Supramolecular catalysis

An enzyme (TEV protease 1lvm) is an example of supramolecularcatalysts in nature. One goal of supramolecular catalysis is tomimic active site of enzymes.

Supramolecular catalysis is not a well-defined field butit generally refers to an application of supramolecularchemistry, especially molecular recognition and guestbinding, toward catalysis.[1][2] This field was originallyinspired by enzymatic system which, unlike classical or-ganic chemistry reactions, utilizes non-covalent interac-tions such as hydrogen bonding, cation-pi interaction, andhydrophobic forces to dramatically accelerate rate of re-action and/or allow highly selective reactions to occur.Because enzymes are structurally complex and difficultto modify, supramolecular catalysts offer a simpler modelfor studying factors involved in catalytic efficiency of theenzyme.[3]:1 Another goal that motivates this field is thedevelopment of efficient and practical catalysts that mayor may not have an enzyme equivalent in nature.A closely related field of study is asymmetric catalysiswhich requires molecular recognition to differentiate twochiral starting material or chiral transition states and thusit could be categorized as an area of supramolecular catal-ysis, but supramolecular catalysis however does not nec-essarily have to involve asymmetric reaction. As thereis another Wikipedia article already written about smallmolecule asymmetric catalysts, this article focuses pri-marily on large catalytic host molecules. Non-discreteand structurally poorly defined system such as micelle anddendrimers are not included.

1 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

An early example of enzyme mimics. Crams 1976 crown etheracyl transfer catalyst.[4]

Breslows Regioselective Hydrolysis of Cyclic Phosphate Catal-ysed by Diimidazole-beta-cyclodextrin[5]

by association of two or more chemical species in hisNobel lecture in 1987,[6] but the concept of supramolecu-lar catalysis was started way earlier in 1946 by Linus Paul-ing when he founded the theory of enzymatic catalysis inwhich rate acceleration is the result of non-covalent sta-bilization of the transition state by the enzymes.[7] Never-theless, it was not until a few decades later that an artificialenzyme was developed. The first simple enzyme mimicswere based on crown ether and cryptand.[8] In 1976, lessthan ten years after the discovery of crown ether, Cramet al. developed a functionalized binapthyl crown etherthat catalyze transacylation.[4] The catalyst makes use thecrown ether motifs ability to capture cation to bind tothe ammonium ion part of the substrate and subsequentlyemploys the nearby thiol motif to cleave the ester.

1

https://en.wikipedia.org/wiki/TEV_proteasehttps://en.wikipedia.org/wiki/Active_sitehttps://en.wikipedia.org/wiki/Supramolecular_chemistryhttps://en.wikipedia.org/wiki/Supramolecular_chemistryhttps://en.wikipedia.org/wiki/Enzymehttps://en.wikipedia.org/wiki/Non-covalent_interactionshttps://en.wikipedia.org/wiki/Non-covalent_interactionshttps://en.wikipedia.org/wiki/Asymmetric_catalysishttps://en.wikipedia.org/wiki/Asymmetric_catalysishttps://en.wikipedia.org/wiki/Micellehttps://en.wikipedia.org/wiki/Dendrimers

2 2 MECHANISM OF CATALYSIS

From the early 1970s, cyclodextrins have been exten-sively studied for its encapsulation properties and usedas binding sites in supramolecular catalyst.[2] Cyclodex-trins have rigid ring structure, hydrophilic surface, andhydrophobic cavity on the inside; therefore, they arecapable of binding organic molecules in aqueous so-lution. In 1978, with the background knowledge thatthe hydrolysis of m-tert-butylphenyl acetate is acceler-ated in the presence of 2-benzimidazoleacetic acid andalpha-cyclodextrin,[9] Brewslow et al. developed a cat-alyst based on a beta-cyclodextrin carrying two imida-zole groups. This cyclodextrin catalytic system mimicsribonuclease A by its use of a neutral imidazole and animidazolium cation to selective cleave cyclic phosphatesubstrates. The rate of the reaction is catalyzed 120 timesfaster, and unlike a hydrolysis by simple base NaOH thatgives a 1:1 mixture of the products, this catalysts yield a99:1 selectivity for one compound.[5]

In 1993, Rebek et al. developed the first self-assemblecapsule[10] and in 1997 the so-called tennis ball struc-ture was used to catalyze a Diels-Alder reaction.[11] Self-assembled molecules have an advantage over crown etherand cyclodextrin in that they can capture significant largermolecules or even two molecules at the same time. Inthe following decades, many research groups, such asMakoto Fujita, Ken Raymond, and Jonathan Nitschke,developed cage-like catalysts also from molecular self-assembly principle.In 2002, Sanders and coworkers published the use ofdynamic combinatorial library technique to construct areceptor[12] and in 2003 they employed the technique todevelop a catalyst for Diels-Alder reaction.[13]

2 Mechanism of catalysis

Three common modes of catalysis are described here.

