Investigating the influence of fluorination on hydrogen bonding properties of functional groups

有机分子的氟化是改善分子性质的一种广泛的策略，而氢键是最重要的非共价分子间相互作用。本项目旨在对氟化对醇和胺（铵）官能团的氢键性质的影响进行彻底调查，最终目的是提供预测工具，计算作为多功能底物一部分的官能团的这些性质。这一点很重要，因为氟化对官能团氢键性质的影响并不直接：我们的第一个结果表明，在醇旁边引入氟可以导致醇氢键供体能力的增加和减少，清楚地表明了相对构型和位置的至关重要。对于每个官能团，提出了一组专门设计的模型化合物，可以研究氟化对氢键性质的特殊影响。为此目的，构象约束的化合物，允许挑选出一个特定的影响将首先进行研究。在第二阶段，构象柔性模型化合物包含不同的相对立体化学将被评估。这些化合物将被合成，然后进行氢键性质的实验测定。官能团氢键性质的预测将通过理论计算合适的分子描述符来实现，然后将其与实验获得的值相关联，以创建一组线性自由能关系（每个氢键性质对应一个）。部分模型化合物旨在评估微妙的取代基效应，如果成功预测，将被视为我们的多功能底物预测工具准确性的重要测试案例。将采用彻底的构象、NBO和AIM分析来帮助对观察到的效果进行合理化。这将导致建立一套规则或指南，描述氟化如何影响上述官能团的氢键性质，这将进一步增加我们对氟化影响的理解。在可行的情况下，氢键特性将与实验亲脂性和pKa（pKa(H)）值进行比较，这两者都是重要的分子性质。

Fluorination of organic molecules is a widespread tactic to improve molecular properties in many areas, and hydrogen bonding is the most important non-covalent intermolecular interaction. This project aims to undertake a thorough investigation of the effects of fluorination on hydrogen-bonding properties of alcohol and amine (ammonium) functional groups, with as ultimate aim the provision of predictive tools in which these properties can be calculated for functional groups as part of a multifunctional substrate. This is important as the influence of fluorination on hydrogen bonding properties of functional groups is not straightforward: our first results have shown that fluorine introduction next to alcohols can lead to an increase as well as a decrease of the alcohol hydrogen bond donating capacity, clearly demonstrating a crucial importance of the relative configuration and position. For each functional group, a set of specifically designed model compounds is proposed that allows the investigation of particular effects of fluorination on the hydrogen bonding properties. For this purpose, conformationally constrained compounds that allow for singling out a particular effect will be investigated first. In a second stage, conformationally flexible model compounds containing different relative stereochemistries will be evaluated as well. These compounds will be synthesised, followed by experimental determination of hydrogen bonding properties.The prediction of H-bond properties of functional groups will be achieved by theoretical calculation of a suitable molecular descriptor, which will then be correlated with the experimentally obtained values to create a set of Linear Free Energy Relationships (one for each hydrogen bond property). Part of the model compounds aim to evaluate subtle substituent effects, which, if successfully predicted, will be viewed as important test cases for the accuracy of our predictive tool for polyfunctional substrates.Thorough conformational, NBO and AIM analyses will be employed to aid the rationalisation of the observed effects. This will lead to the establishment of a set of rules or guidelines describing how fluorination influences H-bond properties of the abovementioned functional groups, which will further increase our understanding of the effects of fluorination.Where feasible, the hydrogen bonding characteristics will be compared with experimental lipophilicity and pKa (pKa(H)) values, both of which are important molecular properties.