Determination of pKa in Non-Aqueous Solution using Chemical Shift Imaging

PKA是分子/离子酸度的量度(即它失去质子的难易程度)。它是催化、药理学和化学合成中广泛使用的参数，可以预测物种在溶液中的化学和物理行为。反应性、溶解性和化学相互作用的性质都由分子的质子化状态以及它的pKa决定。PKA通常在水溶液中测定，但通常化合物太难溶解或太活性而不能这样做。DMSO通常用作替代品，因为它是一种相对惰性的非质子溶剂，支持较宽的pKA范围(最高可达35)。水很好地溶解了阳离子和阴离子，而DMSO很好地溶解了阳离子，而阴离子很差，这使得pKaDMSO和PKA(AQ)之间的有意义的比较变得困难。因此，实验测定DMSO中的pKa是必要的。确定PKA的方法有多种，每种方法都有其优缺点。非水的pKA测量增加了另一个方面的困难。在电位滴定方法的例子中，为水溶液测量设计的设备通常必须适应非水介质，有损坏设备和不准确结果的风险。核磁共振滴定方法在文献中是众所周知的，可用的核磁共振活性核范围包括1H，13C和31P。纯化合物不是必需的(因为它们必须用于电导法)，并且在非水介质中的测量不需要对设备进行改造。传统的核磁共振滴定需要获取一大系列在pH递增变化时获得的核磁共振谱。这是一个劳动密集型的过程，需要大量的样品和很长的仪器时间。作为替代，我们发展了一种一次滴定方法来测定化合物在DMSO溶液中的pKa。使用一组核磁共振pH指示器和化学位移成像技术，我们可以测量样品的pH值作为沿核磁共振管内pH梯度的位置的函数。通过一次测量，我们可以确定酸性或碱性分析物的pKa。用这种方法测定的分析物的pKa与文献值(0.1个单位)很好地符合，并被证明是溶液离子强度的自校正。

pKa is a measure of the acidity of a molecule/ion (i.e. the ease with which it loses a proton). It is a widely used parameter in catalysis, pharmacology and chemical synthesis, allowing the prediction of chemical and physical behaviour of species in solution. Reactivity, solubility and the nature of chemical interaction are all governed by the protonation state of a molecule, and thereby its pKa. pKa is usually determined in aqueous solution, but frequently a compound is too insoluble or too reactive to do so. DMSO is commonly used as an alternative, as it is a relatively inert polar aprotic solvent supporting a wide pKa range (up to 35). Water solvates both cations and anions well while DMSO solvates cations well and anions poorly, making meaningful comparisons between pKaDMSO and pKa(aq) difficult. Experimental determination of pKa in DMSO is therefore necessary. Various methods are available to determine pKa, each with its advantages and drawbacks. Non-aqueous pKa measurements add another dimension of difficulty. In the example of potentiometric methods, equipment designed for aqueous measurements often must be adapted to the non-aqueous medium, risking equipment damage and inaccurate results.NMR titration methods are well known in the literature, with a range of NMR active nuclei available including 1H, 13C and 31P. Pure compounds are not necessary (as they must be for conductimetry) and no equipment modification is needed to measure in non-aqueous medium. The conventional NMR titration requires the acquisition of a large series of NMR spectra taken at incrementally changing pH. This is a labour intensive procedure requiring a large sample volume and long instrument times. As an alternative, we have developed a one-shot titration method for determining the pKa of compounds in DMSO solution. Using a set of NMR pH indicators and chemical shift imaging techniques, we can measure the pH of a sample as a function of position along a pH gradient within an NMR tube. From a single measurement we can determine the pKa of an acidic or basic analyte. The pKa of analytes determined using this method are in good agreement with literature values ( 0.1 units) and have been shown to be self-correcting for solution ionic strength.