Study Notes on Methanol Poisoning, Nucleophilic Substitution Reactions of Ethers and Epoxides

Oxidation by Alcohol Dehydrogenase
- Alcohol dehydrogenase is an enzyme that oxidizes ethanol to acetaldehyde.
- It can also oxidize methanol to formaldehyde.
- Formaldehyde toxicity:
- Damages various tissues, particularly sensitive in eye tissue leading to blindness.
- Chemical Reaction:
- Methanol (CH₃OH) converts to formaldehyde (HCHO) when oxidized.
Treatment:
- If methanol is ingested, ethanol is administered intravenously for several hours.
- Mechanism:
- Ethanol competes for binding at the active site of alcohol dehydrogenase, preventing methanol binding and formaldehyde production.
- Treatment continues until all methanol is excreted in urine.

Basicity of Ether and Alcohol Groups:
- The OR group of an ether has similar basicity to the OH group of an alcohol.
- pKa Values:
- CH₃OH (methanol) : pKa ≈ 15.5
- H₂O (water): pKa ≈ 15.7
- Both are poor leaving groups due to high basicity.
Activation of Ethers and Alcohols:
- Ethers require activation (protonation) similarly to alcohols.
- Ethers react with hydrogen halides; however, hydrogen chloride (HCl) cannot be used as Cl⁻ is a weak nucleophile.
- Reaction with HI or HBr:
- Heating is necessary to facilitate the reaction.
Mechanisms for Ether Cleavage:
- SN1 Mechanism:
- Occurs with stable carbocations (e.g., tertiary carbocations).
- SN2 Mechanism:
- Occurs when unstable carbocations (i.e., methyl, vinyl, or primary) would be formed.
- Results in nucleophile displacing the leaving group.
- Process:
- Protonation from acid sets the stage:
  1. Acid protonates the ether oxygen.
  2. ROH departs forming a carbocation.
  3. Nucleophile attacks the carbocation.
- Example SN2 pathway:
  - CH₃O-CH₂CH₂CH₃ + HI → CH₃I + CH₃CH₂O- (which further reacts)
Ethers as Solvents:
- Common ether solvents:
- Diethyl ether
- Tetrahydrofuran (THF)
- 1,4-Dioxane
- 1,2-Dimethoxyethane (DME)
- tert-Butyl methyl ether (TBME)
- Tetrahydropyran (THP)

Historical Context:
- Diethyl ether was historically used as an inhalation anesthetic.
- Drawbacks include slow onset and unpleasant recovery.
- Modern alternatives include isoflurane, enflurane, and halothane, with diethyl ether still being a safe option for untrained administrators.
Mechanism of Action:
- Anesthetics affect nonpolar cell membranes, leading to swelling and impaired permeability.
Intravenous Anesthetics:
- Sodium pentothal (thiopental sodium): rapid onset, requires care due to high toxicity (75% of lethal dose).
- Propofol: ideal agonist with rapid recovery, can be sole anesthetic administered via drip.

Formation of Epoxides:
- Alkene can be converted into an epoxide using peroxy acids.
- Also possible through Cl₂ and H₂O followed by reaction with NaH.
Increased Reactivity of Epoxides:
- Epoxides are more reactive than ethers due to angle strain in the three-membered ring, allowing relief of strain upon ring-opening during nucleophilic attack.
Mechanism under Acidic Conditions:
- Protonation of the oxygen in epoxides leads to heightened reactivity.
- Nucleophilic Attack:
- Halide ion attacks upon back-side of the epoxide, reacting rapidly at room temperature.
- Epoxides can even be opened by weak nucleophiles like H₂O or alcohols under these conditions.
Nucleophilic Attack under Neutral or Basic Conditions:
- Attack preferentially occurs at the less sterically hindered carbon.
- Mixtures of products can lead to differing outcomes based on the substituents.

Crown Ethers:
- Functionally bind specific metal ions or organic molecules, utilized in a variety of chemical applications, prominently in SN2 reactions with ionic compounds.
Arene Oxides and Cytochrome P450:
- Arene oxides are intermediates formed from aromatic compounds. Their formation is crucial for converting foreign compounds into water-soluble forms for excretion, mediated by cytochrome P450 enzymes.