Carboxylic Acids and Their Derivatives
Carboxylic acids are among the most important functional groups in both organic and biological chemistry. The human body is literally built from carboxylic acids: amino acids (the building blocks of proteins) have both amino (–NH₂) and carboxyl (–COOH) groups; fatty acids (the building blocks of lipids) have long hydrocarbon chains terminating in a carboxyl group; and acetic acid (vinegar) is a product of human metabolism. For HAAD candidates, understanding carboxylic acid chemistry is essential for mastering amino acid and protein chemistry, fatty acid biochemistry, the metabolism of medications by the liver, and the action of local anesthetics (which are typically amine derivatives of aromatic carboxylic acids). This chapter covers carboxylic acids, their nomenclature, properties, and the key reactions that connect them to their derivatives: acid chlorides, anhydrides, esters, and amides.
Structure and Nomenclature of Carboxylic Acids
Carboxylic acids contain the carboxyl functional group (–COOH), which can be viewed as a carbonyl group (C=O) combined with a hydroxyl group (–OH) on the same carbon. This combination creates a unique functional group with distinctive reactivity.
IUPAC nomenclature:
- Suffix: -oic acid
- The carboxyl carbon is always C1
- For dicarboxylic acids: suffix -dioic acid
| Formula | Common Name | IUPAC Name |
|---|---|---|
| HCOOH | Formic acid | Methanoic acid |
| CH₃COOH | Acetic acid | Ethanoic acid |
| CH₃CH₂COOH | Propionic acid | Propanoic acid |
| CH₃(CH₂)₂COOH | Butyric acid | Butanoic acid |
| HOOC–COOH | Oxalic acid | Ethanedioic acid |
| HOOC–CH₂–COOH | Malonic acid | Propanedioic acid |
| HOOC–CH₂–CH₂–COOH | Succinic acid | Butanedioic acid |
| HOOC–CH₂–CH₂–CH₂–COOH | Glutaric acid | Pentanedioic acid |
Aromatic carboxylic acids:
- C₆H₅COOH = Benzoic acid (IUPAC: benzoic acid)
- C₆H₄(COOH)₂ = Phthalic acid, isophthalic acid, or terephthalic acid (depending on substitution pattern)
Physical Properties of Carboxylic Acids
Hydrogen bonding: Carboxylic acids are highly polar and form strong hydrogen bonds with each other (forming dimers) and with water. This gives them unusually high boiling points for their molecular weight:
| Compound | Molecular Weight | Boiling Point |
|---|---|---|
| Acetic acid (CH₃COOH) | 60 | 118°C |
| Propan-1-ol (C₃H₇OH) | 60 | 97°C |
| Butanone (C₄H₈O) | 72 | 80°C |
Even methanoic acid (formic acid, MW = 46) boils at 101°C — higher than ethanol (MW = 46, BP = 78°C).
Solubility: Carboxylic acids with up to four carbon atoms are completely miscible with water (the –COOH group can form hydrogen bonds with water). Solubility decreases as the hydrocarbon chain lengthens. Butanoic acid is somewhat soluble; pentanoic acid and above are practically insoluble.
Acidity: Carboxylic acids are weak acids (pKa ≈ 4.75 for acetic acid). They are significantly more acidic than alcohols (pKa ≈ 16) and phenols (pKa ≈ 10) because the carboxylate anion (R–COO⁻) is resonance-stabilized by delocalization of the negative charge between the two oxygen atoms.
R–COOH ⇌ R–COO⁻ + H⁺ (Ka ≈ 10⁻⁵)
This weak acidity means:
- Carboxylic acids do NOT react with weak bases like NaHCO₃ with vigour (unlike mineral acids which react vigorously)
- Carboxylic acids DO react with NaOH to form salts: CH₃COOH + NaOH → CH₃COONa + H₂O
- Carboxylic acids DO react with NaHCO₃ (slowly) to produce CO₂ bubbles — this distinguishes them from phenols (which do NOT react with NaHCO₃)
Salts of carboxylic acids are named as: sodium ethanoate, potassium acetate, etc.
Chemical Reactions of Carboxylic Acids
Acid-Base Reactions
Carboxylic acids react with:
- NaOH: R–COOH + NaOH → R–COONa + H₂O
- NaHCO₃: 2R–COOH + NaHCO₃ → R–COONa + CO₂↑ + H₂O (slow, effervescence)
- Na₂CO₃: 2R–COOH + Na₂CO₃ → 2R–COONa + H₂O + CO₂↑
- Active metals (Zn, Mg): 2R–COOH + Zn → (R–COO)₂Zn + H₂↑
Ester Formation (Fischer Esterification)
Carboxylic acids react with alcohols under acidic catalysis (H₂SO₄) to form esters: R–COOH + R’–OH →(H⁺) R–COOR’ + H₂O
This is a condensation reaction (also called a dehydration reaction) — water is eliminated. The mechanism involves nucleophilic attack by the alcohol on the carbonyl carbon, followed by proton transfer and loss of water.
The reaction is reversible (equilibrium-controlled). Excess alcohol, removal of water, or use of a dehydrating agent drives the equilibrium toward the ester product.
Famous esters and their smells:
- Methyl salicylate → Oil of wintergreen (minty smell)
- Ethyl acetate → Nail polish remover / fruity smell
- Isoamyl acetate → Banana smell
- Ethyl butyrate → Pineapple smell
- Octyl acetate → Orange smell
Reduction
Carboxylic acids are very difficult to reduce. They are not reduced by NaBH₄ (which reduces aldehydes and ketones). Only LiAlH₄ (LAH) — a powerful reducing agent used in dry ether — can reduce carboxylic acids to primary alcohols: R–COOH →(LiAlH₄) R–CH₂OH
This is an important industrial and laboratory reaction. LiAlH₄ also reduces esters, aldehydes, ketones, and amides.
