Organic Chemistry by hcj

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    William H. Brown
    Christopher S. Foote
    Brent L. Iverson
and Thiols
       Chapter 10

Structure - Alcohols
 Thefunctional group of an alcohol is
 an -OH group bonded to an sp3                       H
 hybridized carbon                               O
  • bond angles about the hydroxyl oxygen        C
    atom are approximately 109.5°                     H
 Oxygen   is sp3 hybridized
  • two sp3 hybrid orbitals form sigma bonds
    to carbon and hydrogen
  • the remaining two sp3 hybrid orbitals each
    contain an unshared pair of electrons

 IUPAC   names
  • the parent chain is the longest chain that contains the
    OH group
  • number the parent chain to give the OH group the
    lowest possible number
  • change the suffix -e to -ol
 Common    names
  • name the alkyl group bonded to oxygen followed by
    the word alcohol

 Examples
                      OH                                                           OH
         1-Propanol                     2-Propan ol                      1-Bu tanol
      (Propyl alcohol)              (Isoprop yl alcoh ol)              (Bu tyl alcoh ol)

                                                  OH                            OH

           2-Butanol               2-Meth yl-1-p ropan ol         2-Meth yl-2-p ropan ol
     (s ec-Butyl alcohol)            (Isobutyl alcohol)            (tert -Butyl alcohol)

                                                 10       2               N umbering of th e
                  3   2
                                                      1           OH
                          1                9                  3           bicyclic ring takes
          4                   OH                                          precedence over
                                            8                 4
              5       6                               6                   the location of -OH
                                                 7        5
  cis-3-Methylcyclohexan ol             Bicyclo[4.4.0]decan -3-ol

Nomenclature of Alcohols
 Compounds  containing more than one OH group
 are named diols, triols, etc.

    CH2 CH2             CH3 CHCH2              CH2 CHCH2
    OH OH                 HO OH               HO HO OH
  1,2-Ethanediol       1,2-Propanediol      1,2,3-Propanetriol
 (Ethylene glycol)   (Propylene glycol)   (Glycerol, Glycerine)

Nomenclature of Alcohols
 Unsaturated   alcohols
  • show the double bond by changing the infix from -an-
    to -en-
  • show the the OH group by the suffix -ol
  • number the chain to give OH the lower number
                  HO       2 3         6
                                 4 5

                 (t rans-2-Hexen-1-ol)

Physical Properties
 Alcohols      are polar compounds

      H              H

  • they interact with themselves and with other polar
    compounds by dipole-dipole interactions
 Dipole-dipoleinteraction: the attraction between
 the positive end of one dipole and the negative
 end of another

Physical Properties
 Hydrogen  bonding: when the positive end of one
 dipole is an H bonded to F, O, or N (atoms of high
 electronegativity) and the other end is F, O, or N
  • the strength of hydrogen bonding in water is
    approximately 21 kJ (5 kcal)/mol
  • hydrogen bonds are considerably weaker than
    covalent bonds
  • nonetheless, they can have a significant effect on
    physical properties

Hydrogen Bonding

Physical Properties
 Ethanol and dimethyl ether are constitutional
 Their boiling points are dramatically different
  • ethanol forms intermolecular hydrogen bonds which
    increase attractive forces between its molecules
    resulting in a higher boiling point
  • there is no comparable attractive force between
    molecules of dimethyl ether
             CH 3 CH 2 OH     CH 3 OCH 3
               Ethanol      Dimethyl ether
               bp 78°         bp -24°C

Physical Properties
   relation to alkanes of comparable size and
 In
  molecular weight, alcohols
  • have higher boiling points
  • are more soluble in water
 The  presence of additional -OH groups in a
  molecule further increases solubility in water and
  boiling point

