Reactions of Phenols

Core Concepts

Deprotonation: making the phenoxide nucleophile

Phenol (pKa ≈ 10) is deprotonated by NaOH or NaH to give the phenoxide ion:

C₆H₅OH + NaOH ⟶ C₆H₅O^-Na⁺ + H₂O

The phenoxide is a far better nucleophile than phenol itself (negative charge on oxygen, delocalized but available). Bicarbonate is too weak a base to do this (see Topic 9).

Williamson ether synthesis

Phenoxide + primary alkyl halide (or methyl/benzyl halide) → aryl alkyl ether via SN2:

C₆H₅O^- + CH₃I ⟶ C₆H₅OCH₃ + I^-

Anisole (methoxybenzene) is made this way. Mechanism: the phenoxide oxygen attacks the back side of the carbon bearing the leaving group; the halide leaves; the C–O bond forms with inversion at carbon. Requirements: a good leaving group and an unhindered carbon — methyl and primary halides work well, secondary poorly, tertiary halides give elimination instead. Aryl halides (e.g., bromobenzene) cannot be used — SN2 does not occur at aromatic carbons, which is why you cannot make diphenyl ether by direct Williamson reaction.

Esterification: the aspirin reaction

Phenols react with acid chlorides or anhydrides (with pyridine or NaOH as base) to give phenyl esters:

C₆H₅OH + CH₃COCl ⟶ C₆H₅OCOCH₃ + HCl

Salicylic acid (o-hydroxybenzoic acid) has both a phenolic –OH and a –COOH. Acetylation with acetic anhydride converts only the phenolic –OH to an ester, giving acetylsalicylic acid — aspirin:

HOC₆H₄COOH + (CH₃CO)₂O ⟶ CH₃COOC₆H₄COOH + CH₃COOH

The –COOH is left free, which is essential because aspirin's anti-inflammatory activity depends on it.

Electrophilic aromatic substitution: the activated ring

The –OH group is a strong ortho/para director and ring activator. Phenol reacts with Br₂ in water even without a Lewis acid catalyst — three bromines add rapidly to give 2,4,6-tribromophenol (a white solid):

C₆H₅OH + 3Br₂ ⟶ Br₃C₆H₂OH + 3HBr

Nitration with dilute nitric acid gives mostly p-nitrophenol (plus the ortho isomer); the isomers separate by steam distillation because the ortho isomer hydrogen-bonds intramolecularly and is more volatile. Compare with benzene, which needs fuming nitric acid, sulfuric acid, and heat — the –OH makes the ring dramatically more reactive.

Kolbe–Schmitt carboxylation

Heating sodium phenoxide with CO₂ under pressure, then acidifying, gives salicylic acid (ortho carboxylation):

C₆H₅O^-Na⁺ + CO₂ ^{125 °C, pressure}⟶ NaOOC–C₆H₄OH ^H₃O+⟶ HOOC–C₆H₄OH

The phenoxide attacks the electrophilic carbon of CO₂, and the carboxylate lands ortho to the –OH. This is the industrial synthesis of salicylic acid.

Oxidation: phenols and quinones

Phenols are easily oxidized (they darken in air). With appropriate oxidants (e.g., Ag₂O, Na₂Cr₂O₇), hydroquinones give quinones:

HOC₆H₄OH ^[O]⟶ O=C₆H₄=O + 2H⁺ + 2e^-

The hydroquinone/quinone pair is a reversible two-electron redox couple — the basis of coenzyme Q in the electron transport chain and of vitamin K's role in blood clotting. Hydroquinone and derivatives are also used as photographic developers and radical scavengers.

How It Works / Step-by-Step Process

Making an aryl alkyl ether (Williamson, general procedure):

1. Deprotonate the phenol: C₆H₅OH + NaOH → C₆H₅O⁻Na⁺ (in water/ethanol), or use NaH in an aprotic solvent.
2. Add the alkyl halide (methyl, primary, or benzyl — never tertiary): C₆H₅O⁻ attacks the carbon back side, halide leaves (SN2).
3. Isolate: pour into water, extract with organic solvent, dry, remove solvent.
4. Verify by spectroscopy: anisole shows aryl C–O (~1240 cm⁻¹ in IR) and a 3H singlet at ~3.8 ppm (OCH₃) in ¹H NMR.

Aspirin synthesis (educational outline, not a procedure to run without supervision):

1. Warm salicylic acid with acetic anhydride and a catalytic amount of acid (e.g., phosphoric acid).
2. The phenolic –OH is acetylated; the –COOH is not.
3. Pour into cold water — aspirin precipitates; wash, recrystallize, dry.
4. A negative FeCl₃ test confirms no free phenol remains.

Common Confusions