Carboxylic Acids and Derivatives

Carboxylic acids (R—COOH) contain the carboxyl group (—COOH), which is a combination of a carbonyl group (C=O) and a hydroxyl group (—OH). The COOH carbon has sp² hybridization. They are weak acids (typical pKₐ 4–5), much more acidic than alcohols (pKₐ 15–18) but less than mineral acids (HCl, H₂SO₄).

Acidity and influencing factors: The greater acidity of carboxylic acids compared to alcohols is due to resonance of the conjugate base (carboxylate ion RCOO⁻): the negative charge is delocalized over two identical oxygen atoms, stabilizing the anion. $$\mathrm{RCOOH \rightleftharpoons RCOO^- + H^+}$$ $$\text{Resonance structures: } \mathrm{R-C(=O)-O^- \leftrightarrow R-C(O^-)=O}$$ Factors that increase acidity (decrease pKₐ):

• Electron-withdrawing substituents (-I, -M): electronegative atoms or groups near the carboxyl stabilize the negative charge of the anion by inductive effect. Example: CCl₃COOH (pKₐ=0.66) is much more acidic than CH₃COOH (pKₐ=4.76). The number of Cl atoms increases acidity: CH₃COOH (4.76) < CH₂ClCOOH (2.86) < CHCl₂COOH (1.29) < CCl₃COOH (0.66).
• Solvent effect: solvation of the carboxylate anion by water stabilizes the conjugate base, increasing acidity.
• Acidity order: aromatic carboxylic acids with electron-withdrawing substituents > simple aliphatic acids > acids with electron-donating substituents.

Real-world applications: acetic acid (CH₃COOH, pKₐ=4.76) is the main component of vinegar (3–6%). Benzoic acid (C₆H₅COOH, pKₐ=4.20) is used as a food preservative (E210). Citric acid is a tricarboxylic acid found in citrus fruits.

Acyl nucleophilic substitution is the characteristic reaction of carboxylic acid derivatives. Unlike simple nucleophilic addition to aldehydes/ketones, here the leaving group (X) is replaced by the nucleophile (Nu), regenerating the carbonyl.

Mechanism (addition-elimination):

1. Addition: the nucleophile Nu⁻ attacks the carbonyl carbon, forming a tetrahedral intermediate (analogous to simple additions).
2. Elimination: the leaving group (X⁻) is expelled, regenerating the C=O bond. The reversibility of the reaction depends on the relative stability of the leaving group.

Reactivity order of acyl derivatives: $$\mathrm{RCOCl > (RCO)_2O > RCOOR' > RCONH_2 > RCOO^-}$$ (Acyl chlorides > Anhydrides > Esters > Amides > Carboxylates)

This order reflects the leaving group's ability to stabilize the negative charge: Cl⁻ is the best leaving group (stable anion), while RCOO⁻, RO⁻, NH₂⁻ are poor leaving groups.

Acyl nucleophilic substitution underlies many transformations:

• Hydrolysis of acyl chlorides → carboxylic acids
• Reaction of acyl chlorides with alcohols → esters
• Reaction of acyl chlorides with ammonia/amines → amides
• Hydrolysis of esters under basic conditions → soaps (saponification)

Real-world applications: acyl chlorides are very reactive intermediates used in synthesis to prepare esters, amides, and anhydrides. Acetylation of salicylic acid with acetic anhydride produces aspirin (acetylsalicylic acid), one of the best-selling drugs worldwide.

Esters (RCOOR') are derivatives of carboxylic acids in which the hydrogen of the —COOH group is replaced by an alkyl group (R'). They are prepared by Fischer esterification: reaction of a carboxylic acid with an alcohol in acidic medium, with loss of H₂O. $$\mathrm{RCOOH + R'OH \xrightleftharpoons[H^+]{\Delta} RCOOR' + H_2O}$$ The reaction is reversible (equilibrium). To shift equilibrium toward products, an excess of alcohol is used or water is removed (by distillation or molecular sieves).

Saponification: basic hydrolysis of an ester. The products are an alcohol and the salt of a carboxylic acid (soap if the fatty acid is long-chain). $$\mathrm{RCOOR' + NaOH \to RCOONa + R'OH}$$ The mechanism: OH⁻ (strong nucleophile) attacks the ester carbonyl → tetrahedral intermediate → elimination of RO⁻ (alkoxide) → carboxylic acid (immediately deprotonated to carboxylate in basic medium). The reaction is irreversible because the carboxylic acid is converted to its anion (not electrophilic).

Transesterification: exchange of the alkyl group of an ester with another alcohol. Can be acid- or base-catalyzed. Important in biodiesel production: triglycerides + methanol (base) → fatty acid methyl esters (biodiesel) + glycerol.

Real-world applications: saponification produces soaps (salts of long-chain fatty acids, e.g., sodium stearate). Transesterification is used to produce biodiesel from vegetable oils. Esters are responsible for many flavors and fragrances (e.g., isoamyl acetate = banana flavor).

Amides (RCONR'R''): derivatives of carboxylic acids in which the —OH group is replaced by —NR'R'' (ammonia or amine). Amides are very stable and have high melting points due to hydrogen bonding. The amide bond (—CO—NH—) is the peptide bond that links amino acids in proteins.

• Prepared by reaction of an acyl chloride (or anhydride) with an amine (or ammonia)
• Hydrolysis of amides requires drastic conditions (HCl 6M, reflux or NaOH, reflux)
• Very weak basic character (the nitrogen lone pair is delocalized onto the carbonyl, pKₐ of the conjugate base ≈ 0)

Anhydrides (RCO—O—COR'): formed by dehydration of two carboxylic acids (mixed or symmetric). Very reactive, used to acylate alcohols and amines (e.g., acetic anhydride for aspirin production). Prepared by reaction of an acyl chloride with a carboxylate.

Acyl chlorides (RCOCl): the most reactive of the acyl derivatives. Prepared by reaction of the carboxylic acid with SOCl₂ (thionyl chloride) or PCl₃, PCl₅. React violently with water, alcohols, and amines. Versatile intermediates in organic synthesis.

Real-world applications: the amide bond is the fundamental building block of proteins (natural polyamides). Nylon is a synthetic polyamide. Acetic anhydride is used to produce cellulose acetate (textile fibers, photographic film), aspirin, and paracetamol. Acyl chlorides are intermediates in the synthesis of polymers, dyes, and drugs.