10.10:
Conversion of Alcohols to Alkyl Halides
Alcohols react with hydrogen halides to generate corresponding alkyl halides.
In the mechanism, the first step is the protonation of the hydroxyl group. Thereafter, while tertiary alcohols interact via the SN1 mechanism, primary alcohols prefer an SN2 route. Secondary alcohols can proceed via either mechanism, where the preference is dictated by the reaction conditions.
Recall that an SN1 mechanism occurs sequentially: a loss of the leaving group, followed by the nucleophilic attack. Since this reaction proceeds via the carbocation intermediate, it is suitable for the tertiary carbocation, which is stabilized by hyperconjugation.
For primary alcohols, the protonation of the hydroxyl group leads to the SN2 mechanism. However, while the SN2 mechanism is straightforward with hydrogen bromide, hydrogen chloride needs an additional catalyst, zinc chloride.
Zinc chloride, being ionic, is limited to water-soluble alcohols. It converts their hydroxyl group into a better leaving group, enabling the subsequent SN2 process.
A more common process for primary alcohols uses thionyl chloride. A primary alcohol interacts with thionyl chloride in the presence of pyridine or a tertiary amine, which forms the corresponding alkyl chlorosulfite intermediate.
As a result, the intermediate bears an excellent leaving group—chlorosulfite—rather than a poor leaving group like water. Subsequently, nucleophilic substitution by the chloride forms the corresponding alkyl halide. The bromination with phosphorus tribromide follows the same route.
Similarly, primary and secondary alcohols react with sulfonyls in the presence of pyridine to form the corresponding reactive products. Here, the sulfonate anion is a weak base, further stabilized by resonance extended to the substituted aromatic ring, making the tosylate anion an excellent leaving group for SN2 reactions. Subsequently, reaction with the hydrogen halide yields the alkyl halides.
Interestingly, the choice of reagent defines stereochemistry. While thionyl chloride inverts the chiral configuration of the native alcohol, the tosyl chlorides retain the chiral configuration. In the latter, the alcohol first undergoes inversion while becoming the tosylate, and then undergoes another inversion with the SN2 mechanism.
10.10:
Conversion of Alcohols to Alkyl Halides
This lesson delves into the conversion of alcohols to corresponding alkyl halides and the mechanism of action for different reagents. Typically, the hydroxyl group is first protonated to convert it to a stable leaving group. Consequently, based on the starting alcohol, the mechanism undergoes either of the nucleophilic substitution routes, SN1 or SN2. Tertiary alkyl halides are made using the two-step SN1 mechanism that occurs via a carbocation intermediate, which is stabilized by hyperconjugation. However, for primary alcohols, the protonation of the hydroxyl group leads to the concerted SN2 route. Secondary alcohols can proceed via either mechanism based on the reaction conditions.
The popular reagents used for converting alcohols to corresponding alkyl halides include the hydrogen halides like hydrogen bromide and hydrogen chloride. However, while it is straightforward with the former, the latter needs an additional catalyst like zinc chloride. This catalyzes the hydroxyl group into a better leaving group enabling the subsequent SN2 process. Other reagents of choice are thionyl chloride and phosphorus tribromide with a similar mechanism. In the presence of relatively weak bases like pyridine/tertiary amine, they generate an excellent leaving group compared to the original leaving group of water.
The most exciting class of reagents is sulfonyls. They react with the alcohols to form corresponding mesylates, tosylates, or triflates to improve their reactivity in an SN2 reaction. In these species, resonance stabilization is inherent to the sulfonyl group. Additional resonance stabilization is contributed by the benzene ring of the tosyl group, and further stability is provided by the strongly electron-withdrawing trifluoromethyl in the triflate.
Stereochemistry
Most importantly, the choice of reagent influences the stereochemistry of the product formed. The use of thionyl chloride leads to an inversion of configuration, while tosyl chlorides retain the chiral configuration in the native alcohol.