Ethers, Epoxides, and Sulfides: Structure, Nomenclature, Synthesis, and Reactivity

Ethers, Epoxides, and Sulfides

Introduction

This unit explores the structure, nomenclature, synthesis, and reactivity of ethers, epoxides, and sulfides. These functional groups are central to organic chemistry due to their unique properties and roles in synthesis and biological systems.

Nomenclature and Structure

Nomenclature of Ethers

• Ethers (general formula R–O–R') can be named as alkoxyalkanes (substitutive) or as alkyl alkyl ethers (functional class).

• Symmetrical ethers: Both R groups are identical (e.g., diethyl ether).

• Unsymmetrical ethers: R groups are different (e.g., ethyl methyl ether).

• Cyclic ethers have unique names, with the oxygen assigned as position 1 (e.g., oxirane for ethylene oxide, tetrahydrofuran for oxolane).

Structure	Name
O	Oxirane (Ethylene oxide)
4-membered ring	Oxetane
5-membered ring	Oxolane (Tetrahydrofuran)
6-membered ring	Oxane (Tetrahydropyran)

Nomenclature of Sulfides

• Sulfides (R–S–R') are named using substitutive (alkylthio-) or functional class (alkyl alkyl sulfide) nomenclature.

• Sulfur analogues of epoxides are called thiiranes.

Structure	Name
CH3CH2SCH2CH3	Diethyl sulfide
Cyclopentyl methyl sulfide	(Methylthio)cyclopentane
3-membered ring with S	Thiirane

Structure and Bonding

• The oxygen in alkyl ethers is sp3 hybridized, but the bond angle is typically wider than 109.5° due to lone pair repulsion and ring strain in cyclic ethers.

• The ether oxygen behaves conformationally like a CH2 group.

Physical Properties

Physical Properties of Ethers

• Ethers cannot hydrogen bond with themselves, unlike alcohols.

• Boiling and melting points are similar to alkanes of comparable size.

• Ethers can hydrogen bond with water, making them relatively soluble in water.

Crown Ethers and Complexation

Crown Ethers: Applied Basicity

• The ether oxygen acts as a Lewis base, forming complexes with metal ions (Lewis acids).

• Crown ethers are cyclic polyethers that can chelate cations, with the size of the ring determining the cation selectivity (e.g., 18-crown-6 binds K+).

Crown Ether	Number of Atoms	Number of Oxygens	Preferred Cation
12-crown-4	12	4	Li+
18-crown-6	18	6	K+

• Complexation increases the solubility of ionic salts in nonpolar solvents by encapsulating the cation.

Synthesis of Ethers

Preparation of Ethers

• Acid-catalyzed condensation of alcohols (dehydration):

$2 ext{ ROH} \xrightarrow{H_2SO_4, 130^ ext{o}C} ext{ ROR} + H_2O$

• Acid-catalyzed addition of alcohol to alkene (alkoxy addition):

$\text{Alkene} + ROH \xrightarrow{H^+} \text{Ether}$

• Haloetherification: Similar to halohydrin formation, but with ROH instead of H2O.

Williamson Ether Synthesis

• Alkoxides (RO–) react with alkyl halides (RX) via SN2 to form ethers:

$RO^- + R'X \rightarrow ROR' + X^-$

• Primary alkyl halides are preferred to avoid E2 elimination.

Reactivity of Ethers

General Reactivity

• Ethers are generally unreactive except in combustion and slow oxidation to hydroperoxides (potentially explosive).

• Hydrohalic acids (HX) can cleave ethers to form alkyl halides and alcohols.

Acid-catalyzed Cleavage of Ethers

• Protonation of the ether oxygen makes the adjacent carbons electrophilic.

• Nucleophilic attack by X– (halide) leads to cleavage:

$ROR' + HX \rightarrow RX + R'OH$

• Excess HX and heat can lead to further substitution.

Epoxides

Synthesis of Epoxides

• Method 1: Intramolecular SN2 from a vicinal halohydrin (two-step process).

• Method 2: Direct oxidation of alkenes with peracids (one-step process).

$R_2C=CR_2 + R'CO_3H \rightarrow R_2C(O)CR_2 + R'CO_2H$

• Both methods require a nucleophilic alkene.

