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ALDEHYDES AND KETONES NUCLEOPHILIC ADDITION TO CARBONYL

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ALDEHYDES AND KETONES NUCLEOPHILIC ADDITION TO CARBONYL Powered By Docstoc
					   ADDITION-ELIMINATION:
NITROGEN AND PHOSPHORUS
      NUCLEOPHILES


     Sections 16.12 - 16.14




                              WWU Chemistry
Compounds that bear an amino group


           G       NH2
form Imines.


The G group can be one of many different
possibilities



                                WWU Chemistry
           Addition-Elimination:
          The Formation of Imines

              R                   R
    ..                    HA
G   NH2   +       C   O               C   N    G   +   H2 O
              R                   R

                                      an imine



All of the imine reactions, regardless of G, go by the
same mechanism.


                                              WWU Chemistry
    Mechanism of Imine Formation
Step 1
                  R                              H   R                                       R
    ..                    ..        slow          +      .. _                           ..       ..
G   NH2       +       C   O
                          ..                 G   N C     O:
                                                         ..                    G        N    C   OH
                                                                                                 ..
                  R                              H   R                                  H    R



Step 2


          R                                                  R
                  ..                  fast                                          _
    ..                                               +
G   N     C       OH      +    HA                G   N   C       +   H2O   +       A
                  ..
    H     R                                          H       R


What is the mechanism of this step?

                                                                       WWU Chemistry
     Mechanism of Imine Formation
             (Part Two)

Step 3

              R                                   R
      +                   _   fast       ..
 G    N   C       +   A              G   N    C       +   H   A

      H       R                                   R




                                              WWU Chemistry
•This is Addition-Elimination
•The first step is carbonyl addition of an amine, and
the second step is a dehydration (elimination) to
yield the C=N double bond.
•HA is the catalyst
•Step #1 is rate-determining, unless the amine is
very basic (e.g., semicarbazide or aniline), in which
case step #2 becomes rate-determining.




                                         WWU Chemistry
Carbonyl compounds react with:




                        WWU Chemistry
     Formation of Simple Imines
 R                               R
                 ..       acid
     C   O   + H2N    R              C   N      R   +   H2O
 R                               R
                                     an imine




•Aldehydes and ketones react with simple primary
amines to yield imines.
•The equilibrium is unfavorable; the products are
much less stable than the reactants.

                                             WWU Chemistry
A Simple Model for Enzyme-Substrate
            Binding.
                                                   O
                                       +
                             NH2                   C
                                           R           R
            enzyme                             substrate




                                               R

                                   N       C

                                               R
                 enzyme-substrate complex

                                           WWU Chemistry
                                        O

  H 2N          CH2         CH2         C
          CH2         CH2         CH        OH

                                  NH2

                      Lysine

If lysine is part of the protein chain of the
enzyme, the terminal amino group is available to
bind to carbonyl groups to form an imine.


                                            WWU Chemistry
•Once the substrate (aldehyde or ketone) is bound
to the enzyme, the active site of the enzyme is in a
position to react with and modify the substrate.
•At the end of the reaction, because imines come
apart easily (remember the “unfavorable”
equilibrium?), the modified substrate can
dissociate from the enzyme and return to the
solution.
•As we can see, often biological substrates
possess carbonyl groups so that they can act as
a “handle” in enzyme-substrate binding. The
carbonyl group may have no other chemical
purpose than just this one!


                                        WWU Chemistry
                Formation of Oximes
R                                   R
                   ..        acid
    C   O   +   H 2N    OH              C   N   OH   +   H2O
R                                   R
            hydroxylamine
                                        an oxime




•Aldehydes and ketones react with hydroxylamine to
yield oximes.
•Oximes are important derivatives in qualitative
organic analysis.

