Chapter 12: The Chemistry of Ethers, Epoxides, Glycols, and Sulfides – Study Notes

Chapter 12: The Chemistry of Ethers, Epoxides, Glycols, and Sulfides

Overview

This chapter explores the structure, properties, synthesis, and reactions of ethers, epoxides, glycols, and sulfides. These functional groups are important in organic synthesis and have unique reactivity due to their heteroatoms (oxygen or sulfur).

12.1 Basicity of Ethers and Sulfides

Weak Basicity

• Ethers and sulfides can accept a proton to form conjugate acid cations, but they are only weakly basic.

• Relative basicity can be compared using pKa values of their conjugate acids.

Species	Structure	pKa
Hydronium ion	H3O+	0
Conjugate acid of ethanol	EtOH2+	-2 to -3
Conjugate acid of diethyl ether	Et2OH+	-3
Conjugate acid of ethanethiol	EtSH2+	-6 to -7
Conjugate acid of diethyl sulfide	Et2SH+	-6 to -7

• Ethers are more basic than sulfides.

Ethers as Lewis Bases

• Ethers can act as Lewis bases by donating a lone pair to Lewis acids (e.g., BF3).

• The etherate complex (e.g., boron trifluoride etherate) is stable enough to be isolated.

• Ethers also solvate metal cations in organometallic reactions via Lewis acid-base interactions.

12.2 Synthesis of Ethers and Sulfides

General Methods

• Ethers can be synthesized from alkyl halides and alcohols via the alkoxide (Williamson ether synthesis).

• Sulfides are prepared analogously using thiols (via thiolate anions).

Williamson Ether Synthesis

• Two-step process:

  1. Deprotonation of alcohol (ROH) with a strong base (NaH, KH, or Na metal) to form an alkoxide (RO-).

  2. Alkoxide reacts with an alkyl halide (R'X) via an SN2 mechanism to form the ether (R–O–R').

• Best for primary alkyl halides; secondary/tertiary alkyl halides may lead to elimination.

Example: Synthesis of tert-butyl methyl ether is best achieved by reacting methyl bromide with potassium tert-butoxide.

Ethers from Alkoxymercuration-Reduction of Alkenes

• Variation of oxymercuration-reduction using an alcohol (ROH) as solvent instead of water (HOH).

• Forms ethers regioselectively from alkenes.

Example: 1-hexene + Hg(OAc)2 + (CH3)2CHOH → 1-acetoxymercuri-2-isopropoxyhexane → 2-isopropoxyhexane (after NaBH4 reduction).

Ethers from Alcohol Dehydration

• Primary alcohols can be dehydrated to form symmetrical ethers under strong acid and heat.

• Secondary and tertiary alcohols tend to form alkenes instead.

• The reaction proceeds via an SN2 mechanism for primary alcohols.

Equation: $2CH_3CH_2OH \xrightarrow{H_2SO_4,\ 140^\circ C} CH_3CH_2OCH_2CH_3 + H_2O$

Synthesis of Unsymmetrical Ethers from Alcohol Dehydration

• Tertiary alcohols can react with primary alcohols in the presence of acid to form unsymmetrical ethers.

• The alcohol in excess should be the one that cannot form a carbocation.

Example: tert-butyl alcohol + ethanol (excess) + H2SO4 → ethyl tert-butyl ether

12.3 Synthesis of Epoxides

Oxidation of Alkenes to Epoxides

• Peroxycarboxylic acids (e.g., mCPBA) oxidize alkenes to epoxides in a single step.

• The reaction is a concerted electrophilic addition (no intermediates).

Equation: $RCH=CHR' + RCO_3H \rightarrow RCH(O)CHR' + RCO_2H$

Stereospecific Syn Addition

• Epoxidation is stereospecific: cis-alkenes give cis-epoxides, trans-alkenes give trans-epoxides.

Epoxides from Halohydrins (Cyclization)

• Halohydrins (β-halo alcohols) can be cyclized to epoxides using base (intramolecular Williamson ether synthesis).

• Mechanism involves opposite-side (anti) substitution, leading to inversion of configuration.

12.4 Cleavage of Ethers

Cleavage with Primary Alkyl Groups

• Strong acids (HI or HBr) cleave ethers to form alkyl halides and alcohols.

• Mechanism: Protonation of ether oxygen, followed by SN2 attack by halide ion.

