Chapter 13 - Ethers, Epoxides, Thiols, and Sulfides

Chapter 13 - Ethers, Epoxides, Thiols, and Sulfides

Ethers

  • An ether group consists of an oxygen atom bonded to two alkyl groups.

    • -R groups can include alkyl, aryl, or vinyl groups; they cannot be acyl groups.

Structure and Bonding of Ethers

  • Ethers serve as common solvents in organic reactions.

  • They have relatively low boiling points, allowing for easy removal by evaporation.

  • Ethers are generally unreactive.

  • Ethers can function only as hydrogen bond acceptors and are classified as polar aprotic solvents.

  • Example solvents:

    • Diethyl ether

    • Tetrahydrofuran (THF)

  • Ethers aid in stabilizing reactions but do not form strong hydrogen bonds.

Crown Ethers

  • Crown ethers demonstrate particularly strong attractions to metal atoms.

  • They form a complex with metal cations, generating soluble complexes.

  • The presence of multiple ether groups enhances the attraction to metals.

  • The size matching between the metal and the crown ether is crucial for strong attraction.

Preparation of Ethers

  • The Williamson ether synthesis is a widely used method to produce asymmetric ethers.

  • Recall the oxymercuration-demercuration pathway used to craft alcohols from alkenes (referencing section 8.7), as an analogous method called alkoxymercuration-demercuration can produce ethers.

    • Reaction characteristic:

    • $R-OH$ \rightarrow \text{alkoxide} \rightarrow \text{Na}^+ \text{H}_2O$ \rightarrow $R-O-R'$

Synthesis Example: Methyl t-Butyl Ether

  • Two possible pathways exist for synthesizing methyl t-butyl ether via the Williamson ether synthesis:

    • Route 1: Successful pathway.

    • Route 2: Not successful due to steric hindrance and SN1 mechanisms associated with tertiary halides.

Reactions of Ethers: Acid-Promoted Cleavage

  • Ethers can undergo cleavage in the presence of acids.

    • Reaction conditions vary based on the structure of the R group:

    • For tertiary R groups, the cleavage occurs via an SN1 mechanism.

    • Aryl or vinyl R groups do not undergo substitution.

    • Example reaction:

    • $Me-O-R + H-X \rightarrow 2 \text{Alkyl Halides}$

Epoxides

  • Formation of Epoxides:

    • Epoxides arise when an alkene reacts with a peroxy acid such as m-chloroperbenzoic acid (MCPBA) or peroxyacetic acid.

    • The epoxidation of alkenes is stereospecific.

Enantioselective Epoxidation

  • Epoxidation methods introduced thus far lack enantioselectivity.

  • The Sharpless catalyst, a chiral complex made from titanium tetraisoproxide and diethyl tartrate (DET), is employed for asymmetric trans-epoxidation.

Ring Opening Reactions of Epoxides

  • Epoxides act as significant synthetic intermediates.

  • They possess significant ring strain, making them susceptible to both weak and strong nucleophiles:

    • Grignard reagents

    • Hydride reagents

    • Alcohols

    • Alkoxides

  • The opening of epoxide rings is regioselective and stereoselective.

Regioselectivity and Stereoselectivity

  • Regioselectivity:

    • The least hindered carbon of the epoxide is preferred for attack by strong nucleophiles due to SN2 mechanism.

  • Stereoselectivity:

    • Inversion of configuration occurs with nucleophilic attack opposite the epoxide.

Acidic Conditions and Ring Opening

  • Acidic conditions allow for epoxide opening using weak nucleophiles (e.g., HCl, HBr, water, or alcohol).

  • Under acidity, nucleophilic attack on the less substituted carbon occurs, provided no tertiary carbon is present.

  • If a tertiary carbon is present, nucleophilic attack occurs at that location instead.

Thiols and Sulfides

  • Thiol (-SH group) is the sulfur analog of alcohol.

  • Compounds containing -SH are termed thiols, differing in nomenclature from alcohols ending in “-ol”.

  • Thiols are characterized by unpleasant odors, common in biological systems (e.g. skunk defense mechanism).

  • Methanethiol is intentionally added to natural gas for leak detection.

  • The hydrosulfide ion (HS−) is a strong nucleophile and a weak base, promoting SN2 reactions rather than E2 reactions.

Preparation of Thiols

  • Primary and secondary thiols are synthesized through an SN2 reaction involving NaSH and an alkyl halide.

  • Typical thiol oxidations convert thiols to disulfides in the presence of bromine (Br2) under basic conditions.

Sulfide Reactions: Oxidation

  • Sulfides can undergo oxidation to yield sulfoxides or sulfones.

  • The choice of oxidizing agent varies depending on whether sulfoxide or sulfone synthesis is desired.

    • Common oxidizing agents include hydrogen peroxide and sodium meta-periodate.

    • Key features of their reactions include oxidation state changes and the expansion of the octet.

Synthesis Strategies: Epoxides

  • Epoxides enable the installation of two functional groups on adjacent carbons.

  • When encountering adjacent functional groups, epoxide (from an alkene) typically serves as the starting point.

  • Reactions involving epoxides and Grignard reagents allow for modifications to the carbon skeleton, yielding connections between functional groups and creating elongated carbon chains conflicting functional groups at various carbon positions.

Example Synthetic Pathway

  • Consider the reagents required for a specific synthesis reaction.

    • Typical reagents: magnesium (Mg) and water (H2O), leading to alkane formation and carbon skeleton alterations.