Reactions of Carboxylic Acid Derivatives

Preparation of Esters, Amides, and Nitriles

Esters, amides, and nitriles are carboxylic acid derivatives that can be prepared starting from either carboxylic acids or other carboxylic acid derivatives.
An ester is an organic compound that contains a carboxyl unit in which a hydroxyl group is replaced by an alkyl or aryl group, giving it RC(=O)OR{\rm {R{-}C({=}O)OR}}' or RCOOR{\rm {R{-}COOR}'} stoichiometry. Esters can be prepared via Fischer esterification. The oxygen from the carbonyl group attacks a proton and in doing so becomes a stronger electrophile. The alcohol attacks the carbocation via a nucleophilic attack. After a proton shift, an ester and a water molecule are produced. This reaction is catalyzed by a small amount of acid to protonate the carbonyl atom and make it more susceptible to nucleophilic attack by an alcohol. The reaction is in equilibrium and reversible depending upon the amount of water or alcohol present.

Fischer Esterification

Esters with different-length carbon chains are created via Fischer esterification of a carboxylic acid and an alcohol.
Esters are also prepared via a base-catalyzed alkylation of a carboxylic acid. Base-catalyzed alkylation refers to the adding of an alkyl group in the presence of a base. In this case, the base reacts with the proton on the hydroxyl group of the carboxylic acid. The carboxylate ion then attacks the alkyl chloride, which results in the chloride leaving. This results in an ester with the same number of carbons being added as was found in the alkyl chloride.

Base-Catalyzed Alkylation of a Carboxylic Acid

The alkyl from the alkyl chloride is added to the deprotonated carboxylate ion to form an ester. The water molecule that is formed has a proton from the carboxylic acid and the hydroxyl group from the base.
Esters are also prepared via transesterification of an ester into an ester with a different R{-}{\rm {R}} group. Transesterification is a reaction that trades the R{-}{\rm {R}} group of the ester with an R{-}{\rm {R}} group of an alcohol. This can result in a smaller ester or a larger ester depending on the alcohol used. In the presence of an acid catalyst and heat, the oxygen on the carbonyl carbon is protonated. The molecule rearranges to form a carbocation. The alcohol then attacks the carbocation to form a complex. The original ester's oxygen is protonated by the acid environment, and then the oxygen and its alkyl chain leave. This results in another carbocation, but the hydroxyl group donates electrons from the oxygen atom to form a double bond. The acidic environment grabs the hydrogen off the oxygen cation, yielding a new ester and a hydronium ion as well as a new alcohol.

Production of Biodiesel by Transesterification

Triglycerides are triesters. In a reaction with methanol, the triester is broken into its three different fatty acid residues, forming new esters via transesterification.
Finally, esters are prepared via an alcohol attack on an acid halide or an anhydride. The alcohol group attacks the carbonyl carbon because it is partially positively charged. This forms a complex where the halide is the leaving group. This leaving group halide then grabs the proton from the oxygen cation, resulting in an ester.

Acid Halide Reaction with Alcohol to Produce Ester

The oxygen atom from the alcohol is the oxygen atom in the ester that substitutes where the halide atom was. The proton from the hydroxyl group becomes part of an ionic compound with the halide.
An amide is an organic compound that contains a carbonyl (C=O{\rm{C{=}O}}) linked to nitrogen atoms through a CN{\rm{C{-}N}} bond. It has a general RC(=O)NRR {\rm{RC({=}O)NRR}}' stoichiometry. Amides are prepared by adding N,N′-dicyclohexylcarbodiimide (DCC) and an amine (ammonia derivative in which one or more hydrogen atoms are replaced by alkyl or aryl units) to a carboxylic acid. The lone pair on one of the nitrogen atoms in DCC deprotonates the hydroxyl group of the carboxylic acid. The resulting carboxylate ion attacks the DCC cation via a nucleophilic attack. This forms a complex that the amine attacks in another nucleophilic attack. There is a proton transfer from one nitrogen atom to another. The complex rearranges, and the leaving group results in dicyclohexylurea and the amide.

Preparation of an Amide via DCC

The mechanism for the preparation of an amide via N,N′-dicyclohexylcarbodiimide (DCC) results in an amide and dicyclohexylurea. The resulting amide contains the same number of carbons as the amine and the carboxylic acid.
Amides are also prepared by the addition of a primary or secondary amine, such as methyl amine or diethyl amine, to an acid chloride, anhydride, or ester. The amine is a nucleophile and attacks the acid chloride, anhydride, or ester. The leaving group leaves, and the nucleophile takes its place.

Preparation of an Amide with an Acid Chloride

The Schotten-Baumann reaction is an example of a preparation of an amide using an acid chloride reaction.
Amide preparation by the addition of an anhydride results in an amide and a carboxylic acid.

Amide Preparation

Amides can be formed by mixing an amine with an acid chloride or an anhydride. The preparation of an amide via an acid chloride results in the R′ group being added to the amide. In the preparation of an amide via an anhydride, one of the R′ groups is added to the amide, and the other becomes part of the carboxylic acid by-product.
Amide preparation by the addition of an ester results in an amide and an alcohol.

Amide Preparation via an Ester and an Amine

In the preparation of an amide reaction, the OR{-}{\rm{OR}}^{\prime} group of the ester is replaced with the NRR′ group from the amide.
A familiar example of an amide is the antibiotic penicillin. Each form of penicillin contains a four-membered ring amide, called a lactam, bonded to a second amide. The lactam is fused to a five-membered ring, forming a strained ring, and a carboxylic acid. The R group on the second amide produces different forms of penicillin.

Penicillin Structure

Penicillin contains two amide groups, with one of them being in a strained ring. The structure shown is a form of penicillin called penicillin G, which is used to treat bacterial infections.
A nitrile, also called a cyano group, is an organic compound that has a carbon triple bonded to a nitrogen with RCN stoichiometry. Nitriles are prepared by adding sodium cyanide (NaCN) to an alkyl halide. The cyanide ion is a strong nucleophile, and it attacks the carbon adjacent to the halide in an SN2 reaction. The halide is the leaving group, and the resulting compounds are a nitrile and a sodium halide. Nitriles are also prepared by the dehydration of primary amides with thionyl chloride (SOCl2) via a nucleophilic attack. A primary amide is an organic compound that contains a carbonyl (C=O{\rm{C{=}O}}) linked to a nitrogen atom that has two hydrogen atoms (NH2). It has one carbon bonded to the nitrogen atom.

Preparation of Nitrile via Sodium Cyanide and Alkyl Halide

An alkyl halide undergoes nucleophilic substitution with sodium cyanide to form a nitrile.

Preparation of Nitrile Using Thionyl Chloride

The preparation of a nitrile from an amide using thionyl chloride is a nucleophilic dehydration reaction. The carbon-nitrogen bond becomes a triple bond in the nitrile.