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    L6 Reactions of Carboxylic Acid Derivatives

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    Cheng Fu
    Carboxylic acid derivatives such as acyl chlorides, anhydrides, esters, and amides can all undergo nucleophilic acyl substitution reactions. Acyl chlorides are the most reactive but generate dangerous byproducts, while anhydrides and esters are less reactive. Esters are common in flavorings and fragrances. Amides are stable and form the basis of polypeptides and proteins.

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    L6 Reactions of Carboxylic Acid Derivatives

    Uploaded by

    Cheng Fu
    25 views21 pages
    Carboxylic acid derivatives such as acyl chlorides, anhydrides, esters, and amides can all undergo nucleophilic acyl substitution reactions. Acyl chlorides are the most reactive but generate dangerous byproducts, while anhydrides and esters are less reactive. Esters are common in flavorings and fragrances. Amides are stable and form the basis of polypeptides and proteins.

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    L6 reactions of Carboxylic Acid Derivatives

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    Carboxylic acid derivatives such as acyl chlorides, anhydrides, esters, and amides can all undergo nucleophilic acyl substitution reactions. Acyl chlorides are the most reactive but generate dangerous byproducts, while anhydrides and esters are less reactive. Esters are common in flavorings and fragrances. Amides are stable and form the basis of polypeptides and proteins.

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    25 views21 pages

    L6 Reactions of Carboxylic Acid Derivatives

    Uploaded by

    Cheng Fu
    Carboxylic acid derivatives such as acyl chlorides, anhydrides, esters, and amides can all undergo nucleophilic acyl substitution reactions. Acyl chlorides are the most reactive but generate dangerous byproducts, while anhydrides and esters are less reactive. Esters are common in flavorings and fragrances. Amides are stable and form the basis of polypeptides and proteins.

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    of 21

    Practice Question:

    Give possible reagents for the preparation of:

    .
    The pre-reading for this lecture covered:

    Carboxylic acid derivatives:


    Acyl chlorides and acid anhydrides
    4.3.3 Acyl (Acid) Chlorides and Acid Anhydrides.- Reactions

    O amide O ester

    R C NHR1 H2N-R R C OR1


    O R1OH
    R C Cl
    O H2O
    R1CO2H O
    R C OH
    Carboxylic acid R C OCOR1
    anhydride

    All nucleophilic acyl substitution.


    Earlier this block we saw that acyl chlorides react with
    Grignard reagents to yield 3o alcohols.

    O OH
    1. 2 R1MgX
    R C Cl R C R1
    2. H3O+
    R1

    Nucleophilic acyl substitution, followed by nucleophilic addition.


    Anhydrides do the same reactions (but are less reactive).

    Can form esters, amides and carboxylic acids but not acyl
    halides.
    O amide O ester

    R C NHR1 H2N-R R C OR1


    R1OH

    O H2O
    R C OH
    Carboxylic acid
    We saw an example of this in lab 1.

    Acetic Acetyl salicylic acid


    anhydride commonly called Aspirin
    CO2H O O CO2H
    OH H3C C O C CH3 OCCH 3
    O
    + CH3CO2H
    Salicylic acid Acetic acid

    Here, the anhydride is symmetrical. What might happen if it


    wasn’t?
    4.3.4 Esters
    Preparation – Acyl Chloride (or anhydride) + Alcohol

    O O
    CH3CH2OH + C CH3CH2OC + HCl
    Cl
    Ethyl benzoate

    O
    OH + CH3CH2COCl O CCH2CH3
    Preparation – Carboxylic Acid + Alcohol

    O H+ O
    CH3COH + CH3OH CH3COCH3 + H2O

    Works well for simple (small) alcohols only


    Reactions of Esters

    Esters do nucleophilic acyl substitution. They are less


    reactive than acyl halides and anhydrides.

    O O
    O
    R 2NH 2 H2O/H3O+ RCOH
    RCNR 2 RCOR1 +
    H amide (H2O/HO-)
    HOR1
    + HOR 1 hydrolysis

    Can be converted into carboxylic acids and amides.


    Re Esters also react with LiAlH4 or 2 equivalents of a
    Grignards to give alcohols.

