Alcohols sit at the centre of organic synthesis. They can be made from alkenes, from carbonyls, from halides; they can be turned into halides, alkenes, ethers, esters, aldehydes, ketones and acids. Almost every synthesis route in this course passes through one. The obstacle is that an alcohol cannot react at its C–O bond until something is done about the hydroxyl group.
Why OH cannot just leave
From Module 2: a good leaving group is the conjugate base of a strong acid — stable once it has taken the electrons and departed. Hydroxide is the conjugate base of water, pKa 15.7, a very weak acid. That makes hydroxide a strong, reactive base and a terrible leaving group.
The practical consequence: an alcohol will not undergo SN1, SN2, E1 or E2 at the C–O bond under ordinary conditions. Any mechanism you draw that pushes hydroxide off a carbon is wrong. The hydroxyl must first be activated.
Two ways to activate
Protonation. Under acidic conditions the oxygen is protonated first, converting OH into OH₂⁺ — now the leaving group is neutral water, conjugate base of H₃O⁺ at pKa −1.7. Seventeen pKa units of improvement from one proton. This is the route for acid-catalyzed dehydration (E1) and for ROH + HX → RX.
Sulfonate ester formation. Treating the alcohol with tosyl chloride or mesyl chloride converts OH into a tosylate or mesylate — outstanding leaving groups, being conjugate bases of very strong sulfonic acids. The reaction happens at sulfur, so the C–O bond is never broken and the configuration of any stereocenter is fully preserved through the tosylation itself. Whatever stereochemistry you get afterwards comes from the substitution step alone.
Converting alcohols to halides
Three routes, and the choice matters.
HX directly. Tertiary alcohols react readily with HCl or HBr by SN1; primary alcohols need more forcing conditions and go by SN2. Secondary alcohols are in between and prone to rearrangement, which is the main drawback.
SOCl₂ converts ROH to RCl, and PBr₃ converts ROH to RBr. Both work under mild, non-acidic conditions, both proceed by SN2 with inversion at the carbon, and crucially neither goes through a carbocation, so neither rearranges. When a secondary alcohol needs to become a halide with its skeleton intact, these are the reagents.
Dehydration: elimination of water
Under strong acid and heat — concentrated H₂SO₄ or H₃PO₄ — a protonated alcohol ionizes to a carbocation and then loses a beta hydrogen. The mechanism is E1, it follows Zaitsev's rule to give the more substituted alkene, and it carries the same rearrangement risk as any carbocation reaction.
Reactivity follows 3° > 2° > 1°, matching carbocation stability. Primary alcohols are reluctant and, when forced, proceed by a concerted E2-like pathway rather than through a primary cation.
This is the exact reverse of the acid-catalyzed hydration from Module 7, with the same intermediates in the same order. Which direction runs is a matter of conditions: dilute acid with excess water gives the alcohol, while concentrated acid with heat and the alkene distilled off as it forms gives the alkene. Le Châtelier's principle, used deliberately.
For a substrate that cannot survive strong acid, POCl₃ with pyridine effects the same dehydration under mild basic conditions by an E2 mechanism — no cation, no rearrangement.
Oxidation: a ladder, not a single step
Oxidation state rises by removing C–H bonds or adding C–O bonds, and how far an alcohol can climb depends entirely on how many hydrogens sit on the carbinol carbon.
| Alcohol | Mild (PCC, DMP, Swern) | Strong (CrO₃, KMnO₄, Jones) |
|---|---|---|
| primary | aldehyde | carboxylic acid |
| secondary | ketone | ketone |
| tertiary | no reaction | no reaction |
A primary alcohol oxidizes first to an aldehyde and then further to a carboxylic acid; stopping at the aldehyde requires a selective reagent such as PCC, Dess–Martin periodinane, or a Swern oxidation. A secondary alcohol oxidizes once, to a ketone, and can go no further because there is no C–H left on that carbon. A tertiary alcohol has no hydrogen on the carbinol carbon at all and simply does not react.
The reason strong aqueous oxidants overshoot with primary alcohols is worth knowing: the aldehyde hydrates in water to a gem-diol, which has a C–H on a carbon bearing two oxygens and is therefore oxidizable again. Remove the water — as PCC in dichloromethane does — and the overshoot stops.
Start with butan-2-ol and choose the reagent.
PBr₃ → 2-bromobutane, with inversion, no rearrangement.
Concentrated H₂SO₄, heat → but-2-ene, the Zaitsev alkene, by E1.
Na₂Cr₂O₇/H₂SO₄ → butan-2-one; a secondary alcohol stops at the ketone whatever the oxidant.
TsCl/pyridine then NaCN → 2-methylbutanenitrile, with clean inversion at the stereocenter.
Four transformations of one substrate, each selected by reagent. Recognizing which reagent buys which outcome is most of what synthesis planning consists of.
The other reactions
Alcohols are weak acids, pKa around 16, so a strong base such as NaH or sodium metal deprotonates them to alkoxides — better nucleophiles and stronger bases, and the starting material for the Williamson ether synthesis in the next section. Alcohols also react with carboxylic acids and their derivatives to form esters, which is Module 10's chemistry seen from the alcohol's side.
What carries forward
Alcohol activation is a reflex you will use in every multi-step synthesis from here on: you cannot do anything at that carbon until the OH becomes a leaving group. The oxidation ladder connects this chapter to the carbonyl chemistry of Modules 9 and 10 — every aldehyde and ketone you meet there can be traced back to an alcohol. And alkoxides made here are the nucleophiles of the next section.