SHARPER NMR: fast and accurate analysis of molecules, reactions and processes

核磁共振（NMR）光谱是一种非常有用的分析技术，它在医学、生物学、地球科学、物理和化学等科学领域都有应用。它可以在生物体、固态材料或溶解在液体中的分子上进行。本文主要研究溶液态核磁共振波谱。溶液态核磁共振是化学家的主要技术。它已经存在了70年，但在发展、改进和提高效率方面没有任何放缓的迹象。核磁共振与其他光谱的区别在于核磁共振实验对象的原子核（我们通常称之为自旋）激发态的寿命。它们的寿命在几毫秒到几秒之间，这使得科学家们可以在信号采集之前，或者现在，在信号采集期间，设计出精细的自旋操纵方法。这些操作的目的是获得有关分子结构或化学状态的特定信息，包括与其他分子的相互作用。这样的操作很重要，有几个原因：(i)有时有太多的东西要看，我们需要简化核磁共振光谱，以便获得我们需要的信息。（ii）核磁共振是一种相对不敏感的技术，与质谱（MS）等其他分析技术相比，核磁共振需要大量的材料（通常是毫克的数量，相比之下，微米、纳克甚至皮克的数量对MS来说就足够了）。（iii）在其标准实现中，NMR可能太慢，无法监控在毫秒到秒时间尺度上发生的快速过程。（iv）理想情况下，溶液态核磁共振是在均相样品上进行的，而标准技术很难提供关于非均相系统的高质量信息，例如，在两种不混相液体的界面上发生的过程的表征，或者当气体在溶液中起泡时。该提案解决了上述困难，旨在设计新的核磁共振技术，允许在尚不可能获得信息的情况下（例如异构系统）获得信息，或者在效率（节省时间）和获得信息质量方面对现有技术进行明显改进。核磁共振参数的准确性将得到提高，这些参数最终被解释为提供化学结构、表征化学反应或确定分子大小。重点是(i)监测快速化学反应；（ii）表征分子大小；（iii）超越分子的一级结构（单个原子彼此连接的顺序），了解原子在三维空间中的排列方式（构象，三级结构）。这些信息对于我们理性化分子间相互作用（例如药物与生物大分子的相互作用）的能力至关重要。所提出的技术的另一个重要方面是它们可以应用于复杂系统。传统上，核磁共振在研究纯化合物方面非常出色，但直到今天，它仍在努力研究它们作为混合物的一部分。在现实生活中，从混合物中分离出单个分子并不总是可能的，因此许多行业必须学会如何有效地处理混合物。我们将与台式核磁共振光谱仪的制造商合作，将开发的技术直接引入通风柜和生产线，走出专门的核磁共振实验室。我们预计，我们将开发的新方法将广泛应用于学术和工业研究。

Nuclear Magnetic Resonance (NMR) spectroscopy is a very useful analytical technique, which has applications across the range of sciences, including medicine, biology, geosciences, physics and chemistry. It can be performed on living organisms, solid state materials, or molecules dissolved in liquids. This proposal focusses on the solution state NMR spectroscopy.Solution state NMR is a bread and butter technique for chemists. It has been around for 70 years, but does not show any sign of slowing down in its development, improvement, and increased efficiency. What distinguishes NMR from other spectroscopies is the longevity of the excited states of nuclei (or spins, as we often called them) that are subjects of NMR experiments. Their lifetime on the order of milliseconds to seconds allows scientists to design elaborate ways of spin manipulation before, or these days also during, signal acquisition. The purpose of these manipulations is to obtain specific information about the structure or the chemical state of the molecule, including interactions with other molecules.Such manipulations are important for several reasons: (i) sometimes there is too much to see and we need to simplify NMR spectra in order to access the information we require. (ii) NMR is a relatively insensitive technique and compared to other analytical techniques, such as for example mass spectrometry (MS), requires large amounts of material (typically milligram quantities, compared to micro, nano grams or even pico grams that are sufficient for MS). (iii) In its standard implementation, NMR can be too slow to monitor fast processes that are occurring on millisecond to second times scales. (iv) Ideally, solution state NMR is performed on homogeneous samples and standard techniques struggle to provide high quality information about heterogeneous system, e.g. characterisation of processes taking place at the interface of two immiscible liquids, or when a gas is bubbled through a solution.This proposal addresses the difficulties outlined above and aims to design novel NMR techniques that allow information to be obtained under circumstances where this is not as yet possible (e.g. heterogeneous systems), or bring evident improvements to existing techniques in terms of efficiencies (time saving) and quality of information obtained. Accuracy of NMR parameters, that are ultimately interpreted to provide chemical structures, characterise chemical reactions, or determine molecular sizes, will be improved. The focus is on (i) monitoring of fast chemical reactions and (ii) characterising molecular sizes and (iii) going beyond the primary structure of molecules (the order in which the individual atoms are connected to each other) to how the atoms are arranged in the three-dimensional space (conformation, tertiary structure). Such information is crucial to our ability to rationalise intermolecular interactions (e.g. interactions of drugs with biomacromolecules). Another important aspect of the proposed techniques is that they can be applied to complex systems. NMR has traditionally been very good in studying pure compounds, but to this day struggles to study them as part of mixtures. In real life situations it is not always possible to separate out individual molecules from mixtures, and many industries must learn how to deal with mixtures efficiently. We will work with a manufacture of benchtop NMR spectrometers to bring the developed techniques directly into fume hoods and production lines, out of the specialised NMR laboratories. We anticipate that the new methods we will develop will be applied across a wide spectrum of academic and industrial research.