18.2 Preparing Ethers

Williamson ether synthesis is a powerful method for creating ethers. It involves an alkoxide ion attacking an alkyl halide, following an SN2 mechanism. This reaction is widely used but has limitations with hindered substrates and certain nucleophiles.

Alkoxymercuration offers an alternative route to ethers from alkenes. This two-step process involves mercury-mediated addition of an alcohol to an alkene, followed by reduction. It provides Markovnikov regioselectivity but uses toxic mercury compounds.

Williamson Ether Synthesis

Williamson ether synthesis mechanism

Top images from around the web for Williamson ether synthesis mechanism

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

1 of 3

Top images from around the web for Williamson ether synthesis mechanism

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

• 

  Organic chemistry 12: SN2 substitution - nucleophilicity, epoxide electrophiles View original

  Is this image relevant?

1 of 3

• Reaction of an alkoxide ion (RO-) with an alkyl halide (R'-X) forms an ether (R-O-R')
  • Alkoxide ion acts as a nucleophile attacking the electrophilic carbon bonded to the halogen (Br, Cl, I)
  • Follows SN2 reaction mechanism (nucleophilic substitution)
    • Backside attack of the alkoxide on the alkyl halide causes inversion of stereochemistry at the electrophilic carbon
  • Alkoxide ion prepared by treating an alcohol (R-OH) with a strong base such as sodium hydride (NaH) or sodium metal (Na) to deprotonate the alcohol
• Limitations of Williamson ether synthesis
  • Hindered alkyl halides (tertiary) may undergo elimination (E2) instead of substitution (SN2) due to steric hindrance
  • Possible side reactions with ambident nucleophiles that have multiple nucleophilic sites (cyanide, nitrite)
  • Not suitable for preparing unsymmetrical ethers with two different bulky groups (t-butyl ethers) due to steric hindrance

Alkoxymercuration for ether preparation

• Two-step process adds an alcohol (R-OH) to an alkene followed by reduction to form ether
  • Step 1: Alkoxymercuration
    • Alkene reacts with mercury(II) salts (Hg(OAc)2) and an alcohol (R-OH) in aqueous solution
    • Electrophilic addition of the mercury complex to the alkene forms a mercurinium ion intermediate
    • Nucleophilic attack by the alcohol on the mercurinium ion forms a mercurinium alkoxide
  • Step 2: Reduction
    • Mercurinium alkoxide reduced using a reducing agent such as sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4)
    • Reduction eliminates the mercury and forms the final ether product
• Regioselectivity follows Markovnikov's rule with the alcohol adding to the more substituted carbon of the alkene
• Stereochemistry determined by the structure of the mercurinium ion intermediate (retention of configuration)

Comparison of ether synthesis methods

• Williamson ether synthesis
  • Starting materials: alkoxide ion (from alcohol + strong base) and an alkyl halide
  • Reaction conditions: polar aprotic solvent (DMF, DMSO), room temp or gentle heating
  • Advantages: wide scope, good yields, can prepare unsymmetrical ethers
  • Disadvantages: limited to primary and some secondary alkyl halides, requires strong base
• Alkoxymercuration
  • Starting materials: alkene and alcohol
  • Reaction conditions: mercury(II) salts (Hg(OAc)2), aqueous solution, then reduction (NaBH4, LiAlH4)
  • Advantages: prepares ethers from alkenes, Markovnikov regioselectivity
  • Disadvantages: uses toxic mercury compounds, two-step process
• Dehydration of alcohols
  • Starting materials: two alcohol molecules
  • Reaction conditions: acid catalyst (H2SO4), high temperature
  • Advantages: simple starting materials, one-step process
  • Disadvantages: limited to symmetrical ethers, harsh conditions, low yields
• Reaction of alcohols with diazomethane ($CH_2N_2$)
  • Starting materials: alcohol and diazomethane
  • Reaction conditions: ether solvent, room temperature
  • Advantages: mild conditions, selective for preparing methyl ethers
  • Disadvantages: diazomethane is toxic and explosive, limited to methyl ethers

Additional Ether Synthesis Methods

• Dehydration of alcohols (acid catalysis)
  • Involves the elimination of water from two alcohol molecules to form an ether
  • Requires high temperatures and an acid catalyst (e.g., H2SO4)
  • Follows an E1 mechanism with carbocation intermediate
• Electrophilic addition to alkenes
  • Addition of alcohols to alkenes under acidic conditions
  • Proceeds through carbocation intermediate
  • Regioselectivity follows Markovnikov's rule