Chapter 19 Aldehydes and Ketones Nucleophilic Addition Reactions Chapter 19 Aldehydes and Ketones Nucleophilic Addition by malj

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									     Chapter 19. Aldehydes and
     Ketones: Nucleophilic
     Addition Reactions


Based on McMurry’s Organic Chemistry, 7th edition
    Aldehydes and Ketones
 Aldehydes (RCHO) and ketones (R2CO) are
  characterized by the the carbonyl functional group (C=O)
 The compounds occur widely in nature as intermediates
  in metabolism and biosynthesis




                                                             2
  Why this Chapter?
 Much of organic chemistry involves the
  chemistry of carbonyl compounds

 Aldehydes/ketones are intermediates in
  synthesis of pharmaceutical agents, biological
  pathways, numerous industrial processes

 An understanding of their properties is essential



                                                      3
 19.1 Naming Aldehydes:
 Aldehydes are named by replacing the terminal -e of the
  corresponding alkane name with –al
 The parent chain must contain the CHO group
      The CHO carbon is numbered as C1




 Ethanal           Propanal
acetaldehyde      Propionaldehyde      2-Ethyl-4-methylpentanal




                                                                  4
19.1 Naming Aldehydes and Ketones




                                    5
Naming Aldehydes
    If the CHO group is attached to a ring, use the
     suffix carbaldehyde.




Cyclohexanecarbaldehyde        2-Naphthalenecarbaldehyde




                                                        6
Naming Aldehydes:
 Common Names end in aldehyde




                                 7
     Naming Ketones
 Replace the terminal -e of the alkane name with –one
 Parent chain is the longest one that contains the ketone grp
    Numbering begins at the end nearer the carbonyl carbon




   3-Hexanone           4-Hexen-2-one         2,4-Hexanedione
(New: Hexan-3-one)   (New: Hex-4-en-2-one) (New: Hexane-2,4-dione)




                                                                 8
    Ketones with Common Names
 IUPAC retains well-used but unsystematic names for a few
  ketones




   Acetone         Acetophenone             Benzophenone




                                                             9
 Ketones and Aldehydes as Substituents
 The R–C=O as a substituent is an acyl group, used with the
  suffix -yl from the root of the carboxylic acid




  The prefix oxo- is used if other functional groups are present
   and the doubly bonded oxygen is labeled as a substituent on a
   parent chain




                                                                    10
Learning Check:
 Name the following:




                        11
   Solution:
    Name the following:
 2-methyl-3-pentanone
                                                  2,6-octanedione
(ethyl isopropyl ketone)




                        3-phenylpropanal
                   (3-phenylpropionaldehyde)




                            4-hexenal


Trans-2-methylcyclohexanecarbaldehyde
                                        Cis-2,5-dimethylcyclohexanone
                                                                    12
19.2 Preparation of Aldehydes
 Aldehydes
  Oxidation of 1o alcohols with pyridinium chlorochromate PCC




   Oxidative cleavage of Alkenes with a vinylic hydrogen with
    ozone




                                                                 13
  Preparation of Aldehydes
Aldehydes
  Reduction of an ester with diisobutylaluminum hydride
   (DIBAH)




                                                           14
   Preparing Ketones
Ketones
 Oxidation of a 2° alcohol
      Many reagents possible: Na2Cr2O7, KMnO4, CrO3
           choose for the specific situation (scale, cost, and acid/base
            sensitivity)




                                                                            15
   Ketones from Ozonolysis
Ketones
 Oxidative cleavage of substituted Alkenes with ozone




                                                         16
   Aryl Ketones by Acylation
Ketones
 Friedel–Crafts acylation of an aromatic ring with an acid
  chloride in the presence of AlCl3 catalyst




                                                              17
 Methyl Ketones by Hydrating Alkynes
Ketones
 Hydration of terminal alkynes in the presence of Hg2+ cat




                                                              18
 Preparation of Ketones
Ketones
 Gilman reaction of an acid chloride




                                        19
 Learning Check:
 Carry out the following transformations:

   3-Hexyne  3-Hexanone


  Benzene  m-Bromoacetophenone


  Bromobenzene  Acetophenone


  1-methylcyclohexene  2-methylcyclohexanone


                                                20
 Solution:
 Carry out the following transformations:
  3-Hexyne  3-Hexanone
                                                 O
 CH3   CH2   C C CH2   CH3
                             Hg(OAc)2,
                                    +
                                       CH3 CH2 C CH2 CH2 CH3
                               H 3O




  Benzene  m-Bromoacetophenone
                                                     O
                             O
                                            Br
                   1) CH3    C Cl , AlCl3

                   2) Br2, FeBr3




                                                               21
 Solution:
 Carry out the following transformations:
 Bromobenzene  Acetophenone
                            1) Mg in ether         O
                      Br             O
                            2) CH3    C H
                            3) H3O+
                            4) PCC




 1-methylcyclohexene  2-methylcyclohexanone
                CH3                          CH3
                           1) BH3
                           2) H2O2, NaOH           O