2.1 Orienting reactive and labile groups

A supramolecular host could bind to a guest moleculein such a way that the guests labile group is positionedclose to the reactive group of the host. The proximityof the two groups enhances the probability that the reac-tion could occur and thus the reaction rate is increased.This concept is similar to the principle of preorganizationwhich states that complexation could be improved if thebinding motifs are preorganized in a well-defined positionso that the host does not require any major conforma-tional change for complexation.[15] In this case, the cat-alyst is preorganized such that no major conformationalchanges is required for the reaction to occur. A notableexample of catalysts that employ this mechanism is Jean-Marie Lehns crown ether.[14] In addition, catalysts basedon functionalized cyclodextrins often employ this modeof catalysis.[16]:88

A chiral substituted crown ether catalyst developed by Jean-MarieLehn for ester cleavage. The crown ether binds the aminium ionso that the labile group (in red) is positioned next to the reactivegroup (in blue).[14]

2.2 Raising the effective substrate concen-tration

Bimolecular reactions are highly dependent on the con-centration of substrates. Therefore, when a supramolecu-lar container encapsulates both reactants within its smallcavity, the effective local concentration of the reactantsis increased and, as a result of an entropic effect, the rateof the reaction is accelerated.[16]:89 That is to say an in-tramolecular reaction is faster than its corresponding in-termolecular reaction.Although high raise in effective concentration is ob-served, molecules that employ this mode of catalysis havetiny rate acceleration compared to that of enzymes. Aproposed explanation is that in a container the substratesare not as tightly bound as in enzyme. The reagents haveroom to wiggle in a cavity and so the entropic effect mightnot be as important. Even in the case of enzymes, compu-tational studies have shown that the entropic effect mightalso be overestimated.[17]

Examples of molecules that work via this mecha-nism are Rebeks tennis ball and Fujitas octahedralcomplex.[11][18]

2.3 Stabilizing transition state

Supramolecular catalysts can accelerate reactions notonly by placing the two reactants in close proximity butalso by stabilizing the transition state of the reaction andreducing activation energy.[16]:89 While this fundamentalprinciple of catalysis is common in small molecule or het-

https://en.wikipedia.org/wiki/Cyclodextrinshttps://en.wikipedia.org/wiki/Ken_Raymondhttps://en.wikipedia.org/wiki/Molecular_self-assemblyhttps://en.wikipedia.org/wiki/Molecular_self-assemblyhttps://en.wikipedia.org/wiki/Supramolecular_chemistry#Template-directed_synthesishttps://en.wikipedia.org/wiki/Molecularityhttps://en.wikipedia.org/wiki/Thermodynamic_activityhttps://en.wikipedia.org/wiki/Catalysis#Reaction_energeticshttps://en.wikipedia.org/wiki/Catalysis#Reaction_energetics

3.1 Design approach 3

Hydrogen-bonded glycouril dimer catalyst developed by JuliusRebek Jr. for Diels-Alder reactions. The catalyst encapsulatesthe diene and dienophile, increasing the effective concentrationof reactants.

Generic potential energy diagram showing the effect of a catalyst.

erogeneous catalysts, supramolecular catalysts howeverhas a difficult time utilizing the concept due to their oftenrigid structures. Unlike enzymes that can change shapeto accommodate the substrates, supramolecules do nothave that kind of flexibility and so rarely achieve sub-angstrom adjustment required for perfect transition statestabilization.[3]:2

An example of catalysts of this type is Sanders por-phyrin trimer. A Diels Alder reaction between two pyri-dine functionalized substrates normally yield a mixtureof endo and exo products. In the presence of the twocatalysts, however, complete endo selectivity or exo se-lectivity could be obtained. The underlying cause of theselectivity is the coordination interaction between pyri-dine and the zinc ion on porphyrin. Depending on theshape of the catalysts, one product is preferred over theother.[19]

