Physical Organic Chemistry Centre, School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK.
Pharmaceutical Chemistry Department, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq.
Angew Chem Int Ed Engl. 2018 Jan 22;57(4):982-985. doi: 10.1002/anie.201709163. Epub 2017 Nov 15.
Racemization has a large impact upon the biological properties of molecules but the chemical scope of compounds with known rate constants for racemization in aqueous conditions was hitherto limited. To address this remarkable blind spot, we have measured the kinetics for racemization of 28 compounds using circular dichroism and H NMR spectroscopy. We show that rate constants for racemization (measured by ourselves and others) correlate well with deprotonation energies from quantum mechanical (QM) and group contribution calculations. Such calculations thus provide predictions of the second-order rate constants for general-base-catalyzed racemization that are usefully accurate. When applied to recent publications describing the stereoselective synthesis of compounds of purported biological value, the calculations reveal that racemization would be sufficiently fast to render these expensive syntheses pointless.
外消旋化对分子的生物性质有很大影响，但在水相条件下，具有已知外消旋化速率常数的化合物的化学范围迄今为止受到限制。为了解决这一显著的盲点，我们使用圆二色性和 H-NMR 光谱法测量了 28 种化合物外消旋化的动力学。我们表明，外消旋化的速率常数（由我们自己和其他人测量）与量子力学（QM）和基团贡献计算的去质子化能很好地相关。因此，这些计算为一般碱催化外消旋化的二级速率常数提供了有用的准确预测。当应用于最近描述具有生物价值的化合物的立体选择性合成的出版物时，这些计算表明外消旋化速度会足够快，使这些昂贵的合成变得毫无意义。
