Organic Chemistry 2 · Reaction Mechanism
Ethers, Epoxides, Thiols, and Sulfides
On this page 7 sections
In 30 seconds
Ethers (R-O-R) are made by the Williamson synthesis, an alkoxide attacking a primary alkyl halide by SN2, or by Alkoxymercuration Alcohol plus alkene via mercury(II), then reduction Full entry → of an alkene. Ethers are inert to most reagents but are cleaved by strong acids (HBr or HI). Epoxides are three-membered cyclic ethers made from alkenes by peroxyacids or through halohydrins, and they open with nucleophiles under acid or base with different regioselectivity. Thiols (R-SH) and sulfides (R-S-R) are the sulfur analogs of alcohols and ethers; thiols are more acidic, their conjugate thiolates are strong nucleophiles, and thiols oxidize to disulfides.
Why this matters
Thiol-disulfide redox chemistry is biologically essential. The amino acid cysteine bears a Thiol R-SH Full entry → side chain, and two cysteines oxidize to a disulfide bond that cross-links and stabilizes the folded three-dimensional structure of proteins such as insulin and antibodies. Drugs that form or disrupt disulfide bonds can alter protein structure and function, and the reducing environment inside cells versus the oxidizing environment outside is maintained in part by thiol/disulfide couples such as glutathione. Epoxides are reactive electrophiles in metabolism: some Epoxide Three-membered cyclic ether Full entry → metabolites are detoxified by epoxide hydrolase, which connects directly to drug safety and toxicology.
The college version
1. Ether synthesis and the Williamson reaction
The Williamson ether synthesis Alkoxide plus primary alkyl halide by SN2 Full entry → joins an alkoxide (RO-) with a primary alkyl halide or tosylate in an SN2 reaction. It works well for primary and methyl substrates but fails for secondary or tertiary halides, which instead undergo E2 elimination to alkenes because the alkoxide is also a strong base. Alkoxymercuration offers a complementary route: an alcohol adds across an alkene in the presence of a mercury(II) salt (Markovnikov addition), followed by reduction, which avoids the elimination problem entirely.
2. Epoxides: preparation and opening
Epoxides form from alkenes in two ways. Peroxyacid epoxidation mCPBA adds oxygen to an alkene Full entry → (for example, mCPBA) delivers oxygen to the alkene in a single concerted step, giving syn addition of oxygen to the double bond. The Halohydrin pathway Halogen plus water, then base closes the epoxide Full entry → first treats the alkene with bromine and water to give a halohydrin, then base deprotonates the O-H and the resulting alkoxide displaces bromide to close the epoxide; the C-O and C-Br bonds form anti to each other, so the two epoxide C-O bonds end up anti to the original double-bond substituents.
3. Thiols and sulfides
Thiols (R-SH) are more acidic than alcohols (pKa roughly 10-11 versus about 16) because sulfur is larger and spreads the negative charge of the thiolate over a bigger, more polarizable atom. Thiolate anions (RS-) are excellent nucleophiles, better than alkoxides, and are used in SN2 reactions to form sulfides and thioethers. Thiols oxidize to disulfides (R-S-S-R) under mild conditions, a reversible redox process central to protein disulfide bonds.
How it works
- Choose the Ether R-O-R, oxygen bonded to two carbons Full entry → route: Williamson for primary halides; alkoxymercuration for hindered or tertiary alkenes.
- Make the epoxide from an alkene using the peroxyacid or halohydrin route.
- Select acid or base conditions to control epoxide-opening regiochemistry.
- Predict the product: acid puts the nucleophile at the more substituted carbon; base puts it at the less substituted carbon.
- For sulfur chemistry, deprotonate the thiol to generate the Thiolate nucleophile RS- Full entry →.
- Account for stereochemistry (anti opening, inversion) before finalizing the structure.
Common confusions
| Do not confuse | With | Difference |
|---|---|---|
| Ether | Epoxide | Ethers are inert; epoxides are strained and reactive |
| Acid-catalyzed opening | Base-catalyzed opening | Acid attacks the more substituted carbon; base attacks the less substituted carbon |
| Williamson | Alkoxymercuration | Williamson is SN2 on a halide; alkoxymercuration adds an alcohol across an alkene |
| Thiol | Alcohol | Thiols are more acidic and their anions are better nucleophiles |
| Thiol | Sulfide | R-SH versus R-S-R (one S-H versus two C-S bonds) |
| Disulfide | Sulfide | R-S-S-R (oxidized) versus R-S-R (not oxidized) |
Memory aids
"Acid Attacks the Abundant (more substituted) carbon; Base Backs into the Bare (less substituted) carbon." For ethers, "Williamson Wants primary" - the SN2 step needs a primary halide.
Quick review
Topic Recap
Ethers are made by the Williamson SN2 synthesis (primary halides only) or alkoxymercuration, and are cleaved only by strong acids. Epoxides are strained cyclic ethers made from alkenes by peroxyacids or the halohydrin pathway; they open regioselectively, at the more substituted carbon under acid and the less substituted carbon under base, with anti stereochemistry. Thiols are more acidic than alcohols, their thiolates are strong nucleophiles that form sulfides, and thiols oxidize reversibly to disulfides, a transformation with deep biological significance.
Knowledge Check
- Why does the Williamson ether synthesis fail with tertiary alkyl halides?
- What is the regiochemical difference between acid- and base-catalyzed epoxide opening?
- Why are thiols more acidic than alcohols?
- What stereochemical relationship do the nucleophile and alcohol have after epoxide ring opening?
- What product forms when two thiols are oxidized?
Answers and Rationales
- Tertiary halides cannot undergo SN2 attack, and the strongly basic alkoxide instead promotes E2 elimination to an alkene.