3 Approaches to makingsupramolecular catalysts

3.1 Design approach

The traditional approach to supramolecular catalysts fo-cuses on the design of macromolecular receptor withappropriately placed catalytic functional groups. These

Porphyrin trimer catalyst developed by Jeremy Sanders for exoselective Diels-Alder reactions. The catalyst stabilizes the exotransition state by strategic binding of zinc (II) ion to pyridinenitrogen atoms on the diene and dienophile.

catalysts are often inspired by the structure of enzymeswith the catalytic group mimicking reactive amino acidresidues, but unlike real enzymes, the binding sites ofthese catalysts are rigid structure made from chemicalbuilding blocks.[20] All of the examples in this article aredeveloped via the design approach.Jeremy Sanders pointed out that the design approach hasnot been successful and has produced very few efficientcatalysts because of rigidity of the supramolecules. Heargued that rigid molecules with a slight mismatch to thetransition state cannot be an efficient catalyst. Ratherthan investing so much synthesis effort on one rigidmolecule that we cannot determine its precise geometryto the sub-angstrom level which is required for good sta-bilization, Sanders suggested the use of many small flex-ible building blocks with competing weak interactions sothat it is possible for the catalyst to adjust its structureto accommodate the substrate better.[21] There is a di-rect trade-off between the enthalpic benefit from flexiblestructure and the entropic benefit from rigid structure.[3]:3Flexible structure could perhaps bind the transition statebetter but it allows more room for the substrates to moveand vibrate. Most supramolecular chemists in the pastprefer to build rigid structures out of fear of entropiccost.[21]

This problem could perhaps be mended by Baker andHouk's inside-out approach which allows a system-atic de novo enzyme development.[22] This computationalmethod starts simply with a predicted transition statestructure and slowly builds outward by optimizing the ar-rangement of functional groups to stabilize the transitionstate. Then it fills out the remainder of the active site and,finally, it generates an entire protein scaffold that couldcontain the designed active site. This method could po-tentially be applied to supramolecular catalysis, althougha plethora of chemical building blocks could easily over-whelm the computational model intended to work with

https://en.wikipedia.org/wiki/David_Baker_(biochemist)https://en.wikipedia.org/wiki/Kendall_Houk

4 4 PROMINENT EXAMPLES OF SUPRAMOLECULAR CATALYSTS

20 amino acids.

3.2 Transition state analogue selec-tion/screening approach

A diagram depicting a use of transition state analog selection ap-proach to select a catalytic antibody.

Assuming that catalytic activity largely depends on thecatalysts affinity to the transition state, one could syn-thesize a transition state analog (TSA), a structure thatresembles the transition state of the reaction. Then onecould link the TSA to a solid-support or identifiable tagand use that TSA to select an optimal catalyst from amixture of many different potential catalysts generatedchemically or biologically by a diversity oriented synthe-sis. This method allows quick screening of a library ofdiverse compounds. It does not require as much syntheticeffort and it allows a study of various catalytic factors si-multaneously. Hence the method could potentially yieldan efficient catalyst that we could not have designed withour current knowledge.[20]

Many catalytic antibodies were developed and studied us-ing this approach.

3.3 Catalytic activity screening approach

A diagram depicting a use of catalytic activity screening ap-proach to screen a catalyst.

A problem with transition state analogue selection ap-proach is that catalytic activity is not a screening criteria.TSAs do not necessarily represent real transition statesand so a catalyst obtained from screening could just bethe best receptor for a TSA but is not necessarily the bestcatalyst. To circumvent this problem, catalytic activity

needs to be measured directly and also quickly. To de-velop a high-throughput screen, substrates could be de-signed to change color or release a fluorescent productupon reaction. For example, Crabtree and coworkers uti-lized this method in screening for a hydrosylation cata-lysts for alkene and imine.[23] Unfortunately the prereq-uisite for such substrates narrow down the range of reac-tions for study.[20]

3.4 Dynamic combinatorial library ap-proach

A diagram depicting a use of dynamic combinatorial library toselect an optimal receptor.

