Alcohols, Phenols, Ethers & Thiols

The hydroxyl group (–OH) is arguably the single most important functional group in pharmaceutical chemistry. If you scan any drug formulary, the majority of small-molecule drugs either carry an –OH group directly or are metabolised to produce one — from ethanol to morphine to cholesterol to almost every steroid hormone in the body. The reason is straightforward: –OH enables H-bonding (improving aqueous solubility and receptor binding), it is a good leaving group when activated, and it sits at the molecular junction between reduction and full oxidation. Everything interesting in organic synthesis either comes from an alcohol or leads to one.

The critical distinction in classification is what type of carbon the –OH is attached to. A primary alcohol has its –OH on a carbon with only one other carbon attached; secondary –OH sits on a carbon flanked by two carbons; tertiary on a carbon flanked by three. The carbon-count rule is important because it directly predicts reactivity: as we will see, 3° alcohols react instantly with HCl, while 1° alcohols need heating; 1° and 2° alcohols are oxidised easily, while 3° are not. It also explains a classic exam trap: a quaternary alcohol (4°) cannot exist, because a carbon surrounded by four other carbons has no room for an –OH.

• gem-diols (two –OH on the same C) are unstable → lose water to give a carbonyl.
• Enols tautomerise to the more stable keto form (covered properly in Chapter 5).

Classification by carbon type bearing –OH:

No 4° alcohol exists — a quaternary C has 4 C-substituents and no room for –OH. (This is the trap in 2019 PP III.7.)

Also classified by number of –OH groups: monohydric (1), dihydric (2, e.g. ethylene glycol), trihydric (3, glycerol), polyhydric (≥ 4, glucose).

Alcohol naming follows exactly the same algorithm as alkane naming, with two modifications. First, the parent chain must be the longest one that includes the carbon bearing –OH. Second, you number from whichever end gives the –OH the lowest locant, and that locant takes priority over alkyl substituents. The suffix changes from "-ane" to "-anol" (or "-ol" with a locant, e.g. propan-2-ol). For multiple –OH groups, the ending becomes "-diol," "-triol," etc. These are not difficult rules — the one slip candidates make is choosing the longest chain overall rather than the longest chain containing –OH.

1. Longest chain containing the –OH-bearing carbon. Replace "-e" of alkane with "-ol".
2. Number from the end nearer the –OH.
3. State the position of –OH (new IUPAC: locant just before "-ol"; old IUPAC: locant before parent name).
4. Two or more –OH → -diol, -triol, etc.

You can mix any amount of ethanol with water without any cloudiness — complete miscibility. Add a few drops of hexan-1-ol (6-carbon alcohol) and the solution immediately becomes two-layered. What changed? The hexyl chain is now long enough that the hydrophobic tail outweighs the hydrophilic –OH head. This balance — how strongly the –OH grips water molecules versus how strongly the alkyl tail repels them — explains the solubility of all alcohols. Small alcohols (up to about 4 carbons) are miscible with water; longer-chain alcohols become increasingly insoluble, behaving more like oils. Fatty alcohols (C12–C18) are essentially insoluble and are used as emulsifiers in cosmetics and food, where both the hydrophilic –OH and the hydrophobic tail are needed simultaneously.

The hydrogen-bonding capacity of –OH also explains why alcohols boil so much higher than alkanes of similar molecular weight. Ethanol (MW 46) boils at 78 °C, yet propane (MW 44) boils at −42 °C — a 120 °C difference. Every ethanol molecule in the liquid state has its –OH hydrogen-bonded to two or three neighbours, forming a transient network. Breaking this network to vapourise the liquid requires far more thermal energy than breaking the weak London dispersion forces of propane. This is the same intermolecular force that gives water its unusually high boiling point and makes liquid water the foundation of biology.

The O in R–OH is sp³; C–O–H angle ~108.5°. Both lone pairs on O can act as H-bond acceptors, and the O–H is a strong H-bond donor.

• Boiling point: alcohols boil much higher than alkanes of comparable MW. e.g. ethanol b.p. 78 °C vs propane −42 °C. Reason: extensive intermolecular H-bonding.
• Water solubility: small alcohols are miscible (MeOH, EtOH, iPrOH, t-BuOH). As the alkyl tail grows, solubility falls (hexan-1-ol weakly soluble; decanol effectively insoluble).
• –OH is the hydrophilic head; the alkyl group is the hydrophobic tail. The balance dictates emulsion-forming, membrane-spanning, and detergent behaviour.

Alcohols sit at a crossroads in organic chemistry. They are the first oxidation product of alkanes (or the reduction product of aldehydes/ketones), they can be dehydrated back to alkenes (exactly reversing the hydration reaction from Chapter 3), and they can be converted to alkyl halides, ethers, esters, and carboxylic acids. Almost every functional-group interconversion in medicinal chemistry passes through an alcohol at some point. The reactions in this section — substitution (HX), elimination (dehydration), and oxidation — each occur by a carbocation mechanism and each has one governing rule you must memorise: Lucas for substitution order, Zaitsev for elimination regioselectivity, and the oxidation ladder for what product to expect from a given substrate.

