Turning alcohols into alkyl halides is a key skill in organic synthesis. This process involves replacing the hydroxyl group with a halogen atom, using various reagents like hydrogen halides or thionyl chloride. The reactivity depends on the alcohol type.

Tertiary alcohols react fastest, while primary ones are slowest. Different strategies exist for making specific halides, including fluorides. The reaction pathway and outcome can be influenced by factors like solvent choice and substrate structure, with elimination reactions sometimes competing.

Synthesis of Alkyl Halides from Alcohols

Alcohol to alkyl halide conversion

• Alcohols react with hydrogen halides (HX) like HCl, HBr, or HI to form alkyl halides through protonation of the hydroxyl group followed by nucleophilic substitution by the halide ion (HI > HBr > HCl in reactivity)
• Thionyl chloride (SOCl$_2$) converts alcohols to alkyl chlorides via nucleophilic addition of the alcohol to SOCl$_2$, then elimination of HCl and SO$_2$ byproducts
• Phosphorus tribromide (PBr$_3$) reacts with alcohols to yield alkyl bromides through nucleophilic substitution of the alcohol with PBr$_3$ followed by hydrolysis of the resulting phosphite ester, producing phosphorous acid (H$_3$PO$_3$) as a byproduct
• The hydroxyl group acts as a leaving group in these reactions, being replaced by the halide

Alcohol reactivity in halogenation

• Tertiary alcohols are most reactive in halogenation due to the stability of the carbocation intermediate, followed by secondary alcohols, with primary alcohols being the least reactive because of the instability of the primary carbocation intermediate
  1. Tertiary (most reactive)
  2. Secondary
  3. Primary (least reactive)
• Secondary and tertiary alcohols can undergo carbocation rearrangements during halogenation reactions to form a more stable carbocation intermediate, while primary alcohols typically do not rearrange
• The stereochemistry of the product depends on the reaction mechanism and the nature of the carbocation intermediate

Strategies for alkyl fluoride synthesis

• DAST (diethylaminosulfur trifluoride) converts alcohols to alkyl fluorides through nucleophilic substitution of the alcohol with DAST, then elimination of diethylamine and sulfur dioxide
• Olah's reagent (pyridinium poly(hydrogen fluoride)) reacts with alcohols to form alkyl fluorides via nucleophilic substitution of the alcohol with the fluoride ion from the reagent
• Perfluorobutanesulfonyl fluoride (PBSF) in the presence of a base forms a perfluorobutanesulfonate ester with the alcohol, which then undergoes nucleophilic substitution with a fluoride ion to yield the alkyl fluoride

Reaction Considerations

• Solvent effects can influence the rate and outcome of these reactions, with polar protic solvents generally favoring substitution reactions
• Reaction mechanisms vary depending on the substrate and conditions, ranging from SN1 to SN2 pathways
• Competing elimination reactions can occur, especially with secondary and tertiary substrates, leading to alkene formation