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 play important roles in organic synthesis and reactivity, with unique mechanisms and applications.

• Ethers: Compounds with an oxygen atom bonded to two alkyl or aryl groups (R–O–R').

• Epoxides: Cyclic ethers with a three-membered ring (oxirane).

• Glycols: Compounds with two hydroxyl groups on adjacent carbons (vicinal diols).

• Sulfides: Sulfur analogs of ethers (R–S–R').

Basicity of Ethers and Sulfides

Weakly Basic Nature

Ethers and sulfides are weak bases, capable of accepting a proton to form conjugate acid cations.

• Conjugate acids of ethers and sulfides are less acidic than hydronium ion.

• pKa values indicate relative basicity:

Species	Conjugate Acid	pKa
Hydronium ion	H3O+	0
Diethyl ether	Et2OH+	-2 to -3
Diethyl sulfide	Et2SH+	-6 to -7

Ethers as Lewis Bases

Ethers act as Lewis bases by donating electron pairs to Lewis acids, such as BF3. The resulting complexes are stable and can be isolated.

• Boron trifluoride etherate is a common example.

• Ethers can solvate metal ions via Lewis acid-base interactions.

Synthesis of Ethers and Sulfides

General Methods

• Williamson Ether Synthesis: Reaction of alkoxide (RO-) with alkyl halide (R'X) via SN2 mechanism.

• Alkoxymercuration-Reduction: Alkenes react with mercuric acetate and alcohol to form ethers.

• Alcohol Dehydration: Symmetrical ethers from primary alcohols under acidic conditions and heat.

• Sulfides: Prepared analogously using thiolates and alkyl halides.

Williamson Ether Synthesis Equation:

• $ROH + NaH \rightarrow RO^- + H_2$

• $RO^- + R'X \xrightarrow{S_N2} R-O-R'$

Example: Synthesis of tert-butyl methyl ether is best achieved by reacting methyl bromide with tert-butoxide, avoiding steric hindrance.

Synthesis of Epoxides

Oxidation of Alkenes

• Peroxycarboxylic acids (e.g., mCPBA) oxidize alkenes to epoxides.

• Mechanism: Concerted electrophilic addition, forming the three-membered ring.

• Stereospecificity: Syn addition preserves the stereochemistry of the alkene.

General Reaction:

• $RCH=CHR + RCO_3H \rightarrow$ epoxide + $RCO_2H$

Cyclization of Halohydrins

• Halohydrins treated with base undergo intramolecular SN2 reaction to form epoxides.

• Opposite-side substitution leads to inversion of configuration.

Cleavage of Ethers

Cleavage with Primary Alkyl Groups

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

• Mechanism involves protonation of ether oxygen followed by SN2 attack.

Equation:

• $R-O-R' + HI \rightarrow R-I + R'-OH$

Cleavage with Tertiary Alkyl Groups

• Occurs under milder conditions, involves carbocation intermediate and SN1 mechanism.

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

Nucleophilic Substitution Reactions of Epoxides

Ring-Opening under Basic Conditions

• Epoxides are highly reactive due to ring strain.

• Nucleophile attacks the less hindered carbon via SN2 mechanism.

• Product is a trans-1,2-diol or ether-alcohol.

Equation:

• $R_2C-O-CR_2 + Nu^- \rightarrow Nu-CR_2-CR_2-OH$

Regioselectivity and Stereochemistry

• Attack occurs at the least substituted carbon.

• Inversion of configuration at the attacked carbon.

Ring-Opening under Acidic Conditions

• Protonation of epoxide oxygen increases electrophilicity.

• Nucleophile attacks the more substituted carbon (carbocation-like character).

• Regioselectivity is reversed compared to basic conditions.

Equation:

• $R_2C-O-CR_2 + H^+ + Nu \rightarrow Nu-CR_2-CR_2-OH$

Reactions of Epoxides with Organometallic Reagents

Grignard and Organocuprate Reagents

• Grignard reagents ($RMgX$) react with epoxides to extend carbon chains by two carbons, forming alcohols.

• Organocuprates ($R_2CuLi$) react via SN2 mechanism at less substituted carbon.

Example:

• $R-MgBr + CH_2CH_2O \xrightarrow{H_2O/H^+} R-CH_2CH_2OH$

Preparation and Oxidative Cleavage of Glycols

Preparation of Glycols

• Oxidation of Alkenes with OsO4 or KMnO4 yields vicinal diols (glycols) via syn addition.

• OsO4 is highly toxic; catalytic amounts can be used with co-oxidants.

Equation:

• $RCH=CHR + OsO_4 \rightarrow RCH(OH)-CH(OH)R$

• $RCH=CHR + KMnO_4 \rightarrow RCH(OH)-CH(OH)R$

Oxidative Cleavage of Glycols

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

Equation:

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

Oxonium and Sulfonium Salts

Structure and Reactivity

• Oxonium salts: Protonated ethers or trialkyloxonium ions.

• Sulfonium salts: Sulfur analogs, highly reactive alkylating agents.

• React with nucleophiles via SN2 mechanism.

Intramolecular Reactions and the Proximity Effect

Intramolecular SN2 Reactions

• Groups within the same molecule react to form cyclic products.

• Intramolecular reactions are faster due to proximity and reduced entropy loss.

Reactant	Product	Approximate Relative Rate
5-membered ring	cyclopentane	2000
6-membered ring	cyclohexane	5700
7-membered ring	cycloheptane	20

Additional info: Favorable entropy and strain effects accelerate ring formation for 5- and 6-membered rings.

Applications to Organic Synthesis

Chain Extension and Functional Group Transformations

• Epoxides and Grignard reagents are used to extend carbon chains and introduce alcohol functionality.

• Control of stereochemistry and regioselectivity is crucial in multi-step synthesis.

Example: Synthesis of (Z)-3-hepten-1-ol from smaller fragments using Grignard addition to epoxide.

Summary Table: Key Reactions and Mechanisms

Reaction	Reagents	Product	Mechanism
Williamson Ether Synthesis	RO-, R'X	R-O-R'	SN2
Epoxidation of Alkenes	RCO3H	Epoxide	Concerted syn addition
Epoxide Ring-Opening (Base)	Nu-	Trans-1,2-diol	SN2, least hindered carbon
Epoxide Ring-Opening (Acid)	Nu, H+	Trans-1,2-diol	SN1-like, more substituted carbon
Glycol Preparation	OsO4, KMnO4	Vicinal diol	Syn addition
Glycol Cleavage	H5IO6	Aldehyde/ketone	Oxidative cleavage