Preparation of Carboxylic Acids

Carboxylic acids are mainly prepared by the oxidation of a number of different functional groups, as the following sections detail.

Oxidation of alkenes

Alkenes are oxidized to acids by heating them with solutions of potassium permanganate (KMnO ₄) or potassium dichromate (K ₂Cr ₂O ₇).

Oxidation of alkenes

The ozonolysis of alkenes produces aldehydes that can easily be further oxidized to acids.

The oxidation of primary alcohols and aldehydes

The oxidation of primary alcohols leads to the formation of alde‐hydes that undergo further oxidation to yield acids. All strong oxidizing agents (potassium permanganate, potassium dichromate, and chromium trioxide) can easily oxidize the aldehydes that are formed. Remember: Mild oxidizing agents such as manganese dioxide (MnO ₂) and Tollen's reagent [Ag(NH ₃) ₂ ⁺OH ⁻] are only strong enough to oxidize alcohols to aldehydes.

The oxidation of alkyl benzenes

Alkyl groups that contain benzylic hydrogens—hydrogen(s) on a carbon α to a benzene ring—undergo oxidation to acids with strong oxidizing agents.

In the above example, t‐butylbenzene does not contain a benzylic hydrogen and therefore doesn't undergo oxidation.

Hydrolysis of nitriles

The hydrolysis of nitriles, which are organic molecules containing a cyano group, leads to carboxylic acid formation. These hydrolysis reactions can take place in either acidic or basic solutions.

The mechanism for these reactions involves the formation of an amide followed by hydrolysis of the amide to the acid. The mechanism follows these steps:

1. The nitrogen atom of the nitrile group is protonated.

2. The carbocation generated in Step 1 attracts a water molecule.

3. The oxonium ion loses a proton to the nitrogen atom, forming an enol.

4. The enol tautomerizes to the more stable keto form.

5. The amide is protonated by the acid, forming a carbocation.

6. A water molecule is attracted to the carbocation.

7. The oxonium ion loses a proton.

8. The amine group is protonated.

9. An electron pair on one of the oxygens displaces the ammonium group from the molecule.

The carbonation of Grignard reagents

Grignard reagents react with carbon dioxide to yield acid salts, which, upon acidification, produce carboxylic acids.

Synthesis of substituted acetic acids via acetoacetic ester

Acetoacetic ester, an ester formed by the self‐condensation of ethyl acetate via a Claisen condensation, has the following structure:

The hydrogens on the methylene unit located between the two carbonyl functional groups are acidic due to the electron withdrawing effects of the carbonyl groups. Either or both of these hydrogens can be removed by reaction with strong bases.

The resulting carbanions can participate in typical S _N reactions that allow the placement of alkyl groups on the chain.

Hydrolysis of the resulting product with concentrated sodium hydroxide solution liberates the sodium salt of the substituted acid.

Addition of aqueous acid liberates the substituted acid.

The second hydrogen on the methylene unit of acetoacetic ester can also be replaced by an alkyl group, creating a disubstituted acid. To accomplish this conversion, the reaction product in step 2 above would be reacted with a very strong base to create a carbanion.

This carbanion can participate in a typical S _N reaction, allowing the placement of a second alkyl group on the chain.

Hydrolysis using concentrated aqueous sodium hydroxide leads to the formation of the sodium salt of the disubstituted acid.

Addition of aqueous acid liberates the disubstituted acid.

The acid formed has a methyl and an ethyl group in place of two hydrogens of acetic acid and is therefore often referred to as a disubstituted acetic acid.

If dilute sodium hydroxide were used instead of concentrated, the product formed would be a methyl ketone. This ketone occurs because dilute sodium hydroxide has sufficient strength to hydrolyze the ester functional group but insufficient strength to hydrolyze the ketone functional group. Concentrated sodium hydroxide is strong enough to hydrolyze both the ester functional group and the ketone functional group and, therefore, forms the substituted acid rather than the ketone.

A reaction between a disubstituted acetoacetic ester and dilute sodium hydroxide forms the following products:

Upon heating, the β ketoacid becomes unstable and decarboxylates, leading to the formation of the methyl ketone.

A Claisen condensation of ethyl acetate prepares acetoacetic ester.

The Claisen condensation reaction occurs by a nucleophilic addition to an ester carboxyl group, which follows these steps:

1. An α hydrogen on the ester is removed by a base, which leads to the formation of a carbanion that is resonance stabilized.

2. Acting as a nucleophile, the carbanion attacks the carboxyl carbon of a second molecule of ester.

3. A pair of unshared electrons on the alkoxide oxygen move toward the carboxyl carbon, helping the ethoxy group to leave.

Synthesis of substituted acetic acid via malonic ester

Malonic ester is an ester formed by reacting an alcohol with malonic acid (propanedicarboxylic acid). Following is the structure of diethyl malonate:

The hydrogen atoms on the methylene unit between the two carboxyl groups are acidic like those in acetoacetic ester. Strong bases can remove these acidic hydrogens.

The resulting carbocation can participate in typical S _N reactions, allowing the placement of an alkyl group on the chain.

A second alkyl group can be placed on the compound by reacting the product formed in the previous step with a very strong base to form a new carbanion.

The resulting carbanion can participate in a typical S _N reaction, allowing the placement of a second alkyl group on the chain.

Hydrolysis of the resulting product with concentrated aqueous sodium hydroxide produces the sodium salt of the disubstituted acid.

Addition of aqueous acid converts the salt into its conjugate acid.

Upon heating, the β ketoacid becomes unstable and decarboxylates, forming a disubstituted acetic acid.

α halo acids, α hydroxy acids, and α, β unsaturated acids

The reaction of aliphatic carboxylic acids with bromine in the presence of phosphorous produces α halo acids. This reaction is the Hell‐Volhard‐Zelinski reaction.

α halo acids can be converted to α hydroxy acids by hydrolysis.

α halo acids can be converted to α amino acids by reacting with ammonia.

α halo acids and α hydroxy acids can be converted to α, β unsaturated acids by dehydrohalogenation and dehydration, respectively.

Organic Chemistry II

Preparation of Carboxylic Acids

The carbonation of Grignard reagents