Characteristic Reactions of Carboxylic Acid Derivatives

							Characteristic Reactions of Carboxylic Acid Derivatives
  • Undergo substitution reactions (called nucleophilic acyl substitution):
    • The nucleophile attacks the acyl carbon to form a tetrahedral
       intermediate.
    • The leaving group (Y) is lost and the C=O is reformed.




  • The nucleophile can be neutral or negatively charged.
    • Nucleophiles: organometallics (Grignard, organolithium, Gilman),
       hydride, water, alcohol, amine

  • The reaction rate depends on the leaving group ability of Y group.
  • Leaving group ability (based on base strength):
                                  O

              Br, Cl    >     O   C   R   >   OR   >    NR 2
         best leaving group                        poor leaving group
          (weakest base)                            (strongest base)
           most reactive                              least reactive
            derivative                                  derivative


  • Hydrogen and alkyl groups (aldehydes and ketones) do not act as
    leaving groups. Why?
    • Hydrides (H) and carbanions (C) are very strong bases and are
       too reactive to act as leaving groups.
• Interconversion of acyl groups is possible: see Figure 21.2
   • A more reactive acyl group can be converted to a less reactive
      group.
       O                         O                           O          O
  R1   C   Cl   +       O        C     R2               R1   C      O   C     R2       +        Cl
                    stronger base                                                      weaker base

                                     equilibrium to products


  • A less reactive acyl group can not be converted to a more reactive
    group.

       O        O                                        O                         O

  R
   1
       C   O    C   R
                        2    +        Cl           R1    C     Cl       +    O     C       R2

                            weaker base                                     stronger base
                                       equilibrium to reactants
Reactions

1. Reactions of Acid Chlorides and Anhydrides
   • Both compounds react similarly: both have good leaving groups
     (that are weak bases).

  a. Reaction with alcohols and water
     • No catalyst (acid or base) needed
     • Synthesis of esters (from alcohols) and carboxylic acids (from
        water)
      O                                            O
CH3   C   Cl        +    H2 O                CH3   C    OH       +    HCl
                                                                     (as gas)

      O         O                                            O                        O
CH3   C   O     C       CH3     +   H2 O               CH3   C   OH    +        HO    C       CH3

              Y group

      O        O                                             O                            O

CH3   C   O    C        CH3     +   CH3 OH             CH3   C   OCH3 +          HO       C    CH3
Mechanism: same for both acid chlorides and anhydrides
  • Involves an initial attack of C=O carbon by H 2O or ROH




  • When using acid chlorides, an amine base (pyridine,
    triethylamine) is added to neutralize HCl by-product
b. Reaction with amines: synthesis of amides from NH 3, 1o or 2o
   amines

• For acid halides, excess amine (2 equivalents) is needed for the
   reaction: the second equivalent will neutralize the acid by-product
   (which may otherwise react with the amide).
      O                                                      O

      C   Cl   +    H   N       CH2 CH3                      C   N       CH2 CH3       + HCl
                        CH2 CH3                                  CH2 CH3
                        o
                       2 amine
                                                                                       H
                    (use in excess)
                                                                                   H   N   CH2 CH3 Cl
                                                                                       CH2CH3




          O                                                      O
          C    Cl     + H       N CH2CH3                         C       N    CH2CH3
                                CH 2CH3                                  CH2CH 3
CH3                                                 CH3

                                                N,N-diethyl-m-toluamide (DEET)
                                                   active ingredient in Off




                            O       O                                     O                     O
      NH 2 + CH 3           C   O   C     CH3                        N    C    CH3     +   HO   C   CH3
                                                                     H


• Only one equivalent of amine needed for anhydride reaction: acetic
  acid is a weak acid and not very reactive with amides.
Mechanistic overview: similar to hydrolysis mechanism
  • Amine nitrogen attacks the C=O carbon to form tetrahedral
    intermediate.
  • The leaving group leaves, then deprotonates the ammonium
    intermediate.