Coordination cages for bimolecular supramolecular catalysis

被称为酶的生物分子是我们所知道的最好的催化剂。他们可以从复杂的混合物中选择一种起始材料（“基底”），并将其结合在一个改变环境的口袋或腔中，从而控制其化学行为。酶通常是非常特异和高效的，与未催化的反应相比，酶能使反应加速数百万倍。它们还允许发生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1巴的压力、温和的温度和接近中性的ph值的水条件下迅速将不需要的蛋白质转化为葡萄糖。目前已知的最好的合成化学也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，将改变整个合成化学。配位笼——具有大中心空腔的伪球形、空心金属/配体组合物——正成为人工催化剂的潜在候选者。疏水的、受空间限制的中心空腔模拟了蛋白质的结合袋，可以以高强度和选择性结合小分子“客人”。在少数情况下，结合的客体已经被证明在不寻常的环境中经历了更快的反应速率，例如，将客体折叠成接近过渡态的构象，或迫使同一腔中的两个小分子靠近。在人工腔中催化的最著名的例子表明，催化速率提高了10E7倍。在这种背景下，我们刚刚报道了一个最著名的笼型催化的例子。当苯并恶唑被束缚在笼腔中时，苯并恶唑与氢氧化物生成2-氰酚酸盐阴离子的Kemp消去反应被加速了2 × 10E5。产品被释放，因为它是强溶剂化的，这允许催化周转：催化剂执行数百次循环，没有明显的性能损失。由于配位笼具有很高的正电荷，在笼表面的极性位置上积累了氢氧根离子，即使在体溶液中ph为8时，局部的HO-离子浓度也使笼周围的环境相当于pH13，因此反应非常迅速。这是一个非常强大的潜在普遍效应。由于疏水效应和良好的尺寸/形状匹配，基底结合在空腔中。阴离子通过离子配对在笼的外表面积累。这两种识别过程是正交的（彼此独立），可以单独变化：这意味着我们可以使用笼将适合腔的任何基质与笼表面相关的任何阴离子类型的高局部浓度紧密接触。因此，我们为中性底物与阴离子的双分子反应的通用催化剂提供了可能的基础：SN2反应，消去反应，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，以及使用不同腔尺寸的不同笼来研究这种催化行为的范围。每个组分对不同笼结合位点（空腔，非极性；或表面，极性）的亲和力可以独立于其他组分进行建模，研究和测量。要评估的反应包括酯和磷酸酯的水解；苯基卤化物亲电试剂的SN2反应；以及环磺酸烷基的开环。由于我们研究的第一个体系的催化速率提高了2 × 10E5，因此有可能开发一个新的催化剂家族，广泛适用于不同的反应，这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