A computational framework for interpretation of kinetic isotope effects for organic reactions in solution

探测跃迁态（TS）性质的最有力的实验技术之一是动力学同位素效应（KIE）的测量。KIE的大小和方向包含了化学反应中机制事件的信息，反映了反应物和TS之间键合的差异。然而，将KIE解释为TS结构的度量需要一个健全的理论框架。以前，定性理论可以得出定性结论，但用于有机反应机制研究的QM技术的发展现在提出了一个问题，即是否可以从ky中获得有意义的定量信息。迄今为止，许多工人对这个问题持乐观态度，但最近一篇重要论文对这个问题投下了一束冰冷而明亮的光芒。结果表明，在氰化物阴离子与氯乙烷在DMSO中进行SN2反应时，现有的传统QM方法不能再现实验中测量到的六个位置的同位素取代的KIEs范围。这一事实是一个尴尬的现实，与计算化学的雄心——为已知化学行为的合理化和未知行为的预测提供可靠的模型——格格不入。本项目的目的是研究如何克服溶液中简单有机反应的量子力学理论与实验之间的差距，从而将物理有机化学的一个重要组成部分带入21世纪。此外，我们希望对过去40或50年来积累的关于在原型有机反应中观察到的KIEs意义的一些公认的智慧进行关键更新，这些智慧主要基于过度简化的理论模型和不合理的假设。我们将介绍的关键进展是对反应态和过渡态区域的结构集合的力常数或频率的集合平均，它提供了许多不同溶剂构型的代表性样品。这些快照集合将从分子动力学模拟中生成，并通过结合量子/经典方法计算反应物种和特定溶剂化分子与周围溶剂的冷冻环境的力常数。首先有必要把一些方法上的发展汇集成一套实际应用的计算代码。这是一项重要的工作，因为所提出的应用是新颖的，需要进行重大调整，以实现分子系统类型和要解决的化学问题的最佳性能。其次，考虑平衡状态分子的同位素效应开始应用工作是有意义的，因为针对这种情况已经开发了推荐的总体平均振动频率协议。第三，所有四种KIE应用都涉及脂肪族亲核取代，PI对此有经验，但仍然存在机制解释方面的重大挑战，现在需要及时解决。

One of the most powerful experimental techniques for probing the nature of the transition state (TS) is the measurement of a kinetic isotope effect (KIE). The magnitude and direction of a KIE contains information about the mechanistic events in a chemical reaction, reflecting differences in bonding between the reactants and the TS. However, the interpretation of a KIE as a measure of TS structure requires a sound theoretical framework. Previously, qualitative theories have allowed qualitative conclusions to be drawn, but the development of QM techniques for the study of organic reaction mechanisms now poses questions regarding whether meaningful quantitative information can be obtained from KIEs. Many workers have hitherto assumed an optimistic stance on this question, but a recent important paper has cast a ray of cold, bright light upon the issue. It concludes that the current portfolio of conventional QM methods is not capable of reproducing the range of KIEs measured experimentally for isotopic substitution at six positions in a prototypical SN2 reaction of cyanide anion with chloroethane in DMSO. This fact is an awkward reality that sits uneasily alongside the ambition of computational chemistry to provide reliable models for the rationalisation of known chemical behaviour and the prediction of unknown behaviour.The aim of this project is to investigate ways to overcome this gap between theory and experiment concerning KIEs for simple organic reactions in solution, and thereby to bring an important part of physical organic chemistry into the 21st century. Furthermore, we wish to perform a critical update on some of the received wisdom concerning the meaning of KIEs observed in prototypical organic reactions that has accumulated over the past 40 or 50 years, largely on the basis of over-simplified theoretical models and unjustified assumptions.The key development we will introduce is ensemble averaging of force constants or frequencies for collections of structures in the region of the reactant state and of the transition state which provide representative samples of many different solvent configurations. These ensembles of snapshots will be generated from molecular dynamics simulations, and the force constants will be computed by combined quantum/classical methods for reacting species and specifically solvating molecules with the frozen environment of the surrounding solvent.It is necessary first to bring together a number of methodological developments into a suite of computational codes for practical application. This is a non-trivial exercise since the applications proposed are novel, and significant tweaking will be required to achieve optimal performance for the types of molecular systems and chemical problems to be addressed. Second, it makes sense to begin the applications work by considering isotope effects for molecules at equilibrium since the recommended protocol for ensemble-averaged vibrational frequencies has been developed for this case. Third, all four KIE applications involve aliphatic nucleophilic substitution, with which the PI has experience but which still present significant challenges for mechanistic interpretation that are timely to address now.