- Email: [email protected]
Molecular recognition of anions by synthetic receptors
475
Molecular recognition of anions by synthetic receptors Paul D Beer* and Philippe Schmitt Over the past year, several
significant
developments
have
been made in the field of anion binding. The fundamental principles better
of molecular
understood,
several
synthetic
in complex
anion
natural
receptors
media.
such as anion specific molecular
recognition
are increasingly
and of particular
recognition
interest
able to perform
Additionally,
electrodes approach
being
are reports
macroscopic
and membranes are now being
of
their task devices based
on a
made.
design principles, which take into account concepts like the macrocyclic effect (enhanced binding properties of cyclic over acyclic structures due to a lower entropic cost upon completion) and preorganization were therefore directly applied to this newborn domain. Whereas cation binding requires converging arrays of Lewis-basic centers, the natural way to recognize anions was to build the corresponding frameworks supporting Lewis-acidic sites.
Organic charged receptors Addresses inorganic Chemistry
Laboratory,
University of Oxford, South Parks
Road, Oxford OX1 3QR, UK *e-mail: [email protected]
Currrent
Biology
in Chemical
Biology
1997, 1:475-462
http:/~biomednet.comlelecref/1367593100100475 0 Current Biology Ltd ISSN
1367-5931
Introduction As all life sustaining processes take place in water, which is the solvent of choice for charged species, it is not surprising to find anions involved in many biochemical reactions. Anions play many different key roles. They may act as cofactors, substrates or signaling devices, each anion being selectively recognized with great efficiency by its receptor. These receptors (or ‘hosts’) are generally composed of comparatively more lipophilic proteins. In this context, it is easy to appreciate how important it is to elucidate the underlying basic chemical processes governing the phenomena of association of these anions and receptors. The synthesis of abiotic anion receptors may therefore first serve a biomimetic goal. More importantly, however, it may provide new sensing devices enabling us to probe in V&J a process of vital interest, and help to generate new biologically active molecules that act as potent drugs. The aim of this short review is to summarize the latest progress in the field of anion recognition by focusing on a selection of the past year’s publications. In order to have a more complete overview of this domain we recommend the consultation of a few recent review articles [1,2,3*]. Compared to the parent field of cation coordination chemistry, anion recognition is a recent discipline. The inherent difficulties of addressing anionic guests characterized by greater sizes (larger than cations in general), a greater variety of shapes as well as pH dependence (certain anions, amphiprotic particularly, occur only in a narrow pH range) may account for this area’s relatively slow development. As an emblematic field within supramolecular chemistry, cation recognition had a tremendous influence on the growing discipline of anion binding. Fundamental
As the proton is the strongest Lewis acid, the first synthetic receptors directly emerging from the principles outlined above were macrocyclic or macropolycyclic arrangements of protonated centers, especially ammonium [l]. Still an ever growing domain, the latest developments of the proton approach, directed at halide [4], carboxylate [S] or phosphates binding [6,7], are periodically being published. Applying this approach to the biologically significant adenosine triphosphate anion (ATP; [8]), which is the energy provider for many life processes [8], or to biscarboxylates like malonate [S], receptors of this class were also shown to display enzyme-like activities which made them comparable to catalytic antibodies (compound 1, Figure 1). The major drawback of polyammonium-based hosts (receptors) is the limited pH range over which they remain protonaced. This factor is particularly important when considering the binding of basic anions such as phosphates or carboxylates. Addressing this problem Sessler and co-workers [9] took advantage of the ease of protonation of sapphyrin, an expanded porphyrin macrocycle, to bind nucleotides (compound 2, Figure 1). They elegantly showed that this receptor operates using a combination of electrostatic, hydrogen bonding and x-stacking interactions [9]. Guanidinium is also protonated over a wider pH range than ammonium-based systems and many research groups are currently involved in developing systems based on this biologically relevant building block. Following a biomimetic design, Murphy et a/. [lo*] prepared a family of receptors which provided crystallographic evidence supporting anion binding capabilities of ptilomycalin A, a potent guanidinium containing antitumor, antiviral and antifungal metabolite [ 10.1 (compound 3, Figure 1). Berger and Schmidtchen also inspired by naturally occurring anion binders, recently reported the synthesis and binding behavior of new elegant hosts (the terms ‘host’ and ‘receptor’ are synonymous in the contaxt of this article) [ 11’1. These zwitterionic systems (compound 4, Figure l), together with the one designed by Smith and co-workers [12*] (compound 5, Figure l), although they use charged binding units, exhibit no overall net charge by virtue of
476
Model
systems
Figure 1
nl, n2=1, 2
X = W&I,
CHCb,
CCls
Current Opinion in Chemical Biology
Organic
anion receptors
of how a protonated
can be separated
aza-macrrocycle
into charged
interacts
(for example,
with an anion which
compound
presents
1, 6) and neutral molecules
a complementary
geometry
(7,8). Compound
(here, malonate).
1 is an example
Compound
2
is a sapphyrin macrocycle which takes advantage of a converging array of both amine amd iminium protons to achieve anion recognition. Guanidinium moieties have also been extensively used. Compounds 3, 4 and 5 takes advantage of an intramolecular coordination bond to promote
the binding
capabilities
skeleton
to produce
receptors
of the urea group. The calix [41 arene structural relying solely on hydrogen
bonds
to achieve
remote covalently bound neutralizing species. In order to perform either transmembrane ion channelling or biphasic specific extractions, these hosts possess the advantage over charged receptors of being only sparingly soluble in water but increasingly compatible with lipophilic media. The preparation of another guanidinium-based sophisticated binder of polyanionic organic substrates was achieved by Anslyn and co-workers [13**] very recently (compound 6, Figure 1). They demonstrated that rational design based on a high degree of preorganization enables the receptor
framework
carboxylate
has been used for both compounds
7 and 8 as a
recognition.
target a very specific polyanionic guest, such as citrate, even in a mixture as complex as natural orange juice. to
All the systems discussed so far use proton-containing positively charged centers. These simultaneously provide a background nondirectional electrostatic attraction for the guest, as well as a highly directional component in the form of a hydrogen bond. In the pursuit of a better understanding of anion binding, however, it is of interest to separate these two contributions. By using quaternized
Molecular recognition of anions by synthetic receptors Beer and Schmitt
polypyridines protons, hydrogen
hosts
which
lack acidic
Beer et al. [14] highlighted bonds for binding halides.
hydrogen the
Metal-based
bonding
importance
of
477
anion receptors
Inorganic-based hosts form the mainstream class of anion receptors nowadays, and the ever growing complexity of their architecture is only limited by the imagination of their
designers.
Organic neutral receptors It is of interest to parallel the traditional cation recognition approach by using neutral receptors that rely solely on hydrogen bond arrays. Amides and their derivatives are particularly suitable for pursuing this objective as they have relatively acidic protons maintained in rigid conformations. Numerous examples can be found in the literature of anion receptors based on this design, many of which have appeared during the past year. Crabtree and co-workers [15] and Davis et al [16], for example, have recently shown that amides, carbamates or toluenesulfonamides bind halides. Yet, as the latter author concluded that selection based on anion size is induced by well-preorganized rigid receptors, the former shows that comparable effects can be obtained by arrays of amide moieties supported by more flexible framework. Preorganization becomes undoubtedly important in achieving segregation of differently shaped anions. Ungaro, Reinhoudt and co-workers [ 171 and Cameron and Loeb [18], for example, have taken advantage of the rigid framework provided by the calix[4]arene macrocycle to design concave hosts able to selectively bind bidentate guests such as acetate (compound 7, Figure 1) or benzoate (compound 8, Figure 1). Targeting tetrahedral anions, Umezawa and co-workers [19] have designed hosts based on xanthene-supported thioureas which, by virtue of their preorganized cavity, display remarkable selectivity for dihydrogen phosphate (HzPOd-). Related to their work on sapphyrins, Sessler’s group [ZO] used neutral porphyrinogens (renamed calix[4]pyrroles) in order to achieve efficient discrimination of the fluoride anion by relying exclusively on hydrogen bonds. They also showed that by functionalizing the macrocycle periphery with electron-withdrawing groups one can address the overall strength of the anion binding affinity without significantly affecting the selectivity trend of the receptor [Zl]. In a recent article describing the binding behavior of a polyfluorinated macrocycle, Suzuki and co-workers [Z] reached the same conclusions. Moreover, by incorporating his system generation
into a PVC matrix he designed a promising perchlorate selective anion sensor.
first
Sensing, namely the translation of a binding event into is another challenging issue for a physical response, anion recognition and many groups are interested in this field. The general strategy in sensor design takes advantage of building blocks that have some conveniently measurable physical properties which can be expected to be influenced by subtle perturbations associated with anion binding. Consequently, the exploitation of notoriously redox active and/or UV-visible absorbing or emitting metal-based centers has appeared as a natural approach.
