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Carboxylic acid reactions overview

Carboxylic acids belong to a class of organic compounds in which a carbon (C) atom is bonded to an oxygen (O) atom by a double bond and to a hydroxyl group (−OH) by a single bond. A fourth bond links the carbon atom to a hydrocarbon group (R). The carboxyl (COOH) group is named after the carbonyl group (C=O) and hydroxyl group.
Diagram of a carboxylic molecule
In general, carboxylic acids undergo a nucleophilic substitution reaction where the nucleophile (-OH) is substituted by another nucleophile (Nu). The carbonyl group (C=O) gets polarized (i.e. there is a charge separation), since oxygen is more electronegative than carbon and pulls the electron density towards itself. As a result, the carbon atom develops a partial positive charge (δ+) and the oxygen atom develops a partial negative charge (δ-). In some cases, in the vicinity of a strong electrophile, the partially negatively charged carbonyl oxygen (δ-) can act as a nucleophile and attack the electrophile (as you will notice in the example of acid chloride synthesis, discussed later in this tutorial).
Compounds in which the −OH group of the carboxylic acid is replaced by other functional groups are called carboxylic acid derivatives, the most important of which are acyl halides, acid anhydrides, esters, and amides.

Overview of the reactions that we would be discussing in this tutorial

Diagram overview of carboxylic molecule reactions
Let’s list down some common properties for the above shown carboxylic acid derivatives
  • Each derivative contains a common group, termed as an acyl group (R-C=O), which is attached to a heteroatom
  • They can all be synthesized from the “parent” carboxylic acid
  • They are all formed through a nucleophilic substitution reaction
  • On hydrolysis (i.e. reaction with Hstart subscript, 2, end subscriptO), they all convert back to their parent carboxylic acid
Now let’s discuss each carboxylic acid derivative individually, and outline the reaction mechanism by which they are formed starting from the parent carboxylic acid

Acid chloride (ROCl)

Acid chlorides are formed when carboxylic acids react with thionyl chloride (SOClstart subscript, 2, end subscript), PClstart subscript, 3, end subscript or PClstart subscript, 5, end subscript. They are the most reactive derivatives of carboxylic acid.
Diagram of the formation of acid chloride (ROCl)

Mechanism of acid chloride formation with SOClstart subscript, 2, end subscript

(Please follow the movement of electrons carefully)
Diagram of the mechanism of acid chloride formation with SOCl2
The electrophilic sulfur atom is attacked by the nucleophilic oxygen of carboxylic acid to give an intermediate six membered transition state; which immediately decomposes to the intermediate (A) and HCl respectively. This intermediate (A) then reacts with the HCl molecule, just produced, to give an intermediate (B) which then collapses to form the corresponding acyl chloride, sulfur dioxide and hydrogen chloride. This final step is irreversible because the byproducts, SOstart subscript, 2, end subscript and HCl, are gases that evaporate off and thus push the reaction in the forward direction.

Ester (RCOOR’)

Esters are derived when a carboxylic acid reacts with an alcohol. Esters containing long alkyl chains (R) are main constituents of animal and vegetable fats and oils. Many esters containing small alkyl chains are fruity in smell, and are commonly used in fragrances.
Diagram of the formation of ester (RCOOR’)
The acid-catalyzed esterification of carboxylic acids with alcohols to give esters is termed Fischer esterification

Mechanism of Fischer esterification

Diagram of the mechanism of Fischer esterification

Thioester (RCOSR’)

Thioesterification: A thioester is formed when a carboxylic acid reacts with a thiol (RSH) in the presence of an acid.
Diagram of the formation of thioester (RCOSR’)
Thioesters are commonly found in biochemistry, the best-known example being acetyl CoA.
The mechanism of thioesterification is the same as esterification (discussed above); only difference being that instead of an alcohol (R’OH), a thioalcohol (R’SH) is involved. As a practice, try writing down the mechanism of thioesterification.

Acid anhydride

Diagram of the formation of acid anhydride
As you can see, an acid anhydride is a compound that has two acyl groups (R-C=O) bonded to the same oxygen atom. Anhydrides are commonly formed when a carboxylic acid reacts with an acid chloride in the presence of a base. Let’s now discuss the mechanism by which a carboxylic acid anhydride is synthesized.
Diagram of mechanism by which a carboxylic acid anhydride is synthesized
Similar to the Fischer esterification, this reaction follows an addition-elimination mechanism in which the chloride anion (Clstart superscript, start text, negative, end text, end superscript) is the leaving group. In the first step, the base abstracts a proton (Hstart superscript, start text, plus, end text, end superscript) from the carboxylic acid to form the corresponding carboxylate anion (1). The carboxylate anion's negatively charged oxygen attacks the considerably electrophilic acyl chloride's carbonyl carbon. As a result, a tetrahedral intermediate (2) is formed. In the final step, chloride - a good leaving group - is eliminated from the tetrahedral intermediate to yield the acid anhydride.