Physical Properties
                                                  bp    Solubility
  Structural Formula       Name             MW   (°C)   in Water
  CH3 OH                   Methanol         32    65    Infinite
  CH3 CH 3                 Ethane           30   -89    Insoluble
  CH3 CH 2 OH              Ethanol          46    78    Infinite
  CH3 CH 2 CH3             Propane          44   -42    Insoluble
  CH3 CH 2 CH2 OH          1-Propanol       60    97    Infinite
  CH3 CH 2 CH2 CH 3        Butane           58     0    Insoluble
  CH3 ( CH 2 ) 2 CH 2 OH   1-Butanol        74   117    8 g/100 g
  CH3 ( CH 2 ) 3 CH3       Pentane          72    36    Insoluble
  HOCH 2 ( CH2 ) 2 CH 2 OH 1,4-Butanediol   90   230    Infinite
  CH3 ( CH 2 ) 3 CH2 OH    1-Pe ntanol      88   138    2.3 g/100 g
  CH3 ( CH 2 ) 4 CH3       Hexane           86    69    Insoluble

Acidity of Alcohols
 Indilute aqueous solution, alcohols are weakly
       CH3 O H + :O H            CH3 O:      + H O H
                  H                              H
                            -       +
                     [ CH3 O ] [H3 O ]
              Ka =                        = 1 0 - 15 .5
                        [ CH3 OH]
             pKa = 1 5 .5

Acidity of Alcohols

     Compoun d               Formula           pK a
     Hyd rogen ch loride     HCl               -7      Stronger
     A cetic acid            CH3 COOH            4.8
     Meth anol               CH3 OH            15.5
     Water                   H2 O              15.7
     Ethanol                 CH3 CH 2 OH       15.9
     2-Prop anol             ( CH3 ) 2 CHOH    17
     2-Methyl-2-prop anol    ( CH3 ) 3 COH     18       acid

     *A lso given for comparison are pK a values for w ater,
      acetic acid, an d hydrogen chloride.

Acidity of Alcohols
 Acidity depends primarily on the degree of
  stabilization and solvation of the alkoxide ion
  • the negatively charged oxygens of methanol and
    ethanol are about as accessible as hydroxide ion for
    solvation; these alcohol are about as acidic as water
  • as the bulk of the alkyl group increases, the ability of
    water to solvate the alkoxide decreases, the acidity of
    the alcohol decreases, and the basicity of the alkoxide
    ion increases

Reaction with Metals
 Alcoholsreact with Li, Na, K, and other active
 metals to liberate hydrogen gas and form metal
       2CH3 OH + 2Na             2CH3 O- Na+ + H2
                             Sodium methoxide
                                (MeO -Na+)
 Alcohols are also converted to metal alkoxides
 by reaction with bases stronger than the alkoxide
  • one such base is sodium hydride
                     +   -                -   +
      CH3 CH2 OH + Na H          CH3 CH2 O Na + H2
       Ethanol    Sodiu m        Sodium ethoxide
Reaction with HX
 • 3° alcohols react very rapidly with HCl, HBr, and HI
               OH + HCl                     Cl + H2 O

         2-Methyl-2-                 2-Chloro-2-
          prop anol                 methylpropane

 • low-molecular-weight 1° and 2° alcohols are unreactive
   under these conditions
 • 1° and 2° alcohols require concentrated HBr and HI to
   form alkyl bromides and iodides
                             H2 O                Br
              OH +     HBr                             +   H2 O
      1-Butanol                        1-Bromobutane

Reaction with HX
 • with HBr and HI, 2° alcohols generally give some
   rearranged product                       a product of
                                                            re arrangement
     OH                            Br
              + HBr                            +                 + H2 O
 3-Pentanol                                               Br
                             3-Bromopentane        2-Bromopentane
                             (major product)

 • 1° alcohols with extensive -branching give large
   amounts of rearranged product
                  OH + HBr                              + H2 O
        2,2-D imethyl-1-           2-Bromo-2-meth ylb utane
            propanol              (a product of rearrangement)

Reaction with HX
 Based   on
  • the relative ease of reaction of alcohols with HX (3° >
    2° > 1°) and
  • the occurrence of rearrangements,
 Chemists propose that reaction of 2° and 3°
 alcohols with HX
  • occurs by an SN1 mechanism, and
  • involves a carbocation intermediate