Generally, the role of the metallic center is two-fold. Firstly for providing the signaling device, and also for promoting anion binding by virtue of either its positive charge (or Lewis acidity) enabling it to perform stabilizing orbital overlap with the anionic guest. The prevalent approach, however, is to avoid interference between the metal coordination chemistry and the anion recognition process. Therefore, it is of primary importance to use metal-based systems that are both thermodynamically and kinetically stable over a wide range of conditions. The organometallic centers ferrocene and cobaltocenium qualify for this requirement in their respective classes of neutral
and charged
redox-responsive
units.
A few years ago, our group reported the syntheses and binding behavior of several mono-cobaltocenium derivatives based on the coupling, by an amide linkage, of the positively charged organometallic center to a variety of both donor and acceptor hydrogen-bonding groups [23-261. Like the organic receptors discussed earlier, the anion selectivity pattern of these derivatives were shown to be tuneable by fine modification of their hydrogenbonding arrays to be complementary to a targeted ion such as dihydrogenphosphate or chloride. Additionally, due to the sensitivity of the reversible cobaltocenium/cobaltocene [(Cp)&o+/(Cp)2Co] redox couple to closely bound anions, these systems represented the first redox-responsive class of anion receptor. Recently, the synthesis of some related derivatives taking advantage of the neutral ferrocene building block in combination with hydrogen-bonding units was reported [27,28*]. These systems also displayed binding behaviors that obey the general rules now established, and a new selectivity criterion named ‘chemical selectivity’ was established. By incorporating a basic amine moiety into the binding cavity, it was shown that the corresponding new receptor displayed a remarkably strong response to an acidic anionic guest like HSOd- over HzPOd[28’]. Usually the selectivity pattern is reversed because of the stronger hydrogen bonding capability of the latter guest. In presence of the receptor basic center, however, the HSOdmoiety transfers a proton to the amine which induces a charge separation in the host-guest complex contributing to the overall binding force (compound 9, Figure 2). It is now well documented that preorganization is directly related to selectivity. Taking this into account we [29,30,31*] and others [32] have proposed new receptors based on the rigid, readily available and versatile calixarene building core. An example is provided by the cross-examination of a series of upper rim bis-cobaltocenium calix[4]arenes characterized by a variable partial tosylation pattern in their phenolic positions [33*] (compounds lOa-b,
470
Model systems
Figure indeed
2). The binding properties of these receptors are strikingly controlled by the lower rim substitution
pattern, presumably through rearrangement triggered by
a long range topological the remote tosyl groups.
This particular case illustrates the sensitivity of a given coordinating site to weak or long range conformational perturbations and may lead, we hope, to the development of new tuneable anion receptors. In pursuit of this objective, Beer et a/. [34,35] recently reported the preparation and complexation properties of a family of ortho-substituted tetra-arylporphyrin atropisomers containing as many as four metallocene groups (compounds lla-b, Figure 2). Considering the cobaltocenium-based porphyrins, these systems exhibit selectivity trends highly dependent on the topological arrangement of the organometallic groups. Although the a,a,a,a-atropisomer lla exhibited the selectivity pattern Cl -> Br> N03- in which all four cobaltocenium moieties cooperatively form a cavity complementary to the spherical halide anion guest, the a,a,B,B-atropisomer llb displays, in contrast, the rare selectivity sequence N03->Br>Clindicating that a complementary crigonal cavity exists for nitrate [Z]. As atropisomers are potentially inter-convertible, this opens the way towards tuning anionic selectivity by controlling the statistical distribution of the topological isomers. Besides metallocenes, metallo-2,2’-bipyridyl complexes offer a suitable platform for new receptors in which the 3,3’-bipyridyl hydrogens, promoted by the electron deficient metal, provide an efficient hydrogen bond donor site. Different platinumand palladium-containing hostswere designed based on this [36], but, in order to create UV-active as well as redox-active sensors, most of these systems use a ruthenium(II), osmium(I1) or rhenium(I) core [37,38,39”,40,41]. Some of these hosts form highly specific receptors for HzPOqable, for example, to sense this particular anion using fluorescence emission and electrochemical methodology, such as cyclic voltammetry, even in the presence of a ten-fold excess of competing HSOJ or Cl- (compound 12, Figure 2). In addition to their development as chemical sensors, the systems described here could see applications as fluorescent indicators for the study of phosphate transport in biological systems where competing anions would also be present.
An
alternative
stabilizing electrostatic
to the
general
hydrogen bonds force provided
approach
that
relies
with directional repulsive forces. An illustration of that strategy is provided by Beer’s group -a receptor which, by means of steric hindrance due to bulky tert-butyl groups toward Atwood of their
nearby the binding site, has an enhanced small halides [38]. and very
co-workers particular
[42**,43”] systems on
selectivity
based the design the same strategy,
but instead of just considering inducing a shapeor size-wise selection by unfavorable steric interactions, they also took advantage of repulsive electrostatic forces to tailor very innovative hosts (such as compound 13, Figure 2). By functionalizing bowl-shaped molecules (calix[4]arene or cyclotriveratrylene) with two or more cationic organometallic centers on their outer surfaces, they created highly charged receptors which present an array of converging electrostatic fields which promote the binding of anions within the shallow cavity. Achieving a difficult goal, these systems proved to perform segregative binding of shape-complementary tetrahedral anions such as TcOJwithin an ostensibly electron-rich binding site. Recently, a few groups reported the syntheses of compounds designed to bind their guests through metal-centered coordination bonds containing as many as one [44], two [45] and three [46] unsaturated zinc complexes maintained in a well defined geometry (compounds 14-16, Figure 2). Even though these systems display very interesting shape-selective recognition behavior, particularly toward barbiturates and phosphates, it must be emphasized that due to competition between anions and coordinating solvents such receptors present generally rather complex and PHI-sensitive coordination chemistries.
Receptors with dual anion and cation binding capabilities. A new research field recently emerged in the development of receptors designed to bind simultaneously both anionic and cationic parts of salts or zwitterions. By incorporating aza-crown moieties into amide-based ruthenium bipyridyl chloride binding was shown to be anion receptors, enhanced by the proximity of bound potassium within the crowns [47] (compound 17, Figure 3). In a similar approach, Reinhoudt and co-workers [48*] took advantage
Figure 2
Metal-based anion receptors takes advantage of various illustration of the concept of ‘chemical selectivity’. When
on
is to fine-tune the underlying by the metal-centered charge
organometallic centers. Compounds 9, which contains a ferrocene unit, provides an interacting with a weakly acidic anion the recognition process relies solely on two
hydrogen bondslf the substrate is a stronger acid, it transfers a electrostatic dipole in the complex, contributing to an overall binding force. Compounds lOa, b and 1 la, b are examples of receptors based on cobaltocenium behavior on anion binding. Compound 12 is illustrative of a receptor based on a ruthenium-tris-bipyridyl center, while 13 is an example of a host which takes advantage of metallic centers bound to the outer side of a bowl-shaped cyclotriveratrylene to promotr tetrahedral anion binding between the guest and the zinc-containing receptor to achieve anion recognition.
