Ethers and Epoxides

Williamson Ether Synthesis

SN2 reaction NaH: forms an ether by forming an alkoxide ion then SN2 with R-X

Ways to prepare ethers (R-O-R)

1. SN2, Williamson Ether synthesis from an alcohol: from a tertiary OH: NaH → alkoxide L.G. → CH3-X → ether

2. Alkoxymercuration from an alkene: 1. Hg(OAc)2, EtOH 2. NaBH4, OH- →

3. Alcohol dehydration: primary alcohol → H2SO4/heat → symmetrical ether (SN2)

tert- alcohol → H2SO4 → asymmetrical ether (SN1)

tert-butyl alcohol w/ Williamson method

when treated w/ a strong base (NaH) -> tert-butoxide which can undergo SN2 -> methyl ether

Can you form methyl-ether from methanol via Williamson method?

no because elimination would occur instead w/ bulky base

What does Alkoxymercuration- Reduction form?

1) Hg(OAc)2, CH3OH/ H2O Et2O

2) NaBH4

similar to oxymerc-red, but adds an ether from an alkene

-markovnikov product

How do you form symmetrical ethers from an alcohol?

Primary alcohol w/ H2SO4 + heat -> symmetrical ether (SN2 reaction)

How do you form asymmetrical ethers from an alcohol?

between tert- and primary alcohols w/ H2SO4 -> unsymmetrical ether (SN1 reaction)

How can ethers be cleaved?

with a strong acid under harsh conditions.

with primary alkyl groups -> SN2 mechanism

tert-alkyl groups -> SN1 mechanism

Preparation of Epoxides (Oxidation)

Oxidation: Alkene + Peroxy acid (mCPBA) --> stereospecific epoxide

Preparation of Epoxides (halohydrins)

Cyclization (intramolecular): Cycloalkene + halohydrin X2/H2O -> Cyclo-halohydrin -> SN2 w/ NaOH -> cyclic epoxide

Ring opening of epoxides (primary and secondary carbon)

Epoxide -> SN2 w/ HX/ether (halogen attaches to primary C) trans and under mild acidity

Ring opening of epoxides (tertiary carbon)

Epoxide -> SN1 w/ HX (halogen attaches to tertiary C)

trans

Ring opening of epoxides under basic conditions

Epoxide -> SN2 w/ NaEtO

or: R-MgBr, R-alkyne Na+, R2CuLi

regioselctive and stereoselective

nucleophile (OEt) reacts the less substituted carbon

Grignard reagent with epoxide

R-MgX + Epoxide w/ 1. ether, heat 2. H3O+ -> R-alcohol

good way to extend a carbon chain

Gilman Reagent

R2CuLi + epoxide -> alcohol w/ carbon chain

acts as a mild nucleophile

attacks less substituted carbon

inversion stereochem

Alkynide as a nucleophile for epoxide ring opening

alkylnide when treated w/ strong base (NaNH2) creates strong nucleophile

Alkylnide Na+ -> 1. epoxide 2. H2O -> alcohol w/ alkyne

Synthesis of Thiols

Thiourea (S=NH2-NH2) reacts with alkyl halide (R-X) -> Thiol (R-SH)

thiolate is a weak base but strong nucleophile

Oxidation of thiols

R-SH -> I2/Zn, H+ -> disulfide (R-S2-R) +HI

thiols can be oxidized to disulfides