Artificial Allosteric Receptors

Artificial Allosteric Receptors

Christopher Kremer and Arne L�tzen*[a]

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REVIEWDOI: 10.1002/chem.201203814

Introduction

Oligo- and multitopic receptors are omnipresent in naturebecause multivalent binding[1,2] and cooperative binding[3–5]

are two major concepts to ensure the necessary efficiencyand selectivity in biological recognition events and the com-plex cascades of processes coupled to these. Allosteric regu-lation is one of the most interesting examples for this be-cause it is arguably the most widely used mechanism inorder to control functions of certain proteins and enzymesin cellular metabolism.[6] The term allosteric, derived fromthe Greek words allos, meaning “the other” and stereos,meaning “solid”, was coined by Monod[7] and Koshland,[8]

and describes cooperative effects in binding of more thanone substrate selectively to different binding sites of a re-ceptor. These effects show in a conformational change ofthe receptor due to the binding of an effector in the so-called “allosteric site”, resulting in an activating (positivecooperation) or deactivating (negative cooperation) mannerin terms of the binding of another substrate at a differentbinding site. One can distinguish homotropic and heterotrop-ic mechanisms, determining if the effector and the substrateare identical or different molecules or ions.

A well-known example for a homotropic allosteric proteinis hemoglobin. Its affinity to oxygen increases with everyoxygen molecule that is bound to one of the four oxygenbinding sites due to conformational changes induced byevery binding event (Figure 1).

Another well-studied example is the aspartate-transcarba-moylase (ATCase) of Escherichia coli. This enzyme self-as-sembles from twelve protein subunits and is liable to multi-ple allosteric regulation. One of them is a feedback inhibi-tion by cytidine triphosphate (CTP)—in this case as an ex-ample for a heterotropic, negatively cooperative allosteric

system. Figure 2 shows a cut-out of the enzyme�s structurethat is formed from two trimeric catalytic and three dimericregulatory subunits in order to demonstrate the conforma-tional changes upon binding of CTP as an effector.[11,12]

Binding of the CTP results in adopting the inactive T-statewhereas the enzyme changes its conformation to the activeR-state in the absence of the effector.

Representing such a powerful tool for controlling bindingproperties and associated processes, the concept of allostericregulation has attracted a lot of interest in supramolecularchemistry and stimulated many efforts to develop artificialreceptor systems that can be controlled by allosteric effectsover the last 30 years. Probably the earliest work in thisfield came from Rebek, Jr. in the late 1970s/early 1980swhen he described heterotropic systems based on crownethers containing a 3,3’-disubstitued 2,2’-bipyridine unit (1,Scheme 1).[13–15] These showed negative cooperative bindingof alkali metal ions in the presence of suitable transitionmetal salts or complex fragments (HgCl2, ZnCl2, PdCl2, or

Abstract: Cooperative effects in the binding of two ormore substrates to different binding sites of a receptorthat are a result of a conformational change caused by thebinding of the first substrate—also referred to as the ef-fector—are called allosteric effects. In biological systems,allosteric regulation is a widely used mechanism to controlthe function of proteins and enzymes in cellular metabo-lism. Inspired by this a lot of efforts have been made insupramolecular chemistry to implement this concept intoartificial systems to control functions as molecular recog-nition, signal amplification, or even reactivity and cataly-

sis. This review gives an up-to-date overview over the dif-ferent approaches that have been reported ever since thefirst examples from the late 1970s/early 1980s. It coversboth homo- and heterotropic examples and is divided ac-cording to the nature of the effector—cationic, anionic, orneutral—effectors and systems that use combinations ofthose.

Keywords: allosteric effects · conformational switches ·cooperativity · molecular recognition · supramolecularchemistry

[a] Dipl.-Chem. C. Kremer, Prof. Dr. A. L�tzenUniversit�t Bonn, Kekul�-Institut f�r Organische Chemieund BiochemieGerhard-Domagk-Strasse 1, 53121 Bonn (Germany)Fax: (+49) 228-73-9608E-mail : [email protected]

Figure 1. X-ray crystal structures of desoxy- (A)[9] and oxyhemoglobin(B).[10] The label shows one of the conformational changes upon bindingdioxygen.

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W(CO)4) that bind to the bipyridine[13,14] but positive coop-erative binding of Hg ACHTUNGTRENNUNG(CF3)2 by the crown ether when PdCl2

was bound to the bipyridine.[15]

Rebek, Jr. and co-workers were also one of the first to in-troduce a homotropic system (2, Scheme 2) which revealednegative cooperative binding of alkali metal ions (probablydue to disruptive coulomb interactions) but positive cooper-ative binding of Hg(CN)2.

[16]

Another early heterotropic example was reported by Beerand co-workers in 1986 when he could demonstrate that

copper(II) ions facilitate binding of potassium ions in asandwich-type manner by bis(crown ether) 3,[17] although, inthis case, the role of who is effector and who is substrate isnot fully determined (Scheme 3).

One year later Dervan and co-workers reported on thefirst system where coordination of an alkaline earth metalion caused a conformational change in 4 that made two ne-tropsin moieties adopt an orientation that allowed both of

Figure 2. Cut-outs of X-ray crystal structures of ATCase in its inactive T-form due to binding of CTP to the regulatory subunits (left) and in itscatalytically active R-form with N-(phosphonacetyl)-l-aspartate (Pala) asa bisubstrate analogue bound in the active site (right).

Scheme 1. Rebek, Jr.�s and co-workers� heterotropic bipyridyl crownether 1: negatively cooperative binding of an alkali metal ion and transi-tion metal complex fragments.

Scheme 3. Beer�s and co-workers� heterotropic bis(crown ether) 3 : posi-tively cooperative binding of two different metal ions in acetone/MeOH3:1.

Dipl.-Chem. Christopher Kremer (left) studied chemistry in Bonn and re-ceived his Diploma in 2010. Since then he has been working on his PhDproject devoted to the development of new artificial allosteric systems.Prof. Dr. Arne L�tzen (right) obtained his PhD from the University ofOldenburg under the supervision of Prof. Dr. Peter Kçll in the field of car-bohydrate chemistry. He then joined the group of Prof. Dr. Julius Rebek,Jr. at the Scripps Research Institute in La Jolla, USA as a postdoc. He re-turned to Oldenburg to work on his habilitation in the field of supramolec-ular chemistry. After a short time at the University of Duisburg-Essen hemoved to the University of Bonn in 2006. His research interests includevarious areas of supramolecular chemistry including self-assembly of met-allo-supramolecular aggregates and p-conjugated molecules, allosteric ef-fects, molecular recognition, and analytical tools for supramolecular chem-istry, and organic synthesis.Scheme 2. Rebek, Jr.�s and co-workers� homotropic bis(crown ether) 2 :

positively cooperative binding of Hg(CN)2 in MeOH.

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REVIEWArtificial Allosteric Receptors

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them to interact with double-stranded DNA in water pre-sumably via minor-groove binding (Scheme 4).[18]

In fact artificial systems often offer the advantage to ex-hibit a stronger conformational coupling compared to theirnatural models because of the smaller and often much morerigid architectures in contrast to the larger and more flexibleframeworks of for example, proteins.[19,20]

To decide if a system is truly allosteric the first task is todemonstrate the conformational changes of a receptor uponbinding to an effector which is the prerequisite for allostericbinding by any analytical tool. Once this is achieved theeasiest way to determine the degree of cooperativity of ef-fector and substrate binding is to compare the associationconstants for the binding of the substrate in presence and inabsence of the effector. A more sophisticated analysis canbe done by ascertaining the so-called Hill coefficient from aHill plot.[21] The idea behind this plot is that the binding of nguest molecules G to a receptor H can be described as asingle step interaction resulting in the binding constant K[Eq. (1)].

K ¼ ½HGn�=ð½H� ½G�nÞ ð1Þ

Introducing the degree of saturation Y which is defined inEquation (2), the Hill equation results as Equation (3).

Y ¼ ½HGn�=ðn ½H�totalÞ ð2Þ

logfY=ð1�YÞg ¼ n log ½G� þ log ½K� ð3Þ

h ¼ d ½logfY=ð1�YÞg�=dðlog½G�Þ ð4Þ

The slope of this plot where [G] is the free guest concentra-tion at 50 % saturation gives the Hill coefficient h accordingto Equation (4). If h= 1 the individual binding events arenon-cooperative. If h < 1 the system shows negative cooper-

ativity and it varies between 1 < h � n for positive coopera-tivity.[22, 23]

A number of supramolecular systems based on the con-cept of allosteric effects have been established since the firstexamples mentioned above and the subject has been issueof some reviews[24–36] already although not all of them werereally focused on allosteric effects.[26,28,31, 34–36] Since most ofthese are at least about 10 years old and almost all coveronly certain aspects of this field the aim of this review is togive a more comprehensive overview of artificial homotrop-ic and heterotropic allosteric receptors where the interactionof a substrate with a synthetic receptor is influenced by aconformational change upon binding of an effector.

Therefore, this review will not cover biomolecules such asDNA, PNA, RNA, proteins, or their folding. It will also notcover pure self-assembly processes such as oligomerisationor ion-pair binding resulting in contact ion pairs unless thereis a clearly detectable conformational change of the receptorupon binding to one of the ions. It will also not describe theuse of electrons or protons as effectors which are usually re-ferred to as redox or pH switches.

We will divide the different approaches according to thenature of the effector—cationic, anionic, or neutral effectorsand systems that use combinations of those—and we will listhomotropic and heterotropic as well as positive and negativecooperative examples in these classes.