Molecular recognition of anions by synthetic receptors Beer and Schmitt
479
Figure 2
BH- : strong acid
.
7I-N
‘, u
10a : X=Tl, Y=H lob : X=H, Y=Ts
0
\/ 23
lla
.
I-N
J=0
\/ 43
o-
-0
0
‘0 Q”” %f+-
o\
”
- “‘0 ,3
P
. 12
Current Opinion in Chemical
Biology
480
Model systems
of the ease of derivatization of calix[4]arenes to build new salt-binders. By functionalizing the metacyclophane on its lower-rim with cation binding features, and functionalizing its upper-rim with hydrogen bonding donors (ureas), they obtained several heterotropic systems (which contain binding sites for different substrates) presenting cooperative binding properties (compound 18, Figure 3). They demonstrated that prior sodium binding induces a large ligand conformational rearrangement which preorganizes the hydrogen-bonding groups for efficient anion complexation. By targeting phosphoryl-choline derivatives, which form a family of biologically relevant zwiterrions, de Mendoza and co-workers [49*] prepared an efficient calix[6]arene-based receptor which binds both cationic and anionic parts of the target and offers a synthetic
alternative to the very costly catalytic antibody (compound 19, Figure 3).
technology
Applications In the introductory part of this review we referred to the great interest of designing devices able to sense biologically relevant anions in viva. By incorporating either neutral [SO] or charged [Sl] organic hosts into polyvinylchlorine (PVC) matrices Umezawa and co-workers [50], and Bachas and co-workers [Sl] succeeded in preparing novel electrodes that are selective for chloride and salicylate respectively. Of particular note is the ability of Umezawa’s and co-workers [SO] urea-based system to measure the chloride content of a complex mixture such as horse serum. Using a related strategy Cammann
Figure 3
fBU
OEt
Current Opinion m Chemical qtology
Compounds 17 and 19 are receptors with dual anionic and cationic binding capabilities. Compound 17 contains both anion and cation binding sites located, respectively, near the amide linkages and within the crown. It was shown that these two sites possess positive cooperative binding behavior characterized by an increase in the receptor’s affinity for chloride while the crown binds to apotassium cation. Similarly, prior complexation of a sodium cation at the lower rim of 18 triggers a conformational change of the receptor which preorganizes the upper rim hydrogen bonding groups in suitable way to bind an anion. Compound 19 is representative of a receptor designed to bind zwitterionic hosts such as phosphocholine derivatives. While the anionic part of the substrate interacts with the guanidinium moiety, the positively cahrged group is complexed within the calix 161arene macrocycle through cation-n: interactions.
Molecular recognition of anions by synthetic receptors Beer and Schmitt
and KrPmer
and co-workers
[SZ] used
a dinuclear
copper
compound embedded into a plasticized membrane to prepare the first cyanide-selective electrode. Perhaps despite being beyond the scope of more impressive,
5.
Fenniri H, Lehn JM, Marquis-Rigault A: Supramolecular catalysis of H/D exchange in malonate ions by macrocyclic polyamines: a model enzyme with enolase activity. Angew Chem Int Ed 1996, 35337-336.
6.
Nation DA, Reibenspies J, Martell AE: Anion binding of inorganic phosphates by the hexaaza macrocyclic ligand 3,6,9,17,20,23hexaazatricyclo[23.3.1 .111~lsltriaconta-1(29),11 (30),12,14,25.27hexaene. lnorg Chem 1996, 35:4597-4603.
7.
Aguilar JA, Garcia-Espaa E, Guerrero JA, Luis VS, Llinares JM, Ramirez JA, Soriano C: Synthesis and protonation behaviour of the macrocycle 2,6,10,13,17,21 -hexaaza[22lmetacyclophane. Thermodynamic and NMR studies on the interaction of 2,6,0,13,17,21 -hexaaza[22lmetacyclophane and on the openchain polyamine 4,6,11 .I 5-tetrazaoctadecane-1 ,I &diamine with ATP, ADP and AMP. lnorg Chim Acta 1996, 246:267-294.
9.
Hosseini MW, Lehn JM, Maggiora L, Bowman Mertes K, Mertes MP: Supramolecular catalysis in the hydrolysis of ATP facilated by macrocyclic polyamines: mechanistic studies. I Am Chem Sot 1967, 109:537-544.
9.
lverson BL, Shreder K, Krll V, Sansom P, Lynch V, Sessler JL: Interaction of sapphyrin with phosphorylated species of biological interest J Am Chem Sot 1996, 118:1606-l 616.
synthetic chemistry, is the work reported recently by Russel and co-workers [53*] consisting of engineering naturally occurring enzymes. By immobilizing bacterium extracted periplasmic nitrate reductase (Nap) [53*] he created a novel device capable of sensing nitrate, a well documented pollutant, at micromolar concentrations in media such as serum and seawater using UV absorption.
Conclusions We have seen in this article that anion recognition encompasses many different disciplines from biochemistry to coordination chemistry, and requires the expertise of researchers from across this scientific spectrum. With such a wide community contributing to the development of that field it is easy to appreciate how difficult it would have been to review the subject exhaustively. This was not our intention. Alternatively, by describing a selection of the past year’s papers from many different origins we have attempted to illustrate the recent significant results of anion recognition chemistry. While the basic principles governing the association process of an anionic guest with its host are now well understood, credit is due to the entire community for the profusion of receptors synthesized; the latest progress in the area involves application of these rules towards chemical sensing molecules. Even receptors of this second generation are now quite numerous, and their design has taken advantage of many inherent electrochemical and optical properties which can signal the binding of a specific anionic guest. Anion recognition is now entering a more mature stage and macroscopic devices based on this technology are being designed to monitor the in Z&M levels of biologically relevant anions. There is no doubt that the tremendous value of these and similar systems will provide the driving force for an even wider expansion of anion molecular recognition.
References
and recommended
. l
*
10 .
Murphy PJ, Williams HL, Hibbs DE, Hursthouse MB, Abdul Malik KM: Crystallographic evidence for the proposed host behaviour of ptilomycalin A. J Chem Sot Chem Commun 1996:445-447. The authors describe the synthesis of a class of concave anionic receptors relevant to the naturally occuring metabolites (ptilomycalin A). Of particular note is the use of a versatile synthetic route to prepare receptors presenting various accessibility in their binding site. 11. .
Berger M, Schmidtchen FP: Electroneutral artificial hosts for oxoanions active in strong donor solvents. J Am Chem Sot 1996, 116:6947-6946. The authors report the synthesis of sophisticated anion receptors which, by virtue of a remote anionic borane moiety, allow exploitation of guanidinium anchor groups while conserving overall host neutrality and hydrophobicity. 12. .
Hughes MP, Shang M, Smith BD: High affinity carboxylate binding using neutral urea-based receptors with internal Lewis acid coordination. J Org Chem 1996, 61:451 O-451 1. The overall affinity of a urea-based host for anions is enhanced by generation of an intramolecular charge separation. A very profitable compromise allowing the combination of efficient charged anchor groups and overall ligand neutrality. 13.
Metzger A, Lynch VM, Anslyn EV: A selective receptor for citrate. Angew Chem Int Ed 1997, 36:662-665. yremarkable achievement in the demonstration that a high degree of preorganization contributes to enhanced selectivity for a target-guest. 14.
Beer PD, Fletcher NC, Grieve A, Wheeler JW, Moore CP, Wear T: Halide anion recognition by new acyclic quaternary polybipyridinium and polypyridinium receptors. J Chem Sot Perkin pans 2 1996, :1545-l 551,
15.
Kavalieratos K, de Gala SR, Austin DJ, Crabtree RH: A readily available non-preorganized neutral acyclic halide receptor with an unusual nonplanar binding conformation. J Am Chem Sot 1997, 119:2325-2326.
16.
