Reactivity of Alcohols, Ethers and Epoxides | Organic Chemistry 1

The reactivity of alcohols, ethers and epoxides are studied in this chapter: typical reactions of alcohols (deprotonation, substitution, elimination, oxidation), preparation of alkoxides, nucleophilic substitutions of alcohols, dehydration of alcohols, carbocation rearrangements, reactivity of ethers, epoxide opening

Typical Reactions of Alcohols

Preparation of Alkoxides

Deprotonation with a base:
 


Mechanism:

Bronsted acid-base reaction. Strong bases are needed to deprotonate alcohols (pKa ~ 16-18). Butyl lithium (BuLi), sodium hydride (NaH) and potassium hydride (KH) are commonly used

 

Deprotonation with a metal:
 


Mechanism:

Reduction with alkali metals

Nucleophilic Substitutions of Alcohols

Formation of alkyl halides:
 


Mechanism:

SN2 reactions

  1. The OH group is converted into a good leaving group (OSOCl or HO+PBr2)
  2. Nucleophilic attack of X- and loss of the leaving group (SO2 / Cl- or HOPBr2)

 

Formation of alkyl halides with HX:
 

HO- is a bad leaving group and can be replaced with a better leaving group to favor SN reactions. HX is for example used:


 

Mechanism:

CH3OH and primary alcohols: SN2 reactions

  1. Protonation of the OH group - Formation of a good leaving group H2O


     
  2. Nucleophilic attack of X-


     

Secondary and tertiary alcohols: SN1 reactions
Carbocations are intermediates and rearrangements can occur

 

Formation of alkyl tosylates:
 


 

This process converts the poor leaving group -OH into a good one -OTs
TsCl is called p-toluenesulfonyl chloride or tosyl chloride. The tosylate -OTs is a good leaving group because it is stabilized by resonance forms


Alkyl tosylates undergo either substitution or elimination, depending on the reagent: 

Substitution reaction:

Mechanism: SN2 reaction with strong nucleophile
 

Elimination reaction:

Mechanism: E2 reaction with strong base

Dehydration of Alcohols

Dehydration using strong acid:
 


Mechanism:

Primary alcohols: E2 reaction

  1. Protonation of the oxygen atom - Formation of HSO4-


     
  2. β elimination using HSO4- as base


     

Secondary and tertiary alcohols: E1 reaction - carbocation rearrangements can occur

  1. Protonation of the oxygen atom - Formation of HSO4-
  2. Heterolytic cleavage of the C-O bond - Formation of a carbocation
  3. β elimination using HSO4- as base

 

Dehydration using POCl3:
 


Mechanism:

E2 reaction - no carbocation rearrangements occurs

  1. Converting OH group into OPOCl2, a good leaving group
  2. β elimination using pyridine as base

Carbocation Rearrangements

Electron-donating groups, such as alkyl groups, stabilize a positive charge ⇒ stability of carbocations: tertiary > secondary > primary. A less stable carbocation can rearrange to a more stable carbocation. These rearrangements involve the migration of an alkyl group or a hydrogen atom from a carbon atom to an adjacent carbon atom. They are respectively called 1,2-alkyl shift and 1,2-hydride shift



Mechanism:

  1. Loss of a good leaving group - Formation of a carbocation


     
  2. 1,2-shift of a hydrogen atom or an alkyl group - Formation of a more stable carbocation


     
  3. SN1 (nucleophilic attack to form the substitution product) or E1 (loss of a proton to form an alkene)

Reactivity of Ethers

Cleavage of C-O bonds with strong acids:
 


Mechanism:

Methyl and primary alkyl groups: SN2 reaction

  1. Protonation of the oxygen atom - Formation of X-


     
  2. Nucleophilic attack of the carbocation by X - Formation of RX and R'OH (which will react with another equiv. of HX)


     

Secondary and tertiary alkyl groups: SN1 reaction

  1. Protonation of the oxygen atom - Formation of X-
  2. Cleavage of a C-O bond - Formation of a carbocation and R'OH (which will react with another equiv. of HX)
  3. Nucleophilic attack of the carbocation by X - Formation of RX

Reactivity of Epoxides


Epoxide opening with strong nucleophiles:

The nucleophile attacks the less hindered carbon atom

Mechanism:

  1. SN2 reaction - backside attack


     
  2. Protonation of the alkoxide with water

 

Epoxide opening with acids:

The nucleophile attacks the more hindered carbon atom

Mechanism:

  1. Protonation of the epoxide oxygen


     
  2. SN2 reaction - backside attack