                                                WWU Chemistry
        What’s a Derivative?
• One of the principal tests for the correct
  identification of an unknown compound
  comes in trying to convert the compound by
  a chemical reaction into another known
  compound -- a derivative
• If the melting point of the derivative
  matches the expected value, according to
  the literature, then one can assume that the
  original substance had been correctly
  identified.
                                   WWU Chemistry
            Formation of Hydrazones
R                                     R
                   ..          acid
    C   O   +    H2N    NH R              C   N   NH R      +   H2O
R                                     R
                a hydrazine
                                          a hydrazone



•Aldehydes and ketones react with substituted
hydrazines to yield substituted hydrazones.
•The equilibrium is generally unfavorable.
•Exception: when R is an aromatic ring.

                                                        WWU Chemistry
      2,4-Dinitrophenylhydrazones
                                NO2
      R
                      ..                                acid
          C   O   + H2N    NH                   NO2
      R
                  2,4-dinitrophenylhydrazine
                                                      NO2
                                  R
                                      C     N    NH              NO2     +   H2O
                                  R
2,4-DNP’s are the most
                                          a 2,4-dinitrophenylhydrazone
important of all
derivatives for aldehydes                        a 2,4-DNP
and ketones.

                                                                 WWU Chemistry
           Formation of Semicarbazones
   R                       O
                    ..                    acid
       C    O   + H2N    NH C   NH2
   R               semicarbazide

                                      R                O
•Aldehydes and ketones react
                                          C      N   NH C   NH2   +   H2O
with semicarbazide to yield
semicarbazones.                       R

•Semicarbazones are the                       a semicarbazone
second-most important of the
derivatives of aldehydes and
ketones.


                                                            WWU Chemistry
   Formation of Phenylhydrazones
   R
                                                     HA
       C   O   +   H 2N     NH

   R
                          Phenylhydrazine

                                    R

                                        C   N
In most cases, the                  R           NH               + H 2O
equilibrium is unfavorable.
However, this reaction is
sometimes used to form                  a phenylhydrazone
derivatives of the sugars.


                                                          WWU Chemistry
As we have already seen, substituted amines
can react with aldehydes and ketones to form a
variety of products.
Primary amines can yield imines by an addition-
elimination process.




                                     WWU Chemistry
           Addition-Elimination:
          The Formation of Imines
              R                R
    ..                    HA
G   NH2   +       C   O            C   N   G   +   H2O
              R                R
                                   an imine




                                        WWU Chemistry
When secondary amines are allowed to react with
aldehydes or ketones, dehydration of the type
shown in the elimination step cannot take place
(there is no labile hydrogen on the nitrogen atom
of the addition product).
                          OH

           R       CH2 C         R

                          N
                   R'           R'

                                      WWU Chemistry
If the starting aldehyde or ketone has an a-
hydrogen, however, dehydration toward the
a-carbon can occur, yielding an enamine.




                                  WWU Chemistry
Formation of Enamines
                          Protonated by
         H       OH       HOTs catalyst        H     OH2

R        C       C        R       slow    R    C    C      R

         R                                     R     N
             H                                  R          R

             N
     R               R


                                               H

     R       C        C       R           R    C    C      R   +       O
                                                                   H       H
             R   N                             R    N
              R      R                          R          R
             An enamine
                                          Resonance-stabilized

    A proton goes back
    to the reaction medium


                                                                   WWU Chemistry
The equilibrium for the formation of
enamine is not favorable. It can be shifted
to the right, however, by removing the
water by azeotropic distillation as it is
formed.




                                  WWU Chemistry
The enamine is quite nucleophilic,
 owing to resonance of the type:
         R'                            R'

 R            N   R'           R            N   R'

     C    C                        C    C

 R            R                R            R



As a consequence of this resonance, the a-carbon
of an enamine has a great deal of carbanion-like
(nucleophilic) character.


