Chapter 10 Carboxylic Acids and their Derivatives by morgossi7a2

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									Chapter 10 Carboxylic Acids and their
            Derivatives
               O
       2
  sp
               C            RCOOH        RCO2H
           R        OH

       Carboxyl group


       Nomenclature: - oic acid

               Br                                           OH      O

       CH3-CH-CO2H                CH2=CH-CO2H           CH3-CH-CH2-C-OH

  2-bromopropanoic acid           propenoic acid        3-hydroxybutanoic acid


                          CO2H

                                     HO2CCH2CH2CO2H



           Benzoic acid              Butanedioic acid
Commonly occuring acids:


HCOOH                             CH3CO2H

Formic acid (methanoic)           Acetic acid (ethanoic)

              O                       O                    O           O

Acyl group   R-C-          e.g.    H-C-               CH3-C-        Ph-C-
                                  Formyl group      Acetyl group   Benzoyl group



i.e. Names derived from common name of the carboxylic acid
10.2 Physical Properties

    Short chain derivatives- liquids with sharp odours

    e.g. Acetic acid (vinegar 4-5%); butyric acid (rancid butter)

    Polar compounds: Form hydrogen bonds-high boiling points for their molecular weights
                      - even higher than alcohols

e.g.                                                       O
                             OH
           H3C                                       CH3-C-OH          Same M.W.

                    97 oC                                118 oC



    Carboxylic acids form hydrogen bonded dimers- held together by 2 H bonds


                   H     O                   Shorter chain acids- H2O soluble due to H bonding
       O
                             C     R
       C
R            O     H     O
  10.3 Acidity

  Carboxylic acids - relatively weak acids; dissociate in water to a carboxylate anion
  and a hydronium ion

     O                                  O

  R-C-O-H        + H2O               R-C-O       + H3O


acidic site


  Ka = [RCO-2] [H3O+]              pKa = -log10Ka = 4.74 (CH3CO2H)
              [RCO2H]


  Much more acidic than alcohols        e.g. CH3CO2H is 1011 times stronger acid than CH3CH2OH


   CH3CH2OH + H2O                     CH3CH2O + H3O           Ka 10-16
         O                                  O
                                                                           Why is this ?
   CH3C-OH + H2O                      CH3CO        + H3O      Ka 10-5
  Resonance stabilisation in the carboxylate anion


                                         O
      O
                                         C
      C
                                 H3C          O
H3C        O

                         O

            H3C      C                 Negative charge equally shared over the 2 oxygen atoms
                                       - stabilises the carboxylate anion considerably
                         O
                                       - no resonance stabilisation in ethoxide anion CH3CH2O-
10.6 Carboxylate salts

Carboxylic acid + base                  salt

e.g.
       CH3-CO2H + Na+ -OH                      CH3CO2- Na+ + H2O

                                               Sodium ethanoate (sodium acetate)


Other bases: Na2CO3, NH3

CH3CO2H + NH3                       CH3CO2- NH4+

                                    ammonium ethanoate

2 CH3CO2H + Na2CO3                        2 CH3CO2- Na+ + CO2 + H2O


Therefore carboxylic acids dissolve in aqueous base
10.7 Preparation of acids
(a) Oxidation of 1o alcohols

CH3CH2OH                    [CH3CHO]                     CH3CO2H

Oxidants: KMnO4, CrO3        Proceeds via aldehyde

Can also oxidise aldehydes to acids:
                    Ag2O                             H2O
CH3CH2CHO                      CH3CH2CO2-   Ag +
                                                               CH3CH2CO2H
                                                      +
                                                     H

(b) Nitrile/cyanide hydrolysis

                                   HCl
      R      C       N + 2 H2O                R-CO2H +      NH4+ Cl-

          Nitrile
           or
          Cyanide
                                            O                              O
                             NaOH                          H3O+
R      C       N   + 2 H2O               R-C-O Na                       R-C-OH

                                           + NH3


Nitrile hydrolysis- can be conducted under either acidic or basic conditions
When conducted under basic conditions the product is the salt (sodium carboxylate).
Neutralisation provides the carboxylic acid

e.g.
           N

           C                                     CO2H


                        hydrolysis
Recall alkyl cyanides can be prepared from the corresponding alkyl halide
by a nucleophilic substitution

                     Na+ -CN
CH3-CH2-CH2-Br                       CH3CH2CH2-C      N     + Na+ Br-


                                               hydrolysis



                                                  O

                                     CH3CH2CH2-C-OH
  2 step route to carboxylic acids

                              O
         (i) NaCN
 R-Br                      R-C-OH          Note: 1 carbon extra in product
         (ii) H3O+
 10.8 Carboxylic Acid Derivatives
    O

 R-C-OH          - OH replaced by other groups

 e.g.


