Supramolecular catalysis

A related field of study is asymmetric catalysis which requires molecular recognition to differentiate enantiomeric starting materials.

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,[5] 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.

[2] 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,[8] 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 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.

Although high raise in effective concentration is observed, molecules that employ this mode of catalysis have tiny rate acceleration compared to that of enzymes.

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.

A Diels Alder reaction between two pyridine functionalized substrates normally yield a mixture of endo and exo products.

[18] The traditional approach to supramolecular catalysts focuses on the design of macromolecular receptor with appropriately placed catalytic functional groups.

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.

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.

[20] This problem could perhaps be mended by Baker and Houk's "inside-out approach" which allows a systematic de novo enzyme development.

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.

To develop a high-throughput screen, substrates could be designed to change color or release a fluorescent product upon reaction.

The catalyst has thiazolium ion, a reactive part of ThDP and flavin, a bare-bones core of FAD, in close proximity and near the substrate binding site.

Manganese (III) ion in the porphyrin is the molecule's catalytic center, capable of epoxidation in the presence of an oxygen donor and an activating ligand.

[25] A supramolecular host M4L6 (4 gallium ions and 6 ligands for each complex) self-assembles via metal-ligand interaction in aqueous solution.

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.

To by pass that problem, the product of the cyclization reaction could be reacted with a dienophile transforming it into a Diels-Alder adduct that no longer fits inside the catalyst cavity.

In this case, the auxiliary 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 asymmetrically catalyze a [2+2] photoaddition of maleimide and inert aromatic compound fluoranthene, which previously have not been shown to undergo thermal or photochemical pericyclic reaction.

A 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 and coworkers invented a self-assembly M4L6 supramolecular host with a tetrahedral hydrophobic cavity that can encapsulate white phosphorus.

An enzyme ( TEV protease , PDB : 1lvb ​) is an example of supramolecular catalysts in nature. One goal of supramolecular catalysis is to mimic active site of enzymes.
An early example of enzyme mimics. Cram's 1976 crown ether acyl transfer catalyst. [ 3 ]
Breslow's Regioselective Hydrolysis of Cyclic Phosphate Catalysed by Diimidazole-beta-cyclodextrin [ 4 ]
A chiral substituted crown ether catalyst developed by Jean-Marie Lehn for ester cleavage. The crown ether binds the aminium ion so that the labile group (in red) is positioned next to the reactive group (in blue). [ 13 ]
Hydrogen-bonded glycouril dimer catalyst developed by Julius Rebek Jr. for Diels-Alder reactions. The catalyst encapsulates the diene and dienophile, increasing the effective concentration of reactants.
Generic potential energy diagram showing the effect of a catalyst.
Porphyrin trimer catalyst developed by Jeremy Sanders for exo selective Diels-Alder reactions. The catalyst stabilizes the exo transition state by strategic binding of zinc (II) ion to pyridine nitrogen atoms on the diene and dienophile.
A diagram depicting a use of transition state analog selection approach to select a catalytic antibody.
A diagram depicting a use of catalytic activity screening approach to screen a catalyst.
A diagram depicting a use of dynamic combinatorial library to select an optimal receptor.
Pyruvate oxidase mimic developed by François Diederich. The cyclophane based catalyst utilizes ThDP mimic and FAD mimic to accelerate the oxidation of aldehyde into ester.
A manganese porphyrin catalyst developed by Nolte et al. capable of successive epoxidation of alkene polymer.
A self-assemble gallium catalyst accelerates Nazarov cyclization by stabilizing the cationic transition state. The structure drawn here shows only one ligand for simplicity sake, but there are six ligands on the edges of the tetrahedral complex.
An asymmetric [2+2] photoaddition catalyst based on a tetrahedral palladium complex. The catalyst has chiral diamine auxiliaries that induces the asymmetric change in the cavity.
A chiral constrained Bronsted acid works as an asymmetric spiroacetalization catalyst.
A subcomponent self-assembly tetrahedral capsule developed by Jonathan Nitschke renders pyrophoric white phosphorus air-stable. The structure drawn here shows only one ligand for simplicity sake, but there are six ligands on the edges of the tetrahedral complex.