Coordination cages for bimolecular supramolecular catalysis

被称为酶的生物分子是我们所知的最好的催化剂。他们可以从复杂的混合物中选择一种起始材料(底物)，并将其绑定在口袋或空腔中，从而改变其环境，从而控制其化学行为。酶通常是非常特异和非常有效的，与非催化反应相比，它可以加速数百万倍的反应。它们还允许其他情况下根本不会发生的反应。例如，使用酶作为催化剂，人体可以在含水、1bar压力、温和的温度和近中性的pH条件下迅速将不需要的蛋白质转化为葡萄糖。已知的最好的合成化学无法达到这种程度的合成灵活性。制备与生物催化剂一样有效的人工催化剂的能力将具有巨大的价值，将改变所有合成化学。配位笼--具有大中心空腔的假球形、中空的金属/配体组合--正在成为潜在的人工催化剂候选者。疏水的、空间受限的中心空腔模仿蛋白质的结合口袋，可以高强度和选择性地结合小分子“客体”。在少数情况下，被束缚的客体在不寻常的环境中发生的反应速度要快得多，例如，这种环境会将客体折叠成接近过渡态的构象，或者迫使同一腔中的两个小分子接近。在人工空腔中最著名的催化例子显示，催化速率提高了10E7倍。在此背景下，我们刚刚报道了最著名的笼状催化例子之一。苯并恶唑与氢氧化物反应生成2-氰基苯酚阴离子的Kemp消除反应，当苯并异恶唑被束缚在笼腔中时，Kemp消除速度加快了2×10E5。该产品被释放，因为它是强烈的溶剂化，这允许催化剂周转：催化剂执行数百次循环，没有明显的性能损失。这种催化之所以起作用，是因为具有高正电荷的配位笼在笼子表面的极性位置积累了氢氧化物离子：即使在主体溶液的pH值为8的情况下，HO-离子的局部浓度也使笼子周围的环境相当于ph13，因此反应非常快。这是一个非常强大和潜在的普遍效应。由于疏水效应和腔的良好尺寸/形状匹配，衬底结合在腔内。通过离子配对，阴离子聚集在笼子的外表面。这两个识别过程是正交的(彼此独立)，并且可以单独变化：这意味着我们可以使用笼子使适合腔内的任何底物与与笼子表面相关的任何阴离子类型的高局部浓度密切接触。因此，对于中性底物与阴离子的双分子反应，我们有了一个通用的通用催化剂的基础：SN2反应，消除反应，水解反应都是可行的。我们将通过不同的底物类型和不同的阴离子，以及通过使用不同空腔尺寸的不同笼子来考察这种催化行为的范围。每个组分对不同笼结合部位(空腔的、非极性的或表面的、极性的)的亲和力可以相互独立地建模、研究和测量。待评价的反应将包括酯和磷酸酯的水解反应；苄基卤化物亲电试剂上的SN2反应；以及环烷基硫酸盐的开环反应。对于我们研究的第一个体系，我们研究的第一个体系的催化速率提高了2×10E5。我们有机会开发出一种新的催化剂家族，该家族具有广泛的适用性，将在该领域处于世界领先地位，并将改变超分子催化领域。

Biological molecules known as enzymes are the best catalysts that we know. They can select a starting material ('substrate') from a complex mixture and bind it in a pocket or cavity which changes its environment so that its chemical behaviour is controlled. Enzymes are typically very specific and very efficient, accelerating reactions by factors of millions compared to the uncatalysed reaction. They also allow reactions that would not occur otherwise at all. For example, using enzymes as catalysts the human body can quickly convert unwanted protein into glucose in aqueous conditions, 1 bar pressure, mild temperatures, and near-neutral pH. The best synthetic chemistry known cannot begin to approach this degree of synthetic flexibility.The ability to prepare artificial catalysts that are as effective as biological ones would be of immense value, transforming all of synthetic chemistry. Coordination cages - pseudo-spherical, hollow, metal/ligand assemblies with large central cavities - are emerging as potential candidates as artificial catalysts. The hydrophobic, sterically restricted central cavities mimic the binding pockets of proteins and can bind small molecule 'guests' with high strength and selectivity. In a small handful of cases, bound guests have been shown to undergo substantially faster reaction rates arising from the unusual environment which (for example) folds up guests into conformations approximating to transition states, or forces two small molecules in the same cavity into close proximity. The best known example of catalysis in an artificial cavity demonstrates a catalytic rate enhancement of 10E7 times.Against this background we have just reported one of the best known examples of cage-based catalysis. The Kemp elimination - reaction of benzisoxazole with hydroxide to generate the 2-cyanophenolate anion - is accelerated by 2 x 10E5 when the benzisoxazole is bound in the cage cavity. The product is released as it is strongly solvated, which allows catalytic turnover: the catalyst performs hundreds of cycles with no noticeable loss of performance. The catalysis works because the coordination cage, which has a high positive charge, accumulates hydroxide ions at polar sites on the cage surface: even at pH8 in the bulk solution, the local concentration of HO- ions makes the environment around the cage equivalent to pH13 so that the reaction is very fast.This is a very powerful and potentially general effect. Substrates bind in the cavity due to the hydrophobic effect and a good size / shape match for the cavity. Anions accumulate on the exterior surface of the cage by ion-pairing. The two recognition processes are orthogonal (independent of one another) and can be varied separately: which means that we can use the cage to bring any substrate that fits in the cavity into close contact with a high local concentration of any anion type that associates with the cage surface. Thus we have a possible basis for a versatile and general catalyst for bimolecular reactions of neutral substrates with anions: SN2 reactions, eliminations, hydrolysis reactions are all feasible.We will investigate the scope of this catalytic behaviour by varying substrate types and varying anions, and by using different cages with different cavity dimensions. The affinity of each component for the different cage binding sites (cavity, non-polar; or surface, polar) can be modelled, investigated and measured independently of the other. Reactions to be evaluated will include hydrolyses of esters and phospho-esters; SN2 reactions on benzylic halide electrophiles; and ring-opening of cyclic alkyl sulfates. Gives the catalytic rate enhancement of 2 x 10E5 for the first system we investigated there is scope to develop a new family of catalysis with wide applicability to different reactions which would be world-leading in the field and would transform the field of supramolecular catalysis