Davis AP, Perry JJ, Williams RP: Anion recognition by tripodal receptors derived from cholic acid. J Am Chem Sot 1997, 119:1793-l 794.
1 7.
Casnati A, Fochi M, Minari P, Pochini A, Reggiani M, Ungaro R, Reinhoudt DN: Upper-rim urea-derivatized calix[4larenes as neutral receptors for monocarboxylate anions. Gazz Chim ha/ 1996, 126:99-l 06.
19.
Cameron BR, Loeb SJ: Bis(amido)calix[4larenes in the pinched cone conformation as tuneable hydrogen-bonding anion receptors. J Chem Sot Chem Commun 1997:573-574.
19.
Biihlmann, Nishizawa S, Xiao KP, Umezawa Y: Strong hydrogen bond-mediated complexation of H,PO,- by neutral bis-thiourea hosts. Tetrahedron 1997, 53:1647-l 654.
20.
Gale PA, Sessler JL, Krll V, Lynch V: Calix[4lpyrroles: old yet new anion-binding agents. J Am Chem Sot 1996, 116:51405141.
21.
Gale PA, Sessler JL, Allen WE, Tvermoes NA, Lynch V: Calix[4lpyrroles: C-rim substitution and tunability of anion binding strength. J Chem Sot Chem Commun 1997, :665-666.
reading
Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest
1.
Dietrich B: Design of anion receptors: applications. Chem 1993, 65:1457-1464.
2.
Beer PD: Anion selective recognition and optical/electro chemical sensing by novel transition metal receptor systems. J Chem Sot Chem Commun 1996:669-696.
3. . A very based
Beer PD, Smith DK: Anion binding and recognition by inorganic based receptors. Progr lnorg Chem 1997, 46:1-96. complete review although more focused on inorganic- than organicreceptors.
4.
Dietrich B, Dilworth B, Lehn JM, Souchez JP, Cesario M, Guilhem J, Pascard C: 52. Anion crypt&es: synthesis, crystal structures, and complexation constants of fluoride and chloride inclusion complexes of polyammonium macrobicyclic ligands. He/v Chim Acta 1996, 79569-587.
481
Pure Appl
402
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systems
22.
Siswanta D, Takenaka J, Suzuki T, Sasakura H, Hisamoto H, Suzuki K: Novel neutral anion ionophores based on fluorinated (poly)ether compounds as a sensory molecule for an ionselective electrode. Chem Letf 1997:195-l 96.
23.
Beer PD, Hesek D, Hodacova J, Stokes SE: Acyclic redox responsive anion receptors containing amide linked cobaltocinium moieties. I Chem Sot Chem Commun 1992:270272.
24.
Beer PD, Hazlewood C, Hesek D, Hodacova J, Stokes SE: Anion recognition by acyclic redox-responsive amide-linked cobaltocenium receptors. I Chem Sot Dalton Titans 1993:13271332.
25.
Beer PD, Drew MGB, Graydon AR, Smith DK, Stokes SE: Quantitative and structural investigations of hydrogen-bonding interactions in anion binding of mono- and l.l’-bis-substituted aryl cobaltocenium receptors. J Chem Sot Dalton Pans 1995: 403-408.
26.
Beer PD, Drew MGB, Hodacova J, Stokes SE: Synthesis, structure and anion co-ordination chemistry of a novel macrocyclic cobaltocenium receptor. J Chem Sot Dalton 7ians 1995:3447-3453.
27.
Beer PD, Drew MGB, Smith DK: Selective electrochemical recognition of bidentete anionic guests in competitive solvents using novel ferrocenyi thiourea and guanidinium receptors. J Organometall Chem 1997, in press.
28. .
Beer PD, Graydon AR, Johnson AOM, Smith DK: Neutral ferrocenoyl receptors for the selective recognition and sensing of anionic guests. lnorg Chem 1997, 36:2112-2118. . . Offers an overvlew 01 several terrocene-based neutral receptors and Introduces the concept of ‘chemical selectivity’. 29.
Beer PD, Drew MGB, Hazlewood C, Hesek D, Hodacova J, Stokes SE: Dicarboxylate anion recognition by a redoxresponsive ditopic bis(cobaltocinium)caIix[4larene receptor molecule. J Chem Sot Chem Commun 1993:229-231.
30.
Beer PD, Chen Z, Goulden Al, Grieve A, Hesek D, Szemes F, Wear T: Anion recognition by novel ruthenium(ll) bipyridyl calixI4larene receptor molecules. / Chem Sot Chem Commun 1994: 1269-1271.
Beer PD, Drew MGB, Hesek D, Nam KC: A new carboxylate anion selective cobaltocenium calixI4larene receptor. J Chem Sot Chem Commun 1997: 107-l 08. The technical achievement of bridging a calix[4larene with a redox-active cobaltocenium group in a very strained conformation confers a very high degree of rigidity and preorganization in this new host.
39. ..
Szemes F, Hesek D, Chen Z, Dent SW, Drew MGB, Goulden AJ, Graydon AR, Grieve A, Mortimer RJ, Wear T et al.: Synthesis and characterization of novel acyclic, macrocyclic, and calix[llarene ruthenium(ll)bipyridyl receptor molecules that recognize and sense anions. lnorg Chem 1996, 35:5868-5879. The authors present a family of anion receptors based on ruthenium(ll) bipyridyl units exhibiting dual optical and electrochemical sensing capabilities. 40.
Beer PD, Dent SW, Hobbs GS, Wear TJ: Novel anion binding selectivity trends exhibited by new dinuclear rhenium(l), ruthenium(ll) and osmium(ll)bipyridyl cleft-type receptors. J Chem Sot Chem Commun 1997:99-l 00.
41.
Beer PD, Mortimer RJ, Szemes F, Weightman JS: Selective fluorimetric recognition of dihydrogen phosphate over chloride anions by a novel ruthenium(ll) bipyridyl receptor complex. Anal Commun 1996, 33:365-366.
42. ..
Atwood JL, Holman KT, Steed JW: Laying traps for elusive preys: recent advances in the non-covalent binding of anions. J Chem Sot Chem Commun 1996:1401-l 407. By using the outer aromatic surfaces of concave building blocks to anchor organometallic charged centers, the authors built very original rigid receptors which perform shape and size selective anion recognition with remarkable efficiency. 43. ..
Holman KT, Haliban MM, Jurisson SS, Atwood JL, Burkhalter RS, Mitchell AR. Steed JW: Inclusion of neutral and anionic quests within the cavity of p-metalated cyclotriveratrylene. J Ai Chem Sot 1996, 118:9567-9576. The authors showed that even aromatic concave surfaces can be used to bind anions selectively provided that their electron density is partially withdrawn by yexternally complexed metal centers. 44.
De Santis G, Fabbrizzi L, Licchelli M, Poggi A, Taglietti A: Molecular recognition of carboxylate ions based on the metal-ligand interaction and signaled through fluorescence quenching. Angew Chem Int Ed 1996, 35:202-204.
45.
Koike T, Takashige M, Kimura E, Fujioka H, Shiro M: Bis(Znllcyclen) complex as a novel receptor of barbiturates aqueous solution. Angew Chem Inf Ed 1996, 2:617-623.
46.
Kimura E, Aoki S, Koike T, Shiro M: A tris(Zn”l,4,7,10tetraaracyclododecane) complex as a new receptor for phosphate dianions in aqueous solution. J Am Chem Sot 1997, 119:3068-3076.
47.
Beer PD, Dent SW, Fletcher NC: Anion and cation recognition by a new mono- and bis-ruthenium00 bipyridyl crown ether receptor molecules. Polyhedron 1996, 15:2983-2996.
31. .
32.
Morzherin Y, Rudkevich DM, Verboom W, Reinhoudt DN: Chlorosulfonated celix[4larenes: precursors for neutral anion receptors with a selectivity for hydrogen sulfate. I Org Chem 1993, 58:7602-7605.
33. .
