Conversion of alcohol into alkyl halide
Abstract
The conversion of an alcohol into an alkyl halide by substitution of the hydroxyl group is one of the most fundamental reactions in organic synthesis. Because the hydroxyl group is a poor leaving group, it must first be activated before a nucleophilic substitution by a halide (Br- or Cl-) can occur. Three common methods are described below.
Keywords
Alcohol, Nucleophilic substitution, Alkyl halide
Category
Alcohol
Mechanism
1) Reaction with hydrochloric acid (HCl) or hydrobromic acid (HBr)
The hydroxyl group is first protonated to form an oxonium ion, which is a good leaving group. For primary alcohols, the halide ion (Cl- or Br-) attacks via an SN2 mechanism, resulting in inversion of configuration at the stereogenic center. Secondary alcohols may react through either SN2 or SN1 pathways depending on the substrate and reaction conditions. For tertiary alcohols, departure of the leaving group generates a stable carbocation, which is subsequently trapped by the halide ion via an SN1 mechanism, yielding a racemic mix of alkyl halide.
2) Reaction with thionyl chloride (SOCl2)
The alcohol oxygen atom attacks the electrophilic sulfur atom of thionyl chloride, displacing a chloride ion and forming an alkyl chlorosulfite ester, an excellent leaving group. For tertiary alcohols, departure of the leaving group generates a carbocation, which is subsequently trapped by halide ion through an SN1-type pathway, leading to racemization. For many primary and secondary alcohols in the absence of a base, the reaction proceeds through an internal nucleophilic substitution (SNi). The chlorosulfite group departs while chloride attacks from the same side, leading to retention of configuration. When a base such as pyridine is added, it scavenges HCl and promotes attack by external chloride ion, favoring a SN2 pathway and therefore inversion of configuration.
3) Reaction with phosphorus trichloride (PCl3) or phosphorus tribromide (PBr3)
By analogy of the reaction with SOCl2, the alcohol oxygen atom attacks the electrophilic phosphorus atom, displacing a halide ion and forming a positively charged phosphorus ester, a good leaving group. The halide ion then displaces this group through an SN2 mechanism, resulting in inversion of configuration at the stereogenic center. This method is mainly used for primary and secondary alcohols.