Cations as Allosteric Effectors

Due to the enormous variety of reliable cation bindingmotifs such as crown ethers, podands, calixarenes, or chelat-ing ligands such as 2,2’-bipyridines, diamines, or salen li-gands, and the relatively large amount of binding energythat can be gained from cation complexation to overcomeenergetic differences between different conformations, cati-ons—in most cases simple metal ions—are by far the mostemployed class of effectors.

Homotropic Systems

As already shown in Scheme 2, the first example of a homo-tropic system was realized by Rebek, Jr.[16] in the early1980s. His bis(crown ether) showed negative cooperativebinding of alkali metal ions.

Later cerium(IV) porphyrin double decker complexes in-troduced by Shinkai and co-workers proved to be a very ver-satile allosteric center that can be decorated with a broadvariety of binding sites for different species, among themcrown ether moieties (5)[37] or simple electron rich aromaticgroups (6).[38,39] In the unbound state the two porphyrins ofthe double decker complex 5 can rotate quite fast which hin-ders complexation of a first potassium ion by 5 in a sand-wich-type manner. Once the first potassium is bound, how-ever, binding of the next three is much facilitated(Scheme 5).

Scheme 4. Dervan�s and co-workers� heterotropic bis(netropsin) DNAbinder 4 : alkaline earth metal ion induced minor groove binding.



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The p-clefts of 6 were used to bind silver(I) ions in a posi-tive cooperative fashion (Scheme 6). Interestingly, however,only three silver(I) ions were found to be bound to 6 despiteits four-fold symmetry. Furthermore, the conformationalchange induced upon binding of the first silver(I) ion mustput the two porphyrins further apart from each other whichresults even in an acceleration of the rotational movement.Thus, the structural impression given in Scheme 6 shouldnot be regarded as granted.[39]

Homotropic negatively cooperative allostery was ob-served for the binding of alkali metal ions by a bis-

ACHTUNGTRENNUNG(calix[4]arene)-based receptor (7) developed by Nabeshimaand co-workers.[40] Here, binding of a first ion changes theconformation of 7 in such a way that the second binding sitegets hardly accessible for the second ion (Scheme 7).

Sessler and co-workers demonstrated homotropic posi-tively cooperative binding of soft metal ions by a Schiff baseoligopyrrolic macrocycle 8.[41] In this case, the binding of asilver(I)-salt like silver(I) trifluoroacetate or silver(I) tosy-late enforces the binding of another silver ion by changingthe orientation of the pyrrolic units and thus creating a less-hindered and better preorganized coordination site

Scheme 5. Shinkai�s and co-workers� homotropic cerium(IV) bis(porphyr-in) double decker complex 5 : positively cooperative binding of alkalimetal ions in CHCl3/CH3CN 1:1. Binding of the first cation slows downthe rotational oscillation of the two porphyrin units, and hence, facilitatesbinding of additional cations.

Scheme 6. Shinkai�s and co-workers� homotropic cerium(IV) bis(porphyr-in) double decker complex 6 : positively cooperative binding of three sil-ver(I) ions in CHCl3/MeOH 4:1.

Scheme 7. Nabeshima�s and co-workers� homotropic bis ACHTUNGTRENNUNG(calix[4]arene) re-ceptor 7: negatively cooperative binding of alkali metal ions in toluene/CH3CN 6:5.




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(Scheme 8). As expected for such a cooperative process,even under conditions of intermediate binding site satura-tion, no NMR-signals ascribable to a mono-AgI-complexwere observed.

Another allosteric homotropic system was presented byYagi and co-workers.[42] By binding of a Ca2+ ion, bis-squar-aine-ligand 9 gets preorganized for the binding of anotherCa2+ ion on the opposite binding site (Scheme 9). This reac-tion can be repeated several times to form metallo-supramo-lecular assemblies. This is an interesting result, for squarainedyes have gained much attention because of their opticaland electrochemical properties.[43]

Rowan and co-workers were able to demonstrate that re-ceptors for organic cations can also show homotropic allos-teric binding.[44] Their porphyrin 10 capped by two glycolur-ils revealed highly negatively cooperative binding of violo-gens (11) because binding of the first guest is only possibleupon expansion of the first cavity. This, however, leads to apinching of the opposite cavity which is then too small to ac-commodate the second viologen ion (Scheme 10).

Isaacs and co-workers designed a receptor 12 that isbased on a nor-seco-cucurbit[10]uril that can take up twoguest molecules.[45] If two different-sized guests are used,only homomeric host–guest complexes can be observed.However, in the case of two similar-sized guests heteromericcomplexes were also formed. This indicates that binding ofthe first guest preorganizes the cavity for the second guest(Scheme 11).

Heterotropic Positively Cooperative Binding ofOther Cations

Heterotropic positively cooperative systems belong to thebest studied allosteric systems and the first examples havealready been published in the early 1980s, for example, re-ceptors 1[15] and 3[17] shown in Schemes 1 and 3. Most ofthese employ transition metal ions as effectors and most ofthem can be divided into two different classes.

Scheme 8. Sessler�s and co-workers� homotropic oligopyrrolic receptor 8 :positively cooperative binding of silver(I) salts in THF.

Scheme 9. Yagi�s and co-workers� bis(squaraine) ligand 9 : homotropicpositively cooperative binding of calcium ions in CHCl3/CH3CN 3:1.

Scheme 10. Rowan�s and co-workers� bis(glycoluril)-capped porphyrin10 : negative cooperative binding of viologens in CHCl3/CH3CN 4:1.

Scheme 11. Isaacs�s and co-workers� nor-seco-cucurbit[10]uril : homotrop-ic positive cooperative binding of adamantane and benzene derivatives inH2O.




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In the first class the effector ions bind to two or three che-lating ligand units such as 2,2’-bipyridines, acetyl acetonates,or hydroxypyridinones to form metalla-crown ether- or-cryptand-like structures that provide cavities suitable forcation binding. Examples are allosteric receptors 13,[46] 14,[47]

15,[48,49] 16,[49] 17,[50] 18,[51] 19 and 20[52] from Furukawa,[46,47]

Kobuke,[48,49, 52] Katoh,[50] and Nabeshima and co-workers,[51]

respectively (Schemes 12–15).The second class is constituted by examples where 2,2’-bi-

pyridines or salen ligands are used as kind of “molecularhinges” that undergo conformational changes upon coordi-nation to a suitable transition metal ion which causes attach-

ed crown ether moieties to adopt structures that are betterpreorganized to bind cations. Due to the fact that binding ofboth cations—the transition metal ion and for example, analkali or alkaline earth metal ion—can cause substantialconformational changes, the roles—effector and substrate—might also be reversed in some of these receptors.Schemes 16–19 show examples of these receptors (21–24)from the groups of Beer,[53,54] Reinhoudt,[55] Rice,[56–58] andNabeshima and co-workers,[59] respectively.

Scheme 12. Furukawa�s and co-workers� heterotropic positively coopera-tive ionophores 13 and 14 used for transport processes between H2O andCHCl3.

Scheme 13. Kobuke�s and co-workers� heterotropic positively cooperativeionophores 15 and 16 used for transport processes between H2O andCHCl3.

Scheme 14. Katoh�s and Nabeshima�s and co-workers� heterotropic posi-tive cooperative cryptand-like ionophores 17 and 18 which operate inCHCl3/CH3CN 1:1 and CH3CN, respectively.

Scheme 15. Kobuke�s and co-workers� heterotropic positive cooperativeionophores 19 and 20 that operate in EtOH.




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Heterotropic Negatively Cooperative Binding ofOther Cations

The use of 2,2’-bipyridines or similar chelating ligands thatundergo significant conformational changes upon coordina-tion to (transition) metal ion as a molecular hinge (or allos-teric center)[60] can also be used to achieve heterotropic neg-atively cooperative binding as already demonstrated by thepioneering work of Rebek, Jr. depicted in Scheme 1.[13, 14]

A similar approach was presented by Rodr�guez-Ubis andBrunet and co-workers who described a strong negativelycooperative allosteric effect in the transport of diammoniumions by receptor 25 in the presence or absence of ZnI2 asthe effector (Scheme 20).[61,62]

Using the approach to form crown ether or cryptand-likestructures upon coordination of a transition metal ion to pe-

ripheral 2,2’-bipyridines could also be demonstrated toresult in negatively cooperative allosteric ionophores(Scheme 21). Kr�mer and co-workers, e. g. observed some-what surprisingly that binding of zinc(II) or copper(II) ions

Scheme 16. Beer�s and co-workers� 2,2’-bipyridine “hinge” 21: hetero-tropic positive cooperative binding of alkali metal ions in MeOH.

Scheme 17. Reinhoudt�s and co-workers� salen ligand 22 : heterotropicpositive cooperative binding of earth alkali metal ions and transitionmetal ions in MeOH.

Scheme 18. Rice�s and co-workers� mercury receptor 23 : controlling of a2,2’-bipyridine�s conformation by different metal ions binding to an at-tached crown ether moiety in CH3CN.

Scheme 19. Nabeshima�s and co-workers� salen-like receptor 24 : homo-or heterotropic positive cooperative binding of metal ions in MeOH/H2O4:1.

Scheme 20. Rodr�guez-Ubis�s and Brunet�s and co-workers� bis(crownether) 25 : heterotropic negative cooperative binding of zinc(II) and dia-mmonium ions in CHCl3/MeOH 5:1.




