Supramolecular catalysis refers to an application of supramolecular chemistry, especially molecular recognition and guest binding, toward catalysis. This field precedented by enzymatic system which, unlike classical organic chemistry reactions, utilizes non-covalent interactions such as hydrogen bonding, cation-pi interaction, and hydrophobic forces to accelerate reaction and/or enhanced selectivity . Because enzymes are structurally complex and difficult to modify, supramolecular catalysts offer a potentially simpler model for studying factors involved in catalytic efficiency of the enzyme. Another goal that motivates this field is the development of efficient and practical catalysts that may or may not have an enzyme equivalent in nature. While supramolecular forces no doubt influence many catalytic processes, especially in asymmetric catalysis, none of the examples below has achieved commercialization.
History
The term supramolecular chemistry is defined by Jean-Marie Lehn as "the chemistry of intermolecular bond, covering structures and functions of the entities formed by association of two or more chemical species" in his Nobel lecture in 1987. The concept of supramolecular catalysis was started way earlier in 1946 by Linus Pauling when he founded the theory of enzymatic catalysis in which rate acceleration is the result of non-covalent stabilization of the transition state by the enzymes. Nevertheless, it was not until a few decades later that an artificial enzyme was developed. Early enzyme mimics were based on crown ether and cryptand. In 1976, less than ten years after the discovery of crown ether, Cram et al. developed a functionalized binapthyl crown ether that catalyze transacylation. The catalyst makes use the crown ether motif's ability to capture cation to bind to the ammonium ion part of the substrate and subsequently employs the nearby thiol motif to cleave the ester.
From the early 1970s, cyclodextrins have been extensively studied for its encapsulation properties and used as binding sites in supramolecular catalyst. Cyclodextrins have rigid ring structure, hydrophilic surface, and hydrophobic cavity on the inside; therefore, they are capable of binding organic molecules in aqueous solution. In 1978, with the background knowledge that the hydrolysis of m-tert-butylphenyl acetate is accelerated in the presence of 2-benzimidazoleacetic acid and alpha-cyclodextrin, Brewslow et al. developed a catalyst based on a beta-cyclodextrin carrying two imidazole groups. This cyclodextrin catalytic system mimics ribonuclease A by its use of a neutral imidazole and an imidazolium cation to selective cleave cyclic phosphate substrates. The rate of the reaction is catalyzed 120 times faster, and unlike a hydrolysis by simple base NaOH that gives a 1:1 mixture of the products, this catalysts yield a 99:1 selectivity for one compound.
1993 witness the first self-assembled capsule and in 1997 the so-called "tennis ball" structure was used to catalyze a Diels-Alder reaction. Self-assembled molecules have an advantage over crown ether and cyclodextrin in that they can capture significant larger molecules or even two molecules at the same time. In the following decades, many research groups, such as Makoto Fujita, Ken Raymond, and Jonathan Nitschke, developed cage-like catalysts also from molecular self-assembly principle.
In 2002, Sanders and coworkers published the use of dynamic combinatorial library technique to construct a receptor and in 2003 they employed the technique to develop a catalyst for Diels-Alder reaction.
Mechanism of catalysis Orienting reactive and labile groups
A supramolecular host could bind to a guest molecule in such a way that the guest's labile group is positioned close to the reactive group of another reactive species. The proximity of the two groups enhances the probability that the reaction could occur and thus the reaction rate is increased. This concept is similar to the principle of preorganization which states that complexation could be improved if the binding motifs are preorganized in a well-defined position so that the host does not require any major conformational change for complexation. In this case, the catalyst is preorganized such that no major conformational changes is required for the reaction to occur. A notable example of catalysts that employ this mechanism is Jean-Marie Lehn's crown ether. In addition, catalysts based on functionalized cyclodextrins often employ this mode of catalysis.
Raising the effective substrate concentration
Bimolecular reactions are highly dependent on the concentration of substrates. Therefore, when a supramolecular container encapsulates both reactants within its small cavity, the effective local concentration of the reactants is increased and, as a result of an entropic effect, the rate of the reaction is accelerated. That is to say an intramolecular reaction is faster than its corresponding intermolecular reaction.
Although high raise in effective concentration is observed, molecules that employ this mode of catalysis have tiny rate acceleration compared to that of enzymes. A proposed explanation is that in a container the substrates are not as tightly bound as in enzyme. The reagents have room to wiggle in a cavity and so the entropic effect might not be as important. Even in the case of enzymes, computational studies have shown that the entropic effect might also be overestimated.
Examples of molecules that work via this mechanism are Rebek's tennis ball and Fujita's octahedral complex.
