17.10 Reactions of Phenols

Electrophilic Aromatic Substitution Reactions of Phenols

Phenols are aromatic compounds with a hydroxyl group ($\ce{-OH}$) bonded directly to a benzene ring. Because the hydroxyl group donates electron density into the ring through resonance, phenols are significantly more reactive than benzene toward electrophilic aromatic substitution (EAS). This activating effect also makes the hydroxyl group ortho/para-directing, meaning electrophiles preferentially attack the ortho and para positions.

Why ortho and para? When an electrophile attacks at those positions, the resulting carbocation intermediate can be stabilized by resonance involving the oxygen lone pairs. Attack at the meta position doesn't benefit from this extra stabilization, so it's disfavored.

Common EAS reactions of phenols include:

• Bromination — Phenol reacts with bromine water ($\ce{Br2 / H2O}$) at room temperature to give 2,4,6-tribromophenol. No Lewis acid catalyst is needed because the ring is so activated. With a single equivalent of $\ce{Br2}$ in a less polar solvent like $\ce{CS2}$, you can get mono-bromination (mainly ortho and para products).
• Nitration — Dilute nitric acid ($\ce{HNO3}$) at low temperature gives a mixture of ortho- and para-nitrophenol. Concentrated $\ce{HNO3}$ can push the reaction toward 2,4,6-trinitrophenol (picric acid).
• Sulfonation — Concentrated sulfuric acid sulfonates phenol, with the product distribution depending on temperature: ortho-hydroxybenzenesulfonic acid is kinetically favored at lower temperatures, while the para isomer is thermodynamically favored at higher temperatures.
• Friedel-Crafts reactions — Phenols can undergo Friedel-Crafts alkylation and acylation, though the free $\ce{-OH}$ group can sometimes coordinate with the Lewis acid catalyst ($\ce{AlCl3}$), which may complicate the reaction.

Additional electron-donating substituents (e.g., alkyl groups) on the ring further increase reactivity toward EAS.

Acidity of Phenols

Phenols are considerably more acidic than typical alcohols (phenol $pK_a \approx 10$ vs. ethanol $pK_a \approx 16$). The reason is resonance stabilization of the phenoxide anion: when phenol loses a proton, the negative charge on oxygen delocalizes into the aromatic ring across several resonance structures. Alcohols can't do this because their oxygen isn't attached to an aromatic system.

Substituents on the ring tune acidity further:

• Electron-withdrawing groups (e.g., $\ce{-NO2}$) stabilize the phenoxide anion and increase acidity. Para-nitrophenol ($pK_a \approx 7.1$) is much more acidic than phenol itself.
• Electron-donating groups (e.g., $\ce{-OCH3}$, $\ce{-CH3}$) destabilize the anion and decrease acidity.

Other Notable Reactions

Kolbe-Schmitt Reaction — Sodium phenoxide reacts with $\ce{CO2}$ under high pressure and temperature, followed by acid workup, to produce salicylic acid (2-hydroxybenzoic acid). This is an industrially important reaction because salicylic acid is the precursor to aspirin.

Nucleophilic Aromatic Substitution — Phenols themselves don't typically undergo nucleophilic aromatic substitution, but the phenoxide ion can act as a nucleophile. True nucleophilic aromatic substitution on the ring requires strong electron-withdrawing groups (like nitro groups) ortho or para to a leaving group, which is a different situation from standard phenol chemistry.

Oxidation and Reduction of Phenols

The Phenol–Quinone–Hydroquinone Cycle

Phenols can be oxidized to quinones, and quinones can be reduced back to hydroquinones. This reversible redox cycle is central to both synthetic chemistry and biology.

Oxidation of phenol to quinone:

1. An oxidizing agent such as chromic acid ($\ce{H2CrO4}$) or potassium dichromate ($\ce{K2Cr2O7}$) removes two hydrogen atoms from the hydroquinone (1,4-benzenediol) form.
2. The two $\ce{-OH}$ groups are converted to carbonyl groups ($\ce{C=O}$), producing 1,4-benzoquinone (para-quinone).

Note that it's specifically hydroquinone (the 1,4-diol) that oxidizes cleanly to para-quinone. Simple phenol (with only one $\ce{-OH}$) requires more forcing conditions and doesn't give a clean quinone product as directly.

Reduction of quinone back to hydroquinone:

1. A reducing agent such as sodium dithionite ($\ce{Na2S2O4}$) or $\ce{H2}$ with a Pt or Pd catalyst adds two hydrogen atoms across the two carbonyl groups.
2. Both carbonyls are converted back to hydroxyl groups, regenerating hydroquinone.

This interconversion is reversible and can be controlled by adjusting pH, temperature, and the choice of reagent.

Ubiquinones in Cellular Respiration

The quinone–hydroquinone redox cycle has a direct biological counterpart: ubiquinones (also called coenzyme Q, or CoQ). These are lipid-soluble benzoquinone derivatives embedded in the inner mitochondrial membrane.

Here's how they function in the electron transport chain:

1. Electron pickup — Ubiquinone (the oxidized form) accepts electrons from Complex I (NADH dehydrogenase) and Complex II (succinate dehydrogenase), becoming reduced.

2. Three redox states — Ubiquinone can exist as fully oxidized (ubiquinone), partially reduced by one electron (semiquinone radical), or fully reduced by two electrons (ubiquinol, $\ce{QH2}$). This stepwise reduction allows flexible one- or two-electron transfers.

3. Electron delivery — Ubiquinol ($\ce{QH2}$) diffuses through the membrane and donates its electrons to Complex III (cytochrome $bc_1$ complex).

4. Proton gradient — These electron transfers are coupled to the pumping of protons ($\ce{H+}$) from the mitochondrial matrix into the intermembrane space, building up an electrochemical gradient.

5. ATP synthesis — Protons flow back down their gradient through ATP synthase, and the energy released drives the phosphorylation of ADP + $\ce{P_i}$ to form ATP (oxidative phosphorylation).

Ubiquinone's lipid solubility allows it to move freely within the hydrophobic core of the membrane, making it an effective mobile electron shuttle between the large, relatively immobile protein complexes. Deficiencies in ubiquinone levels or function impair mitochondrial energy production and are linked to various metabolic and neurodegenerative disorders.