Equation: $CH_3CH_2OCH_2CH_3 + HI \rightarrow CH_3CH_2I + CH_3CH_2OH$

Cleavage with Tertiary Alkyl Groups

• Occurs under milder acid conditions and involves carbocation intermediates (SN1 mechanism).

• Secondary alkyl ethers can react via either SN1 or SN2 mechanisms.

12.5 Nucleophilic Substitution Reactions of Epoxides

Ring-Opening under Basic Conditions

• Epoxides are highly reactive to nucleophilic attack due to ring strain.

• Reaction proceeds via SN2 mechanism; nucleophile attacks the less hindered carbon.

• Stereochemistry: Inversion at the attacked carbon.

Example: 2,2-dimethyloxirane + NaOEt → 1-ethoxy-2-methyl-2-propanol

Ring-Opening under Acidic Conditions

• Protonation of the epoxide increases its electrophilicity.

• Nucleophile attacks the more substituted carbon (due to partial positive charge stabilization).

• Stereochemistry: Inversion at the attacked carbon.

Example: 2,2-dimethyloxirane + CH3OH/H2SO4 → 2-methoxy-2-methyl-1-propanol

12.6 Preparation and Oxidative Cleavage of Glycols

Preparation of Glycols (Vicinal Diols)

• Oxidation of alkenes with OsO4 or KMnO4 gives syn-1,2-diols (glycols).

• OsO4 is highly selective but toxic; NMO or TMAO can be used as co-oxidants.

• KMnO4 is less selective and can over-oxidize.

Equation: $RCH=CHR' + OsO_4 + H_2O \rightarrow RCH(OH)CH(OH)R'$

Oxidative Cleavage of Glycols

• Periodic acid (H5IO6) cleaves the C–C bond between the two OH groups, forming aldehydes or ketones.

• Mechanism involves formation of a cyclic periodate ester intermediate.

Equation: $RCH(OH)CH(OH)R' + H_5IO_6 \rightarrow RCHO + R'CHO + HIO_3 + H_2O$

12.7 Oxonium and Sulfonium Salts

• If the acidic hydrogen of a protonated ether is replaced by an alkyl group, the resulting compound is an oxonium salt.

• The sulfur analog is a sulfonium salt.

Type	Example
Oxonium ion	R3O+
Sulfonium ion	R3S+

12.8 Reactions of Oxonium and Sulfonium Salts

• These salts are highly reactive alkylating agents and undergo SN2 reactions with nucleophiles.

• Used in organic synthesis for introducing alkyl groups.

12.9 Intramolecular Reactions and the Proximity Effect

• Intramolecular reactions occur between groups within the same molecule, often forming rings.

• These reactions are generally faster than intermolecular reactions due to the proximity of reactive groups.

Reactant	Product	Relative Rate
5-membered ring	Cyclopentane derivative	2000
6-membered ring	Cyclohexane derivative	5700
4-membered ring	Cyclobutane derivative	1
7-membered ring	Cycloheptane derivative	20

Additional info: Five- and six-membered rings form most rapidly due to favorable enthalpy and entropy.

12.10 Applications to Organic Synthesis

• Grignard reagents react with epoxides to give alcohols, extending the carbon chain by two carbons.

• Lithium organocuprates (Gilman reagents) also react with epoxides via SN2 mechanism, attacking the less substituted carbon.

Example: $R-MgBr + CH_2OCH_2 \xrightarrow{H_2O} RCH_2CH_2OH$

Summary Table: Key Reactions and Mechanisms

Reaction Type	Reagents/Conditions	Product
Williamson Ether Synthesis	RO- + R'X	R–O–R'
Epoxidation of Alkene	RCO3H	Epoxide
Epoxide Ring-Opening (Basic)	Nucleophile, base	Alcohol (attack at less hindered C)
Epoxide Ring-Opening (Acidic)	Nucleophile, acid	Alcohol (attack at more hindered C)
Glycol Formation	OsO4 or KMnO4	1,2-diol
Glycol Cleavage	H5IO6	Aldehyde/ketone

Key Concepts and Applications

• Ethers and sulfides are weak bases and good solvents; ethers are also important as Lewis bases.

• Epoxides are highly strained and reactive, undergoing ring-opening reactions with nucleophiles under both acidic and basic conditions.

• Glycols are prepared by syn-dihydroxylation of alkenes and can be cleaved oxidatively to carbonyl compounds.

• Oxonium and sulfonium salts are powerful alkylating agents in organic synthesis.

• Intramolecular reactions are favored for forming five- and six-membered rings due to entropic and enthalpic factors.