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Carboxylic acids do not act alone in synthesis. They sit at the centre of a family of derivatives — compounds in which the –OH of –COOH has been replaced by another leaving group. The four members of this family that A-Level Chemistry treats explicitly are acyl chlorides (RCOCl), acid anhydrides ((RCO)₂O), esters (RCOOR'), and amides (RCONH₂, RCONHR', RCONR'R''). They share the same acyl carbon C(=O)–X but differ dramatically in how readily X is displaced by a nucleophile. The reactivity order — acyl chloride > anhydride > ester > amide — controls almost every choice a synthetic chemist makes when introducing a –C(=O)– group. This lesson works through the structure, preparation, and hydrolysis of each derivative, explains the reactivity order in terms of leaving-group ability, signposts the polyester and polyamide chemistry of L7, and frames the biological significance of the amide bond in proteins (§3.3.13).
Spec mapping (AQA 7405): This lesson maps to §3.3.9 (carboxylic acids and their derivatives — acyl chlorides, esters, amides, and acid anhydrides; preparation, hydrolysis, and reactivity). It builds directly on §3.3.9 introductory material covered in L1 (carboxylic acids — acidity, esterification with H₂SO₄ catalyst). It is the conceptual prerequisite for L7 of this course (condensation polymers — polyesters and polyamides as the macromolecular extension of ester and amide chemistry) and for §3.3.13 (amino acids, peptides, proteins — the polyamide linkage in biology). Refer to the official AQA specification document for the exact wording of each section.
Assessment objectives: Recall of the four derivative structures, their IUPAC names, and the standard preparation routes (acid → acyl chloride with SOCl₂; acyl chloride → ester/amide) is AO1 and routinely tested in the multiple-choice section of Paper 2. Writing balanced equations for hydrolysis (acidic vs alkaline) and esterification, and predicting products from a given acyl chloride and nucleophile, is AO2 and appears on every Paper 2 essay question. Rationalising the reactivity order in terms of leaving-group pKa (or in terms of resonance donation from the heteroatom onto the carbonyl), and designing a multi-step synthesis using the most appropriate derivative at each step, is AO3 and is the distinguishing feature of A* answers.
All four derivatives share the same acyl group R–C(=O)– attached to a leaving group X. The general structure is:
| Derivative | Formula | Leaving group X | IUPAC suffix |
|---|---|---|---|
| Acyl chloride | RCOCl | Cl | –oyl chloride |
| Acid anhydride | (RCO)₂O or RCOOCOR' | RCOO | –oic anhydride |
| Ester | RCOOR' | OR' | alkyl –oate |
| Amide | RCONH₂ | NH₂ | –amide |
The carboxylic acid itself, RCOOH, is the parent. Replacing the –OH with –Cl, –OOCR, –OR', or –NH₂ generates the four derivatives. Their shared reactivity pattern is nucleophilic acyl substitution: a nucleophile (water, alcohol, ammonia, amine) attacks the δ+ carbonyl carbon; the C=O reforms; the leaving group X departs. The dramatic difference in rate between the four derivatives — acyl chloride reactions are over in seconds at room temperature, amide hydrolysis requires hours of reflux with concentrated acid — comes entirely from the ease with which X⁻ leaves.
Key Point: All four derivatives are interconvertible by nucleophilic acyl substitution, but the conversion only proceeds spontaneously in the direction of the less reactive derivative. An acyl chloride is readily converted to an ester or amide; the reverse conversion (ester back to acyl chloride) requires harsh non-spec reagents and is not part of A-Level chemistry.
Acyl chlorides are the most reactive of the four derivatives. They are colourless, fuming liquids with sharp, irritating smells (HCl vapour from hydrolysis with atmospheric moisture). The simplest A-Level example is ethanoyl chloride, CH₃COCl (Mᵣ = 78.5, b.p. 51 °C).
Acyl chlorides are prepared from carboxylic acids using thionyl chloride, SOCl₂:
RCOOH + SOCl₂ → RCOCl + SO₂(g) + HCl(g)
The two by-products are both gases — they escape from the reaction mixture, driving the equilibrium fully to the right, so the reaction is irreversible in practice and gives high yields (typically > 90%). The acyl chloride product is then purified by fractional distillation. Alternative reagents (PCl₃, PCl₅) are mentioned in some textbooks but are not required by AQA; SOCl₂ is the canonical reagent because its by-products are gaseous.