    O OH
    RCH2OH 1. LiAlH4 1. 2R2MgX
    RCOR1 RC R2
    + R1OH 2. H3 O+ 2. H3O+
    R2

    Mechanistically, this is nucleophilic acyl substitution


    followed by nucleophilic addition.
    Practice Question:
    Draw all organic products for the following reactions.

    O 1. LiAlH4

    O 2. H3O+

    .
    O H 2O/H3O+

    O
    H 2O/HO-
    O
    Hydrolysis of Esters

    All carboxylic acids can converted back to the corresponding


    carboxylic acid via nucleophilic acyl substitution..

    For acyl halides (and anhydrides) water is sufficient for


    hydrolysis. For esters, either an acid or a base must be used.

    Base-promoted:
    O O
    CH 3 C CH 3 C OCH CH
    HO 2 3
    OCH 2CH 3
    HO - O
    CH 3 C + OCH 2CH 3
    O H
    O
    CH 3 C + HOCH CH
    2 3
    O
    Acid-Catalysed:

    H
    O H O
    O H
    CH3 C CH3 C CH3 C OCH CH
    2 3
    OCH2CH3 OCH 2CH3 O
    H2 O H H

    H
    O H O
    CH3 C + HOCH2CH3 CH3 C OCH CH
    2 3
    OH O
    H H
    O
    CH3 C + H
    OH
    Uses of Esters
    Esters are everywhere.

    O O O O
    O O OCH 2 CH 2 O O
    H 2N O N
    PET – used for plastic bottles

    HO O
    O

    O O O
    Me
    O N
    O O
    H O
    Jasmine lactone –
    O
    H in perfumes
    O
    Zocor –top selling drug - Heroin – the
    another leading anti- diacetylester of
    cholesterol drug morphine
    Esters polymers are used for dissolvable stitches.
    Lactomer is a polyester made from the two alpha-hydroxy
    acids lactic acid and glycolic acid which occur naturally in
    our bodies.

    lactic glycolic
    acid acid
    HOCH(CH3)COOH + HOCH2COOH HOCH(CH3)COOCH2COOH

    Under acid conditions present in biological fluids and


    tissues the polyester hydrolyses slowly over 2-3 weeks
    releasing harmless lactic acid and glycolic acid.
    And even flavourings.

    O O
    CH3CH2CH2COCH3 (CH3)2CHCH2CH2OCCH3
    Methyl butanoate 3-methylbutyl acetate
    Pineapples Bananas
    4.3.5 Amides
    Preparation O
    R2
    Acyl halide or anhydride + amine. R N
    R1
    • Ammonia gives primary amides
    • Primary amine (R-NH2) gives secondary amide
    • Secondary amine (R2NH) gives tertiary amide
    O
    NH2 + CH3COCl NH C CH3
    or (CH3CO)2O

    O
    COCl + HNEt2 C NEt2
    Reactions of Amides

    Amides do nucleophilic acyl substitution. They are much


    less reactive than acyl halides, anhydrides and esters.

    70% aq. H2SO4


    NHCOCH3 NH3
    heat
    + O
    HO O C CH3

    NH2 + H2O

    Can be converted into carboxylic acids and this requires


    strong aqueous acid or base..
    Recall that for amides, there is a significant resonance
    contributor with a C=N bond.

    O O O
    R1 C R1 C R1 C
    NH2 NH2 NH2

    This means amides are neutral. The lone pair is not


    available to react with an H+.
    The amide linkage is stable enough to be the
    fundamental unit from which polypeptides and
    proteins are made in living systems.

    R O R O R O R O
    H 2 N CH C OH HN CH C NH CH C NH CH C O

    Nylon is a synthetic polyamide:


    O O O O
    at interface
    ClC(CH2)8CCl + H2N(CH2) 6NH2 ClC(CH2)8CNH(CH2) 6NH2
    - HCl
    in CHCl3 in H2O
    Summary

    Carboxylic Anhydrides Esters Amides Uses and details


    acids
    O
    Making other derivatives
    R C
    Cl
        Most reactive, generate
    most dangerous byproduct

    O Making other derivatives


    R C
    OCOR
       Safer but slower than ROCl
    but still no household uses

    O Widely used in materials


    R C
    OR
      e.g. aroma compounds,
    in medicines,
    in industrial material

    O Widely used in materials


    e.g. in medicines,
    R C in industrial materials.
    Only derivative that is very
    NR2 biologically stable

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