Small‐molecule reactions at the 2′‐OH groups of RNA enable useful applications for transcriptome technology and biology. To date, all reactions have involved carbonyl acylation and mechanistically related sulfonylation, limiting the types of modifications and properties that can be achieved. Here we report that electron‐deficient heteroaryl species selectively react with 2′‐OH groups of RNA in water via SNAr chemistry. In particular, trialkyl‐ammonium (TAA)‐activated aromatic heterocycles, prepared in one step from aryl chloride precursors, give high conversions to aryl ether adducts with RNAs in aqueous buffer in ~2‐3 h. Remarkably, a TAA triazine previously used only for reaction with carboxylic acids, shows unprecedented selectivity for RNA over water, reacting rapidly with 2′‐OH groups while exhibiting a half‐life in water of >10 days. We further show that a triazine aryl species can be used as a probe at trace‐level yields to map RNA structure in vitro. Finally, we prepare a number of functionalized trialkylammonium triazine reagents and show that they can be used to covalently label RNA efficiently for use in vitro and in living cells. This direct arylation chemistry offers a simple and distinct structural scaffold for post‐synthetic RNA modification, with the potential for utility in multiple applications in transcriptome research.

中文翻译：

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通过 SNAr 与三烷基铵杂环反应选择性芳基化 RNA 2′-OH 基团

RNA 2′-OH 基团上的小分子反应为转录组技术和生物学提供了有用的应用。迄今为止，所有反应都涉及羰基酰化和机械相关的磺酰化，限制了可以实现的修饰类型和性能。在这里，我们报道了缺电子杂芳基物种通过 SNAr 化学选择性地与水中 RNA 的 2'-OH 基团发生反应。特别是，由芳基氯前体一步制备的三烷基铵 (TAA) 活化的芳香杂环，在水性缓冲液中在约 2-3 小时内可高转化为与 RNA 的芳基醚加合物。值得注意的是，以前仅用于与羧酸反应的 TAA 三嗪对 RNA 表现出前所未有的选择性，能够与 2'-OH 基团快速反应，同时在水中的半衰期超过 10 天。我们进一步表明，三嗪芳基物种可以作为痕量水平产量的探针来绘制体外 RNA 结构图。最后，我们制备了许多功能化的三烷基铵三嗪试剂，并证明它们可用于有效地共价标记 RNA，以便在体外和活细胞中使用。这种直接芳基化化学为合成后 RNA 修饰提供了简单而独特的结构支架，具有在转录组研究的多种应用中的潜力。