Ketones and Aldehydes

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					Ketones and Aldehydes
       Properties
     Nomenclature
      Preparation
       Reactions
       Synthesis
Carbonyl Functional Groups
 Large Dipole Controls
Properties and Reactivity
    Boiling Points
Dipole-Dipole Interactions
    Adrogenic/Anabolic Steroids

                  CH3 OH                     CH3 O

       CH3    H                   CH3    H

          H       H                  H       H
O                          O
     Testosterone              Androstenedione
              Anabolic Steroids

                  CH3 OH                          CH3 OH
                                                        CH3
              H                       CH3     H

          H       H    H N               H        H
O                            N
    Nandralone                   Stanozolol
            IUPAC Nomenclature
                         Ketones
                                           Cl
        O

                                            O

                                        Cl
2-methyl-3-pentanone        2,7-dichlorocycloheptanone

             O




                                 Br   Br        O
 1-phenyl-1-propanone
                       (R) 6,6-dibromo-5-cyclopentyl-2-heptanon
propiophenone (common)
       OH
                                 Cl

                O

                   m-chlorophenyl)-3-hexen-2-one
(E) 5(S)-hydroxy-1-(

               O



                          O

     trans 1,3-diacetylcyclohexane
               IUPAC Nomenclature
                       Aldehydes        H

                                   O
    O

H
             octanal           (E) 3-isopropyl-3-hexenal

                       O                                H
        Br             CH
                                       O            O
cis 4-bromocyclohexane-1-carbaldehyde       5-oxohexanal
          Classical Aldehyde
            Nomenclature
Prefix
form      HCHO

acet      CH 3CHO
                                        
propion       CHO                             CHO
                                     

butyr
                 CHO

valer               CHO
Prefix
capro
                            CHO

enanth                       CHO

capryl
                                  CHO

pelargon                            CHO

  capr
                                        CHO

                             CHO
example:
                  Cl   Cl
         classical:   -dichloro--methylenanthaldehyde
         IUPAC:    4,4-dichloro-2-methylheptanal
     Preparation of Ketones and
             Aldehydes
• Friedel-Crafts Acylation (ketones)
• Gatterman-Koch Formylation (aldehydes)
• Hydration of Alkynes (ketones with oxymercuration,
  aldehydes with hydroboration)
• Ozonolysis of Alkenes (aldehydes and ketones
  depending on substitution)
• 1,3-Dithiane alkylations (aldehydes and ketones)
• Reduction of acids, acid chlorides and
  nitriles
• Gilman Reaction (ketones)
Friedel-Crafts Acylation
               Isoflavones
Highly Sought After Natural Products
                  Jamaicin
     CH3          Piscidia erythrina L.

   CH3
           O         O

                                          O

                     O
                     CH3O                 O
                        CH3
                                                           O
                       CH3
                              O               OH         ClCCH2           O
                                                     +
Friedel-Crafts Acylation                                   CH3O           O
A Convergent Synthesis
                                                    TiCl4
    of Flavonoids
                                                    CH2Cl2
                                  CH3

                               CH3
                                        O             OH
                                                                  + HCl
                                                                     O
                               no rxn here           O
                                                     CH3O            O
Price, W.A.; Schuda, P.F. J.Org. Chem. , 1987, 52, 1972-1979
Acylation occurs ortho to OH
              possible complexation
    CH3            via H bond
   CH3
          O              O
                 
                              H
                              O
                      
                      
                                  O


                CH3O              O
Gatterman-Koch Formylation
                                                  O
                                                  CH
               CO, HCl
               AlCl 3/CuCl
benzene or activated benzene needed
  in situ preparation of formyl chloride
                                            O
           C    O + HCl                    HCCl
  Oxymercuration Hydration
               Markovnikov

                                   OH
               HgSO4, H2SO4
CH3CH2C   CH                  CH3CH2C=CH2
                 H 2O
                                 an enol



