Derivatives

Carboxylic acids (R–COOH) are versatile organic compounds whose reactivity is largely determined by the carbonyl carbon, which bears a partial positive charge and is susceptible to nucleophilic attack. When the –OH group of a carboxylic acid is replaced by another functional group, the resulting compounds are called carboxylic acid derivatives. The four most important derivatives are acid chlorides (acyl chlorides), esters, amides, and acid anhydrides. Each retains the acyl group (R–C=O) but differs in the leaving group attached to it, which dramatically affects reactivity and physical properties. The reactivity order of carboxylic acid derivatives follows from the electron-donating ability of the substituent attached to the carbonyl. Acid chlorides are the most reactive because the chloride ion is an excellent leaving group and donates little electron density to stabilise the carbonyl. Anhydrides are next, followed by esters, then amides, which are the least reactive because the nitrogen lone pair delocalises into the carbonyl, raising the activation energy for nucleophilic acyl substitution. This hierarchy means that a more reactive derivative can be converted into a less reactive one, but not vice versa under simple conditions. Understanding acid derivatives is fundamental to biochemistry, polymer chemistry, and pharmaceuticals. Esters give fruits their characteristic odours and are the basis of polyesters such as PET. Amide bonds (peptide bonds) link amino acids in proteins. Anhydrides are used in the industrial synthesis of aspirin and acetic anhydride is a common acetylating agent. Acid chlorides serve as powerful intermediates in organic synthesis. Mastering their preparation and interconversion equips students with the tools to design multi-step synthetic routes.

Key takeaways
  • Acid Chlorides (Acyl Chlorides)
  • Esters
  • Amides
  • Acid Anhydrides
  • Nucleophilic Acyl Substitution Mechanism

Acid Chlorides (Acyl Chlorides)

Acid chlorides have the general formula R–COCl. They are prepared by reacting a carboxylic acid with a chlorinating agent: thionyl chloride (SOCl₂), phosphorus trichloride (PCl₃), or phosphorus pentachloride (PCl₅). The most common method uses SOCl₂ because the by-products (SO₂ and HCl) are gases that escape easily, simplifying purification. Example: CH₃COOH + SOCl₂ → CH₃COCl + SO₂ + HCl. Acid chlorides are colourless, pungent liquids that react vigorously with water (hydrolysis), alcohols (to give esters), amines (to give amides), and carboxylate salts (to give anhydrides). Their high reactivity makes them hazardous but extremely useful in laboratory synthesis.

Esters

Esters have the general formula R–COOR′ and are prepared by: (1) Fischer esterification – reacting a carboxylic acid with an alcohol in the presence of a concentrated acid catalyst (H₂SO₄) under reflux, a reversible reaction driven to completion by removing water; (2) reacting an acid chloride or anhydride with an alcohol (faster, irreversible, higher yield). Esters are characterised by their pleasant fruity smells (ethyl ethanoate smells of pear drops, pentyl pentanoate of banana). They are less polar than acids, have lower boiling points, and are used as solvents, flavourings, and plasticisers. Hydrolysis under acid or base (saponification) regenerates the acid and alcohol.

Amides

Amides have the general formula R–CONH₂ (primary), R–CONHR′ (secondary), or R–CONR′R″ (tertiary). They are prepared by: (1) reacting an acid chloride with ammonia or an amine; (2) reacting an anhydride with ammonia or an amine; (3) heating an ammonium carboxylate salt. The C–N bond in amides has partial double-bond character due to resonance delocalisation of the nitrogen lone pair into the carbonyl (C=O ↔ C⁻–O⁻ resonance with N⁺). This makes amides planar around the C–N bond and raises the boiling point due to hydrogen bonding. Amides are the least reactive of the four derivatives and require vigorous conditions (strong acid/base reflux) to hydrolyse.

Acid Anhydrides

Anhydrides have the general formula (RCO)₂O, formally derived by loss of water between two carboxylic acid molecules. Acetic anhydride, (CH₃CO)₂O, is the most important industrially. Simple anhydrides are prepared by reacting an acid chloride with a sodium carboxylate salt: CH₃COCl + CH₃COONa → (CH₃CO)₂O + NaCl. Cyclic anhydrides such as maleic anhydride and phthalic anhydride form spontaneously when a dicarboxylic acid is heated because the two acid groups are geometrically close. Anhydrides react with water to give two equivalents of carboxylic acid, with alcohols to give an ester and a carboxylic acid, and with amines to give an amide and a carboxylic acid. They are widely used as acetylating agents in synthesis.