In contrast to traditional combinatorial synthesis where alibrary of catalysts were first generated and later screened(as in the two above approaches), dynamic combinato-rial library approach utilizes a mixture of multicompo-nent building blocks that reversibly form library of cat-alysts. With out a template, the library consists of aroughly equal mixture of different combination of build-ing blocks. In the presence of a template which is either astarting material or a TSA, the combination that providesthe best binding to the template is thermodynamically fa-vorable and thus that combination is more prevalent thanother library members. The biased ratio of the desiredcatalyst to other combinatorial products could then befrozen by terminating the reversibility of the equilibriumby means such as change in temperature, pH, or radiationto yield the optimal catalyst.[20] For example, Lehn et al.used this method to create a dynamic combinatorial li-brary of imine inhibitor from a set of amines and a set ofaldehydes. After some time, the equilibrium was termi-nated by an addition of NaBH3CN to afford the desiredcatalyst.[24]

4 Prominent examples ofsupramolecular catalysts

4.1 Diederichs pyruvate oxidase mimic

In nature, pyruvate oxidase employs two cofactorsthiamine pyrophosphate (ThDP) and Flavin adenine din-

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4.3 Raymonds Nazarov cyclization catalyst 5

ucleotide (FAD) to catalyze a conversion of pyruvate toacetyl phosphate. First, ThDP mediates a decarboxyla-tion of pyruvate and generates an active aldehyde as aproduct. The aldehyde is then oxidized by FAD and issubsequently attacked by phosphate to yield acetyl phos-phate.Diederich and coworkers mimicked this system with asupramolecular catalyst based on cyclophane. The cata-lyst has thiazolium ion, a reactive part of ThDP and flavin,a bare-bones core of FAD, in close proximity and near thesubstrate binding site. The catalytic cycle is almost thesame as that in nature, except the substrate is an aromaticaldehyde rather than pyruvate. First, the catalyst bindsthe substrate within its cyclophane ring. Then, it uses thi-azolium ion to condense with the substrate generating anactive aldehyde. This aldehyde is oxidized by flavin andthen attacked by methanol to yield a methyl ester.[25]

Pyruvate oxidase mimic developed by Franois Diederich. Thecyclophane based catalyst utilizes ThDP mimic and FAD mimicto accelerate the oxidation of aldehyde into ester.

4.2 Noltes successive epoxidation catalystfor alkene polymer

Processive enzymes are proteins that catalyze consecu-tive reactions without releasing its substrate. An exampleof processive enzymes is RNA polymerase which bindsto a DNA strand and repeatedly catalyzes nucleotidetransfers, effectively synthesizing a corresponding RNAstrand.Nolte and coworkers developed an artificial processiveenzyme in a form of manganese porphyrin rotaxane thattreads along a long polymer of alkene and catalyze mul-tiple rounds of alkene epoxidation. Manganese (III) ionin the porphyrin is the molecules catalytic center, capa-ble of epoxidation in the presence of an oxygen donorand an activating ligand. With a small ligand such pyri-dine that binds manganese from inside the cavity of therotaxane, epoxidation happens outside the catalyst. Witha large bulky ligand such as tert-butyl pyridine that doesnot fit inside the cavity however, epoxidation happens onthe inside of the catalyst.[26]

A manganese porphyrin catalyst developed by Nolte et al. capa-ble of successive epoxidation of alkene polymer.

4.3 Raymonds Nazarov cyclization cata-lyst

Raymond and coworkers developed a supramolecularhost M4L6 (4 gallium ions and 6 ligands for each com-plex) that self-assembles via metal-ligand interaction inaqueous solution. This container molecule is polyanionicand thus its tetrahedron-shaped cavity is capable of en-capsulating and stabilizing a cationic molecule. Conse-quently, encapsulated molecule can be easily protonatedas a resulting carbocation from protonation is stabilizedby the surrounding anions. Raymond utilized this prop-erty to perform acid-catalyzed Nazarov cyclization. Thecatalyst accelerates the reaction by over one million fold,making it the most efficient supramolecular catalyst todate. It was proposed that such a high catalytic activitydoes not arise just from the increased basicity of the en-capsulated substrate but also from the constrictive bind-ing that stabilize the transition state of the cyclization.Unfortunately, this catalyst has a problem with productinhibition. To by pass that problem, the product of thecyclization reaction could be reacted with a dienophiletransforming it into a Diels-Alder adduct that no longerfits inside the catalyst cavity.[1]

In this case, the supramolecular host was initially de-signed to simply capture cationic guests. Almost a decadelater, it was exploited as a catalyst for Nazarov cyclization.

