Reactivity of Alcohols, Ethers and Epoxides | Organic Chemistry 1

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

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:
 

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

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)

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

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