Beer PD, Drew MGB, Hesek D, Shade M, Szemes F: Anion recognition properties of new upper-rim bis[rhenium(l)bipyridyl. ruthenium(ll)bis(bipyridyl). cobaltoceniumlcalix[4larene receptors dictated by lower-rim substituents. J Chem Sot Chem Commun 1996:2161-2162. A good illustration of hoave the triggering of one ligand binding capabilities can be induced by long-range topological perturbations.
34.
35.
36.
37.
38.
Beer PD, Drew MGB, Jagesaar R: Selective anion recognition by novel 5,10,15,20-tetrakis~o-ferrocenyl-carbonylaminophenylsubstituted) zinc metalloporphyrin receptors. J Chem Sot Dalton Trans 1997:881-886. Beer PD, Drew MGB, Hesek D, Jagessar R: Spectral and electrochemical anion sensing by a novel 5,10,15.20-tetrakis(Rsubstituted)porphyrin receptor (R~sH4NHC(0)C5H~+PF6-). J Chem Sot Chem Commun 1995:1187-l 189. Beer PD, Fletcher NC, Drew MGB, Wear TJ: Chloride anion recognition by neutral platinum(ll) and palladium(ll)5,5’-bisamide substituted bipyridyl receptor molecules. Polyhedron 1997, 16:815-823. Beer PD, Graydon AR, Sutton LR: Luminescent anion recognition: selective induced emission by binding of dihydrogenphosphate. Polyhedron 1996, 15:2457-2461. Beer PD, Dent SW, Wear TJ: Spectral and electrochemical recognition halide anions by acyclic mononuclear ruthenium(ll)bipyridyi receptor molecules. J Chem Sot Dalton pans 1996:2341-2346.
in
Scheerder J, van Duynhoven JPM, Engbersen JFJ, Reinhoudt DN: Solubilization of NaX salts in chloroform by bifunctional receptors. Angew Chem Int Ed 1996, 35:1090-l 093. . This paper describes a new class ot elegant heterotroplc receptors that combine the dual capabilities of binding both cations and anions in a cooperative fashion. 48. .
Magrans JO, Ortiz AR, Molins MA, Lebouille PHP, SanchezQuesada J, Prados P, Pons M, Gago F, de Mendoza J: A designed non-peptidic receptor that mimics the phosphocholine binding site of the &PC603 antibody. Angew Chem Int Ed 1996, 35:1712-l 715. A nice achievement in the biomimetic approach for studying antibodyantigen interactions. The authors report the synthesis of a sophisticated receptor able to perform the multitopic recognition of naturally occuring zwitterions such as phosphocholines.
49. .
50.
Xiao KP, Btihlman P, Nishizawa S, Amemiya S, Umezawa Y: A chloride ion-selective solvent polymeric membrane electrode based on a hydrogen forming ionophore. Anal Chem 1997, 69:1038-l 044.
51.
Hutchins R, Bansal P, Molina P, Alajarin M, Vidal A, Bachas LG: Salicylate-selective electrode based on a biomimetic guanidinium ionophore. Anal Chem 1997, 69:1273-l 278.
52.
Ahlers B, Cammann K, Warzeska S, Krgmer R: Molecular recognition of cyanide by a dicopper(lI)macrocyclic ionophore: construction of a cyanide-selective liquid-membrane electrode. Angew Chem Int Ed 1996, 35:2141-2143.
Aylott JW, Richardson DJ, Russel DA: Optical biosensing of nitrate ions using a sol-gel immobilized nitrate reductase. Analyst 1997, 122:77-80. A very selective and efficient system based on the immobilization of naturally occuring matrices is described which can serve as a reference for future synthetic biosensor applications. 53. .
Molecular recognition of anions by synthetic receptors Paul D Beer* and Philippe Schmitt Over the past year, several
significant
developments
have
been made in the field of anion binding. The fundamental principles better
of molecular
understood,
several
synthetic
in complex
anion
natural
receptors
media.
such as anion specific molecular
recognition
are increasingly
and of particular
recognition
interest
able to perform
Additionally,
electrodes approach
being
are reports
macroscopic
and membranes are now being
of
their task devices based
on a
made.
design principles, which take into account concepts like the macrocyclic effect (enhanced binding properties of cyclic over acyclic structures due to a lower entropic cost upon completion) and preorganization were therefore directly applied to this newborn domain. Whereas cation binding requires converging arrays of Lewis-basic centers, the natural way to recognize anions was to build the corresponding frameworks supporting Lewis-acidic sites.
Organic charged receptors Addresses inorganic Chemistry
Laboratory,
University of Oxford, South Parks
Road, Oxford OX1 3QR, UK *e-mail: [email protected]
Currrent
Biology
in Chemical
Biology
1997, 1:475-462
http:/~biomednet.comlelecref/1367593100100475 0 Current Biology Ltd ISSN
1367-5931
Introduction As all life sustaining processes take place in water, which is the solvent of choice for charged species, it is not surprising to find anions involved in many biochemical reactions. Anions play many different key roles. They may act as cofactors, substrates or signaling devices, each anion being selectively recognized with great efficiency by its receptor. These receptors (or ‘hosts’) are generally composed of comparatively more lipophilic proteins. In this context, it is easy to appreciate how important it is to elucidate the underlying basic chemical processes governing the phenomena of association of these anions and receptors. The synthesis of abiotic anion receptors may therefore first serve a biomimetic goal. More importantly, however, it may provide new sensing devices enabling us to probe in V&J a process of vital interest, and help to generate new biologically active molecules that act as potent drugs. The aim of this short review is to summarize the latest progress in the field of anion recognition by focusing on a selection of the past year’s publications. In order to have a more complete overview of this domain we recommend the consultation of a few recent review articles [1,2,3*]. Compared to the parent field of cation coordination chemistry, anion recognition is a recent discipline. The inherent difficulties of addressing anionic guests characterized by greater sizes (larger than cations in general), a greater variety of shapes as well as pH dependence (certain anions, amphiprotic particularly, occur only in a narrow pH range) may account for this area’s relatively slow development. As an emblematic field within supramolecular chemistry, cation recognition had a tremendous influence on the growing discipline of anion binding. Fundamental
As the proton is the strongest Lewis acid, the first synthetic receptors directly emerging from the principles outlined above were macrocyclic or macropolycyclic arrangements of protonated centers, especially ammonium [l]. Still an ever growing domain, the latest developments of the proton approach, directed at halide [4], carboxylate [S] or phosphates binding [6,7], are periodically being published. Applying this approach to the biologically significant adenosine triphosphate anion (ATP; [8]), which is the energy provider for many life processes [8], or to biscarboxylates like malonate [S], receptors of this class were also shown to display enzyme-like activities which made them comparable to catalytic antibodies (compound 1, Figure 1). The major drawback of polyammonium-based hosts (receptors) is the limited pH range over which they remain protonaced. This factor is particularly important when considering the binding of basic anions such as phosphates or carboxylates. Addressing this problem Sessler and co-workers [9] took advantage of the ease of protonation of sapphyrin, an expanded porphyrin macrocycle, to bind nucleotides (compound 2, Figure 1). They elegantly showed that this receptor operates using a combination of electrostatic, hydrogen bonding and x-stacking interactions [9]. Guanidinium is also protonated over a wider pH range than ammonium-based systems and many research groups are currently involved in developing systems based on this biologically relevant building block. Following a biomimetic design, Murphy et a/. [lo*] prepared a family of receptors which provided crystallographic evidence supporting anion binding capabilities of ptilomycalin A, a potent guanidinium containing antitumor, antiviral and antifungal metabolite [ 10.1 (compound 3, Figure 1). Berger and Schmidtchen also inspired by naturally occurring anion binders, recently reported the synthesis and binding behavior of new elegant hosts (the terms ‘host’ and ‘receptor’ are synonymous in the contaxt of this article) [ 11’1. These zwitterionic systems (compound 4, Figure l), together with the one designed by Smith and co-workers [12*] (compound 5, Figure l), although they use charged binding units, exhibit no overall net charge by virtue of
476
Model
systems
Figure 1
nl, n2=1, 2
X = W&I,
CHCb,
CCls
Current Opinion in Chemical Biology
Organic
anion receptors
of how a protonated
can be separated
aza-macrrocycle
into charged
interacts
(for example,
with an anion which
compound
presents
1, 6) and neutral molecules
a complementary
geometry
(7,8). Compound
(here, malonate).