Reaction with HX - SN1
 Step 1: proton transfer to the OH group gives an
   oxonium ion
                                 rapid and
       CH 3               +                           CH3       H
                                 reversib le

   CH3 -C-OH    +       H O H                  CH3 -C       O       +   :O H
       CH 3               H                           CH3       H       H

 Step 2: loss of H2O gives a carbocation intermediate
                          s low , rate          CH3                 H
          CH3       H
                         determin ing
     CH3 -C     O                          CH3 - C+     +   :O
                +             SN 1
          CH3       H                           CH3                 H
                                         A 3° carbocation
                                          intermed iate

Reaction with HX - SN1
 Step 3: reaction of the carbocation intermediate (an
   electrophile) with halide ion (a nucleophile) gives the
           CH3                          CH3
      CH3 - C+   +   :Cl          CH3 - C- Cl
           CH3                           CH3
                           2-Chloro-2-methylprop ane
                              (t ert-Butyl ch loride)

Reaction with HX - SN2
 1°   alcohols react with HX by an SN2 mechanism
  Step 1: rapid and reversible proton transfer
                               rapid and
                           +                            H
                               reversib le         +
         RCH2 -OH + H O H                    RCH2 - O       +   :O H
                           H                            H       H

  Step 2: displacement of HOH by halide ion
                                slow, rate
                           H                                        H
                       +       determining
        Br:-   + RCH2 -O                      RCH2 -Br      + :O
                           H       SN2                              H

Reaction with HX
 For   1° alcohols with extensive -branching
  • SN1 is not possible because this pathway would
    require a 1° carbocation
  • SN2 is not possible because of steric hindrance
    created by the -branching
 Thesealcohols react by a concerted loss of HOH
 and migration of an alkyl group

Reaction with HX
  • Step 1: proton transfer gives an oxonium ion
                               rapid and
                         +     revers ible
            O       + H O H                          O+ +     O H
                H                                      H
                         H                                    H
  2,2-D imethyl-1-                           An oxonium ion
      prop anol

  • Step 2: concerted elimination of HOH and migration
    of a methyl group gives a 3° carbocation
                    H        s low an d                  H
                O        rate determining            + O
                     H      (concerted)                  H
                                        A 3° carbocation
                                          intermed iate

Reaction with HX
 Step 3: reaction of the carbocation intermediate (an
   electrophile) with halide ion (a nucleophile) gives the
             -         fast         Cl
        Cl       +

                              2-Ch loro-2-meth ylb utane

Reaction with PBr3
 An  alternative method for the synthesis of 1° and
  2° bromoalkanes is reaction of an alcohol with
  phosphorus tribromide
   • this method gives less rearrangement than with HBr
            OH       +                0°                 Br
                          PBr 3                                       +      H3 PO 3
2-Meth yl-1-p ropan ol Phosph orus         1-Bromo-2-methylprop ane       Phosp horous
  (Isobutyl alcohol)    trib romide            (Is ob utyl bromide)           acid

Reaction with PBr3
 Step 1: formation of a protonated dibromophosphite
   converts H2O, a poor leaving group, to a good leaving
   group                               a good leaving group

       ••                                    +
  R-CH2 -O-H + Br P Br             R-CH2    O PBr2 +   Br
                    Br                      H

 Step 2: displacement by bromide ion gives the alkyl
                           +       SN 2
            -                              R-CH2 -Br + HO-PBr 2

       Br       + R-CH2   O PBr2


Reaction with SOCl2
 Thionyl chloride is the most widely used reagent
 for the conversion of 1° and 2° alcohols to alkyl
  • a base, most commonly pyridine or triethylamine, is
    added to catalyze the reaction and to neutralize the
                 OH +    SOCl 2    pyridine

    1-Heptanol          Thionyl
                        chloride                       Cl + SO + HCl

