Reactions of Alcohols

Core Concepts

The leaving-group problem: why –OH must be activated

Hydroxide is a strong base (pKa of water ≈ 15.7), so it never leaves on its own. Two fixes exist:

• Protonation: acid converts –OH into –OH₂⁺, making water (pKa ≈ –1.7) the leaving group — the path for dehydration and HX substitution.
• Derivatization: tosyl chloride converts –OH into –OTs; tosylate (pKa ≈ –2.8) leaves easily. This preserves stereochemistry at carbon and works where protonation would fail.

Dehydration to alkenes (acid-catalyzed)

Heating an alcohol with a strong acid (H₂SO₄ or H₃PO₄) removes water and forms an alkene. The mechanism is E1 for 2° and 3° alcohols: protonation, loss of water to a carbocation, then loss of a β-hydrogen. The alkene obeys Zaitsev's rule — the more substituted alkene predominates. Two exam features:

• Carbocation rearrangements: hydride or alkyl shifts can change the product skeleton (e.g., 3,3-dimethyl-2-butanol rearranges via a methyl shift before elimination).
• Reaction order by class: 3° alcohols dehydrate under mild conditions (dilute acid, ~50 °C); 2° alcohols need stronger conditions; 1° alcohols require concentrated acid and ~180 °C and react by an E2-like pathway, since a 1° carbocation is too unstable to form.

Conversion to alkyl halides with HX

Alcohols react with hydrogen halides to give alkyl halides plus water. Reactivity follows HI > HBr > HCl; HCl is so sluggish with 1° and 2° alcohols that it needs ZnCl₂ (the Lucas reagent) as a Lewis-acid catalyst.

• 3° alcohols: rapid S_N1 — protonation, loss of water, carbocation, halide capture. The Lucas test exploits this: 3° alcohols cloud within seconds.
• 2° alcohols: S_N1 as well, but slow, with possible rearrangement (cloudy in ~5 min).
• 1° alcohols: S_N2 — bromide or iodide displaces the protonated hydroxyl with inversion. Even so, HCl is too slow; 1° alcohols give no Lucas reaction at room temperature.

Conversion to alkyl halides with PBr3 and SOCl2

Using HBr directly risks carbocation rearrangements for 2° alcohols. Phosphorus tribromide avoids this: an S_N2-type displacement at carbon gives inversion and no free carbocation, so the skeleton is preserved. Stoichiometry: 3 mol alcohol per 1 mol PBr₃:

3 ROH + PBr₃ ⟶ 3 RBr + H₃PO₃

Similarly, thionyl chloride (SOCl₂, usually with pyridine) gives alkyl chlorides with inversion and no rearrangement (SO₂ and HCl byproducts).

Tosylate esters: the gateway to SN2

Tosyl chloride in pyridine converts –OH to –OTs with retention of configuration (the C–O bond never breaks). The tosylate is then displaced by any good nucleophile (CN^-, N₃^-, RO^-, I^-, RS^-) in a clean S_N2 step with inversion:

R–OH ^{TsCl, pyridine}⟶ R–OTs ^Nu-⟶ R–Nu + TsO^-

This "activate then displace" sequence converts an alcohol into almost any other functional group with controlled stereochemistry — one clean inversion, never a scrambled product.

Esterification with acid chlorides and anhydrides

Alcohols react with acid chlorides or anhydrides (usually with pyridine to absorb the HCl) to give esters:

ROH + CH₃COCl ⟶ ROCOCH₃ + HCl

This is nucleophilic acyl substitution: the alcohol's oxygen attacks the carbonyl carbon, then chloride leaves. Phenols react the same way (topic 10). Acetylation of hydroxyl groups is also how the body tags molecules for transport or excretion, and how aspirin is made from salicylic acid.

Alkoxide formation

Alcohols are weak acids (pKa ≈ 16–18), so strong bases deprotonate them. With sodium or potassium metal:

2 ROH + 2 Na ⟶ 2 RO^-Na⁺ + H₂

With sodium hydride, the byproduct is hydrogen gas as well. Alkoxides are the nucleophiles/bases in Williamson ether synthesis (Chapter 18) and in many eliminations. Practical warning: an alcohol's O–H proton is acidic, so alcohols quench Grignard and organolithium reagents — protect an –OH (topic 8) before using an organometallic reagent on the same molecule.

Common Confusions