carbonyl derivatives

           O                           O                             O                                 O
                                                                                              R'
R'                          R'
                                           OR
                                                            R'
                                                                          R                                H
               NHR
       H                          H                              H                                 H




       O       O                       O        O                             O       O

R'                 OR             R'                R                R'                   H
           H                               H                                      H




       B. Resonance effect




                                                        2
19.2       Keto-Enol Tautomerism

                                     O
                                                      OH
                            R'
                                         R       R'
                                                           R
                                 H




       A. Mechanism in acidic condition




       B. Mechanism in basic condition




                                             3
19.3       How Enols and Enolate Ions React

       A. Analysis of enols and enolates




                                              4
19.4       Halogenation of the -Carbon of Aldehydes and Ketones

       A. Acid-catalyzed halogenation

           O                                         O
                        X2 (Cl2, Br2, I2)
                             H3O+
               CH3                                       CH2
                                                         X




                                                 5
B. Base-promoted halogenation

    O                  X2 (Cl2, Br2, I2)           O
                          (excess)
              R             HO-                              R
        CH2                                            CX2




C. Haloform reaction

    O             X2 (Cl2, Br2, I2)            O
                     (excess)
                       HO-                         O
        CH3                                                          CHX3
                                                                 +




                                           6
19.5       Halogenation of the -Carbon of Carboxylic Acids: The Hell-Volhard-Zelinski (HVZ)
           Reaction

                   1) PBr3, Br2
       O           2) H2O                      O
R                                     R
            OH                                     OH
                                          Br




                                                    7
19.6   -Halogenated Carbonyl Compounds in Synthesis

       A. Analysis of -halogenated carbonyl Compounds




       B. Examples




                                            8
19.7   Using LDA to form an Enolate


                    N



       lithium diisopropylamide (LDA)




19.8   Alkylation of the -Carbon of Carbonyl Compounds

       A. Analysis of the reaction




                                            9
B. Examples

   (i)
                            1) LDA, THF
                   OCH3     2) CH3I

              O




   (ii)
                     1) LDA, THF
                     2) CH3CH2I
              CN




                             10
C. Potential problem in alkylation of the -carbon of carbonyl compounds

       O
              CH3    1) LDA, THF
                     2) CH3I




                                           11
19.9   Alkylation and Acylation of the -Carbon via an Enamine Intermediate



   O                                                      N
                                    catalytic H+
         +           N                                            +   H2O
                     H

               pyrrolidine
                                                        enamine

       A. Examples
                         1) catalytic H+

              O
                                N
                                H

                         2) CH3Br
                         3) H2O, H+




                                                   12
19.10   Alkylation of the  -Carbon: the Michael Reaction

        A. Michael reaction

                                              O
                  O      O                                  CH3O-
                                    +               CH3
            H3C               CH3




                                               13
B. Examples

   (i)
          O               O       O
                                                 base (?)
              +    H3CO               OCH3




   (ii)
              O                              O
                                                            base (?)
                                                      CN
                  OCH2CH3     +        H3C




                                  14
C. Stork enamine reaction


                            O              HCl
       N                                   H2O
                +               CH3




                                      15
19.11   The Aldol Reaction

                                 OH
                                          O
        O
                  base       R
R                                              H
            H
                                      R



        A. Mechanism




                                          16
19.12   Dehydration of Aldol Addition Products: Formation of  -Unsaturated Aldehydes and
        Ketones

        A. Aldol condensation




        B. Examples

            (i)
                                                     O
                       O
                                                         H       MeO-
                                   +
                               H                                 MeOH




            (ii)
                           O
                                          EtO- Na+
                                           EtOH




                                              17
19.13   The Mixed Aldol Reaction

        A. Potential problem in aldol reaction

            (i)
                      O
                                      EtO- Na+
                                      EtOH




            (ii)
                                                  O
                          O                           MeO- Na+
                                  +
                                                       MeOH
                              H




                                                 18
B. Solution

    (i)
                               O
              O
                                   H   MeO- Na+
                      +
                  H                     MeOH




                          19
19.14   The Claisen Condensation and 19.15   The Mixed Claisen Condensation


                                              O       O
               O
                           base        R
        R                                                 OR'          HOR'
                                                                 +
                   OR'
                                                  R

        A. Mechanism




                                             20
B. Examples

   (i)
              O
                            base (?)
                  OCH2CH3




   (ii)
              O
                                       O
                                                     base (?)
                  OCH3
                            +              OCH2CH3




                                21
19.16   Intramolecular Condensation and Addition Reactions

        A. Intramolecular Claisen reaction (Dieckmann condensation)

            (i)
                   H3CO                                   OCH3        MeO- Na+
                                                                       MeOH
                          O                          O




            (ii)
                                                    O

                                                                      EtO- Na+
                   H3CH2CO
                                                         OCH2CH3       EtOH

                              O




                                              22
B. Intramolecular aldol reaction

    (i)
           H3C                                CH3      MeO- Na+
                                                        MeOH
                 O                      O




    (ii)
                                   O

                                                    EtO- Na+
           H3C
                                        CH3          EtOH

                 O




                                   23
(iii)
                                     O

                                                    EtO- Na+
        H3C
                                           H          EtOH

              O




(iv) Robinson annulation

    O
                           O
                                         base   H+, heat
              +                                                  +   H2O
                               CH3
                                                             O




                                          24
19.17   Decarboxylation of 3-Oxocarboxylic Acids

        A. Easier in acidic condition: mechanism

    O         O                             O        O


R                 OH                   R                     O




        B. Examples of compounds containing 3-oxocarboxylic acid

              O         O                                O           O



        HO                   OH                                          OH

                   R                                             R




                                                25
19.18 The Malonic Ester Synthesis: Synthesis of Carboxylic Acids and 19.19 The Acetoacetic
Ester Synthesis: Synthesis of Methyl Ketones


                    O        O                                         O
                                               ?
                                                              R
        H3CH2CO                   OCH2CH3                                  OH




                                             26
A. Examples:

               O
                             O        O


                   OH
                                 OH       OH




                        27
19.20   Designing a Synthesis VI: Making New Carbon-Carbon Bonds

                                                                   O   O
                                    CO2H

        synthesis of                         from
                                                         H3CO              OCH3




                                           28

				
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