Acyl chlorides react vigorously, often violently, with any nucleophile bearing a lone pair on N or O. All four reactions below proceed at or below room temperature, with HCl evolved as a gaseous (or trapped, as an ammonium salt) by-product. In every case the mechanism is nucleophilic addition–elimination: nucleophile attacks the δ+ carbonyl carbon, the tetrahedral intermediate collapses by ejecting Cl⁻, and the C=O reforms.
| Nucleophile | Product | Observation |
|---|---|---|
| H₂O (water) | RCOOH (carboxylic acid) + HCl | Vigorous reaction; HCl fumes |
| R'OH (alcohol) | RCOOR' (ester) + HCl | Smooth at RT; no catalyst needed |
| NH₃ (ammonia) | RCONH₂ (primary amide) + NH₄Cl | White smoke (NH₄Cl); two equivalents of NH₃ needed |
| R'NH₂ (primary amine) | RCONHR' (secondary amide) + R'NH₃⁺Cl⁻ | Smooth at RT; excess amine acts as base |
The reaction with ammonia is worth a careful equation. Two moles of NH₃ are required: one to act as the nucleophile, one to neutralise the HCl produced (otherwise the amide product would be protonated and the reaction would not go to completion):
CH₃COCl + 2 NH₃ → CH₃CONH₂ + NH₄Cl
Exam Tip: When asked to write the equation for an acyl chloride reacting with ammonia or an amine, always include two moles of the nitrogen nucleophile. The second one mops up the HCl. A common error is writing CH₃COCl + NH₃ → CH₃CONH₂ + HCl, which loses a mark.
Acid anhydrides are less reactive than acyl chlorides but more reactive than esters and amides. They are the preferred industrial reagent for many acylations because they are cheaper than acyl chlorides and the by-product (a carboxylic acid) is easier to handle than corrosive HCl gas.
The simplest A-Level example is ethanoic anhydride, (CH₃CO)₂O (also written CH₃COOCOCH₃; Mᵣ = 102, b.p. 140 °C). Its industrial significance is enormous: it is the acetylating agent in the manufacture of aspirin, paracetamol, cellulose acetate, and many pharmaceutical intermediates.
Acid anhydrides are prepared industrially by dehydration of two equivalents of carboxylic acid, or by the ketene route (CH₂=C=O + RCOOH). A-Level does not require the preparation in detail; the focus is on using anhydrides as acylating agents.
Like acyl chlorides, anhydrides undergo nucleophilic acyl substitution, but more slowly. They react with water, alcohols, ammonia, and amines to give the same products as acyl chlorides, with a carboxylic acid (rather than HCl) as the by-product:
(CH₃CO)₂O + R'OH → CH₃COOR' + CH₃COOH (ester + acid)
(CH₃CO)₂O + 2 NH₃ → CH₃CONH₂ + CH₃COO⁻NH₄⁺ (amide + ammonium ethanoate)
Aspirin (2-acetoxybenzoic acid, also called acetylsalicylic acid) is manufactured by acetylating the phenol –OH of salicylic acid with ethanoic anhydride:
C₆H₄(OH)(COOH) + (CH₃CO)₂O → C₆H₄(OCOCH₃)(COOH) + CH₃COOH
salicylic acid + ethanoic anhydride → aspirin + ethanoic acid
The reaction is carried out by refluxing salicylic acid with a slight excess of ethanoic anhydride and a few drops of concentrated H₃PO₄ (or H₂SO₄) as catalyst. The mixture is cooled, water is added to hydrolyse residual anhydride, and aspirin crystallises out. The crude product is recrystallised from ethanol/water and the melting point checked (literature: 135 °C). A pure sample should show a sharp melting point within ±1 °C of literature; a depressed or broadened m.p. indicates impurity.
Industrial Note: Acid anhydrides are preferred over acyl chlorides for aspirin manufacture because (i) the by-product is ethanoic acid (a useful co-product, recoverable by distillation) rather than corrosive HCl gas; (ii) anhydrides are cheaper to produce on industrial scale; (iii) the milder reactivity gives better selectivity (the phenol –OH is acetylated; the carboxylic acid –OH is not).
Esters are the third most reactive derivative — significantly less reactive than acyl chlorides and anhydrides, significantly more reactive than amides. They are the least reactive derivative students meet at the start of organic chemistry (in §3.3.5, ester preparation by Fischer esterification of an acid with an alcohol), and they are the most common functional group in natural products: fats, oils, waxes, fragrances, flavourings, and many pharmaceuticals.