1 is an example
Compound
2
is a sapphyrin macrocycle which takes advantage of a converging array of both amine amd iminium protons to achieve anion recognition. Guanidinium moieties have also been extensively used. Compounds 3, 4 and 5 takes advantage of an intramolecular coordination bond to promote
the binding
capabilities
skeleton
to produce
receptors
of the urea group. The calix [41 arene structural relying solely on hydrogen
bonds
to achieve
remote covalently bound neutralizing species. In order to perform either transmembrane ion channelling or biphasic specific extractions, these hosts possess the advantage over charged receptors of being only sparingly soluble in water but increasingly compatible with lipophilic media. The preparation of another guanidinium-based sophisticated binder of polyanionic organic substrates was achieved by Anslyn and co-workers [13**] very recently (compound 6, Figure 1). They demonstrated that rational design based on a high degree of preorganization enables the receptor
framework
carboxylate
has been used for both compounds
7 and 8 as a
recognition.
target a very specific polyanionic guest, such as citrate, even in a mixture as complex as natural orange juice. to
All the systems discussed so far use proton-containing positively charged centers. These simultaneously provide a background nondirectional electrostatic attraction for the guest, as well as a highly directional component in the form of a hydrogen bond. In the pursuit of a better understanding of anion binding, however, it is of interest to separate these two contributions. By using quaternized
Molecular recognition of anions by synthetic receptors Beer and Schmitt
polypyridines protons, hydrogen
hosts
which
lack acidic
Beer et al. [14] highlighted bonds for binding halides.
hydrogen the
Metal-based
bonding
importance
of
477
anion receptors
Inorganic-based hosts form the mainstream class of anion receptors nowadays, and the ever growing complexity of their architecture is only limited by the imagination of their
designers.
Organic neutral receptors It is of interest to parallel the traditional cation recognition approach by using neutral receptors that rely solely on hydrogen bond arrays. Amides and their derivatives are particularly suitable for pursuing this objective as they have relatively acidic protons maintained in rigid conformations. Numerous examples can be found in the literature of anion receptors based on this design, many of which have appeared during the past year. Crabtree and co-workers [15] and Davis et al [16], for example, have recently shown that amides, carbamates or toluenesulfonamides bind halides. Yet, as the latter author concluded that selection based on anion size is induced by well-preorganized rigid receptors, the former shows that comparable effects can be obtained by arrays of amide moieties supported by more flexible framework. Preorganization becomes undoubtedly important in achieving segregation of differently shaped anions. Ungaro, Reinhoudt and co-workers [ 171 and Cameron and Loeb [18], for example, have taken advantage of the rigid framework provided by the calix[4]arene macrocycle to design concave hosts able to selectively bind bidentate guests such as acetate (compound 7, Figure 1) or benzoate (compound 8, Figure 1). Targeting tetrahedral anions, Umezawa and co-workers [19] have designed hosts based on xanthene-supported thioureas which, by virtue of their preorganized cavity, display remarkable selectivity for dihydrogen phosphate (HzPOd-). Related to their work on sapphyrins, Sessler’s group [ZO] used neutral porphyrinogens (renamed calix[4]pyrroles) in order to achieve efficient discrimination of the fluoride anion by relying exclusively on hydrogen bonds. They also showed that by functionalizing the macrocycle periphery with electron-withdrawing groups one can address the overall strength of the anion binding affinity without significantly affecting the selectivity trend of the receptor [Zl]. In a recent article describing the binding behavior of a polyfluorinated macrocycle, Suzuki and co-workers [Z] reached the same conclusions. Moreover, by incorporating his system generation
into a PVC matrix he designed a promising perchlorate selective anion sensor.
first
Sensing, namely the translation of a binding event into is another challenging issue for a physical response, anion recognition and many groups are interested in this field. The general strategy in sensor design takes advantage of building blocks that have some conveniently measurable physical properties which can be expected to be influenced by subtle perturbations associated with anion binding. Consequently, the exploitation of notoriously redox active and/or UV-visible absorbing or emitting metal-based centers has appeared as a natural approach.
Generally, the role of the metallic center is two-fold. Firstly for providing the signaling device, and also for promoting anion binding by virtue of either its positive charge (or Lewis acidity) enabling it to perform stabilizing orbital overlap with the anionic guest. The prevalent approach, however, is to avoid interference between the metal coordination chemistry and the anion recognition process. Therefore, it is of primary importance to use metal-based systems that are both thermodynamically and kinetically stable over a wide range of conditions. The organometallic centers ferrocene and cobaltocenium qualify for this requirement in their respective classes of neutral
and charged
redox-responsive
units.
A few years ago, our group reported the syntheses and binding behavior of several mono-cobaltocenium derivatives based on the coupling, by an amide linkage, of the positively charged organometallic center to a variety of both donor and acceptor hydrogen-bonding groups [23-261. Like the organic receptors discussed earlier, the anion selectivity pattern of these derivatives were shown to be tuneable by fine modification of their hydrogenbonding arrays to be complementary to a targeted ion such as dihydrogenphosphate or chloride. Additionally, due to the sensitivity of the reversible cobaltocenium/cobaltocene [(Cp)&o+/(Cp)2Co] redox couple to closely bound anions, these systems represented the first redox-responsive class of anion receptor. Recently, the synthesis of some related derivatives taking advantage of the neutral ferrocene building block in combination with hydrogen-bonding units was reported [27,28*]. These systems also displayed binding behaviors that obey the general rules now established, and a new selectivity criterion named ‘chemical selectivity’ was established. By incorporating a basic amine moiety into the binding cavity, it was shown that the corresponding new receptor displayed a remarkably strong response to an acidic anionic guest like HSOd- over HzPOd[28’]. Usually the selectivity pattern is reversed because of the stronger hydrogen bonding capability of the latter guest. In presence of the receptor basic center, however, the HSOdmoiety transfers a proton to the amine which induces a charge separation in the host-guest complex contributing to the overall binding force (compound 9, Figure 2). It is now well documented that preorganization is directly related to selectivity. Taking this into account we [29,30,31*] and others [32] have proposed new receptors based on the rigid, readily available and versatile calixarene building core. An example is provided by the cross-examination of a series of upper rim bis-cobaltocenium calix[4]arenes characterized by a variable partial tosylation pattern in their phenolic positions [33*] (compounds lOa-b,
470
Model systems
Figure indeed
2). The binding properties of these receptors are strikingly controlled by the lower rim substitution
pattern, presumably through rearrangement triggered by
a long range topological the remote tosyl groups.
This particular case illustrates the sensitivity of a given coordinating site to weak or long range conformational perturbations and may lead, we hope, to the development of new tuneable anion receptors. In pursuit of this objective, Beer et a/. [34,35] recently reported the preparation and complexation properties of a family of ortho-substituted tetra-arylporphyrin atropisomers containing as many as four metallocene groups (compounds lla-b, Figure 2). Considering the cobaltocenium-based porphyrins, these systems exhibit selectivity trends highly dependent on the topological arrangement of the organometallic groups. Although the a,a,a,a-atropisomer lla exhibited the selectivity pattern Cl -> Br> N03- in which all four cobaltocenium moieties cooperatively form a cavity complementary to the spherical halide anion guest, the a,a,B,B-atropisomer llb displays, in contrast, the rare selectivity sequence N03->Br>Clindicating that a complementary crigonal cavity exists for nitrate [Z]. As atropisomers are potentially inter-convertible, this opens the way towards tuning anionic selectivity by controlling the statistical distribution of the topological isomers. Besides metallocenes, metallo-2,2’-bipyridyl complexes offer a suitable platform for new receptors in which the 3,3’-bipyridyl hydrogens, promoted by the electron deficient metal, provide an efficient hydrogen bond donor site. Different platinumand palladium-containing hostswere designed based on this [36], but, in order to create UV-active as well as redox-active sensors, most of these systems use a ruthenium(II), osmium(I1) or rhenium(I) core [37,38,39”,40,41]. Some of these hosts form highly specific receptors for HzPOqable, for example, to sense this particular anion using fluorescence emission and electrochemical methodology, such as cyclic voltammetry, even in the presence of a ten-fold excess of competing HSOJ or Cl- (compound 12, Figure 2). In addition to their development as chemical sensors, the systems described here could see applications as fluorescent indicators for the study of phosphate transport in biological systems where competing anions would also be present.