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was disfavoured in his metallated container 26 compared tothe similar but positively cooperative ionophores of Katohand Nabeshima and co-workers 17 and 18 depicted inScheme 14.[63]

Nabeshima and co-workers also found a general signifi-cant weaker binding of alkali metal ions in his metalla-crown ether Cu+ ·27 compared to the non-metallated recep-tor. Interestingly, however, the selectivity of metallated 27for potassium ions compared to lithium or sodium ions wasstrongly enhanced (Scheme 22).[64]

Other examples were designed by Lhot�k and Stibor andco-workers (28, Scheme 23) and Nabeshima and co-workers

(29 and 30, Scheme 24) to influence the binding of a hardalkali metal ion by interactions of soft silver(I) ions as effec-tors via cation–p[65] interactions or interactions with softdonor atoms[66, 67] or vice versa to achieve heterotropic nega-tively cooperative behavior.

Finally, Costero and co-workers could transform Rebek,Jr.�s and co-workers� receptor 2 from a homotropic positive-ly cooperative system to a heterotropic negatively coopera-tive one by narrowing one of the crown ethers from a 19-membered to a 16-membered ring (31). This subtle changeled to a significant lower transport of sodium ions in thepresence of HgACHTUNGTRENNUNG(SCN)2 which binds to the larger crown ethermoiety (Scheme 25).[68]

Scheme 21. Kr�mer�s and co-workers� iron(II) tris(bipyridyl) cage[Fe(26)]2+ : heterotropic negatively cooperative binding of further transi-tion metal ions in CH2Cl2.

Scheme 22. Nabeshima�s and co-workers� tetrakis(2,2’-bipyridyl) podand27: heterotropic negatively cooperative cation transport of alkali metalions by a dinuclear copper(I) helicate between H2O and CH2Cl2.

Scheme 23. Lhot�k�s and Stibor�s and co-workers� bisACHTUNGTRENNUNG(calix[4]arene) 28 :heterotropic negatively cooperative binding of silver and potassium ionsin CH2Cl2/MeOH 4:1.

Scheme 24. Nabeshima�s and co-workers� negatively cooperative iono-phores 29 and 30 based on calix[4]arenes bearing bipyridyl groups thatoperate in CHCl3/CH3CN 9:1.




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Heterotropic Positively Cooperative Binding ofAnions

Allosteric receptors for the molecular recognition of anionsthat use cations as effectors are in principle ion pair recep-tors. Thus, some receptors were never designed on purposeto act as an allosteric receptor but can be regarded as sucheven if the switching effect was not really studied and/ormetal ions were chosen that bind to chelating ligands suchas salens or 2,2’-bipyridines in a kinetically and/or thermo-dynamically very stable manner. However, one can imaginethat these chelating ligands once again act as “molecularhinges” as described above when exchanging these metalions for kinetically more labile binding ones. Examples forsuch receptors are Reinhoudt�s and co-workers� neutralanion receptors employing the uranyldioxide salenmotif,[69–71] or Beer�s and Sessler�s and co-workers� rheniu-m(I), rhodium ACHTUNGTRENNUNG(III), or ruthenium(II) 2,2’-biypridine com-plexes that were designed to act as anion sensors(Scheme 26).[72, 73]

Tasker and co-workers later on showed how salen ligand(35+2 H) could be used as allosteric systems to achieve sol-vent extraction of metal sulfates (Scheme 27).[74]

Other approaches of Nabeshima,[75] Molina,[76] and Fab-brizzi and co-workers[77] focused on the formation of macro-cyclic or cage-like structures with anion binding sites thatare generated for example, upon coordination of alkalimetal ions to peripheral crown ethers in a sandwich-typemanner like in 36 and 37 (Scheme 28) or of an iron(II) ionto the three peripheral 2,2’-bipyridines of 38, respectively(Scheme 29).

Scheme 26. Examples for anion sensors 32–34 with salen or bipyridine“hinges” that might act as allosteric anion receptors if kinetically morelabile binding cations are used as effectors.

Scheme 27. Tasker�s and co-workers� salen complex 35 : heterotropic posi-tive cooperativity in the binding of metal ions and sulfates in transportexperiments between CHCl3 and H2O.

Scheme 25. Costero�s and co-workers� variant 31 of Rebek Jr. and co-workers� receptor 2 that shows heterotropic negative cooperativity in thebinding of Hg ACHTUNGTRENNUNG(SCN)2 and sodium ions during transport between H2O andCHCl3.

Scheme 28. Formation of a sandwich-type alkali metal bis(crown ether)complexes 36·Cs+ and 37 K+ results in macrocylic anion binding sites inCHCl3/CH3CN 4:1 and CHCl3, respectively.

Scheme 29. Fabbrizzi�s and co-workers� tris(2,2’-bipyridine) 383+ : hetero-tropic positive cooperativity in the binding of iron(II) ions and anions inCH3CN/MeOH 4:1.




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Similarly, Beer�s and co-workers� nickel(II) or copper(II)bis(dithiocarbamate) complexes 39 equipped with additionalcation and anion binding sites[78] showed positive cooperativ-ity. Upon formation of a sandwich-type complex of potassi-um and the two crown ether moieties a macrocyclic is ob-tained with enhanced anion affinity (Scheme 30).

Calixarenes also proved to be very versatile buildingblocks in the design of allosteric receptors as already dem-onstrated with receptors 7 and 28–29 depicted in Schemes 7,23, and 24. This is due to the fact that they can be function-alized in a very diverse yet defined manner on the narrowand the wide rim and the fact that a binding event on eitherrim of these cyclophanes can induce a substantial conforma-tional change on the opposite rim and associated bindingsites there. Successful examples for heterotropic positivelycooperative allosteric receptors for the recognition of anionsare shown in Schemes 31 and 32.

Receptors 40 and 41 were developed by Reinhoudt andco-workers to achieve facilitated transport of hydrophilicsalts in apolar solvents.[79,80] Later on Casnati and Ugozzo-li,[81] Beer,[82,83] and Chung and co-workers[84] reported onfurther examples (42–45) that function in a similar mannerin aqueous or organic solvents.

Receptor 43 was found to be special in the sense that pos-itive cooperativity in anion binding was observed with potas-sium ions as effectors but negative cooperativity in the caseof sodium ions, very likely because sodium does not formthe sandwich complex necessary to arrange the two anionbinding sites in the optimum positions.

Heterotropic Negatively Cooperative Binding ofAnions

The use of a cation to activate an anion receptor is kind of anatural choice since making the receptor more positive

should increase its affinity for a negatively charged guestanyway. However, as seen by receptor 43 already, it is stillpossible to achieve negatively cooperative binding if an ap-propriate cation addresses the cation-binding sites in amanner that does not allow the anion-binding sites to act to-

Scheme 30. Beer�s and co-workers� nickel(II) bis(dithiocarbamate) com-plex 39 : heterotropic positive cooperativity in the binding of potassiumions and anions in CHCl3/CH3CN 4:1.

Scheme 31. Reinhoudt�s and co-workers� calixarene bis ACHTUNGTRENNUNG(urea) 40 and cal-ixarene bisACHTUNGTRENNUNG(thiourea) 41 and Casnati�s and Ugozzoli�s and co-workers�calixarene bis ACHTUNGTRENNUNG(amide) 42 : coordination of sodium ions to the lower rimoxygen functions causes a conformational change of the calixarene thatallows cooperative binding of anions by both urea groups.

Scheme 32. Beer�s and Chung�s and co-workers� calixarene-based recep-tors 43–45 : heterotropic cooperativity in the binding of metal ions andanions.




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gether. A very early example (46) was published by Schneid-er and co-workers already in 1992 (Scheme 33).[85] Here, anethylene diamine acts as the cation binding site that can un-dergo a hinge-like movement upon coordination. However,the interaction of the two ammonium ions that act as bind-ing sites for dicarboxylate ions is better in the absence ofthe metal cation. Thus, addition of cadmium ions led to a re-duction of the binding constants by a factor of two.

Addition of potassium ions to Beer�s and co-workers� re-ceptor 47 led to the formation of a sandwich-type complexincapable of binding anions via hydrogen bonding with thetwo amide groups (Scheme 34).[86] Interestingly, this systemtherefore acts in a negative cooperative fashion while simi-lar receptor 37 (Scheme 28) acted in a positive manner.

2,2’-Bipyridine 48 could be demonstrated to act as a mo-lecular hinge in a negatively cooperative receptor for therecognition of carboxylates by Costero and co-workers.[87]

Only in the absence of a transition metal ion like nickel(II)the two thiourea groups can bind to two anions whereas thisinteraction is strongly hindered in the metallated form(Scheme 35).

Anslyn and co-workers were also able to detect negativecooperative binding of oligocarboxylates with a metallatedammonium ion host.[88] A careful ITC study revealed entro-py as the largest contributing factor for this somehow unex-pected result. However, it is not yet clear whether this effectis due to a conformational effect or rather due to solvent re-lease upon binding.

Heterotropic Positively Cooperative Binding ofNeutral Molecules

The first example (4) for a receptor designed for the recog-nition of neutral molecules or at least neutral parts of a mol-ecule that can be controlled by an allosteric effect was pre-sented by Dervan and co-workers in 1987 and was alreadymentioned in the introduction (Scheme 4).[18] Since then twoother receptors (Scheme 19) have been developed that caninteract with nucleobases or double-stranded DNA upon ac-tivation with a cationic effector. Compound 49 was intro-duced by Inouye and co-workers in 1993 and binds to nucle-obases via hydrogen-bonding and p-stacking after activationwith a sodium ion that coordinates to a podand-like oligoe-thylenglycol chain (Scheme 36, top).[89]

Schneider, Garc�a-EspaÇa, and Luis and co-workers re-ported on negatively cooperative receptor 50 where a cop-per(II) ion serves as the effector that binds to an oligoethy-lene diamine chain.[90] Thereby, it orientates two p-conjugat-ed moieties in a way that they cannot intercalate both intodouble-stranded DNA (Scheme 36, bottom).