Amide

The direct conversion of a carboxylic acid to an amide is difficult because amines are very basic and tend to convert carboxylic acids to their highly unreactive carboxylate ions. Therefore, DCC (Dicyclohexylcarbodiimide) is used to drive this reaction.
Diagram of the formation of amide
The structure of DCC is shown below
Diagram of the structure of DCC (Dicyclohexylcarbodiimide)
A carboxylic acid first adds to the DCC molecule to form a good leaving group, which can then be displaced by an amine during nucleophilic substitution to form the corresponding amide. The reaction steps are shown below:
Step 1: Deprotonation of the acid.
Diagram of deprotonation of the acid
Step 2: Nucleophilic attack by the carboxylate.
Diagram of nucleophilic attack by the amine
Step 3: Nucleophilic attack by the amine.
Diagram of nucleophilic attack by the amine
Step 4: Proton transfer.
Diagram of proton transfer
Step 5: Dicyclohexylurea acts as the leaving group to form the amide product.
Diagram of dicyclohexylurea acting as the leaving group to form the amide product

Relative reactivity of the carboxylic acid derivatives towards a nucleophilic substitution reaction

Diagram of nucleophilic substitution reaction with a nucleophile (Nu)
Let’s view the carboxylic acid derivatives as an acyl group, R-C=O, attached to a substituent (X). These derivatives also undergo a nucleophilic substitution reaction with a nucleophile (Nu) as shown above. The reactivity of these derivatives towards nucleophilic substitution is governed by the nature of the substituent X present in the acid derivative
  • if the substituent (X) is electron donating, it reduces the electrophilic nature of the carbonyl group by neutralizing the partial positive charge developed on the carbonyl carbon, and thus makes the derivative less reactive to nucleophilic substitution
  • if the substituent (X) is electron withdrawing, then it increases the electrophilic nature of carbonyl group by pulling the electron density of the carbonyl bond towards itself, making the carbonyl carbon more reactive to nucleophilic substitution
DerivativeSubstituent (X)Electronic effect of XRelative reactivity
Acid chloride-Clelectron withdrawing1 (most reactive)
Acid anhydride-OC=ORelectron withdrawing2 (almost as reactive as 1)
Thioester-SRweakly electron donating3
Ester-ORalkoxy (-OR) group is weakly electron donating4
Amide-NHstart subscript, 2, end subscript, NRstart subscript, 2, end subscriptvery strongly donating5
Carboxylate ion-Ostart superscript, start text, negative, end text, end superscriptCarboxylate ions are not reactive because their negative charge repels the approach of other nucleophiles6 (least reactive)
Thus, on a reactivity scale, the order of reactivity of various carboxylic acid derivatives towards nucleophilic substitution is as follows:
Acid halide > acid anhydride > thioester > ester > amide

Want to join the conversation?

  • marcimus pink style avatar for user Zoey Wang
    Is it necessary to know the exact reaction mechanism in the MCAT exam?
    (10 votes)
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  • leafers seedling style avatar for user EmilyAWillard
    Hi KA!

    Couple questions on the Fischer esterification:

    1) Are all of these steps reversible?
    2) In a different Fischer esterification video (by Sal, see link below), there is no proton transfer as is shown here. See around of that linked video below. Instead, in the other video, a slightly different mechanism occurs in which the alcohol proton is picked up/deprotonated by something else in the medium. Sal notes in the video that a proton transfer is possible - but does not draw the mechanism in this way. Under what conditions does a proton transfer happen/not happen?

    I love Khan Academy so much. You've all helped me so much through my entire post bac and now while I'm studying for the MCAT - thank you!!

    https://www.khanacademy.org/science/organic-chemistry/carboxylic-acids-derivatives/formation-carboxylic-acid-derivatives-sal/v/fisher-esterification
    (2 votes)
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  • blobby green style avatar for user Daru Seto Bagus Anugrah
    I want to esterification acid (-COOH) with ethanolamine. can I use COCl than attack ethanolamine? I only want to attack -OH group and keep -NH2. Do you have any suggestion for me? thanks in advance
    (2 votes)
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  • blobby green style avatar for user darshak pathiwada
    what are the reaction conditions using DCC?
    (1 vote)
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  • marcimus pink style avatar for user Mehwish Maqsood
    Thank you so much for providing such a comprehensive compilation of data. Please it's a request! Kindly can you provide me references for it I have to add them to my assignment assigned by my university
    (1 vote)
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  • spunky sam red style avatar for user Samuel Fong
    Why is -SR more reactive than -OR? Assuming the same R group, oxygen is more electronegative than sulphur. Since its more attracted to electrons, shouldnt it be less electron-donating?
    (1 vote)
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  • blobby green style avatar for user Jefferson Ebal
    What would happen if a carboxyl group and a hydroxyl group come together?
    (0 votes)
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  • blobby green style avatar for user boruahadityapran
    How can I step down a carboxylic acid?
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  • primosaur seed style avatar for user Syed Musab Ali
    If we discuss esterification in perspective that when alcohol react with carboxylic acid the OH bond cleavage took place and it is in result of attack of nucleophile. So esterification should be electrophillic substitution.
    (0 votes)
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