A-Level requires students to know all three preparation routes and to choose between them.
Route 1: Carboxylic acid + alcohol + H₂SO₄ catalyst (Fischer esterification).
RCOOH + R'OH ⇌ RCOOR' + H₂O
This reaction is slow and reversible (the equilibrium constant is around 4 for typical esters; not strongly product-favoured). Concentrated H₂SO₄ acts as a catalyst (protonating the carbonyl to enhance electrophilicity) and as a dehydrating agent (removing the water by-product, shifting the equilibrium right). Yields are typically 60–70%. Used for laboratory-scale preparation when the cost of acyl chloride is unwarranted.
Route 2: Acyl chloride + alcohol (no catalyst).
RCOCl + R'OH → RCOOR' + HCl
This reaction is fast and irreversible at room temperature. No catalyst needed. The HCl by-product escapes as a gas. Yields are typically > 90%. This is the preferred route when high yield, mild conditions, and a clean product are essential — e.g. in pharmaceutical manufacture.
Route 3: Acid anhydride + alcohol (no catalyst, sometimes mild acid).
(RCO)₂O + R'OH → RCOOR' + RCOOH
Medium speed; medium cost. Industrial choice for bulk acetylations (e.g. cellulose acetate, aspirin) because the carboxylic acid by-product is benign.
| Route | Speed | Yield | Reversible? | When to use |
|---|---|---|---|---|
| Acid + alcohol + H₂SO₄ | Slow | 60–70% | Yes (equilibrium) | Cheap reagents available; laboratory teaching |
| Acyl chloride + alcohol | Fast | >90% | No | High yield needed; clean product needed |
| Anhydride + alcohol | Medium | 80–90% | No | Industrial scale; benign by-product preferred |
Esters are hydrolysed by water in the presence of either acid or alkali. The two routes give different products and behave very differently kinetically.
Acidic hydrolysis (reversible):
RCOOR' + H₂O ⇌ RCOOH + R'OH (H⁺ catalyst, reflux)
This is the reverse of Fischer esterification. The H⁺ protonates the carbonyl to activate it for nucleophilic attack by water; the tetrahedral intermediate collapses to release the alcohol; the carboxylic acid is regenerated. Because the reaction is reversible, conversion is typically incomplete (60–70%).
Alkaline hydrolysis (saponification, irreversible):
RCOOR' + NaOH → RCOO⁻Na⁺ + R'OH (NaOH, reflux)
OH⁻ attacks the carbonyl carbon directly (no protonation needed; OH⁻ is a strong nucleophile). The tetrahedral intermediate collapses to release the alkoxide R'O⁻, which is rapidly protonated to give the alcohol. Crucially, the carboxylic acid product is deprotonated by the excess NaOH to give the carboxylate salt RCOO⁻Na⁺, which is not a nucleophile and cannot react with the alcohol to reform the ester. The deprotonation step thus drives the reaction to completion — alkaline hydrolysis is irreversible and gives near-quantitative conversion.
The term saponification (Latin sapo = soap) refers to the alkaline hydrolysis of triglycerides (the esters of glycerol with long-chain fatty acids that constitute animal fats and vegetable oils). The products are glycerol (propane-1,2,3-triol) and sodium salts of fatty acids — the latter are soap. The traditional industrial process is exactly this: tallow (or palm oil) is refluxed with concentrated NaOH; the mixture is salted out and the soap collected as the solid layer.
Key Point: When asked to compare acidic and alkaline ester hydrolysis, always make three points: (i) acidic is reversible; alkaline is irreversible; (ii) the irreversibility of alkaline hydrolysis comes from deprotonation of the carboxylic acid product to a non-nucleophilic carboxylate salt; (iii) alkaline gives the carboxylate salt, not the free acid — acidification with HCl is required to liberate the free RCOOH.
Amides are the least reactive of the four derivatives. The N–H bond and the resonance donation of the nitrogen lone pair onto the carbonyl (–C(=O)–NH₂ ↔ –C(O⁻)=NH₂⁺) make the C=O significantly less electrophilic than in an ester. Amide hydrolysis requires prolonged reflux (typically several hours) with concentrated acid or alkali.
The IUPAC names use N- locants to specify substituents on the nitrogen.
