RNA chemistry — Why is RNA inherently less stable than DNA in alkaline (basic) solutions?

Difficulty: Easy

Adenine in RNA is easily deaminated under basic conditions
The ribose sugar's 2′-OH group promotes base-catalyzed backbone cleavage
Uracil spontaneously depurinates in alkali
Its single-stranded nature alone causes rapid hydrolysis in base
The phosphodiester bond in RNA is ionic rather than covalent

Correct Answer: The ribose sugar's 2′-OH group promotes base-catalyzed backbone cleavage

Explanation:

Introduction:
RNA is notoriously more labile than DNA in alkaline solutions. This question probes the chemical reason behind that instability, a concept that underpins many laboratory techniques (e.g., RNase-free handling) and explains why DNA, not RNA, is nature’s long-term information store.

Given Data / Assumptions:

RNA contains ribose; DNA contains 2′-deoxyribose.
RNA uses uracil; DNA uses thymine.
Alkaline pH provides hydroxide ions that can act as bases/nucleophiles.
Backbone integrity depends on phosphodiester bonds connecting 3′-OH and 5′-phosphate.

Concept / Approach:
The key structural difference is the 2′-hydroxyl on ribose. Under basic conditions, this 2′-OH can be deprotonated to form a 2′-O⁻ that intramolecularly attacks the adjacent phosphorus, forming a cyclic 2′,3′-phosphodiester intermediate and cleaving the backbone. DNA lacks the 2′-OH, so this pathway is blocked, making DNA far more stable in alkali.

Step-by-Step Solution:

1) In base, OH⁻ abstracts a proton from the 2′-OH of ribose → 2′-O⁻ forms.2) The 2′-O⁻ attacks the adjacent phosphate → a 2′,3′-cyclic phosphate intermediate forms.3) Hydrolysis of this intermediate yields a mixture of 2′ or 3′-monophosphate fragments → backbone cleavage.4) DNA lacks a 2′-OH, preventing this intramolecular transesterification and therefore resisting alkali.

Verification / Alternative check:
Classic lab demonstrations show that RNA incubated at high pH rapidly smears on gels (fragmentation), while DNA remains largely intact. Mild alkaline hydrolysis is even used deliberately to degrade RNA contaminants during DNA prep.

Why Other Options Are Wrong:

a) Adenine is not the determinant; the sugar is.c) Uracil does not depurinate; depurination refers to purines, and base-catalyzed cleavage is sugar-driven.d) Single-strandedness may expose bases but does not cause the specific alkali lability.e) The phosphodiester bond is covalent in both DNA and RNA.

Common Pitfalls:
Confusing base-catalyzed cleavage with acid-catalyzed depurination; attributing instability to uracil rather than the ribose 2′-OH.

Final Answer:
The ribose 2′-OH enables base-catalyzed intramolecular attack on the phosphate, cleaving the RNA backbone.

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RNA chemistry — Why is RNA inherently less stable than DNA in alkaline (basic) solutions?

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