Scheme 34. Beer�s and co-workers� ferrocene-based bis(crown ether) 47:heterotropic negative cooperativity in the binding of potassium and hal-ides in CH3CN.

Scheme 35. Costero�s and co-workers� bisACHTUNGTRENNUNG(urea) substituted 2,2’-bipyri-dine 48 : heterotropic negative cooperativity in the binding of transitionmetal salts and carboxylates in DMSO.

Scheme 36. Allosteric recognition of nucleobases and DNA: heterotropicpositively cooperative receptor 49 (top) and negatively cooperative re-ceptor 50 (bottom) that operate in CHCl3 and H2O.

Scheme 33. Schneider�s tetraamine 46 : heterotropic negative cooperativi-ty in the binding of cadmium salts and aromatic dicarboxylates in H2O.




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Other approaches focused on the allosteric recognition offluorophoric dye molecules because these studies couldeasily be monitored by changes in the light emission. Thefirst report was published by Schneider and co-workers in1990 (Scheme 37). Again he used ethylene diamine groupsin the periphery of receptor 51 to form a complex with azinc(II) ion, thereby forming a macrocyclic hydrophobiccavity capable of binding a dansyl chromophor.[91]

More or less the same concept (52) was used by Schwa-bacher and co-workers in 1999.[92] However, he observed aninteresting difference in guest selectivity depending on themetal ion that was used as the effector. Whereas in case ofzinc(II) a substrate with a naphthyl group was found to bethe preferred guest he observed such with a biphenyl groupto be better in case of copper(II) due to the difference ofthe metal ions� coordination geometries, and hence, thechanges in the shape of the macrocyclic metal complex(Scheme 38).

Similarly, Deshayes and co-workers furnished their recep-tor 53[93] with two peripheral amine diacetate units thatforms a water soluble macrocyclic complex with calcium(II)ions containing a hydophobic cavity. This cavity can accom-modate a dansyl chromophor. Nabeshima and co-workersused two peripheral 2,2’-bipyridines to obtain a cyclophane-like macrocycle Cu+ ·54 upon coordination of the 2,2’-bipyri-dines to copper(I) that was able to bind a flavin mononu-cleotide (Scheme 39).[94]

In a different approach Schneider and co-workers used apolyazacyclophane 55 whose cavity�s shape could be signifi-cantly changed upon coordination of the nitrogen atoms tozinc(II) ions, and hence, showed much better binding of adansyl fluorophor than in the absence of the metal ion(Scheme 40).[95]

In 2004 Liu and co-workers reported on a bis(b-cxclodex-trin) 56[96] that could be allosterically controlled by sodiumion binding to a crown ether moiety (Scheme 41). However,the conformational change could not be determined in fullScheme 38. Schwabacher�s and co-workers� hexaamine 52 : heterotropic

positively cooperative recognition of dansyl dyes in H2O.

Scheme 39. Deshayes�s and Nabeshima�s and co-workers� metallo-cyclo-phanes [Ca(53)]4� (top) and [Cu(54)]2+ (bottom): heterotropic positivelycooperative recognition of dyes in H2O and in transport experiments be-tween H2O and 1,2-dichloroethane, respectively.

Scheme 40. Schneider�s and co-workers� hexaazacyclophane 55 : hetero-tropic positively cooperative recognition of dyes with naphthyl groups inH2O.

Scheme 37. Schneider�s and co-workers� hexaamine 51: heterotropic posi-tively cooperative recognition of dansyl amide in H2O/MeOH 4:1.




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detail since 56 can adopt several different conformationswithout the sodium ion including some folded ones that in-hibit cooperative binding of both cyclodextrin units to asingle guest molecule.

Shinkai and co-workers used calix[4]arenes 57–59 furnish-ed with an alkali metal binding site and a hydrogen bondingmotif capable of binding flavins,[97] simple amides,[98] or bar-biturates.[99] In the absence of sodium ions, however, the(di)aminopyridine groups tend to self-associate via hydrogenbonds similar to the calixarene receptors 40–42 depicted inScheme 31. Only after coordination of a sodium ion to theether and amide oxygen atoms these hydrogen bonds arebroken and the two diaminopyridine groups are orientatedaway from each other and can be addressed by the sub-strates (Scheme 42).

He also developed a number of allosteric receptors (60–64) for the recognition of carbohydrates that bind mono- ordisaccharides via formation of boronic acid esters.[100–106]

Schemes 43 and 44 show a selection of these heterotropicpositively or negatively cooperative systems developed be-tween 1994 and 1999 that use either crown ethers,[100, 102,103]

2,2’-bipyridines,[101, 104,105] or salen ligands[106] as allosteric cen-ters.

Receptors 62 and 63 are found to be relatively complicat-ed mixtures of conformers in the absence of an effector anda substrate. In both cases different alkali metal ions wereable to bind to the crown ether moieties and act as positive-ly or negatively cooperative effectors similar to receptor 43(Scheme 32). Again these effectors stabilize different confor-mations that either show an increased or a decreased bind-ing affinity towards monosaccharides depending on thealkali metal ion used as an effector. Potassium ions, for ex-ample, were found to act as negatively cooperative effectorsin both cases whereas sodium ions acted in a positively co-operative manner in 62 and lithium ions in 63.

About the same time Shinkai and co-workers also intro-duced calix[6]arene 65 and capsular trinuclear palladiumcomplex of homooxacalixarenes 66 which were able to bindC60 when activated by coordination of cesium in toluene/MeOH (44:1) or lithium ions in 1,1,2,2-tetrachloroethane,respectively, as depicted in Scheme 45.[107,108] Again themetal ions were used to stabilize cone conformations suchas in receptors 40 and 57–59. Here, however, this was em-ployed to either create a concave binding site at all (65) orto adjust its curvature (66) in such a manner that it is com-plementary to the fullerene guests. Interestingly, differentalkali metal ions were found to cause different effects:whereas lithium acts as a positive effector, sodium bindingwas found to cause a negative allosteric effect. Two yearslater Fukazawa and co-workers developed another allosteric

Scheme 41. Liu�s and co-workers� crown ether bridged bis(b-cyclodex-trine) 56 : heterotropic positively cooperative recognition of dyes in H2O.

Scheme 42. Shinkai�s and co-workers� calixarene-based allosteric receptor57–59 : heterotropic positive cooperativity in the binding of sodium ionsand neutral organic molecules.

Scheme 43. Shinkai�s and co-workers� bis(boronic acid) receptors 60 (top)and 61 (bottom): heterotropic negatively (60) and positively (61) cooper-ative recognition of monosaccharides in aqueous solutions.




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receptor 67 for the molecular recognition of C60 and C70 in1,1,2,2-tetrachloroethane that binds the fullerene via p-stacking with two calix[5]arene moieties oriented in a capsu-lar arrangement formed upon copper(I) coordination to the2,2’-bipyridines (also Scheme 45).[109]

C3-Symmetrical capsule 68 similar to homooxacalix[3]ar-ene based capsule 66 could be demonstrated to bind guestmolecules of similar symmetry such as tris(2-aminoethyl)a-mine (tren) after allosteric activation with sodium ions inCHCl3/MeOH (9:1) (Scheme 46).[110]

The interaction of alkali metal ions with calixarenes orcalixcrowns was also used by others to control the bindingof apolar substrates in CHCl3 via a positively allostericeffect. Examples from the work of Fukazawa[111] (69) or Po-chini and co-workers (70)[112, 113] are also listed in Scheme 46.

Nolte combined one of his famous glycoluril clips withcrown ether-type groups to get receptor 71 that showed al-losteric recognition behavior towards 1,3-dinitrobenzene inCHCl3/DMSO (9:1) (Scheme 47).[114]

Later on Rowan and co-workers reported in a series ofpublications on glycoluril-based basket-like receptors 72 and73. Compared to his porphyrin 10 that is capped by two gly-colurils and offers two cavities for viologens, 72 and 73 areonly capped by one glycoluril unit, and hence, offer two dif-ferent binding sites—a cavity for a viologen and a zinc(II)porphyrin for the binding of amines. These new receptors

Scheme 44. Shinkai�s and co-workers� bis(boronic acid) receptors 62(top), 63 (middle), and 64 (bottom): heterotropic allosteric recognition ofmonosaccharides in aqueous solutions.

Scheme 45. Allosteric recognition of fullerenes: Shinkai and Fukazawareceptors 65–67.




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showed heterotropic positive cooperative binding of aminesand pyridines upon activation by viologens as effectors inCHCl3/CH3CN (1:1).[115–118] Interestingly, in 72, for example,both the organic cation and the neutral N-donor ligandstrongly enhanced the binding of the other. However, dime-thylviologen 11 is not just a positive effector for the bindingof 4-tert-butylpyridine (74), but also for oligopyridines suchas meso-tetrakis(4-pyridyl)porphyrin (75). Upon binding tothis a complex of four molecules of 72 around 75 is generat-ed which can accommodate another four molecules of 11(Scheme 48, middle).

If four hydroxyl groups were added to the meso-phenylrings of 72, a new receptor 73 is generated that, supportedby the positive allosteric effect of the viologen, forms a pen-tameric complex with 1,4-diazabicyclo ACHTUNGTRENNUNG[2.2.2]octane (dabco),which could not be formed with 72 (Scheme 48).

