Fu Zihuan, Treacy Joseph W, Hosier Brock M, Houk K N, Maynard Heather D
Department of Chemistry and Biochemistry, California NanoSystems Institute, University of California Los Angeles California 90095-1569 USA
Chem Sci. 2024 Jun 7;15(27):10448-10454. doi: 10.1039/d4sc02985b. eCollection 2024 Jul 10.
Hydroxybenzylammonium compounds can undergo a reversible 1,4- or 1,6-elimination to afford quinone methide intermediates after release of the amine. These molecules are useful for the reversible conjugation of payloads to amines. We hypothesized that aromaticity could be used to alter the rate of reversibility as a distinct thermodynamic driving force. We describe the use of density functional theory (DFT) calculations to determine the effect of aromaticity on the rate of release of the amine from hydroxybenzylammonium compounds. Namely, the aromatic scaffold affects the dearomatization reaction to reduce the kinetic barrier and prevent the reversibility of the amine elimination. We consequently synthesized a small library of polycyclic hydroxybenzylammoniums, which resulted in a range of release half-lives from 18 minutes to 350 hours. The novel mechanistic insight provided herein significantly expands the range of release rates amenable to hydroxybenzylammonium-containing compounds. This work provides another way to affect the rate of payload release in hydroxybenzylammoniums.
羟基苄铵化合物在胺释放后可进行可逆的1,4 - 或1,6 - 消除反应，生成醌甲基化物中间体。这些分子可用于将有效载荷与胺进行可逆共轭。我们推测芳香性可作为一种独特的热力学驱动力，用于改变可逆性的速率。我们描述了使用密度泛函理论（DFT）计算来确定芳香性对羟基苄铵化合物中胺释放速率的影响。具体而言，芳香骨架影响脱芳香化反应，以降低动力学势垒并阻止胺消除的可逆性。因此，我们合成了一个小型的多环羟基苄铵文库，其释放半衰期范围为18分钟至350小时。本文提供的新颖机理见解显著扩展了含羟基苄铵化合物适用的释放速率范围。这项工作为影响羟基苄铵中有效载荷释放速率提供了另一种方法。