    O                 O                          O

 R-C-OR1           R-C-Cl                   R-C-Br

 Esters          Acyl halide (chloride)    Acyl bromide

   O      O               O

R-C-O-C-R            R-C-NH2               Esters and amides occur widely in nature
Acid anhydride        Amide
   10.9 Esters
           O                                O                             O

      CH3-C-OCH3                        CH3-C-OCH2CH3           CH3CH2CH2C-OCH3
methyl acetate (methyl ethanoate)       ethyl acetate            methyl butanoate

                  O

                                                Nomenclature:
                       OCH2CH3                  Alkanoic acid             Alkyl Alkanoate


          ethyl benzoate                                                  OR group



  Pleasant odours- flavour/fragrance of fruits and flowers, e.g. ethyl butanoate


    10.10 Preparation of esters: Fischer esterification
      O                                         O
                                    +
                                 H
                        1
    R-C-OH        + R OH                    R-C-OR1      + H2O

carboxylic acid       alcohol                ester
Acid catalyst e.g. HCl, H2SO4

If remove water as it forms can push the reaction to completion.
Alternative: Distill out the ester as it forms

Mechanism:


      O                             OH
                   +                                Protonation activates the C towards
                  H
  R-C-OH                        R-C-OH              attack by nucleophiles
                                  +

          H
   O                                     OH                               OH           H
                                                           +
                                                         H
 R-C-OH                         R        C     OH                   R     C      O
                                                       transfer
                                         O                                OR1          H
                                R1             H
          O
 R1           H                                                                - H2O       Good leaving group

  Nucleophile
                                                                                 H
                                     O                                     O
                                                        - H+
                          R          C       OR1                     R     C      OR1
       O                                          O
                                       H+
CH3-C-OH       + HOCH2CH3                      CH3-C-OCH2CH3 + H2O


                                                      O from the alcohol component

   O                         OH                             O

 R-C-OH                R     C         OH             R     C     OR1

  sp2                              1                        sp2
                             OR

                             sp3
                    Tetrahedral intermediate


Nucleophilic acyl substitution
(i) Nucleophilic addition
(ii) Elimination
10.13 Ester Hydrolysis
   O                                     O
                            H+
 R-C-OR1      + H2O                   R-C-OH         + R1OH
                            or
                           OH-
Can be hydrolysed under acidic or basic conditions- usually conducted in aqueous base (saponification)


   O                                     O
                                                   1
R-C-OR   1       +-
             + Na OH                   R-C-O-Na+ + R OH
                            H2O       sodium carboxylate

                                              H3O+



                                          O             Another example of nucleophilic acyl substitution


                                       R-C-OH
     O                               O

R-C-OR1                      R       C        OR1        Hydroxide anion- powerful nucleophile

                                     OH

             OH           Tetrahedral intermediate


    Nucleophile




         O                               O                                             O

R        C        OR1            R        C     OH   +    OR1                   R      C     O       + HOR1

         OH



Last step is essentially irreversible as alkoxide anion is a strong enough base to completely deprotonate
the carboxylic acid

At the end of reaction addition of aqueous acid protonates the carboxylate anion to form the carboxylic acid
       O                                             O

R      C    O         + H3O+                   R     C       OH   + H2O

Saponification: Used in preparation of soaps

e.g.

                CO2CH3                                        CO2 Na                CO2H
                            NaOH                                   H3O+               Benzoic acid
                             H2O

                                                   + CH3OH

             O                                           O
                               NaOH
CH3CH2CH2C-OCH2CH3                        CH3CH2CH2C-O- Na+            + CH3CH2OH
                               H2O
    ethyl butanoate

                        O

           CH3CH2CH2C-OH

             butanoic acid              H3O+
10.14 Ammonolysis of esters
     O                                                O

CH3-C-OCH2CH3        +     NH3                   CH3-C-NH2        + CH3CH2OH

                                                  1o amide
Ethoxy group replaced by amino group- similar reaction mechanism to saponification using
                                        NH3 as nucleophile in place of -OH


10.16 Ester reduction/carboxylic acid reduction
 O
          (i) LiAlH4                                                LiAlH 4
R-C-OH                       R-CH2OH            e.g. CH3CO2H                   CH3CH2OH
          (ii) H2O
                             1o alcohol             aectic acid                ethanol