Reaction with SOCl2
         of an alcohol with SOCl2 in the
 Reaction
 presence of a 3° amine is stereoselective
  • it occurs with inversion of configuration
             OH                                          Cl
                               3° amine
                  + SOCl2                                        + SO2 + HCl
 (S)-2-Octanol     Thion yl               (R)-2-Ch lorooctan e
                   chlorid e

Reaction with SOCl2
 Step 1: formation of an alkyl chlorosulfite
     R1                                  R1
                     O                                     O
          C O H + Cl-S-Cl                     C   O S           +   H-Cl
    H                                H                     Cl
     R2                               R2
                                       An al ky l
                                     chl orosul fi te
 Step 2: nucleophilic displacement of this leaving group
   by chloride ion gives the chloroalkane
              R1                                  R1
                        O    SN 2                                  O
    Cl    +     C O S               Cl        C            +    O S + Cl
              H         Cl                             H

Alkyl Sulfonates
 Sulfonyl   chlorides are derived from sulfonic
  • sulfonic acids, like sulfuric acid, are strong acids
        O                 O                      O
      R- S- Cl         R- S- OH                R- S- O-
         O                O                       O
    A sulfonyl      A sulfonic acid       A sulfonate anion
     chloride     (a very strong acid) (a very weak base and
                                         stable anion; a very
                                         good leaving group

Alkyl Sulfonates
A commonly used sulfonyl chloride is p-
 toluenesulfonyl chloride (Ts-Cl)
  CH 3 CH 2 OH + Cl-S           CH 3
     Ethanol    p-Toluenes ulfonyl
                         CH 3 CH 2 O-S          CH 3 + HCl
                         Ethyl p- toluen esulfonate
                               (Ethyl tosylate)

Alkyl Sulfonates
        commonly used sulfonyl chloride is
 Another
 methanesulfonyl chloride (Ms-Cl)
          OH    +   Cl-S- CH3
 Cyclohexanol   Methanes ulfonyl
                                                  O-S-CH3 + HCl
                                           methanesulfon ate
                                         (Cyclohexyl mesylate )

Alkyl Sulfonates
 Sulfonate anions are very weak bases (the
  conjugate base of a strong acid) and are very
  good leaving groups for SN2 reactions
 Conversion of an alcohol to a sulfonate ester
  converts HOH, a very poor leaving group, into a
  sulfonic ester, a very good leaving group

Alkyl Sulfonates
 Thistwo-step procedure converts (S)-2-octanol
 to (R)-2-octyl acetate
  Step 1: formation of a p-toluenesulfonate (Ts) ester
                        OH                                                OTs
                              + TsCl        pyrid ine                           + HCl
      (S)-2-Octanol             Tosyl                    (S)-2-Octyl tosylate
                               ch loride

  Step 2: nucleophilic displacement of tosylate
 O                                  OTs                               O
      -     +                                SN 2
     O Na       +                                                             + Na+ OTs-
 S od ium           (S)-2-Octyl tos ylate               (R)-2-Octyl acetate
Dehydration of ROH
 An alcohol can be converted to an alkene by
 acid-catalyzed dehydration (a type of -
  • 1° alcohols must be heated at high temperature in the
    presence of an acid catalyst, such as H2SO4 or H3PO4
  • 2° alcohols undergo dehydration at somewhat lower
  • 3° alcohols often require temperatures at or slightly
    above room temperature

Dehydration of ROH
                        H2 SO 4
       CH 3 CH 2 OH                   CH 2 = CH 2   +    H2 O

                        H 2 SO 4
                                                 + H2 O
       Cyclohexanol                 Cyclohexene

              CH 3                        CH 3
                        H2 SO 4
          CH 3 COH                    CH 3 C= CH 2 +    H2 O
                CH 3
    2-Methyl-2-propanol              2-Methylpropene
     (tert- Butyl alcohol)             (Isobutylene)

