†University Chemical Laboratory, Cambridge CB2 1EW, United Kingdom.
‡Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900 Brazil.
Acc Chem Res. 2015 Jul 21;48(7):1806-14. doi: 10.1021/acs.accounts.5b00072. Epub 2015 Jun 15.
Historically, the chemistry of phosphate transfer-a class of reactions fundamental to the chemistry of Life-has been discussed almost exclusively in terms of the nucleophile and the leaving group. Reactivity always depends significantly on both factors; but recent results for reactions of phosphate triesters have shown that it can also depend strongly on the nature of the nonleaving or "spectator" groups. The extreme stabilities of fully ionised mono- and dialkyl phosphate esters can be seen as extensions of the same effect, with one or two triester OR groups replaced by O(-). Our chosen lead reaction is hydrolysis-phosphate transfer to water: because water is the medium in which biological chemistry takes place; because the half-life of a system in water is an accepted basic index of stability; and because the typical mechanisms of hydrolysis, with solvent H2O providing specific molecules to act as nucleophiles and as general acids or bases, are models for reactions involving better nucleophiles and stronger general species catalysts. Not least those available in enzyme active sites. Alkyl monoester dianions compete with alkyl diester monoanions for the slowest estimated rates of spontaneous hydrolysis. High stability at physiological pH is a vital factor in the biological roles of organic phosphates, but a significant limitation for experimental investigations. Almost all kinetic measurements of phosphate transfer reactions involving mono- and diesters have been followed by UV-visible spectroscopy using activated systems, conveniently compounds with good leaving groups. (A "good leaving group" OR* is electron-withdrawing, and can be displaced to generate an anion R*O(-) in water near pH 7.) Reactivities at normal temperatures of P-O-alkyl derivatives-better models for typical biological substrates-have typically had to be estimated: by extended extrapolation from linear free energy relationships, or from rate measurements at high temperatures. Calculation is free from these limitations, able to handle very slow reactions as readily as very fast ones, and capable of predicting rate constants with levels of accuracy acceptable to the experimentalist. We present an updated overview of phosphate transfer, with particular reference to the mechanisms of the reactions of alkyl derivatives and triesters. The intention is to present a holistic (not comprehensive!) overview of the reactivity of typical phosphate esters, in terms familiar to the working chemist, at a level sufficient to support informed predictions of reactivity for structures of interest.
从历史上看，磷酸转移反应——一类对生命化学至关重要的反应——几乎完全是根据亲核试剂和离去基团来讨论的。反应性始终取决于这两个因素；但最近对磷酸三酯反应的研究结果表明，它也强烈依赖于非离去或“旁观者”基团的性质。完全离子化的单烷基和二烷基磷酸酯的极端稳定性可以看作是同一效应的延伸，其中一个或两个三酯 OR 基团被 O(-)取代。我们选择的主导反应是水解-磷酸转移到水中：因为水是生物化学发生的介质；因为系统在水中的半衰期是稳定性的公认基本指标；并且因为水解的典型机制，其中溶剂 H2O 提供特定的分子作为亲核试剂和通用酸或碱，是涉及更好的亲核试剂和更强的通用物种催化剂的反应的模型。尤其是那些在酶活性位点中可用的催化剂。烷基单酯二阴离子与烷基二酯单阴离子竞争估计最慢的自发水解速率。在生理 pH 值下的高稳定性是有机磷酸酯在生物学中的重要作用，但对实验研究来说也是一个显著的限制。几乎所有涉及单酯和二酯的磷酸转移反应的动力学测量都是通过使用激活系统的紫外可见光谱法进行的，方便的是具有良好离去基团的化合物。（“良好离去基团”OR* 是吸电子基团，并且可以在接近 pH 7 的水中被取代以生成阴离子 R*O(-)。）在正常温度下 P-O-烷基衍生物的反应性——典型生物底物的更好模型——通常必须通过从线性自由能关系的扩展外推或通过高温下的速率测量来估计：计算不受这些限制的影响，能够同样容易地处理非常缓慢的反应和非常快速的反应，并能够以实验化学家可接受的准确度预测速率常数。我们介绍了磷酸转移的最新概述，特别参考了烷基衍生物和三酯反应的机制。目的是以对工作化学家来说熟悉的术语，提供典型磷酸酯反应的反应性的整体（非全面！）概述，以足够支持对感兴趣结构的反应性的明智预测。
