Derivatives of Carboxylic Acids

Welcome to your study notes on derivatives of carboxylic acids! In this chapter, we explore a family of reactive and useful organic compounds derived from carboxylic acids. These compounds are central to organic synthesis and are used in everything from manufacturing pharmaceuticals like aspirin to creating polymers and perfumes. Don't worry if organic mechanisms sometimes seem daunting — we will break down every reaction step-by-step with simple analogies and clear rules.

1. What are Carboxylic Acid Derivatives?

A carboxylic acid derivative is formed when the hydroxyl group (\( -\text{OH} \)) of a carboxylic acid (\( \text{R-COOH} \)) is replaced by another electronegative atom or group.

In the CCEA A2 1 specification, we focus on two key derivatives:
• Acyl Chlorides (where \( -\text{OH} \) is replaced by \( -\text{Cl} \))
• Acid Anhydrides (where \( -\text{OH} \) is replaced by \( -\text{O-CO-R} \))

Nomenclature: Naming the Derivatives

Acyl Chlorides (\( \text{R-COCl} \)):
Change the -oic acid suffix of the parent carboxylic acid to -oyl chloride.
• \( \text{CH}_3\text{COCl} \) is named ethanoyl chloride (derived from ethanoic acid).
• \( \text{CH}_3\text{CH}_2\text{COCl} \) is named propanoyl chloride.
• \( \text{C}_6\text{H}_5\text{COCl} \) is named benzoyl chloride.

Acid Anhydrides (\( \text{R-CO-O-CO-R} \)):
The word anhydride means "without water". Anhydrides are formed conceptually by removing one water molecule from two carboxylic acid molecules. They are named by taking the parent acid name and replacing acid with anhydride.
• \( (\text{CH}_3\text{CO})_2\text{O} \) (or \( \text{CH}_3\text{COOCOCH}_3 \)) is named ethanoic anhydride.
• \( (\text{CH}_3\text{CH}_2\text{CO})_2\text{O} \) is named propanoic anhydride.

Key Takeaway: Acyl chlorides end in -oyl chloride, while symmetrical acid anhydrides replace the word acid with anhydride.

2. Reactivity of Carbonyl Compounds

Why are Acyl Chlorides so Reactive?

Carboxylic acid derivatives contain a carbonyl carbon (\( \text{C}=\text{O} \)). In acyl chlorides, this carbon atom is bonded to two strongly electronegative atoms: oxygen and chlorine.
• Oxygen and chlorine both pull electron density away from the carbon atom via the inductive effect.
• This leaves the carbonyl carbon strongly electron-deficient (\( \delta+ \)), making it an easy target for attack by nucleophiles (electron-pair donors like \( \text{H}_2\text{O} \), \( \text{NH}_3 \), alcohols, and amines).
• In addition, the chloride ion (\( \text{Cl}^- \)) is a very good leaving group, allowing the substitution reaction to happen rapidly at room temperature without a catalyst.

Reactivity Order:
\( \text{Acyl Chlorides} > \text{Acid Anhydrides} > \text{Carboxylic Acids} > \text{Esters} / \text{Amides} \)

Key Takeaway: The large \( \delta+ \) charge on the carbonyl carbon combined with a stable leaving group makes acyl chlorides the most reactive carboxylic acid derivatives.

3. Reactions of Acyl Chlorides

Acyl chlorides react vigorously with nucleophiles containing a lone pair of electrons (usually on an \( \text{O} \) or \( \text{N} \) atom). In every reaction, the \( -\text{Cl} \) is substituted, and misty/steamy white fumes of hydrogen chloride gas (\( \text{HCl} \)) or an ammonium/amine salt are produced.

Reaction A: With Water (Hydrolysis)

Acyl chlorides react vigorously with cold water to form a carboxylic acid and hydrogen chloride.
Equation: \( \text{CH}_3\text{COCl} + \text{H}_2\text{O} \rightarrow \text{CH}_3\text{COOH} + \text{HCl} \)
Observations: Vigorous reaction, temperature rises, and dense, steamy white fumes of \( \text{HCl} \) are observed (turns damp blue litmus paper red).

