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Carbonyl Chemistry by wK0S14F6

VIEWS: 29 PAGES: 46

									     Carbonyl Chemistry               C1

              Part I

          Nomenclature
       General Properties
       Carbonyls as Bases
           Enolization
    Preparation of Aldehydes
     Preparation of Ketones
     Reactivity of Carbonyls
 Nucleophilic Addition Reactions
Nucleophilic Substitution Reactions
                 Carbonyl Chemistry                       C2

            Chemistry of aldehydes & ketones

                  The carbonyl group

                        R'
                              C    O
                   R               planar



                             +
                             C O -
                       R'
polarized          R
                            120o        carbon is sp2 hybridized
          Carbonyl Nomenclature: Aldehydes              C3
    formaldehyde                             acetaldehyde

          O                                        O
    H C                                      H3C C
          H                                        H

    methanal          Aldehydes suffix        ethanal
                            -al

    as a substituent (e.g. on a ring)          aromatic




cyclohexanecarbaldehyde                  benzaldehyde
           Carbonyl Nomenclature: Ketones             C4

 propanone                        methyl ethyl ketone
       O                                 O
       C                                 C
 H3C       CH3                     H3C       CH2CH3
   acetone                            2-butanone
                 Ketones suffix
                     -one
                                     a phenone




cyclopentanone
                                   acetophenone
                 Carbonyl Nomenclature                    C5
            Indicating positions relative to a carbonyl

                                              O
                -CH2-CH2-CH 2-CH2-CH2-C




       should a carbonyl need to be named as a substituent:
                             use “oxo”
e.g.
                          O         O

                      H                 OH
                Carbonyls as Bases                    C6

         Protonation of the carbonyl oxygen

  C O     +   H Cl               C O        +    Cl
                                       H



positive charge enhances electrophilicity of the carbonyl
             group  increase in reactivity
                    Carbonyls as Bases                C7

         Lewis acids are often used (e.g. AlCl3)


Specific example

                                              AlCl3
         O         AlCl3                  O

             CH3                              CH3
                                               "complex"
       acetophenone
                 Carbonyls as Acids                     C8
-hydrogen (to the carbonyl) can be removed with a base.

 O                                 carbanion stabilized by
                                   delocalization
     H
          OH
                               O                    O



     OH
                                   enolate anions


                               keto / enol are tautomers
                                  Enolization                             C9
for acetone.......
                      O                                   OH

             H3C          CH3                       H3C         CH2

                            almost exclusively in keto form


for penta-2,4-dione......(stabilized by diketo-delocalization)
         O        O                                             OH    O

   H3C       C        CH3                  o            H3C        C    CH3
             H2                          25
                                                                   H
      83% ketol                     at equilibrium                17% enol
                          significant proportion in enol form
                             Enolization                         C10

.....already seen base catalyzed enolization (previous slides)

             acid catalyzed enolization also possible.

     O

                        H+
                                        H
         H                          O                    O


     OH                                 H                    H
                       - H3O+
                                                      O
                                                  H          H
                    Preparation of Aldehydes             C11

Mild Oxidation of Primary Alcohols
e.g. pyridinium chlorochromate in dichloromethane
 Me           Me                          Me          Me     O
                     CH2OH
                                                                 H
      citronellol                              citronellal 82%

Ozonolysis of Alkenes
             CH3                      O
                                                         H
            H
                                                     O
  Note: at least one vinylic hydrogen is needed
             Preparation of Aldehydes               C12

Partial Reduction of Carboxylic Acids


  CH3(CH2)10COOCH3                       CH3(CH2)10CHO



  DIBAH = diisobutylaluminiumhydride
               Preparation of Ketones               C13

Oxidation of Secondary Alcohols
can use - Jones reagent (CrO3 in aq. H2SO4)
         - sodium dichromate
         - PCC
                  OH                           O

                                  (CH3)3C       90%
  (CH3)3C

Ozonolysis of Disubstituted Alkenes
       O                               O
                 CH2                            O
                                                    70%
               CH3                            CH3
                 Preparation of Ketones                 C14
Friedel-Crafts Reaction for Aryl Ketones
                                                 O
                         O
             +   H3C C                                 CH3
                         Cl


Hydration of Terminal Alkynes

                                               O
   CH3(CH2)3C CH                      CH3(CH2)3C CH3     78%

  - requires catalytic mercuric ion
  - methyl ketones are produced
               Reactivity of the Carbonyl             C15

The + carbonyl carbon is susceptible to nucleophilic attack
             two product types are possible


substituted products       or             addition products

                           O
                                -
    O          subn                                OH
                                        addn
                           C
                                +
    C                                          R C      X
R       Nu
                       R            X              Nu
                                        Nu
                Addition vs Substitution               C16

                       Substitution

When “Y” is a good leaving group, substitution is favoured


     O                      O             O
     C       + Nu       R C      Y        C        +   Y
 R       Y                  Nu        R       Nu
           Carbonyl Substitution Reactions                C17

Factors influencing Nucleophilic attack........

