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Organic Chemistry
Table of Contents
Unit 18 Overview: Ethers, Epoxides, Thiols, and Sulfides
18.1 Names and Properties of Ethers
18.2 Preparing Ethers
18.3 Reactions of Ethers: Acidic Cleavage
18.4 Cyclic Ethers: Epoxides
18.5 Reactions of Epoxides: Ring-Opening
18.6 Crown Ethers
18.7 Thiols and Sulfides
18.8 Spectroscopy of 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

  • 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

Key Terms to Review (31)

Electrophilic addition reaction: An electrophilic addition reaction is a chemical process in which an electrophile reacts with a nucleophile, typically an alkene or alkyne, forming a new sigma bond by adding across the double or triple bond. This reaction is key in organic synthesis, resulting in the addition of atoms or groups to the carbon atoms involved in the multiple bond.
Alkyl halide: An alkyl halide is an organic compound in which one or more hydrogen atoms in an alkane (saturated hydrocarbon) have been replaced by a halogen atom (fluorine, chlorine, bromine, or iodine). This substitution results in a molecule with distinct chemical and physical properties compared to its alkane precursor.
SN2 reaction: In organic chemistry, an SN2 reaction is a type of nucleophilic substitution where a nucleophile strongly attacks an electrophilic center in one step, leading to the simultaneous displacement of a leaving group. This reaction mechanism is characterized by its bimolecular nature, involving two reacting species in the rate-determining step.
Nucleophilic substitution reactions: Nucleophilic substitution reactions are a class of chemical reactions in organic chemistry where an electron-rich nucleophile selectively bonds with or attacks the positive or partially positive charge of an atom or a group of atoms to replace a leaving group. The reaction is characterized by the substitution of a nucleophile for a leaving group, which can occur via different mechanisms (SN1 or SN2).
Walden inversion: Walden inversion is a stereochemical reaction where the configuration of a chiral center in a molecule is reversed during a nucleophilic substitution process. It illustrates how a molecule can undergo a transformation that results in its mirror image, or enantiomer, without altering any other part of its structure.
Alkoxide ion, RO–: An alkoxide ion is the conjugate base of an alcohol, formed by the deprotonation of the hydroxyl group (OH) in an alcohol molecule, resulting in a negatively charged oxygen atom bonded to an alkyl group (R). It plays a crucial role in various organic reactions, especially as a strong nucleophile.
Williamson ether synthesis: Williamson ether synthesis is a method used in organic chemistry to form ethers by reacting an alkoxide ion with a primary alkyl halide under basic conditions. This reaction involves nucleophilic substitution of the halide leading to the formation of an ether.
Williamson Ether Synthesis: The Williamson ether synthesis is a chemical reaction used to prepare symmetrical and unsymmetrical ethers from alkoxides and alkyl halides. It is a widely used method for the synthesis of ethers, a class of organic compounds with the general formula R-O-R'.
Dehydration: Dehydration is a chemical process in which water is removed from a compound, typically resulting in the formation of a new compound with fewer hydrogen and oxygen atoms. This term is particularly relevant in the context of various organic reactions and transformations, where dehydration plays a crucial role in the preparation and interconversion of different functional groups.
Nucleophilic Substitution: Nucleophilic substitution is a fundamental organic reaction where a nucleophile (a species that donates electrons) replaces a leaving group attached to a carbon atom, resulting in the formation of a new carbon-nucleophile bond. This process is central to many organic transformations and is particularly relevant in the context of alkyl halides, alcohols, carboxylic acids, and amines.
Markovnikov's Rule: Markovnikov's rule is a principle in organic chemistry that describes the orientation of addition reactions involving unsaturated compounds, such as alkenes. It states that in the addition of a hydrogen halide (HX) to an alkene, the hydrogen atom of the HX bond attaches to the carbon atom of the alkene that can best stabilize the resulting carbocation intermediate.
Electrophilic Addition: Electrophilic addition is a type of organic reaction where an electrophile, a species that is attracted to electrons, adds to the carbon-carbon double bond of an alkene. This results in the formation of a new carbon-carbon single bond and the incorporation of the electrophile into the molecule.
Alkyl Halide: An alkyl halide is a type of organic compound that consists of an alkyl group (a hydrocarbon chain) bonded to a halogen atom (fluorine, chlorine, bromine, or iodine). These compounds are important intermediates in many organic reactions, including polar reactions, elimination reactions, and substitution reactions.
Regioselectivity: Regioselectivity refers to the preference of a chemical reaction to occur at a specific site or region of a molecule, leading to the formation of one regioisomeric product over another. This concept is particularly important in the context of electrophilic addition reactions of alkenes, electrophilic aromatic substitution, and other organic transformations.