                                       WWU Chemistry
Amines that are used typically to form enamines:
         CH3 CH2

                 N       H

         CH3 CH2                   N
          Diethylamine
                                   H
                               Piperidine

                                   O

             N

             H                     N

         Pyrrolidine               H
                               Morpholine


                                       WWU Chemistry
        Nucleophilic Character
            of Enamines
             R                            R

R            :N   R     R        _    +N      R
                            ..
    C    C                  C         C

R            R          R                 R




                                     WWU Chemistry
             Reactions of Enamines
                as Nucleophiles
            R                      R       R                             R        R

R           :N   R             R   +N                                R       :N

    C   C                  R   C       C       R                R    C       C        R
                                                                             +
R           R                  R                                     R
                     SN2                           an iminium salt

    R   X
                                                           _
                                               +       X




                                                                WWU Chemistry
      Hydrolysis of Iminium Salts
              (Part One)
1)
              R         R                      R          R                                R         R

          R       +N                       R        N:                                 R   +N            H
                                slow
      R   C        C        R          R   C        C         R               R        C       C         R

          R                                R       +O :                                R       :O        H
                   ..                                                                           ..
                   O                           H           H
                   ..
          H                 H

 2)
              R         R

          R   +N            H                      R                      R        R

      R   C       C         R              R       C       C      R   +       N        H
                                                                              ..

          R       :O        H                      R      +O      H
                   ..                                      ..



                                                                          WWU Chemistry
         Hydrolysis of Iminium Salts
                (Part Two)
3)
         R                    R
                                                  +
     R   C    C    R      R   C   C      R   +   H

         R   +O    H          R   :O :
              ..




                                  WWU Chemistry
       O                         O




       N                         N                   O

                                     CH3                  CH3
                          HOTs             H2O
              +   CH3 I
                                           H+


from cyclohexanone




 Enamines can react with alkyl halides -- Here’s an
 example.
 Apply the previous mechanisms to this synthesis.


                                                 WWU Chemistry
                       Another example:
     O




     N                                              O

                                                         CH2 CH   CH2
                                              H2O
              +      CH2 CH   CH2 Br
                                       HOTs   H+


from cyclohexanone



    Try to apply the mechanisms to this synthesis.



                                                    WWU Chemistry
In each of these reactions, the enamine,
acting as a nucleophile, displaces the halide
ion from the alkyl halide in an SN2 process.




                                  WWU Chemistry
         O                 N
                           H        CH3I         H2O
CH3   CH2 C   CH2 CH3
                         HOTs                    H+


                                             O

                                     CH3 CH2 C        CH    CH3

                                                      CH3


              a-Alkylation of a Ketone


                                           WWU Chemistry
                                             O
                      O    N
                                    Br CH2 C         O       CH2 CH3
                           H

                          HOTs


                                 CH3 CH2 O               O
                                                 C
                 H2O
                                                 CH2
                   +
                  H
                                                               O



a-Alkylation of a Ketone


                                                 WWU Chemistry
Enamine Reactions -- Summary
            R       R           R        R
 O              N                   +N

                                               R
     R2NH               R   X

     HOTs



                                         H2O
                                         H+

                                     O

                                               R




                                         WWU Chemistry
The nucleophilic behavior of enamines has been used to
prepare deuterium-labelled ketones.

  O                              O                             O
            O
                                               D3PO4                D
                                                D2O
       +                         N
            N     HOTs                             0 °C

            H
                                                                   O


                                                               +
                         1-Morpholinocyclohexane                    N

                                                                   D




 This reaction demonstrates that enamines are basic.

                                                          WWU Chemistry
In the previous examples, we have been using
nitrogen as the nucleophilic atom.
Reasoning by analogy and using the periodicity that
we associate with position in the Periodic Table, what
would we predict if phosphorus were the
nucleophile?


When phosphorus is the nucleophilic atom, the
behavior is similar to that of amines, but there are
important differences.
The chief application of phosphorus chemistry in
this type of reaction is in the Wittig reaction.


