- Carboxylic acid questions
- Carboxylic acid reactions overview
- Carboxylic acid nomenclature and properties
- Reduction of carboxylic acids
- Preparation of esters via Fischer esterification
- Preparation of acyl (acid) chlorides
- Preparation of acid anhydrides
- Preparation of amides using DCC
- Alpha-substitution of carboxylic acids
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.
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
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 HO), 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 (SOCl), PCl or PCl. They are the most reactive derivatives of carboxylic acid.
Mechanism of acid chloride formation with SOCl
(Please follow the movement of electrons carefully)
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, SO and HCl, are gases that evaporate off and thus push the reaction in the forward direction.
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.
The acid-catalyzed esterification of carboxylic acids with alcohols to give esters is termed Fischer esterification
Mechanism of Fischer esterification
Thioesterification: A thioester is formed when a carboxylic acid reacts with a thiol (RSH) in the presence of an acid.
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.
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.
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.
The structure of DCC is shown below
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.
Step 2: Nucleophilic attack by the carboxylate.
Step 3: Nucleophilic attack by the amine.
Step 4: Proton transfer.
Step 5: Dicyclohexylurea acts as the leaving group to form the amide product.
Relative reactivity of the carboxylic acid derivatives towards a nucleophilic substitution reaction
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
|Derivative||Substituent (X)||Electronic effect of X||Relative reactivity|
|Acid chloride||-Cl||electron withdrawing||1 (most reactive)|
|Acid anhydride||-OC=OR||electron withdrawing||2 (almost as reactive as 1)|
|Thioester||-SR||weakly electron donating||3|
|Ester||-OR||alkoxy (-OR) group is weakly electron donating||4|
|Amide||-NH, NR||very strongly donating||5|
|Carboxylate ion||-O||Carboxylate ions are not reactive because their negative charge repels the approach of other nucleophiles||6 (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?
- Is it necessary to know the exact reaction mechanism in the MCAT exam?(10 votes)
- I think they might be helpful if a question has radio-labeled atoms in the reactions but probably wouldn't stress over every step.(4 votes)
- 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 around9:02of 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!!
- On step 4 of the Amide group, how does H- transfer from one group to the other? The image is unclear to me, and I'm still trying to wrap my head around the concepts.(2 votes)
- The nitrogen with the lone pair on the former DCC molecule (the one that still has a double bond to the carbon) is the group that attacks. Its lone pair attacks the hydrogen on the positively charged nitrogen of the attached amine group, and the bond between that nitrogen and hydrogen is broken. (This forms the symmetric dicyclohexylurea molecule before it acts as a leaving group in the next step and the corresponding amide).(1 vote)
- 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)
- 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?(2 votes)
- 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)