Mercurinium Ion: The mercurinium ion is a reactive intermediate formed during the oxymercuration-demercuration reaction, a common method for the hydration of alkenes to form alcohols. It is a key species involved in the preparation of alcohols and ethers.
Mercury(II) Salts: Mercury(II) salts are a class of inorganic compounds containing a mercury(II) cation (Hg2+) and one or more anions. These salts are known for their diverse applications and unique properties, particularly in the context of organic chemistry reactions and the preparation of ethers.
Diazomethane: Diazomethane is a highly reactive organic compound with the chemical formula CH2N2. It is a key reagent used in organic synthesis, particularly in the addition of carbenes to alkenes and the preparation of ethers.
SN2 Reaction: The SN2 reaction, or bimolecular nucleophilic substitution, is a type of organic reaction where a nucleophile attacks the backside of a carbon atom bearing a leaving group, resulting in the displacement of the leaving group and the inversion of stereochemistry at the carbon center.
E2 Elimination: E2 elimination is a bimolecular elimination reaction where a base removes a proton from a carbon atom adjacent to a leaving group, resulting in the formation of an alkene. This reaction is a key concept in organic chemistry, with applications in various topics such as the alkylation of acetylide anions, the preparation of ethers, and the alpha halogenation of aldehydes and ketones.
Retention of Configuration: Retention of configuration refers to the preservation of the original stereochemical arrangement of atoms during a chemical reaction. It is an important concept in organic chemistry that describes the ability of a molecule to maintain its spatial orientation throughout a transformation.
Lithium Aluminum Hydride: Lithium aluminum hydride (LiAlH4) is a powerful reducing agent used in organic chemistry for the selective reduction of various functional groups. It is a white, crystalline solid that reacts violently with water and other protic solvents, making it an important reagent in many synthetic transformations.
DMF: DMF, or dimethylformamide, is a versatile organic solvent that has applications in various chemical reactions and processes. It is a polar aprotic solvent that is widely used in organic chemistry, particularly in the context of nucleophilic substitution reactions, nucleophilic aromatic substitution, and the preparation of ethers and crown ethers.
Sodium Borohydride: Sodium borohydride is a powerful reducing agent commonly used in organic chemistry reactions to reduce carbonyl compounds to alcohols. It is a versatile reagent that finds applications in various topics, including the reduction of aromatic compounds, the preparation of alcohols, the synthesis of ethers, and the nucleophilic addition of hydride to carbonyl groups.
Sodium Metal: Sodium metal is a highly reactive alkali metal that is silvery-white in color. It is an essential element that plays a crucial role in various chemical reactions, particularly in the context of preparing ethers.
Alkoxymercuration: Alkoxymercuration is a reaction in organic chemistry where an alkene is treated with mercury(II) salts and an alcohol to form an ether product. It is a key method for preparing ethers, as described in the context of Chapter 18.2 Preparing Ethers.
Sodium Hydride: Sodium hydride (NaH) is a chemical compound consisting of a sodium cation (Na+) and a hydride anion (H-). It is a strong reducing agent and a powerful nucleophile, making it a versatile reagent in organic chemistry.
Inversion: Inversion is a chemical process that involves the reversal of the configuration of a carbon atom, resulting in the formation of a stereoisomer with the opposite orientation. This term is particularly relevant in the context of preparing ethers and the reactions of epoxides during ring-opening.
Acid Catalysis: Acid catalysis is a type of catalysis where an acid compound is used to increase the rate of a chemical reaction. It is a common technique employed in organic chemistry to facilitate various transformations, such as the preparation of ethers and the formation of imines and enamines.
Alkoxide Ion: An alkoxide ion is a negatively charged species formed when an alkyl group (R-) is bonded to an oxygen atom. It is a key intermediate in various organic chemistry reactions, including the preparation of ethers, nucleophilic addition reactions of aldehydes and ketones, and the hydration of carboxylic acids.
Ambident Nucleophiles: Ambident nucleophiles are species that can attack a substrate at multiple distinct sites, leading to the formation of different products. This behavior is particularly relevant in the context of preparing ethers, where the nucleophilic oxygen atom can react at different positions to yield different ether products.
DMSO: DMSO, or dimethyl sulfoxide, is a highly polar organic solvent known for its ability to dissolve both polar and nonpolar compounds. Its unique properties make it a valuable reagent in various chemical reactions, particularly in nucleophilic substitution processes, where it enhances the solubility of reactants and facilitates the formation of intermediates.