                                    O
                              CH3CH2CCH3
                                a k etone
       Hydroboration Hydration
                 Anti-Markovnikov
                                                 OH
                 1) disiamyl borane
CH 3CH 2C   CH                        CH 3CH 2CH=CH 2
                 2) H 2O2, NaOH
                                           an enol



           B                                     O
           H                          CH 3CH 2CH 2CH
      (sia)2BH                         an aldehyde
                                  Ozonolysis
                               Alkene Cleavage

CH3           CH3         1) O3 in CH2Cl2        CH3                     CH3
      C=C                                                C   O +O    C
                          2) CH3SCH3                                           + DMSO
  H           CH3                                    H                   CH3
                            or Zn/HOAc
                                                               DMS
          O
      O         O                            O
                                         O       O                  O O
 CH3                CH3
          C=C                                                 H      O
                                       H
      H         CH3
                                                                    ozonide
Gilman Reagent with
   Acid Chlorides
              DIBAH
    Diisobutyl Aluminum Hydride
Reduction of an Ester to an Aldehyde
O                                 O
COCH2CH3                          CH
       1) DIBAH
                                   + CH3CH2OH
          in toluene
                +
        2) H3O

                        H
                DIBAH
                        Al
          (CH3)2CHCH2        CH2CH(CH3)2
      Nucleophilic Addition Reactions:
                   Strong Nucleophiles
             
         O                                     +           OH
                                    O        H3O
         
         

Nu:                                     Nu                      Nu

       Basic nucleophiles: RMgX, RLi, LiAlH4, NaBH4, RC   CNa
                                -
       Nonbasic nucleophiles: CN
                Carbonyl Reactivity

        
       O                O                O                O
                >                >                >
       C                C                C                C
H               H    R        H       R       R'       R       OR

            decreasing rate of reaction with nucleophile
Cyanohydrin Formation
O                                     OH
CH                                    C    H
     HCN, (KCN trace amt.)
                                          CN
                                     + enant.
                               Mandelonitrile
                H            in defense glands of
           O                 millipede A. corrugata
           CH

                CN
Nucleophilic Addition Reactions:
          Weak Nucleophiles
                              H
O     +                   O                    OH
     H , H2O

                                  OH2               O H
                                               H

                                        H 2O

                      +
               H 3O                            OH

                 -H2O
                                              OH
                                         a hydrate
              Acetal Formation

O       +        HO   OCH3
    H , CH3OH                      +
                                  H , CH3OH    CH3O   OCH3

                 hemiacetal                      acetal



    O                             CH3CH2O     OCH2CH3
                              +
            excess CH3CH2OH, H                  + H2O
                  Acetal Mechanism
O         +           HO       OCH3         +          CH3O     OCH3
         H , CH3OH                         H , CH3OH

                      hemiacetal                          acetal
                                                                       +
                                                                    -H
                           +
                      -H
                               OH2                            H2O
                      H               H                            H
    H
O                                                      OCH3     CH3O       OCH3
                 HO   OCH3           HO   OCH3 -H2O
        HOCH 3
                                                              HOCH 3
        Propose a Mechanism

            +
          H3O                     O
S   S           H   S   S   H +
  Use of Ethylene Glycol to
Protect Ketones and Aldehydes
                              CH2 CH2
 O
                              O   O
                          +
            HOCH2CH2OH, H3O
                                      + H2O

        O                               O

                     ?


 CO2H                             CH2OH
                Synthesis

      O                            +                  O
             1) HOCH2CH2OH, H
             2) LiAlH 4
                       +
              3) H3O

CO2H                                        CH2OH
   LiAlH 4 will reduce the ketone preferentially,
  therefore, protection of the ketone is necessary.
     Aldehydes React Preferentially
O              O                          O    OH
HC             CCH3                       HC   CHCH3


           HOCH 2CH2OH
              +
            H



      O    O          O      1) NaBH4
      HC              CCH3   2) H3O
                                      +
Imine Formation
    Imines and Enamines
                               R
O                          N
        o
       1 amine
       RNH2
                                   + H2O
            +
       H3O
                          imine
            pH = 4-5
                o          NR2
             2 amine
              R2NH
                                    + H2O
                      +
                    H3O
                          enamine
                                                  CH3
    O                                         N