Sharpless Epoxidation

• Uses a hydroperoxide, titanium(IV) isopropoxide, and a chiral tartrate to achieve enantioselective epoxidation (syn addition).

Epoxidation via Vicinal Halohydrin

• Step 1: Formation of a vicinal halohydrin by addition of X and OH to an alkene.

• Step 2: Treatment with base induces intramolecular SN2 to form the epoxide.

Stereochemistry of Epoxidation

• Cohalogenation installs –OH and –X anti to each other.

• SN2 ring closure inverts configuration, resulting in syn addition overall.

Cyclic Epoxides

• In cyclohexane systems, ring-closing SN2 occurs trans-diaxial, leading to trans-epoxides.

Reactivity of Epoxides

Nucleophilic Substitution of Epoxides

• Epoxides are highly electrophilic due to ring strain.

• Nucleophilic ring opening occurs via SN2, with inversion of configuration at the attacked carbon.

• Attack occurs at the less substituted carbon under basic conditions.

Acid-catalyzed Nucleophilic Substitution

• Acid catalysis increases electrophilicity; nucleophile attacks the more substituted carbon (still SN2-like, but with partial positive charge stabilization).

Application: Anti Dihydroxylation

• Acid-catalyzed hydrolysis of epoxides leads to anti dihydroxylation of alkenes.

Biological Epoxidation: Monooxygenases

• Monooxygenase enzymes catalyze epoxidation of alkenes using O2 and NADH as a reducing agent.

$R_2C=CR_2 + O_2 + H^+ + NADH \xrightarrow{enzyme} R_2C(O)CR_2 + H_2O + NAD^+$

• Epoxidation of squalene is a key biological example.

Sulfides

Preparation of Sulfides via SN2

• Thiolate anions (RS–) are strong nucleophiles and react with alkyl halides to form sulfides:

$RS^- + R'X \rightarrow RSR' + X^-$

• Follows the same trends and limitations as the Williamson ether synthesis.

Oxidation of Sulfides

• Sulfides can be oxidized to sulfoxides (one oxidation) or sulfones (two oxidations):

$RSR' \xrightarrow{[O]} R(S=O)R' \xrightarrow{[O]} R(SO_2)R'$

Alkylation of Sulfides

• Sulfides react with alkyl halides to form sulfonium salts via SN2.

• Sulfonium salts are more stable than oxonium salts.

• Nature uses S-adenosylmethionine (SAM), a methylsulfonium salt, as a methylating agent.

Spectroscopy of Ethers and Sulfides

Infrared (IR) Spectroscopy

• Ethers: C–O–C stretch at ~1100 cm–1.

• Sulfides: Weak bands near 600 cm–1.

• Sulfoxides and sulfones: S=O stretches at higher wavenumbers (e.g., 1050–1300 cm–1).

NMR Spectroscopy

• 1H NMR: Ether protons (H–C–OR) appear at δ 3.2–4.0 ppm; sulfide protons (H–C–SR) are further upfield (δ 2.0–3.0 ppm); epoxide protons are at δ ~2.5 ppm.

• 13C NMR: Ether carbons (C–O–C) at δ 57–87 ppm; sulfide carbons (C–S–C) are more shielded.

Mass Spectrometry

• Ethers and sulfides can fragment by loss of an alkyl radical, forming O- or S-stabilized carbocations.

• These fragments are often more abundant than the molecular ion.

Summary Table: Key Reactions and Properties

Class	Key Reaction	Physical Property	Spectroscopic Feature
Ether	Williamson synthesis, acid cleavage	No self-H-bonding, soluble in water	IR: 1100 cm–1 (C–O–C)
Epoxide	Peracid oxidation, ring opening	Strained, highly reactive	1H NMR: δ ~2.5 ppm
Sulfide	SN2 with thiolates, oxidation	More polarizable, less H-bonding	IR: 600 cm–1 (C–S–C)

Practice Questions

• Top Hat Question 1: What is the name of the crown ether shown? (Answer: 18-crown-6)

• Top Hat Question 2: Heating a particular ether with HBr yielded a single organic product. Which conclusions can be reached? (Possible answers: methyl ether, symmetric ether, cyclic ether)

• Top Hat Question 3: Which combination of reagents would accomplish the transformation shown? (Epoxide to anti-diol)