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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 H2O), 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 (SOCl2), PCl3 or PCl5. They are the most reactive derivatives of carboxylic acid.
Diagram of the formation of acid chloride (ROCl)

Mechanism of acid chloride formation with SOCl2

(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, SO2 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 (Cl-) is the leaving group. In the first step, the base abstracts a proton (H+) 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.


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-NH2, NR2very strongly donating5
Carboxylate ion-O-Carboxylate 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

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