Decarboxylation
Heating the sodium salt of a carboxylic acid with soda lime (NaOH + CaO) causes decarboxylation (loss of CO₂) to form an alkane with one fewer carbon: R–COONa + NaOH →(soda lime, heat) R–H + Na₂CO₃
This reaction is useful for removing the carboxyl group from a molecule.
Acid Derivatives: Classification and Nomenclature
The four principal carboxylic acid derivatives are:
- Acid chlorides (R–COCl) — suffix: -oyl chloride
- Acid anhydrides (R–CO–O–CO–R) — suffix: anhydride
- Esters (R–COOR’) — suffix: -oate
- Amides (R–CONH₂, R–CONHR’, R–CONR₂) — suffix: -amide
Relative Reactivity
The reactivity of acid derivatives toward nucleophiles follows the order: Acid chlorides > Acid anhydrides > Esters > Amides
This reactivity order is determined by the leaving group ability of the group attached to the carbonyl carbon:
- Cl⁻ (from acid chloride) is an excellent leaving group
- R–COO⁻ (from anhydrides) is a good leaving group
- R’O⁻ (from esters) is a moderate leaving group
- NH₂⁻/NHR⁻/NR₂⁻ (from amides) is a very poor leaving group (amides are the least reactive)
Acid Chlorides
Prepared by reacting carboxylic acids with thionyl chloride (SOCl₂), oxalyl chloride (COCl)₂, or phosphorus trichloride (PCl₃): R–COOH + SOCl₂ → R–COCl + SO₂↑ + HCl↑
Acid chlorides are the most reactive carboxylic acid derivatives. They react violently with water (hydrolysis) to give the carboxylic acid: R–COCl + H₂O → R–COOH + HCl
They are used as acylating agents in organic synthesis — they transfer the R–CO– group to nucleophiles including alcohols and amines.
Acid Anhydrides
Prepared by reacting acid chlorides with carboxylate salts: R–COCl + R’–COONa → (R–CO)₂O + NaCl
The most important simple anhydride is acetic anhydride ((CH₃CO)₂O), used in aspirin synthesis (acetylating salicylic acid) and in the manufacture of cellulose acetate (for photographic film).
Esters
Esters are formed from carboxylic acids + alcohols (Fischer esterification) or from acid chlorides + alcohols: R–COCl + R’OH → R–COOR’ + HCl
Esters have the structure R–COOR’ (where R’ is the alkoxy group). Their nomenclature: the alkyl group (R’) comes first, followed by the acid name with -oate suffix:
- CH₃COOCH₂CH₃ = Ethyl acetate (ethyl ethanoate)
- CH₃COOC₆H₅ = Phenyl acetate (phenyl ethanoate)
Saponification: Esters react with aqueous NaOH (or KOH) to give a carboxylate salt and an alcohol — this is the hydrolysis of esters in basic conditions: R–COOR’ + NaOH → R–COONa + R’OH
This reaction is called saponification when applied to fats (which are glyceryl triesters of fatty acids) — the products are soap (sodium salts of fatty acids) and glycerol.
Amides
Amides are formed from acid chlorides/anhydrides + amines, or from carboxylic acids + amines with a dehydrating agent (DCC or SOCl₂ followed by amine): R–COOH + R’₂NH →(DCC) R–CONR’₂ + H₂O
Amides are the least reactive of the common acid derivatives. They are not hydrolyzed by aqueous acid or base under normal conditions (strong heating with acid or base is required).
Amides are named as:
- R–CONH₂ = Propanamide (primary amide)
- R–CONHCH₃ = N-methylpropanamide (secondary amide)
- R–CON(CH₃)₂ = N,N-dimethylpropanamide (tertiary amide)
The peptide bond is an amide linkage (–CO–NH–) between amino acids in proteins — this is the most important amide bond in biology.
Polyamides and Nylon
Nylon-6,6 is a synthetic polyamide formed by the condensation polymerization of adipic acid (hexanedioic acid) and hexamethylenediamine (1,6-diaminohexane). The resulting polymer has repeating –[CO–(CH₂)₄–CO–NH–(CH₂)₆–NH]– units and is one of the most widely used synthetic fibers in the world.
Drugs That Are Carboxylic Acids or Their Derivatives
Many pharmaceutical agents are carboxylic acids or their derivatives:
- Aspirin (acetylsalicylic acid): An ester of acetic acid and salicylic acid
- Paracetamol (acetaminophen): An amide (N-acetyl-para-aminophenol)
- Ibuprofen: A propionic acid derivative (2-(4-isobutylphenyl)propionic acid)
- Penicillin antibiotics: Contain a beta-lactam ring fused to a thiazolidine ring and an amide bond
- Lidocaine: An amide (diethylaminoacet-2,6-dimethylanilide) — a local anesthetic
- Sulfa drugs (sulfanilamide): Sulfonamides — derivatives of sulfanilic acid (para-aminobenzenesulfonic acid)
- Chloramphenicol: A dichloroacetamide
⚡ Exam tip: Reactivity order: acid chloride > acid anhydride > ester > amide. Carboxylic acids are weak acids (pKa ~5) — they react with NaOH (form salts) but NOT with NaHCO₃ (unlike mineral acids). Esters hydrolyze in base to give carboxylate + alcohol (saponification). The amide bond is the peptide bond in proteins. Remember the Fischer esterification mechanism (acid-catalyzed nucleophilic addition-elimination).
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