Dehydration of ROH
 • where isomeric alkenes are possible, the alkene
   having the greater number of substituents on the
   double bond (the more stable alkene) usually
   predominates (Zaitsev rule)
                 8 5 % H3 PO 4
                 CH3 CH= CH CH 3 + CH3 CH2 CH= CH2 + H2 O
                    2-Butene           1-Butene
                     (80%)              (20%)

Dehydration of ROH
            of 1° and 2° alcohols is often
 Dehydration
 accompanied by rearrangement
                         H2 SO4
              OH    140 - 170°C
      3,3-Dimethyl-             2,3-Dimethyl-                 2,3-Dimethyl-
        2-butanol                  2-butene                      1-butene
                                     (80%)                         (20%)
  • acid-catalyzed dehydration of 1-butanol gives a
    mixture of three alkenes

                     H2 SO 4
              OH                                   +                   +
                   140 - 170°C
  1-Butanol                      trans- 2-butene       cis- 2-butene       1-Butene
                                      (56%)                 (32%)            (12%)
Dehydration of ROH
 Based   on evidence of
  • ease of dehydration (3° > 2° > 1°)
  • prevalence of rearrangements
 Chemistspropose a three-step mechanism for
 the dehydration of 2° and 3° alcohols
  • because this mechanism involves formation of a
    carbocation intermediate in the rate-determining step,
    it is classified as E1

Dehydration of ROH
 Step 1: proton transfer to the -OH group gives an
   oxonium ion
     H                 rap id and     H + H
         O        +                     O
             + H O H                          +   O H
                H                                 H

 Step 2: loss of H2O gives a carbocation intermediate
         H +H    s low , rate
          O     determin ing
                                              + H2 O
                                A 2° carbocation
                                 intermed iate

Dehydration of ROH
 Step 3: proton transfer from a carbon adjacent to the
   positively charged carbon to water; the sigma
   electrons of the C-H bond become the pi electrons of
   the carbon-carbon double bond
                   rap id and
                   reversible                     +
   H O   +                           +       + H O H
     H       H H                                 H

•Dehydration of ROH
 1° alcohols with little -branching give terminal
  alkenes and rearranged alkenes
  • Step 1: proton transfer to OH gives an oxonium ion
                               rapid an d
                          +    reversib le             +
              O-H +    H O H                          O-H +    O-H
       1-Butanol         H                                     H

  • Step 2: loss of H from the -carbon and H2O from the
    -carbon gives the terminal alkene
                       +    E2                            +
  H O    +            O-H                          + H O H +   O H
    H          H H    H                1-Bu tene       H       H

Dehydration of ROH
 Step 3: shift of a hydride ion from -carbon and loss of
   H2O from the -carbon gives a carbocation
                         1,2-s hift of a
                    +    hydride ion
                   O-H                         +     +    O-H
           H H     H                                      H
                                       A 2° carbocation

 Step 4: proton transfer to solvent gives the alkene
                       E1                                     +
 H O +         +                            +             +H O H
   H                         t rans-2-Butene cis-2-Butene    H

Dehydration of ROH
 Dehydrationwith rearrangement occurs by a
 carbocation rearrangement
          OH       -H2 O       +

  3,3-D imethyl-      A 2° carbocation              H2 O
                                                                    + H3 O+
    2-butan ol         intermed iate
                                                      2,3-D imethyl-
                                                         2-bu tene

                                    A 3° carbocation                + H3 O+
                                     intermed iate   H2 O
                                                       2,3-D imethyl-
                                                          1-bu tene

Dehydration of ROH
 Acid-catalyzed alcohol dehydration and alkene
  hydration are competing processes
               C   C      + H2 O               C   C
                                               H OH
              An alkene                       An alcohol

 Principle   of microscopic reversibility: the
  sequence of transition states and reactive intermediates
  in the mechanism of a reversible reaction must be the
  same, but in reverse order, for the reverse reaction as for
  the forward reaction

Pinacol Rearrangement
 Theproducts of acid-catalyzed dehydration of a
 glycol are different from those of alcohols
            HO      OH
                                   H2 SO4                  + H2 O