           CO2H                                            CH2-OH
                         LiAlH 4



                                          Benzyl alcohol
        O
                     LiAlH 4
  R-C-OR1                       R-CH2OH + HOR1                Note: For reduction of carboxylic acids and esters
                                                              must use LiAlH4. NaBH4- not strong enough
  2 moles of alcohol formed
              O
  e.g.
                                  LiAlH 4
              CH3-C-OCH2CH3                   CH3CH2OH + HOCH2CH3

                                                  2 moles of ethanol
                         O
                                 LiAlH 4
              CH3CH2C-OCH3                    CH3CH2CH2OH + HOCH3


 i.e.
                 O

            R-C          OR1   Molecule broken across C-O bond to form 2 moles of alcohols


Mechanism

          
        O                                   O                                  O
                                   H3C     C     OCH3                    CH3-C-H + OCH3
CH3-C-OCH3

             H                               H

            Al
  H                  H
             H
Aldehyde formed is then rapidly reduced to 1o alcohol- can't easily stop the reduction
at the aldehyde stage

      O
                                                    H2O
CH3-C-H                              CH3-CH2-O                 CH3CH2OH

           H                   (as complex with aluminium)

          Al                                                  2 alcohols isolated after aqueous work-up
  H            H                          H2O
           H                  CH3O                  CH3OH

                       O
                                      LiAlH 4
CH3CH2CH2CH2C-OCH2CH3                               CH3CH2CH2CH2CH2OH + HOCH2CH3

                   O

                   C-OCH3                                    CH2OH
                                LiAlH 4
                                                                     + HOCH3




                   O

                                          LiAlH 4
                           OCH2CH3                                       OH       + HOCH2CH3
10.18 Acyl Halides
- Sometimes known as acid halides
- Usually chloride or bromide

   O             O

 R-C-Cl        R-C-Br        RCOCl/RCOBr          sp2 hybridised at carbon

  Cl/Br strong electronegative substituents
    
   O
     
R-C-X          Carbon more electrophilic than in other carbonyl derivatives
  

 Preparation- from carboxylic acids

   O                                    O

R-C-OH      + SOCl2                  R-C-Cl      + HCl     + SO2
                                                  gaseous byproducts


  O                                     O

R-C-OH      + PCl5                   R-C-Cl     + HCl     + POCl3
    Reactivity

    Due to the highly electrophilic carbon they react rapidly with nucleophiles

      O                                  O

R-C-Cl         + Nu                   R-C-Nu + Cl

Chloride displaced by the incoming nucleophile via an addition-elimination mechanism

        
        O                                    O                             O
                                                                      R-C-Nu + Cl
R       C      Cl                    R       C        Cl

              Nu                             Nu

                                    Tetrahedral Intermediate


                   sp2                sp3                      sp2

Examples
          O                                       O

CH3-C-Cl            + H2O                   CH3-C-OH + H2O             Water as a nucleophile results in hydrolysis
                                                                       of the acyl chloride to the carboxylic acid
    O                                      O

CH3-C-Cl     + HOCH3                  CH3-C-OCH3 + HCl            Alcohol as nucleophile forms
                                                                  the ester



    O                                      O

CH3-C-Cl     + 2 NH3                  CH3-C-NH2     + NH4+ Cl-         Ammonia as nucleophile produces
                                                                       primary amide

Note: 2 moles of NH3 required as 1 mole reacts with the HCl released

Further examples
              O                                         O

                C                                       C
                           EtOH
                    Cl                                        OEt
                                                                         + HCl


                          H2O

        2 NH3                                           O

                                                        C
                O
                                                             OH
                                                                         + HCl
                C
                    NH2



              + NH4+ Cl-
                          O                                                         O

                                          CH3OH
                               Cl                                                        OCH3

                                                                               + HCl
                              2 NH3

            H2O
                                                                                O


                                                                                     NH2
                          O
                                                                           + NH4+ Cl-

                               OH


                  + HCl



Acyl halides are strong acylating agents- transfer acyl groups to a range of nucleophilic species
  O                                   O

R-C-X     + Nu                      R-C-Nu + X



                                 acyl group
       Nomenclature Acyl Halides
                O                        O                              O
e.g.
         CH3-C-Cl                    Ph-C-Cl              CH3CH2CH2-C-Br
       Acetyl chloride            Benzoyl chloride         Butanoyl bromide
       (ethanoyl chloride)




10.19 Acid Anhydrides
        O       O                    O       O

   R-C-O-C-R                 e.g. CH3-C-O-C-CH3
                                  Acetic Anhydride ~ 1 million tons annually
            O                O                            O    O
                                       - H2O
   CH3-C-OH          H-O-C-CH3                       CH3-C-O-C-CH3