                                          WWU Chemistry
                The Wittig Reaction
 R1                          R3              R1      R3

   C   O    +   (C6H5)3P C             R2    C       C    R4
 R2                          R4
                                            : O:   P(C6H5)3
                  an ylide                    .. _ +
                                             a betaine



                                  R1         R3
                                   C    C            +         O   P(C6H5)3
This is a type of condensation
reaction -- we use it to “dock”   R2         R4
two large structures together.
This is another example of
addition-elimination.

                                                         WWU Chemistry
                   Ylide
• A compound or intermediate with both a
  positive and a negative formal charge on
  adjacent atoms.




                                   WWU Chemistry
            Resonance in Ylides

                 R                            _ R
                                          +   ..
 (C6H5)3P    C                     (C6H5)3P   C
                 R                                 R




The ylide is nucleophilic, owing to the negative
charge character on carbon (structure on the
right).
                                        WWU Chemistry
           Typical Solvents
• Ylides are highly reactive with water,
  alcohols, acids, carbonyl compounds, and
  esters.
• So, the solvents must exclude these classes
  of compounds.
• That limits us to hydrocarbons (and perhaps
  ethers). Toluene and xylene are used
  frequently.

                                   WWU Chemistry
Example of a Wittig Reaction


C   O   + (C6H5)3P=CH2   C   CH2                     C   CH2

                         O   P(C6H5)3




                                        +   (C6H5)3P=O




                                        WWU Chemistry
                 Mechanism (???)
      :O:
                                     .. _
      C                             :O:                _
                                                          .. +
 R1         R2                                          : O: P(C6H5)3
                      slow        R1 C      R2
                                    +                R1 C      C   R3
                 R3          (C6H5)3P C     R3   =
(C6H5)3P C                                                 R2 R4
                                       R4
                 R4



                                                          ..
                             R1        R3               : O    P(C6H5)3
        O    P(C6H5)3    +     C   C                  R1 C     C   R3
                             R2        R4
                                                           R2 R4



                                                     WWU Chemistry
            Preparation of the Ylide
     R2                                        R1
                                              +                  _
R1   CH X      +   (C6H5)3P            (C6H5)3P CH R2           X

                                        a phosphonium salt

Typical bases:
                                                    base
     •NaOCH3
     •NaH                                                  R1
                                         (C6H5)3P     C
     •LiC4H9
                                                           R2


This reaction is not stereospecific.                       + "HX"


                                              WWU Chemistry
  Preparation of trans,trans-1,4-Diphenyl-1,3-butadiene

                        CH2 Cl   + (C6H5)3P:                          CH2 P(C6H5)3

                                                                                  Cl
                                            H
                                      H         C O                   NaOCH3
                                          C C
                                                H


                                                                      CH      P(C6H5)3




                         H                                    H               H

                H            C   C                    H           C       C

Major product       C    C            H         +         C   C                          Minor product
                             H                                    H


                        trans,trans                           trans,cis



                                                                              WWU Chemistry
Green Chemistry Application
            CH2 Cl   + (C6H5)3P:                            CH2 P(C6H5)3

                                                                        Cl
                                H
                          H         C O                     K3PO4              More
                              C C                           no solvent!
                                    H                                          grinding!

                                                            CH      P(C6H5)3




             H                                      H               H

    H            C   C                      H           C       C

        C    C            H             +       C   C

                 H                                      H


            trans,trans                             trans,cis



                                                                        WWU Chemistry
       The Wittig Reaction: A Reminder
 R1                          R3              R1      R3

   C    O   +   (C6H5)3P C             R2    C       C    R4
 R2                          R4
                                            : O:   P(C6H5)3
                  an ylide                    .. _ +
                                             a betaine



                                  R1         R3
                                   C    C            +         O   P(C6H5)3
                                  R2         R4

This is a type of condensation
reaction -- we use it to “dock”
two large structures together.

                                                         WWU Chemistry

				
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