A researcher designs an ester prodrug intended to hydrolyze in vivo. They compare two esters with the same acyl group: methyl ester (RCOCH) and tert-butyl ester (RCOC(CH)). Assuming the same conditions and no special catalysts, which is expected to hydrolyze more slowly and why?
- Methyl ester, because smaller alkyl groups make poorer leaving groups
- tert-Butyl ester, because steric hindrance reduces nucleophilic attack at the carbonyl (correct answer)
- Methyl ester, because it cannot form a tetrahedral intermediate in water
- tert-Butyl ester, because tertiary carbons undergo SN2 faster than primary carbons
Explanation: This question assesses understanding of Alcohols, Carboxylic Acids, and Acid Derivatives within biological systems. Tert-butyl esters hydrolyze more slowly than methyl esters due to steric hindrance reducing nucleophilic attack at the carbonyl. In this scenario, designing a prodrug compares ester stability in vivo. Choice B is correct because steric hindrance in tert-butyl slows hydrolysis. Choice A is incorrect because smaller alkyl groups do not make poorer leaving groups in this context. When evaluating ester stability, consider steric effects on the mechanism of hydrolysis.