                           3) PCC

                                                       22
19.3 Oxidation of Aldehydes & Ketones
 CrO3 in aqueous acid oxidizes aldehydes to carboxylic
  acids (acidic conditions)




 Tollens’ reagent Silver oxide, Ag2O, in aqueous ammonia
  oxidizes aldehydes (basic conditions)




                                                            23
   Hydration of Aldehydes
 Aldehyde oxidations occur through 1,1-diols (“hydrates”)
 Reversible addition of water to the carbonyl group
 Aldehyde hydrate is oxidized to a carboxylic acid by
  usual reagents for alcohols




                                                             24
  Ketones Oxidize with Difficulty
 Undergo slow cleavage with hot, alkaline KMnO4
 C–C bond next to C=O is broken to give carboxylic acids
 Reaction is practical for cleaving symmetrical ketones




                                                            25
 19.4 Nucleophilic Addition Reactions of
 Aldehydes and Ketones
 Nu-
  approaches
  75° to the
  plane of C=O
  and adds to C

 A tetrahedral
  alkoxide ion
  intermediate is
  produced




                                           26
Nucleophiles




               27
Reactions variations




                       28
Relative Reactivity of Aldehydes and
Ketones
 Aldehydes are generally more reactive than ketones in
  nucleophilic addition reactions
      The transition state for addition is less crowded and lower
       in energy for an aldehyde (a) than for a ketone (b)
      Aldehydes have one large substituent bonded to the C=O:
       ketones have two




                                                                     29
   Relative Reactivity of Aldehydes
   and Ketones
 Aldehydes are generally more reactive than ketones in
  nucleophilic addition reactions

       Aldehyde C=O is more polarized than ketone C=O
       Ketone has more electron donation alkyl groups,
        stabilizing the C=O carbon inductively




                                                          30
  Reactivity of Aromatic Aldehydes
 Aromatic Aldehydes Less reactive in nucleophilic addition
  reactions than aliphatic aldehydes
      Electron-donating resonance effect of aromatic ring makes
       C=O less reactive electrophile than the carbonyl group of
       an aliphatic aldehyde




                                                                   31
 19.5 Nucleophilic Addition of H2O:
 Hydration
 Aldehydes and ketones react with water to yield 1,1-diols
 (geminal (gem) diols)
 Hydration is reversible: a gem diol can eliminate water




                                                              32
 Base-Catalyzed Addition of Water
 Addition of water
  is catalyzed by
  both acid and
  base
 The base-
  catalyzed
  hydration
  nucleophile is
  the hydroxide
  ion, which is a
  much stronger
  nucleophile than
  water
                                    33
  Acid-Catalyzed Addition of Water
 Protonation
  of C=O
  makes it
  more
  electrophilic




                                     34
   Addition of H-Y to C=O
 Reaction of C=O with H-Y, where Y is electronegative,
  gives an addition product (“adduct”)
 Formation is readily reversible




                                                          35
19.6 Nucleophilic Addition of HCN:
Cyanohydrin Formation
 Aldehydes and unhindered ketones react with HCN to yield
  cyanohydrins, RCH(OH)CN
 Addition of HCN is reversible and base-catalyzed,
  generating nucleophilic cyanide ion, CN-




                                           A cyanohydrin


                                                             36
    Uses of Cyanohydrins
 The nitrile group (CN) can be reduced with LiAlH4 to
  yield a primary amine (RCH2NH2)




 Can be hydrolyzed by hot acid to yield a carboxylic acid
                                                             37
19.7 Nucleophilic Addition of Grignard Reagents
and Hydride Reagents: Alcohol Formation

 Treatment of aldehydes or ketones with Grignard
  reagents yields an alcohol
      Nucleophilic addition of the equivalent of a carbon anion,
       or carbanion. A carbon–magnesium bond is strongly
       polarized, so a Grignard reagent reacts for all practical
       purposes as R :  MgX +.




                                                                    38
 Mechanism of Addition of Grignard
 Reagents
 Complexation of
  C=O by Mg2+,
  Nucleophilic
  addition of R : ,
  protonation by
  dilute acid yields
  the neutral alcohol

 Grignard additions
  are irreversible
  because a
  carbanion is not a
  leaving group



                                     39
  Hydride Addition
 Convert C=O to CH-OH
 LiAlH4 and NaBH4 react as donors of hydride ion
 Protonation after addition yields the alcohol




                                                    40
19.8 Nucleophilic Addition of Amines: Imine
and Enamine Formation
 RNH2 adds to C=O to form imines, R2C=NR (after loss of HOH)
 R2NH yields enamines, R2NCR=CR2 (after loss of HOH)
 (ene + amine = unsaturated amine)




                                                               41
Mechanism of
Formation of Imines
 Primary amine adds to
    C=O
   Proton is lost from N
    and adds to O to yield
    a neutral amino
    alcohol
    (carbinolamine)
   Protonation of OH
    converts into water as
    the leaving group
   Result is iminium ion,
    which loses proton
   Acid is required for
    loss of OH – too much
    acid blocks RNH2