    2,3-Dimethyl-2,3-butaned iol     3,3-Dimethyl-2-bu tanone
             (Pinacol)                     (Pinacolone)

Pinacol Rearrangement
 Step 1: proton transfer to OH gives an oxonium ion
                               rapid an d         H
      HO        OH         +   reversib le   HO       O H
                     + H O H                                +   O H
                           H                                    H
                                          An oxoniu m ion

 Step 2: loss of water gives a carbocation intermediate
           HO        O H             HO
                                                  + H2 O

                                  A 3o carb ocation

Pinacol Rearrangement
 Step 3: a 1,2- shift of methyl gives a more stable
    H O                    H O                         H O

                        A res on ance-s tabilized cation intermed iate

 Step 4: proton transfer to solvent completes the reaction
                    O                          +       O
     H2 O   +                           H3 O       +

Oxidation: 1° ROH
 Oxidationof a primary alcohol gives an aldehyde
 or a carboxylic acid, depending on the
 experimental conditions
           OH                 O                   O
                  [O]                  [O]
      CH3 -C H           CH3 -C- H           CH3 -C- OH
      A primary         An alde hyde         A carboxylic
        alcohol                                  acid
  • to an aldehyde is a two-electron oxidation
  • to a carboxylic acid is a four-electron oxidation

Oxidation of ROH
A common oxidizing agent for this purpose is
 chromic acid, prepared by dissolving
 chromium(VI) oxide or potassium dichromate in
 aqueous sulfuric acid
                              H2 SO4
             CrO3   + H2 O                H2 CrO 4
        Chromium(VI)                    Chromic acid

                  H2 SO4                H2 O
     K2 Cr 2 O7            H2 Cr 2 O7           2 H2 CrO 4
     Potassium                                 Chromic acid

Oxidation: 1° ROH
 Oxidation   of 1-octanol gives octanoic acid
  • the aldehyde intermediate is not isolated
                          H2 CrO4
                  OH                                     H
                       H 2O, aceton e
     1-Hexan ol                           Hexan al
                                        (not isolated)

                                                         Hexan oic acid

Oxidation: 2° ROH
 2°alcohols are oxidized to ketones by chromic

                     OH                                  O           3+
                          + H2 CrO4                           + Cr
                                      aceton e

       2-Isoprop yl-5-methyl-              2-Is op ropyl-5-methyl-
            cycloh exanol                      cycloh exanone
             (Men thol)                          (Men thone)

Chromic Acid Oxidation of ROH
 • Step 1: formation of a chromate ester
                         O            fas t and
               OH                    revers ible          O-Cr-OH
                    + HO-Cr-OH                                      + H2 O
             H                                             H
    Cycloh exanol        O
                                                   An alkyl chromate

 • Step 2: reaction of the chromate ester with a base,
   here shown as H2O
                    chromiu m(V I)         chromiu m(IV)
                      slow , rate                                       -
                                                       H            O
           O   Cr-OH determining
                                                   O + O H +        Cr-OH
           H                                              H         O
                                     Cyclohexan on e
   H       H                                                                10-55
Chromic Acid Oxidation of RCHO
   • chromic acid oxidizes a 1° alcohol first to an aldehyde
     and then to a carboxylic acid
   • in the second step, it is not the aldehyde per se that is
     oxidized but rather the aldehyde hydrate
                  fas t and
    O                           OH                   O-CrO3 H
                 revers ible            H2 CrO4
  R-C-H + H2 O                 R-C-OH              R-C-OH
                               H                     H
An ald ehyde               An ald ehyde     H2 O
                                                     R-C-OH + HCrO3 - + H3 O+
                                                   A carb oxylic

Oxidation: 1° ROH to RCHO
 Pyridinium chlorochromate (PCC): a form of
 Cr(VI) prepared by dissolving CrO3 in aqueous
 HCl and adding pyridine to precipitate PCC as a
 solid                      pyrid inium ion
                                                   chlorochromate ion