             CH3NH2
                +                                   + H2O
             H3O , pH = 4-5


                                                        H         CH3
                                       H 2O
                                                              N




                                   +
                            H 3O                                  -H2O
O   NH2CH3             HO     NHCH3                     H2O       NHCH3


        intermolec.
         +
        H transfer     carbinolamine
Imine Derivatives
    Wolff-Kishner Reduction
O                       H   H
        NH2NH2, KOH
                                + N2
          DMSO


                 NH2
             N




          a hydrazone
Mechanism from Hydrazone
Deoxygenation
       Enamine Mechanism
    (same as imine mech. until last step)
                         CH3        CH3
O
                               N
       (CH3)2NH
           +
        H3O , pH = 4-5


                                   CH3       CH3   OH2
                                         N
                                               H
Wittig Reaction:
  C=O into C=C
                 Ylide Synthesis
                      SN 2
(C6H5)3P   + CH3Br                 (C6H5)3P    CH3 Br


(C6H5)3P   CH3 + CH3CH2CH2CH2Li            (C6H5)3P   CH2


                       phosphorous ylide

                                           (C6H5)3P   CH2

                              methylene triphenylphosphorane
                      Mechanism
(C6H5)3P   CH2
                        O
                                 (C6H5)3P    O
                      HC
(C6H5)3P   CH2    +                    CH2 C
                                           H
methylene triphenylphosphorane




                                  (C6H5)3P    O
           CH2=CH                       CH2 C
(C6H5)3PO +                                 H

                                        an oxaphosphetane
                                            CH3       CH3
           O                                      C
                   (C6H5)3P=C(CH3)2
(CH3)2CHCH 2CCH3                      (CH3)2CHCH 2CCH3

                                      + (C6H5)3P=O
Pure Alkene is Formed in Wittig Rxn
                         CH3            CH2
        1) CH3MgBr
        2) POCl3, pyr.          +
O
                         9          :      1

                         CH2

        (C6H5)3P=CH2           methylenecyclohexane
                                 exclusively
(Methoxymethylene)-triphenylphosphorane
          an Aldehyde Prep
                                        O
                         H   OCH3
O                                       CH
                                    +
     (C6H5)3P   CHOCH3          H3O
Propose a Sequence of Steps…

O    O               CHCH3   O

         H                       H
            Provide a Mechanism

O   OCH3              O   *OH     same
            +   *                                   *
           H , H2O              conditions HO        O
     *O is O-18
                                                H
                     + CH3OH
                                      +
                                  H
O      OCH3                  O        *OH     same
                +  *                                                     *
              H , H2O                       conditions HO                 O
           *O is O-18
                                                                     H
                            + CH3OH

       H
O      OCH3                                                              *
                                                          HO              O
                                                +                             H
                                            H
                                                                 H
                            H2O
                                                               H2O
    - CH3OH
                            H               H
                             *                      *OH
O        *              O   OH              O
          OH2
   Conjugate Addition to
,-Unsaturated C=O groups
 O         O                                  O




            O
                    
                               2 electrophilic
                                   sites
                            
                        
         1,2- vs. 1,4-Addition
                             CH3       OH
             1) CH3MgBr
O             2) H3O
                       +
    

                                  O
         
                                            H
             1) Li(CH3)2Cu
                       +
              2) H3O
                                            CH3
     Gilman Reagents add 1,4

CH3CH2
             O                           CH3CH2       O
                      1) Li(CH3CH2)2Cu
                 H              +
                       2) H3O                             H
                                                  H

                 Li
 CH3CH2      O

                 H

         H
    Synthesis

                      OH
O    ??
                      CN
          CH3CH2CH2
Carry Out Conjugate Addition 1st