Attaching –OH directly to a benzene ring creates something fundamentally different from an alcohol. In a simple alcohol, the oxygen's lone pairs are essentially private — they interact with the C–O σ bond, but the ring isn't there to compete. In phenol, those lone pairs can delocalise into the aromatic π system. Resonance structures place negative charge on the ortho and para ring positions, meaning the ring is electron-rich and highly reactive toward electrophiles — so reactive, in fact, that phenol brominates three times in aqueous solution without any Lewis acid catalyst. The same resonance that activates the ring also stabilises the phenoxide anion (the deprotonated phenol): the negative charge on oxygen is spread over the ring, making phenol a much stronger acid (pK_a 10) than a typical alcohol (pK_a ~16).

This acidity difference has direct clinical consequences. Paracetamol (acetaminophen) contains a phenol group whose pK_a is low enough that Phase II liver enzymes (glucuronyl transferase, sulfotransferase) rapidly conjugate it for excretion. When those enzymes are overwhelmed in overdose, cytochrome P450 produces NAPQI — a reactive quinone intermediate — which depletes glutathione and alkylates liver proteins, causing acute hepatic necrosis. The antidote, N-acetylcysteine, replenishes glutathione. The entire toxidrome flows from one structural feature: the phenol group.

–OH on an aromatic ring (sp² C). The O lone pair delocalises into the ring → resonance gives phenol distinct properties from alcohols.

Phenol + NaOH → sodium phenoxide + H₂O. Bubble in CO₂ → phenol regenerated.

Electrophilic substitution — phenol is strongly activated, o/p directing. Phenol is so reactive that:

Ethers have one property that makes them indispensable as laboratory solvents: they are almost chemically inert. The oxygen is tucked between two alkyl groups, its lone pairs are shielded, and there is no O–H for hydrogen bonding. Diethyl ether, THF (tetrahydrofuran), and diglyme dissolve both polar and nonpolar substrates, they don't react with most reagents at room temperature, and they are easy to remove by evaporation. However, this apparent docility conceals one serious hazard: on standing in air, ethers slowly absorb oxygen and form hydroperoxides (ROOOH) at the α-carbon. These are shock-sensitive and can explode violently on concentration or distillation. This is why old bottles of diethyl ether in a fume hood are one of the most dangerous items in a chemistry laboratory.

The Williamson ether synthesis is the cleanest and most reliable laboratory route to unsymmetrical ethers. It is a two-step process: first, an alcohol is deprotonated by Na or NaH to generate the alkoxide nucleophile; second, the alkoxide attacks a primary alkyl halide by S_N2, displacing the halide and forming the ether. The restriction is that the alkyl halide must be primary (or methyl) — a secondary or tertiary alkyl halide would instead undergo E2 elimination because the alkoxide is a bulky base. When in doubt, choose the more complex fragment as the alkoxide and the simpler (less branched) fragment as the alkyl halide.

R–O–R′ — O is sp³, C–O–C ~112°. No O–H → no H-bond donation. Acts as H-bond acceptor. Small ethers partially water-soluble.

Names: "alkyl alkyl ether" (diethyl ether, methyl t-butyl ether) or IUPAC alkoxy substituent (methoxyethane).

The smell of a skunk is primarily caused by (E)-2-butene-1-thiol — and the human nose can detect it at concentrations as low as one part per billion. This extraordinary olfactory sensitivity evolved because thiols reliably signal danger in nature: they are produced by rotting proteins, sulphur-reducing bacteria, and stale gas. The same property that makes thiols biologically important as olfactory signals also makes them essential in biochemistry: cysteine residues carry –SH groups, and these are the most chemically reactive side chains in all of protein chemistry. The thiol group on cysteine can be oxidised to a disulfide, alkylated by electrophiles, coordinated to metal ions (zinc fingers, haem biosynthesis), or used as the nucleophile in enzyme active sites (cysteine proteases including cathepsins, caspases, papain).

The structural differences from alcohols flow directly from sulfur's position in the periodic table. Sulfur sits below oxygen — it is larger, more polarisable, and less electronegative. As a result: S–H bonds are weaker and more polar toward S (making thiols more acidic, pK_a ~10, than alcohols, pK_a ~16); sulfur makes a poor H-bond donor (its lone pairs are too diffuse), so thiols boil much lower than alcohols of the same MW; and sulfur is an outstanding nucleophile (soft–soft HSAB match with soft electrophiles), making the thiolate anion (RS⁻) one of the best nucleophiles in organic chemistry — far better than an alkoxide at the same pK_a.

R–SH (thiol / "mercaptan"). Sulfur analog of alcohol. Sulfur is less electronegative and larger than O:

• Thiols are more acidic than alcohols (pK_a ~10–11 vs 16–18).
• S–H is a poor H-bond donor → thiols boil lower than alcohols of the same MW.
• S is much more nucleophilic (soft nucleophile in HSAB theory).
• Thiols have powerful odours (skunks, onions, garlic, natural gas odorant).