Receptor 72 was further examined in a very detailed way,including the complete thermodynamics and kinetics of both

inhibition and activation of the receptor for the binding ofviologens.[118] There were also made first attempts to buildup an allosteric photosynthetic antenna based on 72 and agold–bipyridine complex[116] and other multicomponentarrays using modified viologens that carry additional violo-gen groups or N-donor functions.[117]

Scheme 46. Calixarene-based allosteric receptors for the recognition ofother organic guest molecules: Shinkai�s and co-workers� receptor 68, Fu-kuzawa and co-workers� receptor 69, and Pocchini�s and co-workers� re-ceptor 70.

Scheme 47. Nolte�s and co-workers� allosteric glycoluril clip 71.

Scheme 48. Rowan�s and co-workers� allosteric porphyrin glycoluril bas-kets 72 and 73.




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Other groups developed porphyrin tweezers whose bind-ing affinity towards diamines could be controlled in a heter-otropic allosteric manner. Three different approaches weredescribed. The first published by Monti and co-workers (76)involves a podand-like structure with peripheral porphyrinstructures that folds into the tweezer-like conformationupon coordination of a sodium ion and then can complex4,4’-bipyridine or 1,2-trans-diaminocyclohexane in CH3CN/CHCl3 (9:1) (Scheme 49).[119]

The second one was reported by Shinkai and co-workers(77) and uses a palladium(II) diphosphane complex withtwo free cis-configured coordination sites as an effector thatbinds to two pyridines. This causes a switch from an anti- toa syn-conformation arranging the porphyrins in a positioncapable of recognizing C60 in toluene/CH2Cl2 (50:1)(Scheme 50).[120]

The third approach of Kobuke and co-workers[121] againmakes use of a 2,2’-bipyridine 78 as a molecular hinge thatundergoes conformational switching from the anti- to thesyn-conformation upon coordination of a suitable transition-metal ion (Scheme 51). Due to this conformational changethe two porphyrin units can then interact in a cooperativemanner to bind diamines in 1,12,2-tetrachloroethane.

The 2,2’-bipyridine hinge approach was also used by us toprepare allosteric hemicarcerands like 79 (Scheme 52).[122] Inthese bipyridine bridged bis ACHTUNGTRENNUNG(resorcin[4]arenes), coordinationof transition metal ions or complex fragments[123] led to cap-sular structures with the two resorcinarene moieties capableof binding non-polar organic molecules like adamantine car-boxylic acid adamantylester 80 in a cooperative fashion inbenzene/CH3CN (20:1).

In a slightly different approach Rebek, Jr. and co-workersused the bipyridine hinge in their ouroborand 81 to open a

Scheme 49. Monti�s and co-workers� positively allosteric porphyrin tweez-er 76.

Scheme 50. Shinkai�s and co-workers� positively allosteric porphyrintweezer 77.

Scheme 51. Kobuke�s and co-workers� positively allosteric porphyrintweezer 78.

Scheme 52. Heterotropic positively allosteric hemicarcerand 79.




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cavity closed by self-complexation of an appended cyclohex-yl group by coordination induced decomplexation. Thus, thecavity gets accessible for inclusion of an external guest mol-ecule in mesitylene/CH3CN (4:1) (Scheme 53).[124]

Positively cooperative allosteric recognition of tryptophanwith receptor 82 was described by Nabeshima and co-work-ers.[125] Following a similar concept employed in receptor 54the formation of a copper(I) bis(bipyridine) complex yieldsa chiral macrocyclic ionophor capable of transporting thezwitterionic amino acid through a liquid membrane(Scheme 54).

Heterotropic Negatively Cooperative Binding ofNeutral Molecules

Binding of neutral guest molecules cannot only be facilitat-ed but also prohibited or at least greatly hindered by allos-teric effects with cationic effectors. However, the number ofexamples is much lower than for the positively cooperativesystems as already shown by receptor 50. The first examplewas presented by Kubo and co-workers in 1999. In his bis-(porphyrin) receptor 83 a bridging biphenyl unit bears acrown ether moiety.[126] Binding of a barium ion changes thedistance of the zinc(II) ions embedded in the porphyrins,and hence, decreases the receptor�s binding affinity towardsdiamine substrates like 1,4-bis(3-aminopropyl)piperazine 84(Scheme 55).

Branda and co-workers then came up with a series of re-ceptors (85–87) that showed negatively cooperative bindingof copper(I) ions and organic substrates such as alkylateduracil (88) or barbiturates (89).[127–129] In all of these systemscoordination of the copper(I) to two 2,2’-bipyridines causesthe receptor to adopt a closed conformation in which thehydrogen bonding motifs are not accessible. Only in the ab-sence of copper(I) (85, 86, Scheme 56)[127, 128] or after oxida-

Scheme 54. Nabeshima�s and co-workers� positively allosteric trypto-phane receptor 82.

Scheme 55. Kubo�s and co-workers� porphyrin tweezer 83 : heterotropicnegative cooperativity in the binding of barium ions and diamine 84 inCH2Cl2/CH3CN 9:1.

Scheme 53. Rebek, Jr.�s and co-workers� allosteric ouroborand 81.




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tion to copper(II) and changing the coordination site (87,Scheme 57)[129] the organic guests can approach the hydro-gen bonding sites.

Changing the substitution pattern of the central 2,2’-bipyr-idine from 4,4’ or 6,6’ to 4,6’, we were able to change themode of cooperativity in our allosteric hemicarcerands frompositive (79)[122] to negative (90) which could be demonstrat-ed by size selective allosteric recognition of small esters inmesitylene (Scheme 58).[123, 130]

Anions as Allosteric Effectors

Although anions have not been studied as intensively as cat-ions as allosteric effectors there have still been reportedquite a number of interesting homo- and heterotropic sys-tems.

Homotropic Systems

Elaborating his cerium(IV) bis(porphyrinate) double deckermotif (cf. Schemes 2 and 3) Shinkai and co-workers coulddemonstrate positive cooperative homotropic binding of di-carboxylates such as di-O-benzoyl tartrate 92 by receptor 91(Scheme 59).[131]

Swager�s and co-workers� porphyrin 93 is only able tobind fluoride ions but no larger anions because of its smallcavity.[132] However, it is not only this selectivity but also thefact that it has a homotropic allosteric aspect that is specialabout this compound. The binding of one fluoride distortsthe macrocycle from planarity and thereby favors the bind-ing of another fluoride. There is also the assumption thatthere are bridging F-H-F interactions which support thiseffect (Scheme 60).

Gale and Loeb and co-workers showed that two differentamido complexes of platinum(II) (94, 95) can show contrarymodes of allosteric function.[133] Both bind oxoanions suchas triflate, nitrate, hydrogensulfate, or carboxylates. Howev-er, complex 94 shows a positive allosteric binding behaviourwith regard to the binding of two acetates in CH3CN/DMSO (9:1), whereas binding of another anion (e.g., ni-trate) by complex 95 is disfavoured after the binding of thefirst in CH3CN. This is due to the fact that complex 94 hasto adopt an 1,2-alternate conformation first which explainsthe positive cooperativity as the first binding leads to thisconformation. Although in principle better preorganizedcomplex 95, however, experiences a pinching of two amidogroups towards each other in order to establish two hydro-gen bonds upon binding to an oxoanion such as nitratewhich causes a widening of the gap between the two other

Scheme 57. Branda�s and co-workers� hydrogen bonding receptors 87:coupling allosteric regulation with a copper(I)–copper(II) redox switch tocontrol the binding of alkylated uracil 88 in CH3CN.

Scheme 58. Heterotropic negatively allosteric hemicarcerand 90.

Scheme 56. Branda�s and co-workers� hydrogen bonding receptors 85 and86 : heterotropic negative cooperativity in the binding of copper(I) ionsand alkylated uracil 88 and barbiturate 89 in DMSO, respectively.




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amido groups, and hence, leads to a decreased affinity to-wards the second anion (Scheme 61).

An example for a positive allosteric receptor for acetateions was presented by Shinkai and co-workers.[134] Bicyclicreceptor 96 is able to bind acetate via hydrogen bonds totwo amido-hydrogens. This binding event results in anaction referred to as a “turnstile”, as a fluorinated phenylgroup, that blocks the binding sites otherwise, is switchedand, with that, opens and preorganizes the site for anotheracetate ion (Scheme 62).

Setsune�s and co-workers� receptor 97 showed positive ho-motropic allosteric binding behaviour towards carboxylicacids in CH2Cl2.

[135] The first binding enhances the basicityof the neighbouring-pyridine-N and the acidity of the neigh-bouring-pyrrole-NH which enhances the binding of a secondand a third acid (Scheme 63).

Positive homotropic cooperativity in the binding of chlor-ide ions was observed with Steed�s and co-workers� receptor97.[136] Here, the tetrapodal imidazolium-based calix[4]areneadopts a 1,3-alternate conformation upon binding of the

Scheme 61. Gale�s and Loeb�s and co-workers� homotropic anion bindingcomplexes 94 and 95 : positive and negative cooperativity in the bindingof oxoanions.

Scheme 62. Shinkai�s and co-workers� molecular turnstile 96 : homotropicpositively cooperative binding of acetate in THF/DMSO 5:1.

Scheme 59. Shinkai�s and co-workers� homotropic cerium(IV) bis(por-phyrin) double decker complex 91: positively cooperative binding of twotartrates 92 in THF/DMSO 1:1.

Scheme 60. Swager�s and co-workers� doubly-caped porphyrin 93 : homo-tropic positive cooperativity in the binding of fluoride anions in CH2Cl2.




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first chloride ion which enhances the affinity for the secondchloride ion (Scheme 64).