Nucleophilic Acyl Substitution Mechanism

All four derivatives react via the same two-step mechanism: (1) Nucleophilic addition – a nucleophile (Nu:) attacks the electrophilic carbonyl carbon, forming a tetrahedral intermediate in which the oxygen bears a negative charge; (2) Elimination – the leaving group (Cl⁻, OR⁻, NR₂⁻, or OCOR⁻) departs, restoring the C=O bond. The rate depends on both electrophilicity of the carbonyl carbon and the ability of the leaving group to depart. Acid chlorides react fastest (Cl⁻ is an excellent leaving group and does not donate electrons to the carbonyl), while amides react slowest (N lone pair stabilises the C=O, reducing electrophilicity; NH₂⁻ is a poor leaving group).

The Key Equation

\ce{CH3COOH + SOCl2 -> CH3COCl + SO2 ^ + HCl ^}
  • \ce{CH3COOH} — Ethanoic acid (—): The carboxylic acid reactant; the –OH group is replaced during the reaction.
  • \ce{SOCl2} — Thionyl chloride (—): Chlorinating agent; provides the chlorine atom and produces only gaseous by-products, aiding purification.
  • \ce{CH3COCl} — Ethanoyl chloride (acetyl chloride) (—): The acid chloride product; the most reactive carboxylic acid derivative.
  • \ce{SO2} — Sulfur dioxide (—): Gaseous by-product that escapes the reaction mixture, driving the equilibrium forward.
  • \ce{HCl} — Hydrogen chloride (—): Gaseous by-product; also escapes from the reaction mixture.

Worked Example

Problem. Starting from propanoic acid (CH₃CH₂COOH), describe how you would prepare (a) propanoyl chloride, (b) ethyl propanoate, and (c) propanamide. Write a balanced equation for each step.

\ceCH3CH2COOH−>[(1) SOCl2][(2) CH3CH2OH]CH3CH2COOC2H5\ce{CH3CH2COOH ->[(1)\,SOCl2][(2)\,CH3CH2OH] CH3CH2COOC2H5}

Answer. (a) Propanoyl chloride via SOCl₂; (b) Ethyl propanoate via acid chloride + ethanol (or Fischer esterification); (c) Propanamide via acid chloride + excess NH₃.

Figure
Diagram
Reactivity of Carboxylic Acid DerivativesNucleophilic Acyl Substitution: Most Reactive → Least ReactiveAcid ChlorideR–COClMost reactiveAnhydride(RCO)₂O2nd most reactiveEsterR–COOR′ModerateAmideR–CONH₂Least reactiveNucleophilic Acyl Substitution Mechanism (General)R–C=O+ Nu:→TetrahedralIntermediate[R–C(Nu)(O⁻)(LG)]→R–C=O+ LG⁻ReactantStep 1: AdditionStep 2: EliminationLeaving Group Ability and Carbonyl Electrophilicity• Acid chloride: Cl⁻ is excellent leaving group; little electron donation to C=O → high reactivity• Amide: N lone pair delocalises into C=O (resonance) → lowers electrophilicity → lowest reactivity
Origins · 1 minEmil Fischer and how this was discovered
EF
Emil Fischer
1852–1919 · German

Emil Fischer developed the acid-catalysed esterification reaction (Fischer esterification) in the 1890s, showing that carboxylic acids and alcohols react reversibly under acid catalysis to form esters and water. This reaction, now named after him, remains one of the most widely taught organic reactions. Fischer also made landmark contributions to understanding carbohydrates, purines, and proteins, including the first synthesis of glucose and the lock-and-key model of enzyme specificity. Fischer synthesised over 130 different sugars during his career and won the Nobel Prize in Chemistry in 1902. He is often called the 'father of biochemistry' for connecting organic chemistry to biological molecules. His work on peptide synthesis directly laid the groundwork for understanding amide (peptide) bonds in proteins.

  • Carboxylic Acids: Structure and Properties — Acid derivatives are formed by replacing the –OH of a carboxylic acid; understanding the parent acid's structure and acidity is essential.
  • Nucleophilic Acyl Substitution Mechanism — All four acid derivatives react via nucleophilic acyl substitution; the mechanism and energy profile underpin every interconversion discussed here.
  • Alcohols: Reactions — Alcohols act as nucleophiles in ester formation (Fischer esterification and reaction with acid chlorides/anhydrides).
  • Amines: Basicity and Reactions — Amines are the nucleophiles that react with acid chlorides and anhydrides to form amides; their basicity relates to the stability of the resulting amide bond.
  • Peptide Bonds and Protein Structure — Peptide bonds are amide bonds; the planar geometry and partial double-bond character of the amide linkage directly determines secondary protein structure.