10 Carboxylic Acids and Their Derivatives

Structure and functional groups

A carboxylic acid contains a Carboxyl group, written $\mathrm{R-C(=O)-OH}$. The carbonyl carbon is bonded to a hydroxyl group. Replacing the hydroxyl hydrogen or the hydroxyl group with another atom or group produces a carboxylic acid derivative.

These compounds share an Acyl group, $\mathrm{R-C(=O)-}$, but differ in what is bonded to its carbonyl carbon:

• Carboxylic acids: $\mathrm{R-C(=O)-OH}$

• Acid chlorides: $\mathrm{R-C(=O)-Cl}$

• Acid anhydrides: $\mathrm{R-C(=O)-O-C(=O)-R'}$

• Esters: $\mathrm{R-C(=O)-OR'}$

• Amides: $\mathrm{R-C(=O)-NR'R''}$

• Thioesters: $\mathrm{R-C(=O)-SR'}$

The groups $\mathrm{R}$, $\mathrm{R'}$, and $\mathrm{R''}$ represent carbon-containing groups, which may be identical or different. Anhydrides can be symmetrical or mixed. Cyclic esters and cyclic amides are called lactones and lactams, respectively.

Takeaway: Identify the group bonded to the acyl carbon to distinguish the major families of carboxylic acid derivatives.

Naming the compounds

Naming starts by identifying the acid-derived carbon chain and the group attached to its carbonyl carbon.

• Carboxylic acids: Choose the longest chain containing the carboxyl carbon; that carbon is carbon 1. Change the corresponding alkane ending to -oic acid. For example, $\mathrm{CH_3CH_2CH_2COOH}$ is butanoic acid. If the carboxyl group is attached to a ring but its carbon is not part of that ring, use -carboxylic acid, as in cyclohexanecarboxylic acid.

• Acid chlorides: Change -oic acid to -oyl chloride. Butanoic acid becomes butanoyl chloride.

• Esters: Name the group attached to oxygen first, then the acid-derived part with the ending -oate. For example, $\mathrm{CH_3CH_2COOCH_3}$ is methyl propanoate.

• Amides: Change -oic acid to -amide. Groups attached to nitrogen are identified with N-, as in N-methylpropanamide.

• Anhydrides: Name the corresponding acid or acids followed by anhydride. A symmetrical anhydride derived from ethanoic acid is ethanoic anhydride.

Takeaway: For acids and several derivatives, the ending signals the functional group; ester names additionally identify the group attached to oxygen.

How acyl substitution works

The characteristic reaction of these derivatives is Nucleophilic acyl substitution: a nucleophile replaces the group attached to the acyl carbon.

The usual mechanism is an addition–elimination sequence:

1. The nucleophile attacks the electrophilic carbonyl carbon. The carbonyl pi electrons move to oxygen, forming a Tetrahedral intermediate.

2. The oxygen reforms the carbonyl, and the group $\mathrm{Y}$ leaves.

3. Proton transfers may occur to produce neutral products and regenerate a catalyst when applicable.

This is substitution rather than simple addition because an acyl derivative has a group attached to the carbonyl carbon that can leave when the intermediate collapses. Acidic conditions can activate the carbonyl by protonating oxygen; basic conditions often provide a stronger nucleophile. Proton transfers may accompany either pathway.

For example, under basic hydrolysis conditions, hydroxide converts an ester to a carboxylate and an alcohol:

Acid workup then converts the carboxylate to the carboxylic acid.

Takeaway: Follow the nucleophile's attack, formation of the tetrahedral intermediate, and departure of the leaving group to understand the overall substitution.

What controls reactivity

For comparable nucleophiles and conditions, the general reactivity order toward nucleophilic acyl substitution is:

Thioesters are generally more reactive than ordinary esters and are important in biological acyl transfer. Exact comparisons depend on the conditions and on which reaction is being measured.

Two effects help explain the broad trend:

• Leaving-group ability: Weaker bases are generally better leaving groups. Chloride, for example, leaves more readily than an amide-derived anion.

• Resonance donation: A substituent that donates electron density into the carbonyl makes the carbonyl carbon less electrophilic. Nitrogen donates strongly, helping make amides less reactive. Carboxylates are especially unreactive because they are negatively charged and their two carbon–oxygen bonds are resonance-stabilized.

This trend provides a planning principle: a more reactive derivative can often be converted into a less reactive one by substitution. The reverse generally requires activation or a different synthetic strategy.

Takeaway: Reactivity depends in large part on how well the attached group leaves and how strongly it donates electron density into the carbonyl.

Interconversion and synthesis planning

The derivative families form a network of conversions. Reagents and conditions determine the product and whether the process is reversible.

• Treat a carboxylic acid with thionyl chloride, $\mathrm{SOCl_2}$, to replace $\mathrm{-OH}$ with $\mathrm{-Cl}$ and form an acid chloride.

• React an acid chloride with a carboxylate ion to form an anhydride.

• React an acid chloride or anhydride with an alcohol to form an ester, or with ammonia or an amine to form an amide.

• A carboxylic acid and an alcohol can form an ester and water under acid catalysis, often with heat. This Fischer esterification is an equilibrium reaction; excess alcohol or removal of water can shift it toward ester formation.

• Ester Hydrolysis with aqueous acid or base produces a carboxylic acid or carboxylate and an alcohol, depending on conditions and workup. Amides can also be hydrolyzed in aqueous acid or base, usually with heat, to give a carboxylic acid or carboxylate and an ammonium or amine product.

A useful sequence is butanoic acid to butanoyl chloride to ethyl butanoate. Thionyl chloride first activates the acid by forming the acid chloride; reaction with ethanol then forms the ester, typically with a base present to neutralize the hydrogen chloride produced. Direct substitution on the unactivated acid is less effective because its hydroxyl group is a poor leaving group.

Acid chlorides and anhydrides readily form esters and amides. By contrast, a stable amide does not become an acid chloride through simple nucleophilic substitution. It must first be hydrolyzed or otherwise transformed, and the resulting acid then activated.

Takeaway: Plan conversions in the direction of decreasing reactivity when possible; converting a less reactive derivative into a more reactive one usually requires an additional activation step.