An example for a negative allosteric system was present-ed by Lhot�k and Stibor and co-workers.[137] They showedthat calixarene 99, although having two equal binding sitesbecause of its 1,3-alternate conformation, forms only 1:1complexes with various anions such as chloride, bromide,acetate, and others. This can be explained by assuming thatbinding of one anion widens one of the rims of the calixar-ene and thereby narrows the other, so that the binding ofthe other anion is not possible in CHCl3/CH3CN (4:1) any-more (Scheme 65).

Heterotropic Systems

Most of the heterotropic systems published so far are de-signed to affect cation binding by an anionic effector. The

first example for these was described by Kubik and co-work-ers in 1999.[138] Sulfonates and phosphonate were found togreatly enhance the cyclopeptide�s (100) affinity towardscations such as tetraalkylammonium ions or alkali metalcrown ether complexes due to changes of the conformationof 100 in a way that it can interact with the cation viacation–p interactions and further electrostatic interactions inCHCl3 (Scheme 66).

In 2001 Pochini and co-workers reported on calix[4]arenederivative 101 that can encapsulate a tetramethylammoniumion when adopting a capsular structure upon binding to a to-sylate ion (Scheme 67).[139]

Dalla and Jabin and co-workers achieved allosteric bind-ing of a propylammonium ion with calix[6]arenetrisurea 102after the three urea groups bound a chloride ion via hydro-gen bonding in 2008.[140] Two years later, Jabin and co-work-ers were able to extend this approach and presented cappedcalix[6]arenetrisurea 103 that also showed positive coopera-tivity in the binding of ammonium ions in the presence offluoride ions as effectors (Scheme 68).[141] Similarly, the cor-responding triammonium ion precursor (cf. Scheme 84)shows much higher affinity towards neutral guests like imi-dazolidin-2-one after binding of trifluoroacetate.[142]

An allosteric receptor for the recognition of C60 consistingof two subunits has been put forward by Sessler and Jeppe-

Scheme 65. Lhot�k�s and Stibor�s and co-workers� homotropic negativelycooperative receptor 99.

Scheme 66. Kubik�s and co-workers� heterotropic positively allostericcyclic peptide receptor 100.

Scheme 63. Setsune�s and co-workers� allosteric bimacrocyclic anion re-ceptor 97.

Scheme 64. Steed�s and co-workers� receptor 98 : homotropic positivelyallosteric recognition of chloride ions in CH3CN.

Scheme 67. Pochini�s and co-workers� calixarene-based receptor 101: het-erotropic positively allosteric recognition of tosylate and tetramethylam-monium in CHCl3.




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sen and co-workers.[143] They found that calixpyrrole 104forms a bowl-shaped structure when a chloride ion is boundvia four hydrogen-bonds in the center of the molecule. Twoof these bowls then have an optimal size to encapsulate C60

(Scheme 69).Jang and co-workers reported on porphyrin tweezer 105

whose affinity towards dabco is greatly enhanced by bindingof a chloride ion to a biindole bridge that acts as a molecu-lar hinge (Scheme 70).[144]

Neutral molecules as Allosteric Effectors

Like anions neutral molecules have not been studied to agreat extend yet. Nevertheless, some interesting homo- andheterotropic systems have been developed.

Homotropic Systems

Probably the first example of a homotropic positively coop-erative system (106) for the binding of two neutral mole-cules was published by Rebek, Jr. and co-workers in1990.[145] Tetracarboxylic acid 106 was able to bind two mol-ecules of dabco in a cooperative manner (Scheme 71)

It should be noted, though, that proton transfer is verylikely in this case. The same is true for the first example ofShinkai�s and co-workers� allosteric cerium(IV) bis(porphyr-inato) double decker complex 107 published in 1998.[146]

Compound 107 carries four pyridine groups on each por-phyrin unit which can rotate freely relative to each other.Each binding of a dicarboxylic acid in tetrachloroethane/THF (30:1) enhances the affinity for the next ones signifi-cantly resulting in a large overall positive cooperativity

Scheme 69. Sessler�s and Jeppesen�s and co-workers� calixpyrrole-basedtetrathiofulvalene receptor 104 : heterotropic positively allosteric recogni-tion of chloride and C60 in CH2Cl2.

Scheme 70. Jang�s and co-workers� porphyrin tweezer 105 : heterotropicpositively allosteric recognition of chloride and dabco in THF.

Scheme 68. Jabin�s and co-workers� calix[6]arene-based tris ACHTUNGTRENNUNG(urea) recep-tors 102 and 103 : heterotropic positively allosteric recognition of halideions and alkylammonium ions in CHCl3.




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(Scheme 72). Later on this receptor could also be demon-strated to act as an enantioselective positive allosteric recep-tor,[147] for example, in the binding of cyclohexane-(1R,2R)-dicarboxylic acid ((R,R)-108). To study the enantioselectivi-ty, Shinkai�s group synthesized receptor 109, which is analo-gous to preorganized 107 and demonstrated that binding of(R,R)-108 is preferred over (S,S)-108, as assumed.

In the following years Shinkai�s group elaborated this ap-proach much further (see also Schemes 2, 3, and 37). Greatefforts were made to establish homotropic allosteric recep-tors for the recognition of carbohydrates based on thismotif.[148–151] Therefore, the bis(porphyrinato) double decker110 was equipped with boronic acid functions to bind sac-charides via boronic acid ester formation in aqueous solu-tion (Scheme 73).

A variation of this theme led to related system 111 alsocapable of homotropic allosteric binding of l-fucose (112)via boronic acid ester formation (Scheme 74).[151]

Porphyrin tetramer 113 was designed by Takeuchi andShinkai and co-workers to bind diamines such as 2,5-diiodo-1,4-bis(N-methylaminomethyl)-benzene (114) in an alloster-ic fashion.[152] Binding of the first diamine disturbs the rota-tion and thus preorganizes the cavity for the second guestmolecule (Scheme 75). Based on this result they could alsoshow that preorganization upon effector binding facilitatesring closing metathesis of pendant terminal alkenes at bothends of the receptor. However, these functions offer addi-tional attractive interactions that stabilize the conformationfavourable for binding of the diamine. Thus, the overall af-finity for guest molecules increased whereas the cooperativeeffect decreased.[153] Based on a similar design Takeuchi andShinkai and co-workers then published tetra(tweezer-type)ligand 115 that was found to bind a low-molecular weightrepeating unit analogue of polyaniline emeralidine base as atetrakis(palladium) complex in a positively cooperativemanner. This approach could then even be used to organizepolyaniline emeraldine salts into ordered assemblies.[154]

Kawai and Tsuji and co-workers designed a hydrinda-cene-based receptor 116 for the recognition of dihydroxy-benzenes such as resorcin (117).[155] The free receptor is veryflexible due to the more or less unrestricted rotational free-dom of the amide groups. If one guest molecule binds, how-ever, this motion gets strongly restricted, which preorganizesthe binding site for the second guest molecule resulting in a

33 times higher binding affinity for the second substratecompared to the first one (Scheme 76).

Sessler and Jeppesen and co-workers synthesized receptor118, which is similar to 104, but has other properties.[156]

Upon binding of a first 1,3,5-trinitrobenzene (119), the rota-tional freedom is reduced and also the pyrrolic N-H is acidi-fied. This facilitates the binding of a second molecule of 119

Scheme 72. Shinkai�s and co-workers� double-decker porphyrin receptors107 and 109.

Scheme 71. Rebek, Jr.�s and co-workers� tetracarboxylic acid receptor106 : homotropic positively allosteric recognition of dabco in CHCl3.




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to a great extent as the association constants for binding ofthe second substrate was determined to be up to 31 timeshigher than for binding of the first one (Scheme 77).

Ikeda�s and co-workers� bis-b-cyclodextrin receptor 120catalyzes the cleavage of p-nitrophenyl-2-[2-(2-methoxy-ethoxy)ethoxy]acetate (121) in H2O.[157] The cleavage rate isincreased by the fact that another ester molecule rigidifiesthe conformation of the receptor by reducing the rotationalfreedom. This was shown by adding a non-reactive dummymolecule that is in its form similar to the ester and thus canalso act as an effector and increases the initial rates for thecleaving reaction by a factor of 1.2–1.3 (Scheme 78).

Another set of examples for homotropic allosteric recep-tors was presented by Jeong.[158] They designed five metallo-supramoleculer aggregates that can adopt different confor-mations, for example, [Pd2ACHTUNGTRENNUNG(122)2]

4+ . Each of these can takeup two molecules of N,N,N’,N’-tetramethylterephthalamide(123) in a positive allosteric manner once binding of thefirst guest leads to a stabilization of a figure-eight-like con-formation (Scheme 79).

Negative cooperativity in a homotropic system designedfor the recognition of neutral molecules was observed byDiederich and co-workers. His bridged bis ACHTUNGTRENNUNG(BINOL) recep-tors 124 were found to bind only one N-protected aminoacid such as N-Cbz-glutamic acid (125) despite its ditopicnature (Scheme 80).[159]

Heterotropic Systems

So far only a very limited number of heterotropic systemshave been reported that employ a neutral effector. Probablythe first one was developed by Tashiro and Aida and co-workers in 2005.[160] His receptor 126 contains two fused zincporphyrin arrays that rather bind a fused bisfullerene or twodifferent guest molecules—a fullerene and a diamine suchas 4,4’-bipyridine (127) in a positively cooperative fashion intoluene than two fullerenes or two diamines in a homotropicmanner which was even found to be negatively cooperative(Scheme 81).