       Use name of acid e.g. acetic acid and replace "acid" with "anhydride"

       Acetic anhydride or ethanoic anhydride
Preparation

(i) Dehydration of carboxylic acids
(ii) Reaction of acyl halide with carboxylate salt

      O                           O                            O    O

 CH3-C-Cl         +      Na O-CCH3                         CH3C-O-C-CH3 + Na+ Cl-
acetyl chloride          sodium acetate

     Acetate anion as nucleophile                    from acyl halide   from acetate anion



 Acid anyhdrides react in similar fashion to acyl halides but are less reactive


     O    O                            O

CH3C-O-C-CH3                      CH3-C-Cl




          O                                Cl
                                       chloride ion leaving group
         OCCH3
      acetate ion leaving group
    O    O                             O                O
                    H2O
CH3C-O-C-CH3                      CH3-C-OH         + HOC-CH3         Acids

Use of water as nucleophile results in hydrolysis to 2 carboxylic acids



    O    O                                  O                    O
                   CH3CH2OH
CH3C-O-C-CH3                         CH3-C-OCH2CH3          + HOC-CH3
                                           ester

Use of alcohol as nucleophile forms the ester


   O    O                                  O                O
                     NH3
CH3C-O-C-CH3                         CH3-C-NH2       + HOC-CH3
                                        amide

Use of ammonia as nucleophile forms the amide


Note: 1 mole of carboxylic acid formed in each reaction
Synthesis of Aspirin
                                                                    O

                 OH               O     O                        O-C-CH3              O

                          + CH3-C-O-C-CH3                                      + HOCCH3

                 CO2H                                             CO2H

Salicylic Acid                                      Acetylsalicyclic Acid (Aspirin)



-OH of salicyclic acid as nucleophile       ester
10.20 Amides

- Occur widely in nature e.g. proteins

                     O                                   O                                     O
                                                                                                       R1
Primary amides     R-C-NH2         Secondary amides     R-C-NH-R1        Tertiary amides R     C   N
                                                                                                       R2


      O                        O                             O                  O
                                                                                             CH3
H      C     NH2      H3C      C         NH2   H3CH2CH2C           NH2     H    C     N
                                                                                             CH3
  Methanamide              Ethanamide                 Butanamide
  (Formamide)              (Acetamide)                                    N,N-Dimethylformamide
                                                                          (DMF)
 Preparation of Amides

 (i) Acylation of Amines
           O                                    O

      CH3-C-Cl       + NH3                 CH3-C-NH2        + HCl

                                                                    NH3


                                                                  NH4Cl
 Overall reaction

          O                                    O

      CH3-C-Cl      + 2 NH3               CH3-C-NH2        + NH4 Cl

 Can also use acetic anhydride


 (ii) Heating ammonium carboxylates   - not as efficient as (i)



 O                                    O                                    O
                                                           Heat
R-C-OH     + NH3                  R-C-O        NH4                        R-C-NH2   + H2O
Alkaloids        - pg 332


- Basic, N containing compounds of plant or animal origin

- Potent pharmacological properties e.g. morphine, nicotine

Dart poison frogs- Ecuador
Potent compounds in skin secretions

In 1992 a compound was isolated which is a much stronger painkiller than morphine- Epibatidine


            H                               Cl
            N

                                      N
 Amides: Very polar
 - Form strong hydrogen bonds


                  O
                             H
           R      C     N
                                              H
                             H
                                                 H
                                  O        N
                                      C
                                       
                                      R


Reactions:

(a) Hydrolysis

      O                                                     O
                  H                   H+ or
R     C     N            + H2O                        R     C   OH   + NH3
                  H                   OH

Reaction slower than esters, acid chlorides or anhydrides
(b) Reduction to amines

      O
                         LiAlH 4
R     C      NH2                        R-CH2NH2


Must use strong reducing agent, not NaBH4 which is not reactive enough to reduce an amide

N.B. Compared to esters the reduction pathway is different- there is no cleavage of the
C-N bond


      O
                           LiAlH 4
R     C      OCH2CH3                     CH3CH2OH + HOCH2CH3



      O
                           LiAlH 4
R      C     NH2                          CH3CH2NH2


       Bond not
       broken
10.21 Summary
      O

R     C        Cl
                                        Decreasing reactivity
                                        towards reaction with nucleophiles
     O               O

R    C         O     C       CH3


     O

R    C         OR1

     O

R     C        NH2


Same products formed in many reactions, e.g. Hydrolysis of any of the 4 derivatives forms the carboxylic acid

                               O
     H2O
                         R     C   OH     + HX
    H     or
    OH                                     Depends on which derivative is used

								
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