4.4 Fujitas chiral self-assembled catalystfor asymmetric [2+2] photoadditions

Fujita and coworkers discovered a self-assemble M6L4(6 palladium ions and 4 ligands in each complex)supramolecular container that could be enhanced into achiral supramolecule by an addition of peripheral chiralauxiliary. In this case, the auxiliary diethyldiaminocy-clohexane does not directly activate the catalytic site butinduces a slight deformation of the triazine plane to cre-ate chiral cavity inside the container molecule. This

https://en.wikipedia.org/wiki/Flavin_adenine_dinucleotidehttps://en.wikipedia.org/wiki/Cyclophanehttps://en.wikipedia.org/wiki/Processivityhttps://en.wikipedia.org/wiki/Product_inhibitionhttps://en.wikipedia.org/wiki/Product_inhibitionhttps://en.wikipedia.org/wiki/Diels%E2%80%93Alder_reaction

6 6 PROBLEMS AND LIMITATIONS

A self-assemble gallium catalyst developed by Ken Raymond ac-celerates Nazarov cyclization by stabilizing the cationic transitionstate. The structure drawn here shows only one ligand for sim-plicity sake, but there are six ligands on the edges of the tetrahe-dral complex.

container could then be used to asymmetrically catalyzea [2+2] photoaddition of maleimide and inert aromaticcompound fluoranthene, which previously have not beenshown to undergo thermal or photochemical pericyclicreaction. The catalyst yields an enantiomeric excess of40%.[27]

An asymmetric [2+2] photoaddition catalyst based on a tetrahe-dral palladium complex developed by Makoto Fujita. The cat-alyst has chiral diamine auxiliaries that induces the asymmetricchange in the cavity.

4.5 Lists confined Bronsted acid as a cata-lyst for asymmetric spiroacetalization

Inspired by enzymes with deep active site pocket, Listand coworkers designed and constructed a set of con-fined Bronsted acids with an extremely sterically demand-ing chiral pocket based on a C2-symmetric bis(binapthyl)imidodiphosphoric acid. Within the chiral microenvi-ronment, the catalysts has a geometrically fixed bifunc-tional active site that activates both an electrophilic partand a nucleophilic part of a substrate. This catalystenables stereoselective spiroacetal formation with highenantiomeric excess for a variety of substrates.[28]

A chiral constrained Bronsted acid developed by Benjamin Listworks as an asymmetric spiroacetalization catalyst.

5 Supramolecular inhibitors

Supramolecular containers do not only have an applica-tion in catalysis but also in the opposite, namely, inhi-bition. A container molecule could encapsulate a guestmolecule and thus subsequently renders the guest unreac-tive. A mechanism of inhibition could either be that thesubstrate is completely isolated from the reagent or thatthe container molecule destabilize the transition state ofthe reaction.Nitschke and coworkers invented a self-assembly M4L6supramolecular host with a tetrahedral hydrophobic cav-ity that can encapsulate white phosphorus. Pyrophoricphosphorus, which could self-combust upon contact withair, is rendered air-stable within the cavity. Even thoughthe hole in the cavity is large enough for an oxygenmolecule to enter, the transition state of the combustionis too large to fit wthin the small cage cavity.[29]

6 Problems and limitations

After many decades since its inception, supramolecularchemistrys application in practical catalysis remains elu-sive. Supramolecular catalysis has not yet made signif-icant contribution in the area of industrial chemistry orsynthetic methodology.[21] Here are few problems asso-ciated with this field.

https://en.wikipedia.org/wiki/Allotropes_of_phosphorus#White_phosphorushttps://en.wikipedia.org/wiki/Pyrophoricity

7

A subcomponent self-assembly tetrahedral capsule developed byJonathan Nitschke renders pyrophoric white phosphorus air-stable. The structure drawn here shows only one ligand for sim-plicity sake, but there are six ligands on the edges of the tetrahe-dral complex.