Mirkin�s and co-workers� BINOL-based receptor [Cu-ACHTUNGTRENNUNG(128)]+ has not just an positive allosteric function but alsoshows a certain enantioselectivity in CH3CN.[161] If 2,2’-bipyr-idine (129) is added, [Cu ACHTUNGTRENNUNG(128) ACHTUNGTRENNUNG(129)]+ forms and opens up achiral pocket for mandelic acid (130). If the (S)-form of 128is used, (S)-mandelic acid is encapsulated with an associa-tion constant of 764 m

�1, whereas its optical antipode (R)-mandelic acid shows an association constant of 367 m

�1. Thisfinding was confirmed by using the (R)-form of 128 and get-ting almost exact the contrary numbers, as expected(Scheme 82).

More Complex Systems with More Than OneEffector

We have already described in the Section on HeterotropicPositively Cooperative Binding of Anions with Cations asEffectors that some receptors were never designed on pur-pose to act as an allosteric receptor but can be regarded assuch even if the switching effect was not really studied and/or metal ions were chosen that bind to chelating ligandssuch as salens, 2,2’-bipyridines, or dithiocarbamates in a ki-netically very stable manner. However, one can imaginethat these chelating ligands once again act as molecularhinges as described above when exchanging these metal ionsfor kinetically more labile binding ones.

Examples are Reinhoudt�s and co-workers� uranyldioxidesalen complex 131 equipped with additional cation and

Scheme 73. Shinkai�s and co-workers� double-decker porphyrin receptor110 : homotropic positively allosteric recognition of saccharides.

Scheme 74. Shinkai�s and co-workers� allosteric tetraboronic acid recep-tor 111: homotropic positively allosteric recognition of l-fucose (112) inH2O/MeOH 1:1.




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anion binding sites,[162] Smith�s and co-workers� rutheniu-m(II) 2,2’-bipyridine complex 132 bearing additional bindingsites for the recognition of phosphate and saccharides,[163]

Beer�s and co-workers� rhenium(I) 2,2’-bipyridine complexes

133–135 with cation and anion-binding sites,[164–166] and Liu�sand co-workers� copper(I) 2,2’-bipyridine complex 136 with ad-ditional binding sites for cop-per(I) ions and dye moleculesor steroids (Scheme 83).[167,168]

An example of an allosteri-cally coupled double induced fitwas presented by Reinaud andJabin and co-workers.[169] Theyhad already proven ammonium-functionalized calixarene 1373+

to be allosterically activethrough rigidifying its structureby binding of trifluoroaceticacid (TFA) to the peripheralamino groups and thus beingable to take up guest moleculessuch as amides, alcohols or ni-triles.[142] But when they tried toexchange TFA by acid-func-tionalized calixarene 1383�, theywere not successful. Only whenthey allowed an ammoniumcation such as ethylammoniumor propylammonium to enterthe cavity of 1383�, a complex(1373+ ·imidazolidin-2-one)·(1383�·alkylNH3

+) was formed.This means that only due to therigidifying effect of the guestsin each cavity the system is ableto form the desired 1+1+ 1+

1-complex (Scheme 84).Hamilton and co-workers

presented an allosteric ap-proach to control the self-as-sembly of guanine-quartetquadruplexes.[170] To enhancethe possibility of forming those

Scheme 75. Takeuchi�s and Shinkai�s and co-workers� allosteric tetraporphyrin receptor 113 : homotropic posi-tively allosteric recognition of diamine 114 in CHCl3, and their allosteric tetra(tweezer-type) ligand 115.

Scheme 76. Kawai�s and Tsuji�s and co-workers� allosteric receptor 116 :homotropic positively allosteric recognition of resorcin (117) in CHCl3.

Scheme 77. Sessler�s and Jeppesen�s and co-workers� allosteric calixpyr-role 118 : homotropic positively allosteric recognition of trinitrobenzene(119) in CHCl3.




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quadruplexes, porphyrins were attached to guanidine chains.These porphyrins stabilize the self-assembly of quadruplexes(139)4·4 K+ by aromatic p-stacking interactions. However, if(2-hydroxypropyl)-b-cyclodextrin is added, the porphyrinsget masked and the stability of the quadruplexes is reducedin such a manner that the structure falls apart due to stericcrowding and the loss of the p-stacking (Scheme 85).

Finally, Mirkin and co-workers introduced p-stacked com-plexes [Rh2ACHTUNGTRENNUNG(140)2]

2+ [171] and [Rh2ACHTUNGTRENNUNG(141)2]2+ [172] with (thio-)-

etherphoshine hemilabile ligands. These closed structurescan be opened up by binding a combination of carbon mon-oxide and chloride to give cavities that can be used for en-capsulation of guests like dabco or dihexylviologen (yieldinga pseudorotaxane), respectively (Schemes 86 and 87).

In fact, the halide proved to be more important here.That is why this concept was called “halide-induced ligandrearrangement” (HILR) later.[173] Furthermore, this reactionproved to be reversible, as addition of NaBArF (NaB ACHTUNGTRENNUNG[3,5-C6H3ACHTUNGTRENNUNG(CF3)2]4) abstracts the chloride ion and, by that, de-stroys for example, the pseudorotaxane build from 140 andthe viologen.[171]

Allosteric Control of Reactivity

As already pointed out in some of the reviews citedabove[32,33] or in Mirkin�s and co-workers� recent review onenzyme mimics based on supramolecular coordinationchemistry[174] one of the most prominent goals in this area isto achieve allosteric control of reactivity following nature�sexample.[6] In fact, there have already been a number of suc-cessful reports that will be summarized in the following sec-tion.

Mirkin�s and co-workers� HILR-concept could not onlybe used to design allosteric receptors but also a number ofallosteric catalysts. p-stacked complex [Rh2{Cr ACHTUNGTRENNUNG(142)Cl}2]

2+

with (thio-)ether-phoshine hemilabile ligands andchromiumACHTUNGTRENNUNG(III) salen entities,[175] for example, could be dem-onstrated to catalyze epoxide opening with trimethylsilyla-zide (TMSN3) in a very efficient manner—even more effec-tive than a monomeric chromiumACHTUNGTRENNUNG(III) salen complex afteropening the reactive site inside the cavity upon coordinationof chloride and carbon monoxide (Scheme 88).

Tweezer-like complex [Rh{CrACHTUNGTRENNUNG(143)Cl}2]+ is also able to

catalyse the asymmetric ring opening of cyclohexene oxide

Scheme 78. Ikeda�s bis-b-cyclodextrin receptor 120.

Scheme 79. Jeong�s and co-workers� metallo-supramolecular receptor[Pd2 ACHTUNGTRENNUNG(122)2]

4+ : homotropic positively allosteric recognition of terephtalicdiamide 123 in CHCl3/CH3CN 7:3.




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by TMSN3 in a more effective way than a monomeric salencomplex.[176] In this case, however, the selectivity can be de-creased by the addition of chloride ions and carbon monox-ide which break the RhI�thioether bond, and hence, changethe conformation from a defined cavity to a less selectiveenvironment in [Rh{Cr ACHTUNGTRENNUNG(143)Cl}2(CO)Cl] (Scheme 89). Thedifference of selectivity between those two conformations isincreased for lower concentrations of the catalyst. It couldalso be shown that the “on–off switching” is reversible byremoving CO under reduced pressure.

Another interesting catalyst that uses HILR was present-ed in 2005.[177] Double-decker receptor [Rh2{Zn ACHTUNGTRENNUNG(142)}2]

2+ (aderivative of [Rh2{Cr ACHTUNGTRENNUNG(142)Cl}2]

2+ containing zinc(II) salenunits instead of the respective chromium ACHTUNGTRENNUNG(III) salens) is ableto catalyse the acylation of pyridyl carbinol with acetic an-hydride. In contrast to [Rh{Cr ACHTUNGTRENNUNG(143)Cl}2]

+ , where the addi-tion of chloride and carbon monoxide decreases the activityof the catalyst, however, the addition of those two effectormolecules increased the reaction rate dramatically (~25times higher) here because the cavity is widened and thusmore accessible for this specific reaction (Scheme 90).

Further investigations with [Rh2{Zn ACHTUNGTRENNUNG(142)}2]2+ [178] revealed

that the acyl transfer can be used as a kind of signal amplifi-cation to detect chloride ions in concentrations as low as800 nm. Furthermore, it was demonstrated that similar to128 (Scheme 82) phenanthroline can be used as the effectorinstead of CO and Cl� when rhodium(I) is exchangedagainst copper(I). Hence, phenanthroline can also be detect-ed through signal amplification by [Cu2{Zn ACHTUNGTRENNUNG(142)}2]

2+in con-centrations down to 200 mm.

Scheme 81. Tashiro�s and Aida�s and co-workers� heterotropic allostericreceptor 125.

Scheme 80. Diederich�s and co-workers� ditopic receptor 124 : homotropicnegatively allosteric recognition of glutamic acid derivative 125 inCH2Cl2.

Scheme 82. Mirkin�s and co-workers� BINOL-based receptor [CuACHTUNGTRENNUNG(127)]+ .




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However, [Rh2{ZnACHTUNGTRENNUNG(142)}2]2+ can even be used for further

purposes as it proved to be useful in a PCR-like cascade re-action.[179] Here, the acetate, that is formed during the reac-tion of acetic anhydride with pyridyl carbinol, can act as aneffector such as chloride and activates further molecules ofinactivated catalyst [Rh2{ZnACHTUNGTRENNUNG(142)}2]

2+ , and hence, starts achain reaction-like cascade (Scheme 91).

Diphosphine 141 shown in Scheme 87 is very similar to142 and 143 except for the fact that 141 contains zinc por-phyrins instead of the salens.[171] After activation upon bind-ing of CO and Cl� it could not only bind dabco but also cat-alyse the acyl transfer from acetylimidazole to 4- and 3-pyr-

idyl carbinol with a rate twice as high as the not activatedreceptor and 14 times faster than the monomer.