An
alternative
stabilizing electrostatic
to the
general
hydrogen bonds force provided
approach
that
relies
with directional repulsive forces. An illustration of that strategy is provided by Beer’s group -a receptor which, by means of steric hindrance due to bulky tert-butyl groups toward Atwood of their
nearby the binding site, has an enhanced small halides [38]. and very
co-workers particular
[42**,43”] systems on
selectivity
based the design the same strategy,
but instead of just considering inducing a shapeor size-wise selection by unfavorable steric interactions, they also took advantage of repulsive electrostatic forces to tailor very innovative hosts (such as compound 13, Figure 2). By functionalizing bowl-shaped molecules (calix[4]arene or cyclotriveratrylene) with two or more cationic organometallic centers on their outer surfaces, they created highly charged receptors which present an array of converging electrostatic fields which promote the binding of anions within the shallow cavity. Achieving a difficult goal, these systems proved to perform segregative binding of shape-complementary tetrahedral anions such as TcOJwithin an ostensibly electron-rich binding site. Recently, a few groups reported the syntheses of compounds designed to bind their guests through metal-centered coordination bonds containing as many as one [44], two [45] and three [46] unsaturated zinc complexes maintained in a well defined geometry (compounds 14-16, Figure 2). Even though these systems display very interesting shape-selective recognition behavior, particularly toward barbiturates and phosphates, it must be emphasized that due to competition between anions and coordinating solvents such receptors present generally rather complex and PHI-sensitive coordination chemistries.
Receptors with dual anion and cation binding capabilities. A new research field recently emerged in the development of receptors designed to bind simultaneously both anionic and cationic parts of salts or zwitterions. By incorporating aza-crown moieties into amide-based ruthenium bipyridyl chloride binding was shown to be anion receptors, enhanced by the proximity of bound potassium within the crowns [47] (compound 17, Figure 3). In a similar approach, Reinhoudt and co-workers [48*] took advantage
Figure 2
Metal-based anion receptors takes advantage of various illustration of the concept of ‘chemical selectivity’. When
on
is to fine-tune the underlying by the metal-centered charge
organometallic centers. Compounds 9, which contains a ferrocene unit, provides an interacting with a weakly acidic anion the recognition process relies solely on two
hydrogen bondslf the substrate is a stronger acid, it transfers a electrostatic dipole in the complex, contributing to an overall binding force. Compounds lOa, b and 1 la, b are examples of receptors based on cobaltocenium behavior on anion binding. Compound 12 is illustrative of a receptor based on a ruthenium-tris-bipyridyl center, while 13 is an example of a host which takes advantage of metallic centers bound to the outer side of a bowl-shaped cyclotriveratrylene to promotr tetrahedral anion binding between the guest and the zinc-containing receptor to achieve anion recognition.
Molecular recognition of anions by synthetic receptors Beer and Schmitt
479
Figure 2
BH- : strong acid
.
7I-N
‘, u
10a : X=Tl, Y=H lob : X=H, Y=Ts
0
\/ 23
lla
.
I-N
J=0
\/ 43
o-
-0
0
‘0 Q”” %f+-
o\
”
- “‘0 ,3
P
. 12
Current Opinion in Chemical
Biology
480
Model systems
of the ease of derivatization of calix[4]arenes to build new salt-binders. By functionalizing the metacyclophane on its lower-rim with cation binding features, and functionalizing its upper-rim with hydrogen bonding donors (ureas), they obtained several heterotropic systems (which contain binding sites for different substrates) presenting cooperative binding properties (compound 18, Figure 3). They demonstrated that prior sodium binding induces a large ligand conformational rearrangement which preorganizes the hydrogen-bonding groups for efficient anion complexation. By targeting phosphoryl-choline derivatives, which form a family of biologically relevant zwiterrions, de Mendoza and co-workers [49*] prepared an efficient calix[6]arene-based receptor which binds both cationic and anionic parts of the target and offers a synthetic
alternative to the very costly catalytic antibody (compound 19, Figure 3).
technology
Applications In the introductory part of this review we referred to the great interest of designing devices able to sense biologically relevant anions in viva. By incorporating either neutral [SO] or charged [Sl] organic hosts into polyvinylchlorine (PVC) matrices Umezawa and co-workers [50], and Bachas and co-workers [Sl] succeeded in preparing novel electrodes that are selective for chloride and salicylate respectively. Of particular note is the ability of Umezawa’s and co-workers [SO] urea-based system to measure the chloride content of a complex mixture such as horse serum. Using a related strategy Cammann
Figure 3
fBU
OEt
Current Opinion m Chemical qtology
Compounds 17 and 19 are receptors with dual anionic and cationic binding capabilities. Compound 17 contains both anion and cation binding sites located, respectively, near the amide linkages and within the crown. It was shown that these two sites possess positive cooperative binding behavior characterized by an increase in the receptor’s affinity for chloride while the crown binds to apotassium cation. Similarly, prior complexation of a sodium cation at the lower rim of 18 triggers a conformational change of the receptor which preorganizes the upper rim hydrogen bonding groups in suitable way to bind an anion. Compound 19 is representative of a receptor designed to bind zwitterionic hosts such as phosphocholine derivatives. While the anionic part of the substrate interacts with the guanidinium moiety, the positively cahrged group is complexed within the calix 161arene macrocycle through cation-n: interactions.
Molecular recognition of anions by synthetic receptors Beer and Schmitt
and KrPmer
and co-workers
[SZ] used
a dinuclear
copper
compound embedded into a plasticized membrane to prepare the first cyanide-selective electrode. Perhaps despite being beyond the scope of more impressive,
5.
Fenniri H, Lehn JM, Marquis-Rigault A: Supramolecular catalysis of H/D exchange in malonate ions by macrocyclic polyamines: a model enzyme with enolase activity. Angew Chem Int Ed 1996, 35337-336.
6.
Nation DA, Reibenspies J, Martell AE: Anion binding of inorganic phosphates by the hexaaza macrocyclic ligand 3,6,9,17,20,23hexaazatricyclo[23.3.1 .111~lsltriaconta-1(29),11 (30),12,14,25.27hexaene. lnorg Chem 1996, 35:4597-4603.
7.
Aguilar JA, Garcia-Espaa E, Guerrero JA, Luis VS, Llinares JM, Ramirez JA, Soriano C: Synthesis and protonation behaviour of the macrocycle 2,6,10,13,17,21 -hexaaza[22lmetacyclophane. Thermodynamic and NMR studies on the interaction of 2,6,0,13,17,21 -hexaaza[22lmetacyclophane and on the openchain polyamine 4,6,11 .I 5-tetrazaoctadecane-1 ,I &diamine with ATP, ADP and AMP. lnorg Chim Acta 1996, 246:267-294.
9.
Hosseini MW, Lehn JM, Maggiora L, Bowman Mertes K, Mertes MP: Supramolecular catalysis in the hydrolysis of ATP facilated by macrocyclic polyamines: mechanistic studies. I Am Chem Sot 1967, 109:537-544.
