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

探索过渡态(TS)本质的最强大的实验技术之一是测量动力学同位素效应(KIE)。KIE的大小和方向包含有关化学反应中的机械性事件的信息，反映了反应物和TS之间成键的差异。然而，将KIE解释为TS结构的度量需要一个完善的理论框架。以前，定性理论可以得出定性的结论，但用于研究有机反应机理的QM技术的发展现在提出了一个问题，即是否可以从KIES中获得有意义的定量信息。到目前为止，许多工人在这个问题上采取了乐观的立场，但最近的一篇重要论文给这个问题带来了一丝冷淡和光明。其结论是，目前的常规QM方法组合不能重现在DMSO中氰离子与氯乙烷的典型SN2反应中六个位置的同位素取代实验测得的Kie范围。这一事实是一个尴尬的现实，它与计算化学的雄心并存，即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。这个项目的目的是研究如何克服关于溶液中简单有机反应的Kies的理论和实验之间的差距，从而将物理有机化学的重要部分带入21世纪。此外，我们希望对过去40或50年来在典型有机反应中观察到的Kie含义的一些公认智慧进行批判性更新，这些智慧主要基于过于简化的理论模型和不合理的假设。我们将介绍的关键发展是反应态和过渡态结构集合的力常数或频率的集合平均，这些集合提供了许多不同溶剂组态的代表性样本。这些快照集合将从分子动力学模拟中产生，力常数将通过结合量子/经典方法来计算，用于反应物种，特别是将分子与周围溶剂的冻结环境相结合。首先有必要将一些方法学的发展集中到一套计算代码中，以便实际应用。这是一项不平凡的工作，因为所提出的应用是新颖的，需要进行重大调整才能针对要解决的分子系统和化学问题类型实现最佳性能。其次，考虑处于平衡状态的分子的同位素效应来开始应用工作是有意义的，因为推荐的系综平均振动频率方案已经为这种情况开发出来了。第三，所有四种KIE应用都涉及脂肪族亲核取代，PI在这方面有经验，但仍然对机械性解释构成重大挑战，目前需要及时解决。

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.