Experimental dissection of dispersion energies from electrostatic contributions and solvent effects in face-to-face pi-stacking complexes

我们提出了一个新的实验工具箱来评估面对面“堆叠”芳香体系的结合能，这将有助于分离典型pi-pi配合物的静电和色散贡献。我们的方法是对现有实验方法的补充，例如，小分子结合复合物的研究，分子平衡技术或双突变周期分析，迄今为止，这些方法在审查pi-pi堆叠相互作用的竞争性理论模型方面还没有完全结论性。稳定且几何上定义良好的大环葫芦bbbburil和合适的芳香成分的轮烷化配合物将作为结合第二芳香客体的受体片段。在这个设计中，两种芳香族化合物，即旋转化的芳香族化合物和进入的第二芳香族客体，都保持在面对面的方向（=>高几何控制），并且几乎完全屏蔽与溶剂分子接触（=>最小化溶剂化对总体pi-pi堆叠能的影响）。我们还提出了一条途径，如何在不需要计算处理的情况下，用实验方法解释结合伙伴的解溶剂能量成本。高几何控制性和消除溶剂化效应是其他结合络合物研究的重要优势。此外，生成一个数据库将是直接的，因为第二个芳香结合伙伴可以很容易地混合在一起，而不需要像分子平衡那样以共价拴住。事实上，我们的超分子方法也避免了探测“非最佳”结合几何形状，这可能是共价分子平衡设置的一个缺点。在研究中，我们将首先制备轮烷化配合物，然后用等温滴定量热法（ITC）测量它们与芳香第二客体形成的pi-pi-配合物的结合焓和自由焓。直接获得结合焓将有助于与计算出的pi-pi相互作用能进行比较，因为计算上难以处理的熵分量可以忽略不计。获得自由能（以及熵）将为检验未来改进的理论模型提供有价值的数据集。关于pi-pi堆积几何的信息将通过基于结构的方法获得，如溶液中的核磁共振波谱和结晶配合物的x射线衍射结构分析。通过系统地改变芳香结合伙伴，包括具有典型的“极性”取代基或具有“分散供体”的系统，我们将致力于面对面pi-pi相互作用基序的静电和分散效应的实验分离。这项研究将补充分散相互作用对分子识别和自组装的重要性。

We propose a novel experimental toolbox for evaluating the binding energies of face-to-face “stacking” aromatic systems, which will be of help to separate electrostatic from dispersive contributions for typical pi-pi complexes. Our approach is complementary to existing experimental approaches, e.g. studies with association complexes of small molecules, the molecular balance technique or the double mutant cycle analysis, which have to date not been fully conclusive in scrutinizing competing theoretical models about pi-pi stacking interactions.Stable and geometrically well-defined rotaxanated complexes of the large macrocycle cucurbit[8]uril and a suitable aromatic component will serve as the receptor moiety for binding a second aromatic guest. In this design, both aromatic compounds, i.e. the rotaxanated one, and the incoming second aromatic guest, are hold in a face-to-face orientation (=> high geometric control) and are each almost completely shielded from contact with solvent molecules (=> minimization of solvation effects on the overall pi-pi stacking energy). We also propose a path how the desolvation energy cost of the binding partners can be experimentally accounted for without the need for computational treatments. Both the high geometric control and the subtraction of solvation effects are important advantages over other association-complex-based studies. Furthermore, it will be straightforward to generate a data library, because the second aromatic binding partner can be readily mixed in and does not need to be covalently tethered, as is the case for molecular-balances. In fact, our supramolecular approach also avoids probing a “non-optimal” binding geometry, which can be a shortcoming for covalent molecular-balance setups.In the proposed line of research, we will first prepare the rotaxanated complexes and will then measure by isothermal titration calorimetry (ITC) the binding enthalpies and free enthalpies of their pi-pi-complex formation with aromatic second guests. Having direct access to binding enthalpies will facilitate the comparison to computed pi-pi interaction energies, as the computationally difficult to treat entropic component can be disregarded. Having access to free energies (and thus entropies) will provide a valuable data sets to test future improved theoretical models.Information about the pi-pi stacking geometry will be obtained by structure-based methods such as NMR spectroscopy in solution and X-ray diffraction structure analysis of crystallized complexes. By systematically varying both the aromatic binding partners, including systems with typical “polar” substituents or with “dispersion donors”, we will aim towards an experimental separation of electrostatic and dispersive effects for the face-to-face pi-pi interaction motif. This study will complement the emerging picture of the importance of dispersive interactions for molecular recognition and self-assembly.