10.5 Preparing Alkyl Halides from Alcohols

Synthesis of Alkyl Halides from Alcohols

Alcohol to Alkyl Halide Conversion

Replacing an $-OH$ group with a halogen is one of the most common transformations in organic synthesis. The problem is that $OH^-$ is a terrible leaving group on its own, so every method here works by converting it into something that can leave.

Reaction with hydrogen halides (HX). Treating an alcohol with HCl, HBr, or HI protonates the hydroxyl group first, turning it into water, which is an excellent leaving group. The halide ion then displaces water through nucleophilic substitution. Reactivity of the hydrogen halides follows acid strength and nucleophilicity of the halide:

$HI > HBr > HCl$

Thionyl chloride ($SOCl_2$). The alcohol attacks the sulfur of $SOCl_2$, forming a chlorosulfite intermediate. Chloride ion then displaces this activated leaving group, releasing $SO_2$ gas and $HCl$ as byproducts. Because both byproducts are gases that leave the reaction mixture, the equilibrium is driven forward and purification is straightforward. This makes $SOCl_2$ a go-to reagent for converting primary and secondary alcohols to alkyl chlorides.

Phosphorus tribromide ($PBr_3$). $PBr_3$ reacts with the alcohol to form a protonated phosphite ester, which sets up bromide as the nucleophile for an $S_N2$ displacement. The byproduct is phosphorous acid ($H_3PO_3$). One equivalent of $PBr_3$ can convert three equivalents of alcohol, since phosphorus has three $P-Br$ bonds available.

Alcohol Reactivity in Halogenation

Reactivity order with HX reagents:

1. Tertiary (most reactive)
2. Secondary
3. Primary (least reactive)

This trend exists because tertiary alcohols react through an $S_N1$ pathway. After protonation, the tertiary carbocation that forms is stabilized by hyperconjugation and inductive effects from three alkyl groups. Primary carbocations are far too unstable to form under normal conditions, so primary alcohols with HX are sluggish and typically require $S_N2$ conditions or stronger reagents like $SOCl_2$ or $PBr_3$.

Carbocation rearrangements are a real concern with secondary and tertiary substrates reacting via $S_N1$. A secondary carbocation can undergo a 1,2-hydride or 1,2-methyl shift to form a more stable tertiary carbocation, giving you a product you didn't intend. If you see a secondary alcohol and HX, always check whether rearrangement is possible.

Stereochemistry depends on the mechanism. $S_N2$ reactions invert configuration at the carbon (Walden inversion). $S_N1$ reactions produce racemization because the planar carbocation can be attacked from either face, though in practice you often see partial racemization rather than a perfect 50/50 mix.

Strategies for Alkyl Fluoride Synthesis

HF is too weak an acid and fluoride is a poor nucleophile in protic media, so simple $HF$ treatment doesn't work well for making alkyl fluorides. Specialized reagents are needed:

• DAST (diethylaminosulfur trifluoride): The alcohol attacks DAST to form an activated intermediate, and fluoride then displaces it. DAST works well for primary and secondary alcohols but is moisture-sensitive and can be hazardous at scale.
• Olah's reagent (pyridinium poly(hydrogen fluoride)): Provides a convenient, safer source of $HF$ that converts alcohols to alkyl fluorides through nucleophilic substitution by fluoride.
• PBSF (perfluorobutanesulfonyl fluoride): Used with a base, PBSF first converts the alcohol to a sulfonate ester, creating an excellent leaving group. A fluoride source then displaces the sulfonate in a second step.

Reaction Considerations

• $S_N1$ vs. $S_N2$: Tertiary alcohols with HX react via $S_N1$. Primary alcohols with $PBr_3$ or $SOCl_2$ react via $S_N2$. Secondary alcohols can go either way depending on conditions.
• Solvent effects: Polar protic solvents (water, alcohols) stabilize carbocations and favor $S_N1$. Using a non-nucleophilic base or an aprotic solvent can push things toward $S_N2$.
• Competing elimination: Secondary and tertiary substrates are prone to $E1$ or $E2$ elimination, producing alkenes instead of alkyl halides. Higher temperatures and strong bases increase elimination. If your goal is substitution, keep temperatures moderate and avoid excess base.