Stabilizing transition state
Supramolecular catalysts can accelerate reactions not only by placing the two reactants in close proximity but also by stabilizing the transition state of the reaction and reducing activation energy. While this fundamental principle of catalysis is common in small molecule or heterogeneous catalysts, supramolecular catalysts however has a difficult time utilizing the concept due to their often rigid structures. Unlike enzymes that can change shape to accommodate the substrates, supramolecules do not have that kind of flexibility and so rarely achieve sub-angstrom adjustment required for perfect transition state stabilization.
An example of catalysts of this type is Sander's porphyrin trimer. A Diels Alder reaction between two pyridine functionalized substrates normally yield a mixture of endo and exo products. In the presence of the two catalysts, however, complete endo selectivity or exo selectivity could be obtained. The underlying cause of the selectivity is the coordination interaction between pyridine and the zinc ion on porphyrin. Depending on the shape of the catalysts, one product is preferred over the other.
Approaches to making supramolecular catalysts
Design approach
The traditional approach to supramolecular catalysts focuses on the design of macromolecular receptor with appropriately placed catalytic functional groups. These catalysts are often inspired by the structure of enzymes with the catalytic group mimicking reactive amino acid residues, but unlike real enzymes, the binding sites of these catalysts are rigid structure made from chemical building blocks. All of the examples in this article are developed via the design approach.
Jeremy Sanders pointed out that the design approach has not been successful and has produced very few efficient catalysts because of rigidity of the supramolecules. He argued that rigid molecules with a slight mismatch to the transition state cannot be an efficient catalyst. Rather than investing so much synthesis effort on one rigid molecule that we cannot determine its precise geometry to the sub-angstrom level which is required for good stabilization, Sanders suggested the use of many small flexible building blocks with competing weak interactions so that it is possible for the catalyst to adjust its structure to accommodate the substrate better. There is a direct trade-off between the enthalpic benefit from flexible structure and the entropic benefit from rigid structure. Flexible structure could perhaps bind the transition state better but it allows more room for the substrates to move and vibrate. Most supramolecular chemists in the past prefer to build rigid structures out of fear of entropic cost.
This problem could perhaps be mended by Baker and Houk's "inside-out approach" which allows a systematic de novo enzyme development. This computational method starts simply with a predicted transition state structure and slowly builds outward by optimizing the arrangement of functional groups to stabilize the transition state. Then it fills out the remainder of the active site and, finally, it generates an entire protein scaffold that could contain the designed active site. This method could potentially be applied to supramolecular catalysis, although a plethora of chemical building blocks could easily overwhelm the computational model intended to work with 20 amino acids.
Transition state analogue selection/screening approach
Assuming that catalytic activity largely depends on the catalyst's affinity to the transition state, one could synthesize a transition state analog (TSA), a structure that resembles the transition state of the reaction. Then one could link the TSA to a solid-support or identifiable tag and use that TSA to select an optimal catalyst from a mixture of many different potential catalysts generated chemically or biologically by a diversity oriented synthesis. This method allows quick screening of a library of diverse compounds. It does not require as much synthetic effort and it allows a study of various catalytic factors simultaneously. Hence the method could potentially yield an efficient catalyst that we could not have designed with our current knowledge.
Many catalytic antibodies were developed and studied using this approach.
Catalytic activity screening approach
A problem with transition state analogue selection approach is that catalytic activity is not a screening criterion. TSAs do not necessarily represent real transition states and so a catalyst obtained from screening could just be the best receptor for a TSA but is not necessarily the best catalyst. To circumvent this problem, catalytic activity needs to be measured directly and also quickly. To develop a high-throughput screen, substrates could be designed to change color or release a fluorescent product upon reaction. For example, Crabtree and coworkers utilized this method in screening for a hydrosylation catalysts for alkene and imine. Unfortunately the prerequisite for such substrates narrow down the range of reactions for study.
Dynamic combinatorial library approach
In contrast to traditional combinatorial synthesis where a library of catalysts were first generated and later screened (as in the two above approaches), dynamic combinatorial library approach utilizes a mixture of multicomponent building blocks that reversibly form library of catalysts. With out a template, the library consists of a roughly equal mixture of different combination of building blocks. In the presence of a template which is either a starting material or a TSA, the combination that provides the best binding to the template is thermodynamically favorable and thus that combination is more prevalent than other library members. The biased ratio of the desired catalyst to other combinatorial products could then be frozen by terminating the reversibility of the equilibrium by means such as change in temperature, pH, or radiation to yield the optimal catalyst. For example, Lehn et al. used this method to create a dynamic combinatorial library of imine inhibitor from a set of amines and a set of aldehydes. After some time, the equilibrium was terminated by an addition of NaBH3CN to afford the desired catalyst.
Examples of supramolecular catalysts
Pyruvate oxidase mimic