- Acid-catalyzed opening Protonation, then attack at the more substituted carbon Full entry → adds the nucleophile to the more substituted carbon (more positive-charge character there); Base-catalyzed opening Direct SN2-like attack at the less substituted carbon Full entry → adds it to the less substituted carbon (SN2, sterics).
- Sulfur is larger and more polarizable than oxygen, so the thiolate anion spreads its negative charge over a bigger atom and is more stable, making the S-H proton easier to lose.
- Anti; they add to opposite faces of the former C-C bond because opening proceeds by backside (SN2-like) attack.
- A disulfide (R-S-S-R) forms by oxidative coupling of two thiols.
Eli explains
The same idea, in plain words
Explain it like I’m 10
An ether is like a water molecule with both hydrogens replaced by carbon groups, so it can no longer form the strong hydrogen bonds that make alcohols sticky and high-boiling. Because the oxygen is capped on both sides, ethers are chemically lazy: they sit out most reactions, which makes them excellent, unreactive solvents.
An epoxide is an ether bent into a tiny three-membered triangle. Triangles are strained, with bonds under tension like a stretched rubber band, so epoxides snap open when a nucleophile comes along, releasing that strain. That makes epoxides the reactive, spring-loaded relatives of ordinary ethers.
Thiols are alcohols with sulfur in place of oxygen. Sulfur is bigger, and its bond to hydrogen is weaker, so the S-H proton comes off more easily and thiols are more acidic than alcohols. Swapping one atom changes the whole personality of the molecule.
Where it stops being exact: calling ethers inert is shorthand, because they do react under forcing conditions such as strong acid, and the triangle-snaps-open picture hides the fact that acid and base opening proceed by different mechanisms and give different products. The analogies set the stage; the mechanisms decide the details.
Simple Example
2-Methylpropene treated with a peroxyacid gives 2,2-dimethyloxirane, an epoxide. Opening that epoxide with methanol under acid gives the more substituted methoxy alcohol, whereas opening it with methoxide under base gives attack at the less substituted carbon. The same epoxide yields two different regiochemical outcomes depending on acid versus base.
Worked example
Acid- versus base-catalyzed epoxide opening, with electron accounting:
Acid-catalyzed (for example, HBr, or methanol plus acid):
- The epoxide oxygen is protonated, placing a formal positive charge on oxygen and weakening both C-O bonds.
- The nucleophile attacks the carbon that can best stabilize developing positive charge, the more substituted carbon (more SN1-like character), so the nucleophile adds at the more substituted carbon and the O-H ends up on the less substituted carbon.
- Deprotonation of the protonated alcohol gives the final 1,2-disubstituted product.
Base-catalyzed (for example, NaOH, NaOMe, or a Grignard reagent):
- No protonation occurs; the nucleophile attacks directly by an SN2-like backside pathway.
- Sterics dominate, so the nucleophile attacks the less substituted carbon and the alkoxide forms on the more substituted carbon.
- Protonation (workup) delivers the alcohol.
Stereochemistry: SN2-type opening proceeds with inversion at the attacked carbon, and ring opening of a substituted epoxide always places the nucleophile and the new O-H anti (on opposite faces) across the former C-C bond.
Key takeaways
- High yield: Williamson synthesis requires a primary alkyl halide; secondary and tertiary halides give elimination.
- High yield: Epoxide opening is acid-catalyzed at the more substituted carbon and base-catalyzed at the less substituted carbon.
- High yield: Epoxide ring opening places the nucleophile and the alcohol anti to each other.
- High yield: Thiols are more acidic than alcohols (pKa roughly 10-11 versus about 16), so thiolates are better nucleophiles.
- Peroxyacids (mCPBA) epoxidize alkenes in one step.
- The halohydrin route (halogen plus water, then base) closes the epoxide through anti addition.
- Strong acids HBr and HI cleave ethers; HCl is much slower.
- Thiols oxidize reversibly to disulfides (R-S-S-R), the basis of protein disulfide cross-links.
Study tools & related lessonsYou’ll learn to · Key vocabulary · Related
You’ll learn to
- Describe ether structure and the Williamson ether synthesis, including its SN2 requirements and limitations.
- Explain epoxide preparation from alkenes (peroxyacid epoxidation and the halohydrin pathway) and the resulting anti stereochemical relationship.
- Compare acid-catalyzed versus base-catalyzed epoxide opening and predict the regiochemistry of each.
- Contrast thiols and sulfides with their oxygen analogs, and explain thiol acidity, thiolate nucleophilicity, and thiol oxidation.
Key vocabulary
- Ether
- R-O-R, oxygen bonded to two carbons
- Williamson ether synthesis
- Alkoxide plus primary alkyl halide by SN2
- SN2 limitations
- Requires a primary or methyl substrate
- Alkoxymercuration
- Alcohol plus alkene via mercury(II), then reduction
- Ether cleavage
- Strong acid (HBr/HI) breaks ethers
- Epoxide
- Three-membered cyclic ether
- Epoxide preparation from alkenes
- Peroxyacid or halohydrin route
- Peroxyacid epoxidation
- mCPBA adds oxygen to an alkene
- Halohydrin pathway
- Halogen plus water, then base closes the epoxide
- Acid-catalyzed opening
- Protonation, then attack at the more substituted carbon
- Base-catalyzed opening
- Direct SN2-like attack at the less substituted carbon
- Regioselectivity differences
- Acid versus base control where the nucleophile adds
- Anti relationship
- Nucleophile and O-H on opposite faces
- Thiol
- R-SH
- Sulfide
- R-S-R
- Thiol acidity
- S-H proton is readily lost (pKa roughly 10-11)
- Thiol oxidation
- Thiol to disulfide
Educational content only. It is not medical, legal or professional advice. Found an error? Tell us.