6.1 Product inhibition

In many supramolecular catalytic systems designed towork with bimolecular addition reactions like the Diels-Alder, the product of the reaction binds more strongly tothe supramolecular host than the two substrates do, con-sequently leading to inhibition by the product. As a result,these catalysts has a turnover number of one and are nottruly catalytic. A stoichiometric quantity of the catalystsis needed for a full conversion.[30]

6.2 Poor transition state stabilization

Most supramolecular catalysts are developed from rigidbuilding blocks because rigid blocks are less complicatedthan flexible parts in constructing a desired shape andplacing functional groups where the designer wants. Dueto the rigidity, however, a slight mismatch from the tran-sition state inevitably leads to poor stabilization and thuspoor catalysis. In nature, enzymes are flexible and couldchange their structures to bind a transition state betterthan their native form.[21]

6.3 Difficulty in synthesis and further ad-justment

Syntheses of large complex catalysts are time and re-source consuming. An unexpected deviation from thedesign could be disastrous. Once a catalyst is discovered,modification for further adjustment could be so syntheti-cally challenging that it is easier to study the poor catalystthan to improve it.[21]

7 See also

Supramolecular Chemistry

Host-Guest Chemistry

Molecular Encapsulation

Artificial enzyme

Asymmetric catalysis

8 References[1] Raymond, K. N.; Hastings, C. J.; Pluth, M. D.; Bergman,

R. G. (2010). Enzymelike Catalysis of the Nazarov Cy-clization by Supramolecular Encapsulation. Journal ofthe American Chemical Society 132 (20): 69386940.doi:10.1021/ja102633e.

[2] Nolte, R. J. M.; Vriezema, D. M.; Aragone, M. C.; Ele-mans, J. J. A. W.; Cornelissen, J. J. L. M.; Rowan, A. E.(2005). Self-Assembled Nanoreactors. Chemical Re-views 105 (4): 14451489. doi:10.1021/cr0300688.

[3] van Leeuwen, P. W. N. M. (2008). SupramolecularCatalysis. Weinheim: Wiley-VCH Verlag GmbH & Co.KGaA. ISBN 978-3-527-32191-9.

[4] Cram, D. J.; Chao, Y. (1976). Enzyme Mechanisms,Models, and Mimics. Journal of the American ChemicalSociety 98 (4): 10151017. doi:10.1021/ja00420a026.

[5] Breslow, R.; Doherty, J. B.; Guillot, G.; Lipsey, C.(1978). The Use of Cycloamylose to Probe the Charge-Relay System. Journal of the American Chemical Society100 (10): 32273229. doi:10.1021/ja00478a052.

[6] Lehn, J. (1988). Selection and Amplification ofa Catalyst from a Dynamic Combinatorial Library.Angewandte Chemie International Edition 27 (1): 89112.doi:10.1002/anie.198800891.

[7] Pauling, L. (1946). Molecular Architecture and Biolog-ical Reactions. Chemical and Engineering News 24 (10):13751377. doi:10.1021/cen-v024n010.p1375.

[8] Kirby, A. J. (1996). Enzyme Mechanisms, Models, andMimics. Angewandte Chemie International Edition 35(7): 706724. doi:10.1002/anie.199607061.

[9] Bender, M. L.; Komiyama,M.; Breaux, E. J. (1977). TheUse of Cycloamylose to Probe the Charge-Relay System.Bioorganic Chemistry 6 (2): 127136. doi:10.1016/0045-2068(77)90015-3.

[10] Rebek, J. Jr.; Wyler, R.; de Mendoza J. (1993). A Syn-thetic Cavity Assembles Through Self-ComplementaryHydrogen Bonds. Angewandte Chemie International Edi-tion 32 (12): 16991701. doi:10.1002/anie.199316991.

[11] Rebek, J. Jr; Kang, J. (1997). Acceleration of a DielsAlder Reaction by a Self-Assembled Molecular Capsule.Nature 385 (661): 5052. doi:10.1038/385050a0.

