Chapter 23Substitution Reactions of Carbonyl Compounds at the

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					           Chapter 23:Substitution Reactions of
          Carbonyl Compounds at the α-Carbon


                      SCHM 332 Organic Chemistry




                                                                             Section 23.2


                        A Review of Tautomerism
A carbonyl compound possessing α hydrogens rapidly interconverts between its keto
tautomer (carbonyl compound) and its enol tautomer (vinyl carbon bonded to a hydroxy
group). The interconversion process is called tautomerization (aka enolization, keto-enol
interconversion, keto-enol tautomerism).


                      α


                keto tautomer                        enol tautomer

        Generally the equilibrium favor formation of the keto tautomer…




                                                                                            1
                                                                       Section 23.2


     Mechanism of Acid Catalyzed Tautomerization




Applying the schematic above, what is the acid catalyzed enolization
mechanism for acetone?




                                                                       Section 23.2


     Mechanism of Base Catalyzed Tautomerization




Applying the schematic above, what is the base catalyzed enolization
mechanism for acetone?




                                                                                      2
                                                                         Section 23.3


                    Acidity and Alpha Hydrogens
    Alpha hydrogens on carbonyl compounds are acidic due to the
    electron withdrawing capability of carbonyl group.
                                                       acetone
              propane                                  pKa = 20
             pKa = ~50




                              2,4-petanedione
                                  pKa = 9                                 acidic
                                                                       α-hydrogens




                                                       less acidic
                                                      α-hydrogens
        most acidic
        α-hydrogens




                                                                         Section 23.3


      Acid-Base Reactions Involving Alpha Hydrogens
    Alpha hydrogens can be abstracted by extremely strong bases (sodium hydride and
    lithium diisopropyl amide) to form an enolate ion!


                                                 enolate ion

                                            Why are alkoxide and hydroxide anions
Example Reaction:                           insufficient deprotonating agents for
                                            ketones but sufficient for diketones?




                                                                                        3
                                                                              Section 23.3

               Alkylation of Ketones, Ester, & Nitriles:
                 Lithium Diisopropyl Amide (LDA)


                                                              Low yield of
α          α                                                  enolate ion




                                                             High yield of
                                                             enolate ion
α      α




                                                                 LDA
    The α-hydrogens in molecules containing one carbonyl group are not as acidic
    as β -diketones ∴ a very strong base, lithium diisopropyl amide, is required.




                                                                              Section 23.3


       Reasons for Acidic Nature of Alpha Hydrogens
The acidity of alpha hydrogens is attributed to charge stabilization of the
resultant conjugate base by resonance.




                                                                                             4
                                                                              Section 23.3


                             Trends in Acidity
  Amides and esters are less acidic than aldehydes and ketones because the
  electrons in the enolate ion are not readily delocalized!




   Nitriles are weaker acids than aldehydes and ketones because the partial
   positive character of α hydrogen is less!




                                                                              Section 23.2


                Reactivity of Enols and Enolate Ions

Enol Resonance
 Contributors




   Carbonyl compounds that tautomerize to enols undergo electrophilic
   substitution reactions at the α carbon!



 Enolate Ion
  Resonance
 Contributors



 Nucleophilic sites exist on the carbonyl oxygen and the α carbon! Electrophilic
 substitution can occur at both sites; however, substitution at the α carbon is preferred.




                                                                                             5
                                                                             Section 23.6

         General Mechanism of Acid & Base Catalyzed
                  Carbonyl α-Substitution
                                            α
Acid catalyzed Carbonyl α-Substitution: (α-Halogenation)
Step 1: Acid catalyzed Enolization
Step 2: Electrophilic Substitution at the α carbon




                                            α
Base catalyzed Carbonyl α-Substitution: (α-Alkylation, Acetoacetic/Malonic Ester Synthesis)
Step 1: Base catalyzed Enolization
Step 2: Electrophilic Substitution at the α carbon




                                                                             Section 23.7

              Carbonyl α-Substitution Reactions:
          Alpha Halogenation of Aldehydes & Ketones



           aldehyde or ketone             α-halogenated aldehyde or ketone
Example Reaction:

                                                           What is the mechanism for the
                                                           reactions below?




        Bromine in acetic acid solvent (Br2, CH3COOH) is a common reagent
        used in alpha halogenation reactions




                                                                                              6
                                                   Sections 23.3 & 23.8


           Alkylation of Ketones, Esters, and Nitriles




  where Y is an alkyl or alkoxy group
Example Reactions:




  Why are the products above optically inactive?




                                                   Sections 23.3 & 23.8


                         Mechanism of Alkylation
Overall Reaction:




Mechanism:
1 Formation of Enolate
2 Substitution (SN2)




                                                                          7
                                                                          Section 23.9


       Introduction to Malonic and Acetoacetic Esters
MEMORIZE!

                                                   α         α
               α


         a malonic ester
                                                   an acetoacetic ester



The substitution occurs at the α hydrogens sandwiched between the carbonyl groups.
Alkylation reactions of these esters are common and involve two basic steps:
1 Formation of the enolate ion
2 Substitution (SN2)




                                                                          Section 23.9

                        Alkylation of Enolate Ions:
                         Malonic Ester Synthesis

General Reaction:




        malonic ester                           α-substituted malonic ester



General Mechanism:




                                                                                         8
                                                                             Section 23.9


      Hydrolysis and Decarboxylation of Malonic Esters
  α-Substituted malonic esters can be hydrolyzed (under acidic and basic conditions)
  into dicarboxylic acids (nucleophilic acyl substitution, ch. 21) followed by
  decarboxylation to yield a monocarboxylic acid!




α-substituted malonic ester                                    α-substituted
                                                             monocarboxylic acid
Mechanism of Decarboxylation:




      Hydrolysis and decarboylation can also be achieved under basic conditions.
      How would the mechanism differ?




                                                                             Section 23.9

               Synthesis of Monocarboxylic Acids via
                           Malonic Esters

3 step synthesis:
1 Formation of Enolate
2 Substitution
3 Hydrolysis and Decarboxylation


Mechanism:




                                                                                            9
                                                                              Section 23.10

                        Alkylation of Enolate Ions:
                        Acetoacetic Ester Synthesis

General Reaction:




        an acetoacetic ester                      an α-substituted acetoacetic ester



General Mechanism:




                                                                              Section 23.10

                    Hydrolysis and Decarboylation of
                          Acetoacetic Esters
  α-Substituted acetoacetic esters can be hydrolyzed (under acidic and basic
  conditions) into monocarboxylic acids (nucleophilic acyl substitution, ch. 21) followed
  by decarboxylation to yield a ketone!




   an α-substituted                                           α-substituted ketone
   acetoacetic ester

Mechanism for Hydrolysis and Decarboxylation:




                                                                                              10
                                                                             Section 23.10


           Synthesis of Ketones via Acetoacetic Esters
3 step synthesis:
1 Formation of Enolate
2 Substitution
3 Hydrolysis and
Decarboxylation




General Mechanism:




         Malonic Ester & Acetoacetic Ester Synthesis:
                      Practice Problems

Propose reagents and write a mechanism for the reactions below:




Propose a synthesis from diethyl malonate or ethylacetoacetate for the following structures:




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