Question

A primary or secondary alcohol can be protected by conversion to its tetrahydropyranyl ether. Why is formation of THP ethers by this reaction limited to primary and secondary alcohols?

Short answer

Answer: The protection of alcohols using THP ethers is limited to primary and secondary alcohols due to the mechanism of the reaction. The nucleophilic attack of the alcohol oxygen on dihydropyran is a key step in forming the THP ether. However, tertiary alcohols have a sterically more hindered oxygen atom, making the nucleophilic attack thermodynamically and kinetically unfavorable. Therefore, THP ether formation is limited to primary and secondary alcohols with less steric hindrance, allowing the reaction to proceed with reasonable rates.

Step-by-step solution

Understand the THP protection of alcohols

To protect a primary or secondary alcohol, it can be converted to its tetrahydropyranyl ether. This protection allows the alcohol to be temporarily hidden from potential reactions during synthetic work, and can be removed afterwards to reveal the alcohol group again. This protection is achieved through the reaction of the alcohol with dihydropyran in the presence of an acid catalyst.

Compare primary, secondary, and tertiary alcohols

Primary alcohols have the hydroxyl group attached to a carbon that is bonded to only one other carbon atom. Secondary alcohols have the hydroxyl group attached to a carbon that is bonded to two other carbon atoms. Tertiary alcohols have the hydroxyl group attached to a carbon that is bonded to three other carbon atoms.

Analyze the mechanism of THP ether formation

The mechanism for the formation of THP ethers involves the nucleophilic attack of the alcohol oxygen on the electrophilic carbon of dihydropyran. The resulting intermediate, an oxocarbenium ion, is then attacked by another dihydropyran molecule. The intermediate collapses to afford the protected THP ether product. The driving force for this reaction is the formation of the stable THP ring structure.

Determine the reason for the limitation to primary and secondary alcohols

In the mechanism of THP ether formation, the nucleophilic attack of the alcohol oxygen on dihydropyran is a key step. As tertiary alcohols have a sterically more hindered oxygen atom due to the presence of three carbon atoms bonded to the central carbon, the nucleophilic attack becomes thermodynamically and kinetically unfavorable. Consequently, the formation of THP ethers is limited to primary and secondary alcohols, having less steric hindrance, allowing the reaction to proceed with reasonable rates.