https://en.wikipedia.org/wiki/Supramolecular_chemistryhttps://en.wikipedia.org/wiki/Host%E2%80%93guest_chemistryhttps://en.wikipedia.org/wiki/Molecular_encapsulationhttps://en.wikipedia.org/wiki/Artificial_enzymehttps://en.wikipedia.org/wiki/Asymmetric_catalysishttps://en.wikipedia.org/wiki/Ken_Raymondhttps://en.wikipedia.org/wiki/Journal_of_the_American_Chemical_Societyhttps://en.wikipedia.org/wiki/Journal_of_the_American_Chemical_Societyhttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1021%252Fja102633ehttps://en.wikipedia.org/wiki/Chemical_Reviewshttps://en.wikipedia.org/wiki/Chemical_Reviewshttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1021%252Fcr0300688https://en.wikipedia.org/wiki/International_Standard_Book_Numberhttps://en.wikipedia.org/wiki/Special:BookSources/978-3-527-32191-9https://en.wikipedia.org/wiki/Journal_of_the_American_Chemical_Societyhttps://en.wikipedia.org/wiki/Journal_of_the_American_Chemical_Societyhttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1021%252Fja00420a026https://en.wikipedia.org/wiki/Journal_of_the_American_Chemical_Societyhttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1021%252Fja00478a052https://en.wikipedia.org/wiki/Angewandte_Chemiehttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1002%252Fanie.198800891https://en.wikipedia.org/wiki/Chemical_and_Engineering_Newshttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1021%252Fcen-v024n010.p1375https://en.wikipedia.org/wiki/Angewandte_Chemiehttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1002%252Fanie.199607061https://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1016%252F0045-2068%252877%252990015-3https://dx.doi.org/10.1016%252F0045-2068%252877%252990015-3https://en.wikipedia.org/wiki/Julius_Rebekhttps://en.wikipedia.org/wiki/Angewandte_Chemiehttps://en.wikipedia.org/wiki/Angewandte_Chemiehttps://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1002%252Fanie.199316991https://en.wikipedia.org/wiki/Julius_Rebekhttps://en.wikipedia.org/wiki/Nature_(journal)https://en.wikipedia.org/wiki/Digital_object_identifierhttps://dx.doi.org/10.1038%252F385050a0

8 8 REFERENCES

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[13] Otto, S.; Brisig, B.; Sanders, J. K. M. (2003). Selectionand Amplification of a Catalyst from a Dynamic Combi-natorial Library. Angewandte Chemie International Edi-tion 42 (11): 12701273. doi:10.1002/anie.200390326.

[14] Lehn, J.; Sirlin, C. (1978). Molecular Catalysis: En-hanced Rates of Thiolysis with High Structural and ChiralRecognition in Complexes of a Reactive Macrocyclic Re-ceptor Molecule. Chemical Communications (21): 949951. doi:10.1039/C39780000949.

[15] Cram, D. J. (1988). The Design of MolecularHosts, Guests, and Their Complexes. AngewandteChemie International Edition 27 (8): 10091020.doi:10.1002/anie.198810093.

[16] Beer, P.; Gale, P. A.; Smith, D. K. (1999). Supramolecu-lar Chemistry. New York: Oxford University Press. ISBN0-19-850447-0.

[17] Warshel, A.; Aaqvist, J. (1993). The Design of Molec-ular Hosts, Guests, and Their Complexes. Chemical Re-views 93 (7): 25232544. doi:10.1021/cr00023a010.

[18] Fujita, M.; Yoshizawa, M.; Tamura, M. (2006). Diels-Alder in Aqueous Molecular Hosts: Unusual Regioselec-tivity and Efficient Catalysis. Science 312 (5771): 251254. doi:10.1126/science.1124985.

[19] Sanders, J. K. M.; Walter, C. J.; Anderson, H.L. (1993). Exo-Selective Scceleration of an Inter-molecular DielsAlder Reaction by a Trimeric Por-phyrin Host. Chemical Communications (5): 458460.doi:10.1039/C39930000458.

[20] Motherwell, W. B.; Bingham, M. J.; Six, Y. (2001).Recent Progress in the Design and Synthesis of Ar-tificial Enzymes. Tetrahedron 57 (22): 46634686.doi:10.1016/S0040-4020(01)00288-5.

[21] Sanders, J. K. M. (1998). Supramolecular Catal-ysis in Transition. Chemistry - A European Jour-nal 4 (8): 13781383. doi:10.1002/(SICI)1521-3765(19980807)4:83.0.CO;2-3.

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History Mechanism of catalysis Orienting reactive and labile groups Raising the effective substrate concentration Stabilizing transition state

Approaches to making supramolecular catalysts Design approach Transition state analogue selection/screening approach Catalytic activity screening approach Dynamic combinatorial library approach

Prominent examples of supramolecular catalysts Diederichs pyruvate oxidase mimic Noltes successive epoxidation catalyst for alkene polymer Raymonds Nazarov cyclization catalyst Fujitas chiral self-assembled catalyst for asymmetric [2+2] photoadditions Lists confined Bronsted acid as a catalyst for asymmetric spiroacetalization

Supramolecular inhibitors Problems and limitations Product inhibition Poor transition state stabilization Difficulty in synthesis and further adjustment

See also References Text and image sources, contributors, and licensesTextImagesContent license