Reaction B: With Alcohols (Esterification)

Acyl chlorides react readily with alcohols at room temperature to form an ester and hydrogen chloride.
Equation: \( \text{CH}_3\text{COCl} + \text{CH}_3\text{CH}_2\text{OH} \rightarrow \text{CH}_3\text{COOCH}_2\text{CH}_3 + \text{HCl} \)
Products: Ethyl ethanoate and hydrogen chloride gas.
Advantage over using carboxylic acids: This reaction is irreversible, goes to completion quickly at room temperature, gives a higher yield, and does not require an acid catalyst (such as concentrated \( \text{H}_2\text{SO}_4 \)).

Reaction C: With Ammonia (Amide Formation)

Acyl chlorides react vigorously with concentrated aqueous ammonia to form a primary amide and ammonium chloride.
Equation: \( \text{CH}_3\text{COCl} + 2\text{NH}_3 \rightarrow \text{CH}_3\text{CONH}_2 + \text{NH}_4\text{Cl} \)
Products: Ethanamide and ammonium chloride.
Why 2 moles of ammonia? One molecule of \( \text{NH}_3 \) acts as the nucleophile to form the amide, while the second molecule neutralises the acidic \( \text{HCl} \) by-product to form solid white \( \text{NH}_4\text{Cl} \).

Reaction D: With Primary Amines (N-Substituted Amide Formation)

Acyl chlorides react vigorously with primary amines to produce an N-substituted amide (secondary amide) and an alkylammonium chloride salt.
Equation: \( \text{CH}_3\text{COCl} + 2\text{CH}_3\text{NH}_2 \rightarrow \text{CH}_3\text{CONHCH}_3 + \text{CH}_3\text{NH}_3^+\text{Cl}^- \)
Products: N-methylethanamide and methylammonium chloride.

Quick Memory Aid:
Whenever an acyl chloride reacts with an \( \text{H-X} \) nucleophile, the \( -\text{Cl} \) takes the \( \text{H} \) away as \( \text{HCl} \), and the remaining fragment snaps directly onto the carbonyl carbon.

4. The Nucleophilic Addition-Elimination Mechanism

All the reactions of acyl chlorides follow a nucleophilic addition-elimination pathway.

Step-by-Step Mechanism (using general nucleophile \( \text{Nu-H} \)):

Step 1: Nucleophilic Addition
The nucleophile uses its lone pair of electrons to attack the partially positive carbonyl carbon (\( \text{C}^{\delta+} \)). Simultaneously, the \( \pi \)-bond of the \( \text{C}=\text{O} \) double bond breaks, transferring a pair of electrons onto the oxygen atom to give an intermediate with a negative charge on oxygen and a positive charge on the nucleophile.

Step 2: Elimination
The lone pair on the oxygen reforms the \( \text{C}=\text{O} \) double bond, expelling the chloride ion (\( \text{Cl}^- \)) as a leaving group.

Step 3: Loss of a Proton (\( \text{H}^+ \))
A proton is lost from the positively charged nucleophilic group (picked up by \( \text{Cl}^- \) to form \( \text{HCl} \) or by excess base), yielding the neutral substituted product.

Key Takeaway: It is called addition-elimination because the nucleophile first adds across the carbonyl bond, and then the leaving group is eliminated.

5. Reactions of Acid Anhydrides

Acid anhydrides undergo the exact same types of reactions as acyl chlorides (reacting with water, alcohols, ammonia, and amines). However, they are less reactive than acyl chlorides and produce a carboxylic acid by-product instead of \( \text{HCl} \).