                                   OH
  O
      1) Li(CH3CH2CH2)2Cu
             +                     CN
       2) H3O
       3) HCN, (KCN) CH3CH2CH2
      MCAD Deficiency, a Genetic
             Disease
• Children with any of these enzyme deficiencies
  have a significant risk (20%) of death during the
  first, clinical episode of hypoglycemia (low blood
  glucose).
• Those patients affected show episodes of acute,
  life-threatening attacks that are symptomatically
  consistent with Reye’s Syndrome and sometimes
  misdiagnosed as S.I.D.S.
• The most common of these in-born errors is
  MCAD Deficiency. (Medium Chain Acyl-CoA Dehydrogenase)
• ~1/50 Caucasians carry the gene.
               MCAD Enzyme
• (MCAD) is one of the enzymes involved in
  mitochondrial fatty acid -oxidation, which fuels
  hepatic ketogenesis, a major source of energy once
  hepatic glycogen stores become depleted during
  prolonged fasting and periods of higher energy
  demands.
• Typically, a previously healthy child with MCAD
  deficiency presents with hypoketotic hypoglycemia,
  vomiting, liver dysfunction, skeletal muscle weakness
  and lethargy triggered by a common illness. On
  average, this occurs between 3 and 24 months of age.
  Ackee Fruit
(Bligia Sapida)   Ingestion of the unripe seeds
 from Jamaica     from the fruit of the Jamaican
                  Ackee tree causes a disruption
                  of the dehydrogenase enzymes
                  needed to metabolize fatty
                  acids. This “vomiting sickness”
                  is a result of the enzyme
                  inhibitor Hypoglycin A.
                                    CO2H

                                 NH2
          (R)(-) MCPA is the Toxic
          Metabolite of Hypoglycin-A

                     metabolism
             CO2H                                   OH

   H     NH2                               H    O
 Hypoglycin-A                            (R)(-) MCPA
from Bligia sapida                     binds irreversibly to
                      medium-chain acyl-CoA dehydrogenase enzymes
              Wittig Approach to Both
                    Enantiomers
O              1) Ph3P=CH2
         Cl    2) KOC(CH3)3      HO                            (S )(+) MCPA
  H            3) n-BuLi, HCHO
                                 (S) via initial S N2
(R)(-)

                                                               (R)(-) MCPA
                                 HO
                                  (R) via initial epoxide opening
       Wittig Approach to (S)(+)-MCPA
                     Start with (R)(-) Epichlorohydrin
                        SN2 on 1o Alkyl Chloride?

O                     (C6H5)3P=CH2   O                            KOC(CH3)3
                                                       P(C6H5)3
             Cl
      H                                  H             Cl
    (R)(-)                                     (S)



O                                        O                               O
                  P(C6H5)3                                                      P(C6H5)3
                                                     P(C6H5)3
     H
                                             (R,R)                      (R,R)
              Wittig Sequence Affords
        (S) (Methylenecyclopropyl)methanol
        O                            O
                P(C6H5)3                                    n-butyl Li
                                                 P(C6H5)3

        (R,R)                            (R,R)

O                                                                    OH
                 paraformaldehyde    O
    P(C6H5)3                                 P(C6H5)3                     P(C6H5)3
                                                                           O
    H       H                               CH2O
        C
                                    OH
        O        - (C6H5)3PO

                                     (S)
Homologation to (S)(-)-MCPA
OH                        OSO2CH3         CN
           CH3SO 2Cl                KCN
            pyridine                DMF
 (S)                       (S)             (S)


   hydrolysis
     or            HO2C
 1) DIBAH
                          (S)
 2) CrO3, H2SO 4
       Approach to (R)-(+)-MCPA
           Same Wittig Approach with Ylide
             Opening the Epoxide First?
 O                                   O
           Cl                                  Cl
    H                    (C6H5)3P
     (R)                              H
H2C=P(C6H5)3

                                                O
                   O                (C6H5)3P
(C6H5)3P               KOC(CH3)3
           (R) H                               (S,S)

				
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posted:6/23/2012
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