                             42
    Imine Derivatives:
 Addition of amines with an atom containing a lone pair of electrons on
    the adjacent atom occurs very readily, giving useful, stable imines.
        These are usually solids and help in characterizing liquid ketones or
        aldehydes by melting points

 For example,
       hydroxylamine
        forms oximes




  2,4-dinitrophenylhydrazine
   readily forms
2,4-
   dinitrophenylhydrazones



                                                                                43
 Enamine
 Formation
 After
  addition of
  R2NH,
  proton is
  lost from
  adjacent
  carbon




                44
Imine / Enamine Examples




                           45
19.9 Nucleophilic Addition of Hydrazine: The
Wolff–Kishner Reaction
 Treatment of an
  aldehyde or
  ketone with
  hydrazine,
  H2NNH2 and
  KOH converts
  the compound to
  an alkane
 Originally carried
  out at high
  temperatures but
  with dimethyl
  sulfoxide as
  solvent takes
  place near room
  temperature
                                               46
The Wolff–Kishner Reaction: Examples




                                       47
19.10 Nucleophilic Addition of Alcohols:
Acetal Formation
 Alcohols are weak nucleophiles but acid promotes
  addition forming the conjugate acid of C=O
 Addition yields a hydroxy ether, called a hemiacetal
  (reversible); further reaction can occur
 Protonation of the OH and loss of water leads to an
  oxonium ion, R2C=OR+ to which a second alcohol adds
  to form the acetal




                                                         48
Acetal Formation




                   49
     Uses of Acetals
 Acetals can be protecting groups for aldehydes & ketones
 Use a diol, to form a cyclic acetal (reaction goes faster)




                                                               50
19.11 Nucleophilic Addition of Phosphorus
Ylides: The Wittig Reaction
 The sequence converts C=O  C=C
 A phosphorus ylide adds to an aldehyde or ketone to
  yield a dipolar intermediate called a betaine
 The intermediate spontaneously decomposes through a
  four-membered ring to yield alkene and
  triphenylphosphine oxide, (Ph)3P=O




                                                  An ylide




                                                             51
Mechanism of the Wittig
Reaction




                          52
   Uses of the Wittig Reaction
 Can be used for monosubstituted, disubstituted, and
  trisubstituted alkenes but not tetrasubstituted alkenes
  The reaction yields a pure alkene of known structure
 For comparison, addition of CH3MgBr to cyclohexanone
  and dehydration with, yields a mixture of two alkenes




                                                            53
 19.12 The Cannizaro Reaction
 The adduct of an aldehyde and OH can transfer hydride
  ion to another aldehyde C=O resulting in a simultaneous
  oxidation and reduction (disproportionation)




                                                            54
  19.13 Conjugate Nucleophilic Addition to -
  Unsaturated Aldehydes and Ketones
 A nucleophile
  can add to the
  C=C double
  bond of an ,-
  unsaturated
  aldehyde or
  ketone
  (conjugate
  addition, or 1,4
  addition)
 The initial
  product is a
  resonance-
  stabilized
  enolate ion,
  which is then
  protonated
                                                  55
    Conjugate Addition of Amines
 Primary and secondary amines add to , -unsaturated
  aldehydes and ketones to yield -amino aldehydes and
  ketones




          Reversible so more stable product predominates
                                                           56
    Conjugate Addition of Alkyl Groups:
    Organocopper Reactions
 Reaction of an , -unsaturated ketone with a lithium
    diorganocopper reagent
 Diorganocopper
   (Gilman) reagents
   form by reaction of 1
   equivalent of
   cuprous iodide and 2
   equivalents of
   organolithium

 1, 2, 3 alkyl, aryl
   and alkenyl groups
   react but not alkynyl
   groups




                                                          57
 Mechanism of Alkyl Conjugate
 Addition
 Conjugate nucleophilic addition of a diorganocopper
  anion, R2Cu, to an enone
 Transfer of an R group and elimination of a neutral
  organocopper species, RCu




                                                        58
  19.14 Spectroscopy of Aldehydes
  and Ketones
 Infrared
  Spectroscopy
 Aldehydes and
  ketones show a
  strong C=O peak
  1660 to 1770
  cm1
 aldehydes show
  two characteristic
  C–H absorptions
  in the 2720 to
  2820 cm1
  range.



                                    59
C=O Peak Position in the IR
Spectrum
 The precise position of the peak reveals the
  exact nature of the carbonyl group




                                                 60
NMR Spectra of Aldehydes
 Aldehyde proton signals are at  10 in 1H NMR -
  distinctive spin–spin coupling with protons on the
  neighboring carbon, J  3 Hz




                                                       61
13C   NMR of C=O
 C=O signal is at  190 to  215
 No other kinds of carbons absorb in this range




                                                   62
Mass Spectrometry – McLafferty
Rearrangement
 Aliphatic aldehydes and ketones that have hydrogens
  on their gamma () carbon atoms rearrange as shown




                                                        63
Mass Spectroscopy:
-Cleavage
 Cleavage of the bond between the carbonyl group
  and the  carbon
 Yields a neutral radical and an oxygen-containing
  cation




                                                      64

								
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