Reactivity of Alcohols, Ethers and Epoxides | Organic Chemistry 1
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
- The OH group is converted into a good leaving group (OSOCl or HO+PBr2)
- 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
- Protonation of the OH group - Formation of a good leaving group H2O
- 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
- Protonation of the oxygen atom - Formation of HSO4-
- β elimination using HSO4- as base
Secondary and tertiary alcohols: E1 reaction - carbocation rearrangements can occur
- Protonation of the oxygen atom - Formation of HSO4-
- Heterolytic cleavage of the C-O bond - Formation of a carbocation
- β elimination using HSO4- as base
Dehydration using POCl3:
Mechanism:
E2 reaction - no carbocation rearrangements occurs
- Converting OH group into OPOCl2, a good leaving group
- 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:
- Loss of a good leaving group - Formation of a carbocation
- 1,2-shift of a hydrogen atom or an alkyl group - Formation of a more stable carbocation
- 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
- Protonation of the oxygen atom - Formation of X-
- 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
- Protonation of the oxygen atom - Formation of X-
- Cleavage of a C-O bond - Formation of a carbocation and R'OH (which will react with another equiv. of HX)
- 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:
- SN2 reaction - backside attack
- Protonation of the alkoxide with water
Epoxide opening with acids:
The nucleophile attacks the more hindered carbon atom
Mechanism:
- Protonation of the epoxide oxygen
- SN2 reaction - backside attack