20.6 Reactions of Carboxylic Acids: An Overview

Reactions of Carboxylic Acids

Categories of carboxylic acid reactions

Carboxylic acids react in several distinct ways, each targeting a different part of the molecule. Knowing which category a reaction falls into helps you predict products and choose the right reagents.

• Nucleophilic acyl substitution — A nucleophile attacks the electrophilic carbonyl carbon, and the $\text{-OH}$ group departs as a leaving group. Common nucleophiles include alcohols, amines, and ammonia. This is how esters and amides are formed.
• Reduction — Adding hydrogen across the carbonyl using strong reducing agents like $\text{LiAlH}_4$ or $\text{BH}_3$, converting the acid to a primary alcohol.
• Decarboxylation — The carboxyl group is lost as $\text{CO}_2$. This typically requires heat and works best on $\beta$-keto acids or malonic acid derivatives, yielding the corresponding alkane or alkene.
• $\alpha$-Substitution — The hydrogen on the $\alpha$-carbon (the carbon next to the carbonyl) is replaced by an electrophile. This proceeds through an enolate ion intermediate. The Hell–Volhard–Zelinsky (HVZ) reaction, which brominates the $\alpha$-position, is a classic example.
• Esterification — A specific type of nucleophilic acyl substitution where a carboxylic acid reacts with an alcohol (usually with an acid catalyst) to form an ester and water. This is called Fischer esterification.

Reduction to primary alcohols

Carboxylic acids are resistant to mild reducing agents, so you need powerful reagents to reduce them all the way to primary alcohols.

$\text{LiAlH}_4$ (lithium aluminum hydride): This is the go-to reagent. It's a strong hydride donor that reduces the carboxyl group to a $\text{-CH}_2\text{OH}$ group. The reaction must be run in anhydrous solvents like diethyl ether or THF under an inert atmosphere because $\text{LiAlH}_4$ reacts violently with water.

$\text{BH}_3$ (borane): A useful alternative because it selectively reduces carboxylic acids even in the presence of other carbonyl groups (like esters or amides). The reaction is run in THF, and the intermediate alkylborane is hydrolyzed during workup to give the primary alcohol.

The general reduction mechanism follows two key steps:

1. Nucleophilic addition of hydride ($\text{H}^-$) to the electrophilic carbonyl carbon
2. Protonation of the resulting alkoxide ion during aqueous workup to yield the alcohol

Reactivity vs. alcohols and ketones

Carboxylic acids sit at a unique reactivity level compared to other oxygen-containing functional groups. Understanding these differences helps you predict selectivity in multifunctional molecules.

Nucleophilic acyl substitution:

• Carboxylic acids undergo substitution because the $\text{-OH}$ group can leave (especially when protonated), and the carbonyl carbon is electrophilic.
• Alcohols and ketones lack a good leaving group attached to the carbonyl (ketones) or lack a carbonyl entirely (alcohols), so they don't undergo this reaction type.

Acid-base properties:

• Carboxylic acids are weak acids with $\text{p}K_a$ values around 4–5. The conjugate base (carboxylate ion, $\text{RCOO}^-$) is stabilized by resonance, with the negative charge delocalized over both oxygens.
• Alcohols are far less acidic ($\text{p}K_a \approx 16$) because the resulting alkoxide has no resonance stabilization. Ketones are not meaningfully acidic at the carbonyl oxygen.

Reduction:

• Carboxylic acids require strong reducing agents ($\text{LiAlH}_4$, $\text{BH}_3$) and yield primary alcohols.
• Ketones are more easily reduced, even by $\text{NaBH}_4$ or catalytic hydrogenation, and yield secondary alcohols.
• Alcohols are already at a low oxidation state. To reduce them further to hydrocarbons, you first need to convert the $\text{-OH}$ to a better leaving group (e.g., a tosylate or halide).

Carboxylic Acid Derivatives and Reactions

Carboxylic acids serve as starting materials for several important derivative classes:

• Acid anhydrides form when two carboxylic acid molecules undergo condensation, losing one molecule of water. In practice, anhydrides are more commonly made using acyl chlorides rather than direct condensation.
• Acidity and substituent effects — Electron-withdrawing groups near the carboxyl group (such as halogens) stabilize the carboxylate ion and increase acidity. For example, $\text{ClCH}_2\text{COOH}$ (chloroacetic acid, $\text{p}K_a \approx 2.9$) is significantly more acidic than $\text{CH}_3\text{COOH}$ (acetic acid, $\text{p}K_a \approx 4.75$). Electron-donating groups have the opposite effect.
• Carboxylic acids can also be oxidized, though they are already at a high oxidation state. Oxidative decarboxylation and other specialized reactions exist, but simple oxidation of the carboxyl group itself is uncommon.