   CrO3 + HCl   +                       ClCrO3 -
                    N               N
                Pyrid ine   Pyrid inium ch lorochromate

  • PCC is selective for the oxidation of 1° alcohols to
    aldehydes; it does not oxidize aldehydes further to
    carboxylic acids
Oxidation: 1° ROH
 • PCC oxidizes a 1° alcohol to an aldehyde

                     OH                                H
          Geraniol                      Geranial

 • PCC also oxidizes a 2° alcohol to a ketone

                OH   PCC            O

         Men thol            Men thone

Oxidation of Alcohols by NAD+
 • biological systems do not use chromic acid or the
   oxides of other transition metals to oxidize 1° alcohols
   to aldehydes or 2° alcohols to ketones
 • what they use instead is a NAD+
                            The b usines s
   A p yridine                           +          An amid e grou p
   ring           O         end of N AD      O
                      OH                         NH2       The p lus sign in N AD +
                                                           represents th is ch arge
             N                          N                  on nitrogen
        N icotinic acid         N icotinamide aden ine
    (N iacin; Vitamin B6)
                                 d inucleotide (N AD + )
 • the Ad part of NAD+ is composed of a unit of the sugar
   D-ribose (Chapter 25) and one of adenosine
   diphosphate (ADP, Chapter 28)
Oxidation of Alcohols by NAD+
 • when NAD+ functions as an oxidizing agent, it is
   reduced to NADH
 • in the process, NAD+ gains one H and two electrons;
   NAD+ is a two-electron oxidizing agent
              O                                     H H O
              CNH2                   reduction          CNH2
                     +   H+ + 2 e-
          N+                         oxid ation       N
          Ad                                          Ad
           NAD +                                      N AD H
      (oxid ized form)                            (red uced form)

Oxidation of Alcohols by NAD+
 • NAD+ is the oxidizing in a wide variety of enzyme-
   catalyzed reactions, two of which are
                      d ehydrogenase
  CH3 CH2 OH + NAD                     CH3 CH + NADH + H+
   Eth anol                           Eth anal
                                  (A cetaldehyde)
     OH               d ehydrogenase       O
           -    +                                 -
 CH3 CHCOO + NAD                       CH3 CCOO + NADH + H+
   Lactate                              Pyru vate

Oxidation of Alcohols by NAD+
 • mechanism of NAD+ oxidation of an alcohol
                   1   -
                           B     E

                                                                B   E
              •   H                                         H


              O 2                                       O
              C                                         C
              HH       O
          3                          redu ction   H H O
                       C-NH2                               C-NH2
                                     of N AD +
                                     oxid ation    ••
                  N+                               N
                                     of N AD H
                  Ad                                Ad
              N AD +                              N AD H
 • hydride ion transfer to NAD+ is stereoselective; some
   enzymes catalyze delivery of hydride ion to the top
   face of the pyridine ring, others to the bottom face
Oxidation of Glycols
 Glycolsare cleaved by oxidation with periodic
 acid, HIO4
                        +    HIO 4                  + HIO 3
      cis- 1,2-Cyclo-       Periodic   Hexanedial     Iodic
       hexanediol             acid                     acid

Oxidation of Glycols
 Themechanism of periodic acid oxidation of a
 glycol is divided into two steps
  Step 1: formation of a cyclic periodate
                         O                     O
           C OH                       C   O
                   + O   I    OH               I    OH + H2 O
           C OH                       C   O
                         O                     O
                                   A cyclic period ate
  Step 2: redistribution of electrons within the five-
    membered ring
                   O                                O
           C   O                      C    O
                    I    OH                     +    I   OH
           C   O                       C O
                   O                                O
Oxidation of Glycols

  • this mechanism is consistent with the fact that HIO4
    oxidations are restricted to glycols that can form a
    five-membered cyclic periodate
  • glycols that cannot form a cyclic periodate are not
    oxidized by HIO4
               OH                     OH

            OH                                              O
    The t rans is omer is   Th e cis is omer forms
    un reactive tow ard     a cyclic periodate and
      periodic acid                is cleaved