Another similar receptor was synthesized in 2007.[180]

[Rh2{Zn ACHTUNGTRENNUNG(144)}2]6+ (Scheme 92) is able to catalyze the hy-

drolysis of 2-(hydroxypropyl)-p-nitrophenyl phosphate onlywhen activated upon binding of Cl� and CO, whereas itshows no catalytic activity in the absence of these effectors.

Mirkin�s group also designed an allosteric triple-layer rho-dium-complex [Rh2{Al ACHTUNGTRENNUNG(145)OEt} ACHTUNGTRENNUNG(146)2]

2+ .[181] In its activat-ed form it is able to catalyze the reaction of e-caprolactoneto polycaprolactone. Again, the inactive p-stacked form of

Scheme 83. Examples for complex receptor systems 131–136 that could inprinciple show more than one allosteric effect although they have notbeen designed for this purpose. Scheme 84. Reinaud�s and Jabin�s and co-workers� receptor for the recog-

nition of cyclic ureas: two-fold allosteric control in CHCl3.




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the complex can be converted into the active form byadding a chloride ion (HILR-concept) that coordinates toRh to form [Rh2{Al ACHTUNGTRENNUNG(145)OEt} ACHTUNGTRENNUNG(146)2Cl2] making the activesite of the catalyst—an AlIII salen complex—accessible(Scheme 93). As already demonstrated for receptor 140(Scheme 86) the catalyst can be deactivated by addinghalide abstracting agents like NaBArF or LiB ACHTUNGTRENNUNG(C6F5)4·Et2O.

Further examples for allosterically controlled catalystsmainly focus on artificial (phosphodi-)esterases (seeScheme 95). Probably the earliest reports came from thegroup of Tee and co-workers who reported on allosteric acti-

vation of transesterificationswith cyclodextrins.[182,183] A cy-clodextrin scaffold was alsoused by Liu and co-workers intheir allosteric supramolecularhydrolase model. Their cyclo-dextrin 147 bears a tren group.The catalytic activity of thecopper(II) complex [Cu-ACHTUNGTRENNUNG(147)(OH)]+ in H2O was great-ly enhanced when guanidiumion 148 was encapsulated insidethe cyclodextrin (Scheme 94).[184]

Kubo and co-workers usedcrown ether 149 with appendedthiourea functions to cleave aphosphodiester bond after itwas activated by coordinationof a potassium ion in CH3CN(Scheme 95).[185]

Kr�mer and co-workers thenpublished a series of articles onartificial phosphodiesterasesemploying oligodentate ligands150[186–188] and 151[189] each withthree metal binding sites(Scheme 96) that operate inaqueous solutions.

In 2002 Scrimin and co-work-ers introduced a tren derivative152 with three peptide armswhose catalytic activity con-cerning the cleavage of phos-phate esters could be signifi-cantly enhanced by addition ofzinc(II) ions acting as a positivecooperative effector.[190] Fiveyears later he was able tofollow up on this by reportingon a modified catalyst 153(Scheme 97) whose transphos-phorylation activity could alsobe controlled by zinc(II) ins ina positively cooperativemanner.[191]

Another class of oligodentateligands with multiple metal binding sites was developed byShinkai. The activity of his catalyst 154 in H2O/EtOH (2:1)was also found to depend on the presence of zinc(II) ionsacting as a positive allosteric effector (Scheme 98).[192, 193]

Summary and Outlook

Allosteric regulation is one of the most widely used mecha-nisms in order to control functions of certain proteins andenzymes in cellular metabolism. The term allosteric recogni-

Scheme 85. Allosteric control of G-quartet quadruplex formation and deaggregation in H2O.




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tion describes cooperative effects in binding of more thanone substrate selectively to different binding sites of a re-ceptor. These effects show in a conformational change ofthe receptor due to the binding of an effector in the socalled “allosteric site”, resulting in an activating (positivecooperation) or deactivating (negative cooperation) mannerin terms of the binding of another substrate at a differentbinding site. One can distinguish homotropic and heterotrop-

ic mechanisms, determining if the effector and the substrateare identical or different molecules or ions.

Representing such a powerful tool for controlling bindingproperties and associated processes by an external chemicalinput in a reversible manner, the concept of allosteric regu-lation has attracted a lot of interest in supramolecular chem-istry and stimulated many efforts to develop artificial sys-tems that can be controlled by allosteric effects. Since thefirst example was described in 1979 by Rebek, Jr. around140 artificial allosteric receptors have been developedworldwide that have been summarized here. Although inmost cases cations, dominantly metal ions, have been used

Scheme 86. Mirkin�s and co-workers� p-stacked complex [Rh2 ACHTUNGTRENNUNG(140)2]2+ :

formation of a pseudorotaxane after binding of chloride and carbon mon-oxide in CH2Cl2.

Scheme 87. Mirkin�s and co-workers� p-stacked complex [Rh2 ACHTUNGTRENNUNG(141)2]2+ :

recognition of dabco after binding of chloride and carbon monoxide inCH2Cl2.

Scheme 88. Mirkin�s and co-workers� epoxide opening catalyst [Rh2{Cr-ACHTUNGTRENNUNG(142)Cl}2]2+ :activation through allosteric chloride and carbon monoxide

binding in PhCN.

Scheme 89. Mirkin�s and co-workers� catalyst [Rh{Cr ACHTUNGTRENNUNG(143)Cl}2]+ : alloster-

ic deactivation through chloride and carbon monoxide binding in PhCN.




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as effectors there are also quite a number of exampleswhere anions or neutral molecules act as such and there areexamples for homotropic and heterotropic systems for eachof these classes. For many of the receptors, the allosteric ef-fects are large, resulting in a huge difference in binding af-finity or even a true on–off switching of the ability to bind a

Scheme 90. Mirkin�s and co-workers� catalyst [Rh{ZnACHTUNGTRENNUNG(142)}2]+ : allosteric

control of acyl transfer by activation through binding of chloride andcarbon monoxide in CH2Cl2.

Scheme 91. PCR-like cascade reaction of allosterically controlled catalyst[Rh2{ZnACHTUNGTRENNUNG(142)}2]

2+ upon use of acetate ions as effectors in CH2Cl2.

Scheme 92. Mirkin�s and co-workers� phosphate hydrolysing catalyst[Rh2{ZnACHTUNGTRENNUNG(144)}2]

6+ : allosteric activation through binding of chloride andcarbon monoxide.

Scheme 93. Mirkin�s and co-workers� triple-layer catalyst [Rh2{Al-ACHTUNGTRENNUNG(145)OEt} ACHTUNGTRENNUNG(146)2]2+: allosteric activation of ring opening polymerisation

of e-caprolactone in CH2Cl2.

Scheme 94. Liu�s and co-workers� allosteric hydrolase model [Cu-ACHTUNGTRENNUNG(147)(OH)]+ based on a functionalized b-cyclodextrin.




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certain substrate. Others led to substantial changes in sub-strate selectivity. In some cases the use of different effectorsled to negative or positive cooperativity in the binding of asubstrate to the allosteric receptor.

Despite all the progress that has been made the field isstill far from being mature. However, the systems created sofar provide a great tool box of switchable binding motifsand building blocks that proved successful to achieve allos-teric effects. The next steps will be either to couple them tofurther functions like catch and release transport, signal am-plification, analytical sensing, chemomechanical materials,or control of reactivity or to develop more sophisticated al-losteric cascades where binding of more than one effector isnecessary to achieve a certain function. Some pioneering ex-amples for this have been described in the last decade.These pave the avenue for exciting developments of thisconcept in the future.

Acknowledgements

Financial support from the Deutsche Forschungsgemeinschaft (Sonder-forschungsbereich 624) is gratefully acknowledged. C.K. thanks the Stud-ienstiftung des Deutschen Volkes for a doctoral scholarship.

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Scheme 95. Kubo�s and co-workers� allosteric phosphodiesterase model149K+ based on a bis ACHTUNGTRENNUNG(thiourea)-functionalized crown ether.

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Scheme 97. Scrimin�s and co-workers� allosteric transphosphorylation cat-alyst 153 : coordination of copper(II) or zinc(II) to the tris(triazacyclono-nane)-functionalized tren ligand gives [M ACHTUNGTRENNUNG(153)]2+ that can bind three ad-ditional zinc ions which can act as the catalytic site in H2O.

Scheme 98. Shinkai�s and co-workers� allosteric artificial phosphodiester-ase model 154 : based on a bis ACHTUNGTRENNUNG(thiourea)-functionalized crown ether.




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Molecular Recognition

C. Kremer, A. L�tzen* . . . . . . &&&&—&&&&

Artificial Allosteric Receptors

Widely used : In biological systems,allosteric regulation is a widely usedmechanism to control the function ofproteins and enzymes. Inspired by thisa lot of efforts have been made insupramolecular chemistry over the last30 years to implement this conceptinto artificial systems to control func-tions such as molecular recognition,signal amplification, or even reactivityand catalysis which are summarizedhere.

Artificial ReceptorsIn order to control the function of artificial supramolec-ular systems it is wise to take lessons from nature to adoptsuccessful approaches that have evolved in biologicalsystems. One of these is the concept of allosteric regula-tion. The Review of C. Kremer and A. L�tzen on page &

&ff. summarizes the efforts made to implement thisconcept into synthetic systems to control functions likemolecular recognition, signal amplification, or even reac-tivity.




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Artificial Allosteric Receptors

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