* Steric hinderence         the more highly substituted the
                            carbonyl, the less susceptible to
  Nu                             attack

* Electronegativity         the more electronegative “Y”....the
                            greater the + on the carbonyl
                            carbon  the more reactive to Nu
                            attack
              Carbonyl Substitution Reactions                     C18




      O                     O                O               O
(CH3)3CCCl        (CH3)2CHCCl          CH3CH2CCl        CH3CCl

                     increasing reactivity

          O                        O                     O
          C                        C                     C
    CH3        NH2           CH3       OH           CH3      Cl
    acetamide                 acetic acid          acetyl chloride
               Carbonyl Addition Reactions                  C19
                      Addition Reactions
If “Y” cannot stabilize a -ve charge, it is a poor leaving group
             Nu attacks yields addition products

           O                 O                     OH
                   Nu                  +H
           C             R C      Y            R C      Y
       R       Y             Nu                    Nu

e.g. if Y = “H”      leaving group would be a hydride ion
                                                o
     if Y = “CH3” leaving group would be a 1 methyl ion
  both examples are not stablized  are poor leaving groups
                Nu addition reaction occurs
    Nucleophilic Addition Reactions of Carbonyls
Nucleophilic addition of HCN
 - formation of Cyanohydrins
 - use of carbon nucleophiles
              O         i) NaCN/H2O              OH
                        ii) H2SO4/H2O          R C R'
          R       R'
                                                 C N
                             O            H+
           CN
                          R C R'
                            C N

Note: synthetic utility in * addition of 1 x extra carbon
                           * addition of 2 x functional groups
          Nucleophilic attack by Cyanide Ions              C21
                              CH3CHO
specific example


                                OH
                             H3C C C N
                                H             nitrile hydrolysis

           OH                                OH O
       H3C C CH2 NH2                     H3C C C
                                             H   NH2
             H
                                              H3O+, 
  cyano-reduction yielding
         an amine                          OH O
                                       H3C C C           lactic
                                           H   OH         acid
 Functional Group Interconversions                        C22
         consider the previous example
                     aldehyde (C2)

                          nucleophilic addition

                    cyanohydrin (C3)


nitrile reduction              nitrile hydrolysis

        amine (C3)               amide (C3)
                                       amide hydrolysis

                               carboxylic acid (C3)
                                                       C23
Further examples of the nucleophilic addition of cyanide ions
              O                               OH

                  H                               CN
                                                 H
                                                    88%
         an aldehyde                    a cyanohydrin




              O                                  OH

        H3C       CH3                      H3C         CH3
                                                   H
          a ketone
   Nucleophilic Addition Reactions of Carbonyls C24
Nucleophilic addition of Organometallic Nucleophiles

     Organometallic nucleophiles are carbon nucleophiles

              Organometallic nucleophiles




 organolithium reagents         Grignard reagents
        e.g. R-Li                  e.g. R-MgBr
 Organolithium Reagents as Carbon Nucleophiles
                                                                 C25
             R X + Li                     R X



                                 “carbon nucleophile”
                             can attack electrophilic centre
specific example
                   Br                                      Li + LiBr
  1-bromohexane
       (C6)



                        OH                                     O Li
      1-heptanol                                   (C7)
  Organolithium Reagents as Carbon Nucleophiles
specific example                                      C26
               Cl                      Li
                    +   2 Li                 + LiCl




                               H   O    Li
           H
 100% Ph        OH
               Ph
      Grignard Reagents as Carbon Nucleophiles   C27
General Reaction......

      O                           O MgX     OH
             + R'' MgX            C R''     C R''
  R       R'                    R   R'    R   R'
             nucleophilic
                attack



carbonyls that can be reacted
              Reactions of Grignards with......       C28
with carbon dioxide....

                                                         O
  O C O + CH3CH2MgBr                        CH3CH2C
                                                         OH
                                           carboxylic acid

                    Note: addition of
                   one (1) extra carbon
with formaldehyde....
      O       CH3CH2CHCH3                  CH3CH2CHCH2OH
 HC       +
      H            MgBr                            CH3

                                             primary alcohol
             Reactions of Grignards with......          C29
with aldehydes....
       O
             + n-C4H9MgBr
 H3C       CH3


                                        secondary alcohol


with ketones....
       O
             + n-C4H9MgBr
 H3C       CH3

                                          tertiary alcohol
            Reactions of Grignards with......                C30
with esters....

                                                      O MgBr
                     O
CH3CH2MgBr + CH3C
                                                    C OCH2CH3
                     OCH2CH3                    H3C   CH2CH3
                                     - CH3CH2OMgBr
                                       (loss of ethoxy)
    OH               i) CH3CH2MgBr                   O
    C CH2CH3             2nd mole equivalent
H3C   CH2CH3         ii) H+/H2O                H3C        CH2CH3
  tertiary alcohol
    Nucleophilic Addition Reactions of Carbonyls
                                                         C31
Hydrides as Nucleophiles

        O                      O                   OH
    R       R'                      H          R     H
                           R       R                R


hydride source: reducing agents
  e.g.    LiAlH4 - lithium aluminiun hydride
          NaBH4 - sodium borohydride

