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Overview
Supramolecular catalysis is not a well-defined field but it generally refers to an application of supramolecular chemistry, especially molecular recognition and guest binding, toward catalysis. This field was originally inspired by enzymatic system which, unlike classical organic chemistry reactions, utilizes non-covalent interactions such as hydrogen bonding, cation-pi interaction, and hydrophobic forces to dramatically accelerate rate of reaction and/or allow highly selective reactions to occur. Because enzymes are structurally complex and difficult to modify, supramolecular catalysts offer a 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.

A closely related field of study is asymmetric catalysis which requires molecular recognition to differentiate two chiral starting material or chiral transition states and thus it could be categorized as an area of supramolecular catalysis, but supramolecular catalysis however does not necessarily have to involve asymmetric reaction. As there are other wikipedia articles already written about small molecule asymmetric catalysts, this article focuses primarily on large catalytic host molecules. Non-discrete and structurally poorly defined system such as micelle and dendrimers are not included.

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, but 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. The first simple 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.

In 1993, Rebek et al. developed the first self-assemble 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
Supramolecular catalysts can accelerate the rate of reaction by a variety mechanisms.Three common modes of catalysis are described here.

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 the host. 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.



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. Unlike real enzymes, the binding sites of these catalysts however are rigid structure made from large building blocks.

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.

All of the examples in the above section are developed via the design approach.

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 a TSA to a solid-support or easily 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 studied using this approach.

Catalytic activity screening approach
One problem with transition state analogue selection approach is that catalytic activity is not the screening criteria. The TSA does not necessarily represent the real transition state and so the screened catalyst is just the molecule that best bind to TSA but is not necessarily the best catalyst in the pool. In order to directly and quickly measure the catalytic activity, substrate could be designed to change color or release a fluorescent product upon reaction. Unfortunately the prerequisite for such substrates narrow down the range of reactions for study.

Crabtree et al utilized this method in screening for a hydrosylation catalysts for alkene and imine.

Dynamic combinatorial library approach


In contrast to traditional combinatorial synthesis where a library of catalysts were first generated and later screened, dynamic combinatorial library approach utilizes a mixture of multicomponent building blocks that reversibly form library of catalysts in the presence of the molecule to which binding is desired. This molecule could be the starting material or transition state analog. In equilibrium, the combination of building blocks that affords the best binding to the molecule of interest is thermodynamically favorable and thus that combination is more prevalent than other library members. The high 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, radiation and addition of other chemicals.

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.

Pyruvate oxidase mimic
In nature, pyruvate oxidase employs two cofactors flavin and thiamine pyrophosphate (ThDP) to catalyze a conversion of pyruvate to acetyl phosphate. Diederich et al. mimicked this system by developing a supramolecular catalyst based on cyclophane with two prosthetic arms of flavin and thiazolium group arranged in proximity to the binding site. The enzyme mimic could catalyze an oxidation of aromatic aldehydes to their corresponding methyl ester. This is an example of the design approach.



Successive epoxidation of alkene polymer
Processive enzymes, like DNA polymerase, are biological catalysts that function by attaching to a polymer, performing catalysis repeatedly while moving along the polymer chain, and then dissociating from the polymer. Noite et al mimicked this system by developing a Mn porphyrin rotaxane that treads along a long polymer of alkene and catalyze multiple rounds of alkene epoxidation. Manganese (III) ion in porphyrin is the catalytic center, capable of epoxidation in the presence of an oxygen donor and an activating ligand. Mn has two open faces in the porphyrin complex. With a small ligand such pyridine that binds inside the cavity of the rotaxane, epoxidation happens outside the catalyst. With a large bulky ligand such as tert-butyl pyridine that does not fit inside the cavity however, epoxidation happens on the inside of the catalyst. This is also an example of the design approach.



Nazarov cyclization accelerated by supramolecular encapsulation
Raymond et al. developed a supramolecular host Ga4L6 that self-assembles via metal-ligand interaction in aqueous solution. This container molecule is polyanionic and thus its tetrahedral symmetry cavity is capable of encapsulating and stabilizing a cationic molecule. Consequently, surrounded by negative charges, the encapsulated molecule can be easily protonated. Raymond et al. utilized this property to perform acid-catalyzed Nazarov cyclization. The catalyst accelerates the reaction by over one million fold, making it the most efficient supramolecular catalyst to date. It was proposed that such a high catalytic activity does not arise just from the increased basicity of the encapsulated substrate but also from the constrictive binding that stabilize the transition state of the cyclization. The catalyst has a problem with product inhibition. To by pass that problem, the product of the cyclization reaction was trapped by a dienophile to result in a Diels-Alder adduct that does not fit inside the catalyst cavity anymore.

In this case, the supramolecular host was initially designed to simply capture cationic guests. It was later exploited as a catalyst for Nazarov cyclization.



Asymmetric [2+2] photoadditions in chiral self-assembled supramolecular host
Fujita et al. developed a self-assemble M6L4 supramolecular container that could be converted into a chiral form by an addition of peripheral chiral auxillary. The auxillary diethyldiaminocyclohexane does not directly activate the catalytic site but induces a slight deformation of the triazine plane to create chiral cavity inside the container molecule. This container could then be used to catalyze a [2+2] photoaddition of maleimide and inert aromatic compound fluoranthene, unknown to undergo thermal or photochemical pericyclic reaction, with an enantiomeric excess of 40%.



Asymmetric spiroacetalization catalysed by confined bronsted acids
Inspirted by enzymes with deep active site pocket, List et al. designed and constructed a set of confined Bronsted acids with an extremely sterically demanding chiral pocket based on a C2-symmetric imidodiphosphoric acid. Within the chiral microenvironment, the catalysts has a geometrically fixed bifunctional active site that activates both an electrophile and a nucleophile. This catalyst enables stereoselective spiroacetal formation with high enantiomeric excess in a variety of substrates.



Supramolecular inhibitors
Supramolecules do not only have application in catalysis but also in the opposite, namely, inhibition. A container molecule could encapsulate a guest molecule and thus subsequently renders the guest unreactive. The mechanism of inhibition could either be that the substrate is completely isolated from the reagent or that the container molecule destabilize the transition state of the reaction.

Nitschke et al developed a self-assembly M4L6 supramolecular container with a tetrahedral hydrophobic cavity that can encapsulate white phosphorous inside. Hydrophoric phosphorous, which could self-ignites upon contact with air, is rendered air-stable within the cavity. Even though the hole in the cavity is large enough for oxygen molecule to enter, the transition state of the combustion reaction is too large to fit inside the small cage cavity.



Problems and limitations
After many decades since its birth, supramolecular chemistry’s application in catalysis remains elusive. Supramolecular catalysis has not made significantly contribution to the field of industrial chemistry or synthetic methodology. Here are few problems associated with the catalysis by supramolecules.

Product inhibition
In many catalytic systems, especially ones which were designed to accommodate two substrates, the product of the reaction binds more strongly to the supramolecular catalyst than the substrates do, thus leading to inhibition by the product. As a result, the catalyst is not truly catalytic. A stoichiometric is needed for a full conversion.

Poor transition state stabilization
Most supramolecular catalysts are developed from rigid building blocks in a design to increase enthalpy of complexation. Due to the rigidity even a slight mismatch to the transition state leads to poor stabilization and thus poor catalysis.

Difficulty in synthesis and further adjustment
Syntheses of large complex catalysts are time and resource consuming. An unexpected deviation from the design could be disastrous. Once a catalyst is discovered, modification for further adjustment could be so synthetically challenging that it is easier to study the poor catalyst than to improve it.