Comparison of Reactions (using Ethanoic Anhydride):

• With Water:
\( (\text{CH}_3\text{CO})_2\text{O} + \text{H}_2\text{O} \rightarrow 2\text{CH}_3\text{COOH} \)
Product: 2 molecules of ethanoic acid.

• With Alcohols:
\( (\text{CH}_3\text{CO})_2\text{O} + \text{CH}_3\text{CH}_2\text{OH} \rightarrow \text{CH}_3\text{COOCH}_2\text{CH}_3 + \text{CH}_3\text{COOH} \)
Products: Ethyl ethanoate + ethanoic acid.

• With Ammonia:
\( (\text{CH}_3\text{CO})_2\text{O} + \text{NH}_3 \rightarrow \text{CH}_3\text{CONH}_2 + \text{CH}_3\text{COOH} \)
Products: Ethanamide + ethanoic acid (which reacts with excess \( \text{NH}_3 \) to form ammonium ethanoate).

• With Primary Amines:
\( (\text{CH}_3\text{CO})_2\text{O} + \text{CH}_3\text{NH}_2 \rightarrow \text{CH}_3\text{CONHCH}_3 + \text{CH}_3\text{COOH} \)
Products: N-methylethanamide + ethanoic acid.

6. Case Study: The Industrial Synthesis of Aspirin

Aspirin (also called acetylsalicylic acid or 2-ethanoyloxybenzoic acid) is synthesised by the esterification of the phenolic \( -\text{OH} \) group on salicylic acid (2-hydroxybenzoic acid).

The Reaction:

Salicylic acid + Ethanoic anhydride \( \rightarrow \) Aspirin + Ethanoic acid
Equation: \( \text{HOC}_6\text{H}_4\text{COOH} + (\text{CH}_3\text{CO})_2\text{O} \rightarrow \text{CH}_3\text{COOC}_6\text{H}_4\text{COOH} + \text{CH}_3\text{COOH} \)

Why is Ethanoic Anhydride preferred over Ethanoyl Chloride in industry?

In industry, ethanoic anhydride is chosen instead of ethanoyl chloride for several key reasons:
1. Safety / Non-toxic by-product: Ethanoic anhydride produces harmless ethanoic acid, whereas ethanoyl chloride produces toxic, corrosive, and dangerous hydrogen chloride (\( \text{HCl} \)) fumes.
2. Less vigorous / easier to control: The reaction with ethanoic anhydride is less violently exothermic, making large-scale production safer.
3. Cost: Ethanoic anhydride is cheaper to purchase and handle.
4. Corrosion: Anhydrides do not corrode industrial metal reaction vessels like acidic chloride solutions do.

Key Takeaway: Ethanoic anhydride is safer, cheaper, and avoids producing corrosive \( \text{HCl} \) fumes during the industrial manufacture of aspirin.

7. Quick Review & Common Mistakes to Avoid

Summary Table

• Acyl Chloride + Water \( \rightarrow \) Carboxylic Acid + \( \text{HCl} \)
• Acyl Chloride + Alcohol \( \rightarrow \) Ester + \( \text{HCl} \)
• Acyl Chloride + Ammonia \( \rightarrow \) Primary Amide + \( \text{NH}_4\text{Cl} \)
• Acyl Chloride + Primary Amine \( \rightarrow \) N-substituted Amide + Amine Salt
• Acid Anhydride + Alcohol \( \rightarrow \) Ester + Carboxylic Acid

Common Student Pitfalls:

• Forgetting the 1:2 ratio: Remember that reactions of acyl chlorides with ammonia and amines require two moles of base for every mole of acyl chloride (one to make the amide, one to neutralise \( \text{HCl} \)).
• Incorrect naming: Do not confuse an amide (\( \text{R-CONH}_2 \)) with an amine (\( \text{R-NH}_2 \)).
• Esterification comparison: Remember why acyl chlorides/anhydrides are better for making esters in the lab than carboxylic acids: higher yields, irreversible reaction, and no need for refluxing with a concentrated sulfuric acid catalyst.