                 -
   hydride “H ” is basic & a very strong nucleophile
      Hydrides as Nucleophiles; Examples                     C32
            O
                     + NaBH4                 4x
4x               H                                          OH
       butanal                                    butanol 85%
                               -
* all four hydrides (H ) from the borohydride are used
* LiAlH4 & NaBH4 do NOT reduce isolated double bonds

      CH3            O
                                   NaBH4
H3C                      CH3       ethanol
                                                       95%
    Nucleophilic Addition Reactions of Carbonyls
Nucleophilic Addition by Oxygen Containing Species      C33
                Hydrates, Acetals & Ketals




   Reaction with       Reactions of      Reactions of
      water           aldehydes with     ketones with
                         alcohols          alcohols
  Nucleophilic Addition Reactions of Carbonyls
                                                     C34
Reactions with Water: Formation of Hydrates
general example


  C O + H2O            HO C OH                C O + H2O

                       a geminal diol
 Nucleophilic Addition Reactions of Carbonyls           C35
Hydrate formation (reactions with water) Specific
 Examples
           H3C            H2O             OH
                 C O                          CH3
           H3C                      H3C      OH
             99.9%                        0.1%

            acetone                  acetone hydrate


             H            H2O             OH
                 C O                         H
             H                         H   OH
             0.1%                        99.9%
         formaldehyde            formaldehyde hydrate
    Nucleophilic Addition Reactions of Carbonyls C36
Reactions of Alcohols with Aldehydes: Acetal Formation
General Example
                                    i) loss of water
    O                      OH                                 OR'
               R' OH                ii) gain of alcohol
                             OR'                                  OR'
R       H              R                                  R
                            H                                    H
    aldehyde           hemiacetal                             acetal
 Nucleophilic Addition Reactions of Carbonyls        C37

Reactions of Alcohols with Aldehydes: Acetal Formation
Specific Example
      O                   OH                       OCH3
           H3C OH
                            H                        H
H3C       H         H3C                      H3C
                           OCH3                     OCH3

 aldehyde
  Nucleophilic Addition Reactions of Carbonyls
                                                                  C38
Reactions of Alcohols with Ketones: Acetal Formation
General Example
                                  i) loss of water
      O                    OH                               OR"
               R" OH              ii) gain of alcohol
                             R'                               R'
  R       R'           R    OR"                         R
                                                             OR"
  ketone
  Nucleophilic Addition Reactions of Carbonyls C39

Reactions of Alcohols with Ketones: Acetal Formation
Specific Example
         O                                      OH
                   +   CH3 OH                      CH3
   H3C       CH3                          H3C     OCH3
                                           0.3%


hemiacetals & hemiketals are unstable (and reversible)
unless both functional groups are part of the same molecule
  Nucleophilic Addition Reactions of Carbonyls
                                                      C40
Reactions of Alcohols with Aldehydes: Acetal Formation
                   O                               H      OH
                   C H
                     OH                                   O

      4-hydroxybutanal                       2-hydroxytetrahydrofuran
                     11%                             89%
                                  at equilibrium

       H                                               H
           CH2OH H                                         CH2OH
                       OH                                             H O
   HO                                              HO
     HO                     CHO                      HO                         OH
               H       OH                                         H    OH
           H                                                  H             H
  glucose as hydroxyaldehyde                  glucose as stable hemiacetal
  Nucleophilic Addition Reactions of Carbonyls
                                                            C41
                     for acetals &ketals.....
 reverse reaction is simply hydrolysis in the presence of acid

Mechanism of acetal/ketal formation & hydrolysis.........
  Nucleophilic Addition Reactions of Carbonyls
Nucleophilic Addition of Thiols                               C42
*                                      R-OH
                                  c.f. R-SH
*
* products are generally more stable
General Example
               SH                  S          Raney
                                              nickel      H
   C O    +
                                       S    (reduction)       H
               SH
                             a thioacetal
(Raney nickel will reduce any R-s group to R-H)
     Nucleophilic Addition Reactions of Carbonyls
Nucleophilic Addition of Thiols                           C43


Specific Example


             O                    S
                                      S
Me                       Me                      Me



Note: no strong acids or bases required (important with
 sensitive molecules)
Nucleophilic Substitution Reactions of Carbonyls
                                                        C44
Nucleophilic Substitution by Nitrogen Containing Species
                         O

                                      R'
            R-NH2
                             H             NH
                                      R

        R                                   R       R'
            N                                   N


                H
   Nucleophilic Substitution Reactions of Carbonyls
Preparation of Derivatives                                     C45
* oximes
                                                 OH
    O                                        N

             + H2N OH                                 + H2O

             hydroxylamine           cyclohexanone oxime (mp 91o)


* hydrazones
        O                                    H3C
                  + H2N-NH Ph                         N-NH-Ph
 H3C        CH3                                            mp 42o
                   phenylhydrazine           H3C
              Preparation of Derivatives                 C46
* semicarbazones
                                                H
                                                N       NH2
       CHO           O                      N
          + HN N                            C       O
             2           NH2                    H        + H2O
               H
                                                               o
                          benzaldehyde semicarbazone (mp 222 )



* 2,4-dinitrophenylhydrazine (DNP)

								
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