Thiols: Structure
 The  functional group of a thiol is an
  SH (sulfhydryl) group bonded to an
  sp3 hybridized carbon
 The bond angle about sulfur in
  methanethiol is 100.3°, which
  indicates that there is considerably
  more p character to the bonding
  orbitals of divalent sulfur than there
  is to oxygen

 IUPAC   names:
  • the parent is the longest chain that contains the -SH
  • change the suffix -e to -thiol
  • when -SH is a substituent, it is named as a sulfanyl
 Common     names:
  • name the alkyl group bonded to sulfur followed by the
    word mercaptan
             SH                   SH                         OH
    1-Butaneth iol  2-Methyl-1-prop anethiol     2-Sulfanylethan ol
  (Butyl mercaptan)   (Isobutyl mercaptan)     (2-Mercap toeth anol)

Thiols: Physical Properties
 Because of the low polarity of the S-H bond,
 thiols show little association by hydrogen
  • they have lower boiling points and are less soluble in
    water than alcohols of comparable MW
            Thiol        bp (°C)   Alcohol   bp (°C)
            Methanethiol 6         Methanol 65
            Ethanethiol 35         Ethanol    78
            1-Butanethiol 98       1-Butanol 117

  • the boiling points of ethanethiol and its constitutional
    isomer dimethyl sulfide are almost identical
               CH3 CH2 SH        CH3 SCH3
               Ethanethiol    Dimethyl sulfide
                (bp 35°C)        (bp 37°C)             10-68
Thiols: Physical Properties
 Low-molecular-weight            thiols = STENCH
  • the scent of skunks is due primarily to these two thiols

            2-Buten e-1-th iol 3-Meth yl-1-b utanethiol
                                (Isopen tyl mercaptan)

  • a blend of low-molecular weight thiols is added to
    natural gas as an odorant; the two most common of
    these are
                        SH                        SH

          2-Methyl-2-propan ethiol       2-Propan eth iol
           (t ert -Bu tyl mercaptan) (Isoprop yl mercaptan)
Thiols: preparation
 The most common preparation of thiols depends
 on the very high nucleophilicity of hydrosulfide
 ion, HS-
                           +     -    SN 2                                + -
 CH3 (CH2 ) 8 CH2 I + Na SH                     CH3 (CH2 ) 8 CH2 SH + Na I
                                     ethan ol
  1-Iod od ecane        S od ium                 1-D ecan ethiol
                     h yd rosu lfid e

                           O                           O
            +    -             -   +   SN 2                -   +    + -
         Na SH + ICH2 CO Na                      HSCH2 CO Na + Na I
         Sodium        Sodiu m                Sodiu m mercaptoacetate
       hydros ulfide iod oacetate             (Sodiu m th ioglycolate)

Thiols: acidity
 Thiols   are stronger acids than alcohols
                                    -      +
  CH3 CH2 OH + H2 O        CH3 CH2 O + H3 O       pK a = 15.9
  CH3 CH2 SH + H2 O        CH3 CH2 S   + H3 O+    pK a = 8.5

  • when dissolved an aqueous NaOH, they are converted
    completely to alkylsulfide salts
     CH3 CH2 SH + Na OH
                               CH3 CH2 S- Na+ +   H2 O
       pK a 8.5                                p Ka 15.7
   (Strong er aci d)                         (Weak er acid )

Thiols: oxidation
 Thesulfur atom of a thiol can be oxidized to
 several higher oxidation states
                                    A disu lfid e
                                       O                     O
        A th iol             [O]                    [O]
                                     R-S-OH                R-S-OH
                                    A s ulfinic           A s ulfon ic
                                       acid                  acid

  • the most common reaction of thiols in biological
    systems in interconversion between thiols and
    disulfides, -S-S-
                   2 RSH +    1 O                 RSSR + H2 O
                              2 2
                   A thiol                   A disulfide                 10-72
   End of Chapter 10


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