Alcohols/Ethers/Epoxides Review

Alcohols/Ethers/Epoxides Review

I. Alcohols

A. Preparations

1. Fermentation

   • Definition: Anaerobic degradation of glucose to produce ethanol.

2. Hydration of Alkenes

   • Process: Treatment of an alkene with H2O and a catalytic amount of H+.

   • Intermediate: Possible rearrangements through a carbocation.

   • Rule: Follows Markovnikov’s rule.

3. Oxymercuration-Demercuration

   • Process:

     • (1) Treatment of an alkene with Hg(OAc)2 and H2O.

     • (2) Followed by reduction with NaBH4.

   • Rule: Follows Markovnikov’s rule.

   • Rearrangement: No rearrangements occur as no carbocation is produced.

4. Hydroboration-Oxidation

   • Process:

     • (1) Treatment of an alkene with BH3 (or variation).

     • (2) Followed by reaction with NaOH and H2O2.

   • Rule: Follows anti-Markovnikov’s rule.

   • Rearrangement: No rearrangements occur; the pathway is concerted.

5. Hydride Reducing Agents with Carbonyls

   • Types of agents:

     • NaBH4 (mild)

     • LAH (strong)

   • Reactions:

     • With Aldehydes: Forms primary ROH.

     • With Ketones: Forms secondary ROH.

   • Note: The carbon skeleton is retained.

6. Grignard Reagents with Carbonyls

   • Reactions:

     • With Aldehydes: Produces secondary ROH.

     • With Ketones: Produces tertiary ROH.

   • Note: The carbon skeleton is increased.

7. Grignard Reagents with Ethylene Oxide

   • Outcome: Allows for the preparation of a primary ROH.

II. Ethers

A. Preparations

1. Acid Catalysts with Alcohols

   • Process: Treatment of 2 moles of an alcohol with H2SO4 under mild warming.

   • Mechanism: May proceed through an SN1 or SN2 mechanism.

2. Williamson Ether Synthesis

   • Process:

     • Treatment of an alkoxide with an RX (methyl, primary; restrict to secondary, no tertiary).

   • Preparation of Alkoxide:

     • Obtained by reacting alcohol with Na or NaH.

   • Mechanism: Proceeds through SN2.

3. Alkoxy Mercuration-Demercuration

   • Process:

     • Treatment of an alkene with (1) Hg(CF3CO2)2 and ROH; (2) followed by NaBH4.

   • Rule: Follows Markovnikov’s rule.

   • Rearrangement: No carbocation; thus, no rearrangements occur.

   • Mechanism: Proceeds through a mercurinium ion.

III. Epoxides

A. Preparations

1. Industrial Method (Not in Scope for Exams)

   • Process: Treatment of ethylene gas with O2 passing through a silver membrane at 250°C.

2. Halohydrin Method

   • Process:

     • Treatment of an alkene with (1) X2 (Cl2 or Br2) and excess ROH; (2) treat the resulting halohydrin with NaH.

   • Outcome: Formation of the epoxide from the halohydrin via an intramolecular SN2 reaction.

3. m-Chloroperoxybenzoic Acid (MCPBA)

   • Method: Treatment of an alkene with MCPBA.

   • Reaction Process: Concerted reaction.

   • Geometry: The geometry is retained in the epoxide:

     • Trans alkene yields trans epoxide.

     • Cis alkene yields cis epoxide.

IV. Reactions

A. Alcohols

1. Addition of HX to Yield Alkyl Halide (RX)

   • Process: Treatment of an ROH with HX (HI > HBr > HCl >>> HF).

   • Mechanism:

     • 1° ROH proceeds through an SN2 mechanism.

     • 2° ROH is less common.

     • 3° ROH proceeds through an SN1 mechanism (rearrangements possible).

2. Reaction with PX3 or PX5

   • Outcome: Yields alkyl halide.

   • Mechanism: Proceeds through an SN2 mechanism.

   • Driving Force: Formation of the P-O bond.

3. Dehydration (Elimination Reaction)

   • Process: Treatment of ROH with H2SO4 or H3PO4 and heat, yields alkene.

   • Catalysts: Both H2SO4 and H3PO4 function as catalysts.

   • Reactivity Order: 3° > 2° > 1°.

   • Mechanism: Possibility of rearrangements, E1 mechanism.

4. Reaction with Active Metals

   • Process: Treatment of ROH with Na yields alkoxide (RONa) and half H2.

   • Mechanism: Proceeds via single electron transfer (SET) from Na to ROH.

   • Reactivity Order: Me > 1° > 2° > 3°.

   • Base Strength: RONa base strength follows 3° > 2° > 1° > Me.

5. Oxidation

   • Water-Based Oxidizing Agents (Strong):

     • K2Cr2O7/H2SO4

     • CrO3/H2SO4

     • KMnO4/OH-

     • Outcomes: CH3OH and 1° ROH yield carboxylic acids; 2° ROH yield ketones.

   • Non-Water Based Oxidizing Agents (Mild):

     • PCC (Pyridinium Chlorochromate)

     • Swern Reaction (Oxalyl Chloride, Dimethyl Sulfoxide, Triethyl Amine)

     • Outcomes: CH3OH and 1° ROH yield aldehydes; 2° ROH yield ketones.

6. Converting OH to a Leaving Group

   • Process: Treatment of ROH (Me, 1° or 2°) with p-toluenesulfonyl chloride.

   • Outcome: The OH is converted to a tolyslate (resonance stabilized leaving group).

7. Protecting Group (Masking of OH)

   • Process: Treatment of ROH with chlorotrimethylsilane (Me3SiCl) in presence of an organic base (e.g., triethyl amine or imidazole).

   • Outcome: Alcohol is protected as a siloxane.

   • Removal: To remove the protecting group, treat siloxane with KF in H2O (high affinity of Si for F-).

B. Ethers

1. Acid Cleavage (HX)

   • Purpose: Allows for bond cleavage of ethers.

   • Reactivity Order of HX: HI > HBr > HCl >>> HF.

   • Reaction Outcomes:

     • Product: ROH and RX.

     • Nature of Ether governs the outcome:

     • 1° ether cleavage: SN2 process.

     • 3° ether cleavage: SN1 process.

     • Aromatic aliphatic ethers yield alkyl halide and phenol (e.g., anisole, phenatole).

C. Epoxides (Acidic or Basic Ring Cleavage)

1. Acidic Conditions

   • Can use a variety of mild nucleophiles.

   • With Alcohols:

     • Process: Treatment of epoxide with excess ROH under acid catalyst.

     • Outcome: Alkoxy-alcohol formed.

     • Mechanism: Ring opening follows Markovnikov’s addition.

   • With H2O:

     • Process: Treatment of an epoxide with excess H2O under acid catalyst.

     • Outcome: Glycol (1,2-diol) formed.

2. Basic Conditions

   • Can use a variety of good anionic nucleophiles.

   • With Grignard Reagents:

     • Process: Treatment of an epoxide with RMgX followed by HCl workup.

     • Outcome: Yields an alcohol; the attack follows the least steric pathway.

   • With Alkoxides:

     • Process: Treatment of an epoxide with RO- followed by HCl workup.

     • Outcome: Yields alkoxy-alcohol.