The standard A-Level route to amides is acyl chloride + amine (or ammonia):
RCOCl + 2 NH₃ → RCONH₂ + NH₄Cl (primary amide)
RCOCl + 2 R'NH₂ → RCONHR' + R'NH₃⁺Cl⁻ (secondary amide)
RCOCl + 2 R'R''NH → RCONR'R'' + R'R''NH₂⁺Cl⁻ (tertiary amide)
The same products are accessible from anhydrides (slower, requires gentle heating), or by direct dehydration of an ammonium carboxylate salt (RCOO⁻NH₄⁺ → RCONH₂ + H₂O, heated strongly — industrial route for cheap amides like ethanamide). The acyl chloride route is cleanest for laboratory and pharmaceutical use.
Amide hydrolysis is the reverse of the preparation, and is slow:
Acidic hydrolysis: RCONH₂ + H₂O + HCl → RCOOH + NH₄Cl (reflux, several hours)
Alkaline hydrolysis: RCONH₂ + NaOH → RCOO⁻Na⁺ + NH₃(g) (reflux; NH₃ is evolved as a gas)
The alkaline route can be used as a qualitative test: warming an unknown compound with NaOH(aq) and observing damp red litmus paper turn blue (NH₃ evolved) confirms an amide. The acidic route is used preparatively when the carboxylic acid is the desired product.
Biological amide hydrolysis is fundamental: every protein in your body is hydrolysed back to its constituent amino acids by digestive proteases (pepsin, trypsin, chymotrypsin). These enzymes are nature's catalysts for amide hydrolysis at body temperature — at pH 1–2 in the stomach and pH 7–8 in the small intestine, respectively. Without enzymatic catalysis, protein hydrolysis at body temperature would take centuries.
The observed reactivity order has two complementary explanations. Both are correct, and A* answers typically mention both.
The rate-determining step of nucleophilic acyl substitution is loss of the leaving group X⁻ from the tetrahedral intermediate. Good leaving groups are the conjugate bases of strong acids — they are stable as anions because the parent acid is willing to give up the proton. The relevant pKa values are:
| Leaving group X⁻ | Parent H–X | pKa(HX) | Leaving ability |
|---|---|---|---|
| Cl⁻ | HCl | −7 | Excellent |
| RCOO⁻ | RCOOH | ~5 | Good |
| RO⁻ | ROH | ~16 | Poor |
| NH₂⁻ | NH₃ | ~35 | Very poor |
The lower the pKa of HX, the more stable X⁻ is, the easier it departs, the faster the substitution. Chloride (pKa(HCl) = −7) is the best leaving group; amide anion (pKa(NH₃) = 35) is the worst by 42 orders of magnitude in the parent-acid acidity scale. This translates directly into the observed reactivity order.
The other half of the story is the electrophilicity of the carbonyl carbon. In all four derivatives, the heteroatom X has a lone pair that can donate into the C=O π* orbital, partially neutralising the δ+ at carbon:
R–C(=O)–X ↔ R–C(O⁻)=X⁺
The stronger the donation, the less electrophilic the carbonyl, the slower the reaction with nucleophiles. Donation strength tracks the energy match between the X lone pair and the C=O π*: nitrogen (2p, well-matched, strong donation) > oxygen (2p, moderate donation) > chlorine (3p, poor energy match, weak donation). The carbonyl group in an amide therefore has substantial C=N partial double-bond character — exactly what gives the peptide bond in proteins its planarity and restricted rotation (a fact you will meet again in §3.3.13). The amide carbonyl is the least electrophilic; the acyl chloride carbonyl is the most.
Both effects — leaving-group ability and electrophilicity — point in the same direction and reinforce each other. The reactivity order is one of the most consistent and reliable trends in organic chemistry.
Both ester and amide chemistry scale up to polymers. The principle is condensation polymerisation: a difunctional monomer (e.g. a diacid HOOC–R–COOH) reacts with another difunctional monomer (e.g. a diol HO–R'–OH or a diamine H₂N–R'–NH₂) to give a polymer with –COO– (ester) or –CONH– (amide) linkages running along the chain, plus water as a by-product.
Both reactions are nucleophilic acyl substitution writ large. The full mechanism, the structural drawing conventions, the recycling chemistry (PET back to terephthalic acid by alkaline hydrolysis), and the comparison with addition polymers are developed in L7 of this course. The amide-bond chemistry of proteins (§3.3.13) is the same reaction operating on amino acid monomers, with the further wrinkle that the side-chain identity of each monomer determines the protein's folded structure and biological function.
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