9.
lverson BL, Shreder K, Krll V, Sansom P, Lynch V, Sessler JL: Interaction of sapphyrin with phosphorylated species of biological interest J Am Chem Sot 1996, 118:1606-l 616.
synthetic chemistry, is the work reported recently by Russel and co-workers [53*] consisting of engineering naturally occurring enzymes. By immobilizing bacterium extracted periplasmic nitrate reductase (Nap) [53*] he created a novel device capable of sensing nitrate, a well documented pollutant, at micromolar concentrations in media such as serum and seawater using UV absorption.
Conclusions We have seen in this article that anion recognition encompasses many different disciplines from biochemistry to coordination chemistry, and requires the expertise of researchers from across this scientific spectrum. With such a wide community contributing to the development of that field it is easy to appreciate how difficult it would have been to review the subject exhaustively. This was not our intention. Alternatively, by describing a selection of the past year’s papers from many different origins we have attempted to illustrate the recent significant results of anion recognition chemistry. While the basic principles governing the association process of an anionic guest with its host are now well understood, credit is due to the entire community for the profusion of receptors synthesized; the latest progress in the area involves application of these rules towards chemical sensing molecules. Even receptors of this second generation are now quite numerous, and their design has taken advantage of many inherent electrochemical and optical properties which can signal the binding of a specific anionic guest. Anion recognition is now entering a more mature stage and macroscopic devices based on this technology are being designed to monitor the in Z&M levels of biologically relevant anions. There is no doubt that the tremendous value of these and similar systems will provide the driving force for an even wider expansion of anion molecular recognition.
References
and recommended
. l
*
10 .
Murphy PJ, Williams HL, Hibbs DE, Hursthouse MB, Abdul Malik KM: Crystallographic evidence for the proposed host behaviour of ptilomycalin A. J Chem Sot Chem Commun 1996:445-447. The authors describe the synthesis of a class of concave anionic receptors relevant to the naturally occuring metabolites (ptilomycalin A). Of particular note is the use of a versatile synthetic route to prepare receptors presenting various accessibility in their binding site. 11. .
Berger M, Schmidtchen FP: Electroneutral artificial hosts for oxoanions active in strong donor solvents. J Am Chem Sot 1996, 116:6947-6946. The authors report the synthesis of sophisticated anion receptors which, by virtue of a remote anionic borane moiety, allow exploitation of guanidinium anchor groups while conserving overall host neutrality and hydrophobicity. 12. .
Hughes MP, Shang M, Smith BD: High affinity carboxylate binding using neutral urea-based receptors with internal Lewis acid coordination. J Org Chem 1996, 61:451 O-451 1. The overall affinity of a urea-based host for anions is enhanced by generation of an intramolecular charge separation. A very profitable compromise allowing the combination of efficient charged anchor groups and overall ligand neutrality. 13.
Metzger A, Lynch VM, Anslyn EV: A selective receptor for citrate. Angew Chem Int Ed 1997, 36:662-665. yremarkable achievement in the demonstration that a high degree of preorganization contributes to enhanced selectivity for a target-guest. 14.
Beer PD, Fletcher NC, Grieve A, Wheeler JW, Moore CP, Wear T: Halide anion recognition by new acyclic quaternary polybipyridinium and polypyridinium receptors. J Chem Sot Perkin pans 2 1996, :1545-l 551,
15.
Kavalieratos K, de Gala SR, Austin DJ, Crabtree RH: A readily available non-preorganized neutral acyclic halide receptor with an unusual nonplanar binding conformation. J Am Chem Sot 1997, 119:2325-2326.
16.
Davis AP, Perry JJ, Williams RP: Anion recognition by tripodal receptors derived from cholic acid. J Am Chem Sot 1997, 119:1793-l 794.
1 7.
Casnati A, Fochi M, Minari P, Pochini A, Reggiani M, Ungaro R, Reinhoudt DN: Upper-rim urea-derivatized calix[4larenes as neutral receptors for monocarboxylate anions. Gazz Chim ha/ 1996, 126:99-l 06.
19.
Cameron BR, Loeb SJ: Bis(amido)calix[4larenes in the pinched cone conformation as tuneable hydrogen-bonding anion receptors. J Chem Sot Chem Commun 1997:573-574.
19.
Biihlmann, Nishizawa S, Xiao KP, Umezawa Y: Strong hydrogen bond-mediated complexation of H,PO,- by neutral bis-thiourea hosts. Tetrahedron 1997, 53:1647-l 654.
20.
Gale PA, Sessler JL, Krll V, Lynch V: Calix[4lpyrroles: old yet new anion-binding agents. J Am Chem Sot 1996, 116:51405141.
21.
Gale PA, Sessler JL, Allen WE, Tvermoes NA, Lynch V: Calix[4lpyrroles: C-rim substitution and tunability of anion binding strength. J Chem Sot Chem Commun 1997, :665-666.
reading
Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest
1.
Dietrich B: Design of anion receptors: applications. Chem 1993, 65:1457-1464.
2.
Beer PD: Anion selective recognition and optical/electro chemical sensing by novel transition metal receptor systems. J Chem Sot Chem Commun 1996:669-696.
3. . A very based
Beer PD, Smith DK: Anion binding and recognition by inorganic based receptors. Progr lnorg Chem 1997, 46:1-96. complete review although more focused on inorganic- than organicreceptors.
4.
Dietrich B, Dilworth B, Lehn JM, Souchez JP, Cesario M, Guilhem J, Pascard C: 52. Anion crypt&es: synthesis, crystal structures, and complexation constants of fluoride and chloride inclusion complexes of polyammonium macrobicyclic ligands. He/v Chim Acta 1996, 79569-587.
481
Pure Appl
402
Model
systems
22.
Siswanta D, Takenaka J, Suzuki T, Sasakura H, Hisamoto H, Suzuki K: Novel neutral anion ionophores based on fluorinated (poly)ether compounds as a sensory molecule for an ionselective electrode. Chem Letf 1997:195-l 96.
23.
Beer PD, Hesek D, Hodacova J, Stokes SE: Acyclic redox responsive anion receptors containing amide linked cobaltocinium moieties. I Chem Sot Chem Commun 1992:270272.
24.
Beer PD, Hazlewood C, Hesek D, Hodacova J, Stokes SE: Anion recognition by acyclic redox-responsive amide-linked cobaltocenium receptors. I Chem Sot Dalton Titans 1993:13271332.
25.
Beer PD, Drew MGB, Graydon AR, Smith DK, Stokes SE: Quantitative and structural investigations of hydrogen-bonding interactions in anion binding of mono- and l.l’-bis-substituted aryl cobaltocenium receptors. J Chem Sot Dalton Pans 1995: 403-408.
26.
Beer PD, Drew MGB, Hodacova J, Stokes SE: Synthesis, structure and anion co-ordination chemistry of a novel macrocyclic cobaltocenium receptor. J Chem Sot Dalton 7ians 1995:3447-3453.
27.
Beer PD, Drew MGB, Smith DK: Selective electrochemical recognition of bidentete anionic guests in competitive solvents using novel ferrocenyi thiourea and guanidinium receptors. J Organometall Chem 1997, in press.
28. .
Beer PD, Graydon AR, Johnson AOM, Smith DK: Neutral ferrocenoyl receptors for the selective recognition and sensing of anionic guests. lnorg Chem 1997, 36:2112-2118. . . Offers an overvlew 01 several terrocene-based neutral receptors and Introduces the concept of ‘chemical selectivity’. 29.
Beer PD, Drew MGB, Hazlewood C, Hesek D, Hodacova J, Stokes SE: Dicarboxylate anion recognition by a redoxresponsive ditopic bis(cobaltocinium)caIix[4larene receptor molecule. J Chem Sot Chem Commun 1993:229-231.
30.
Beer PD, Chen Z, Goulden Al, Grieve A, Hesek D, Szemes F, Wear T: Anion recognition by novel ruthenium(ll) bipyridyl calixI4larene receptor molecules. / Chem Sot Chem Commun 1994: 1269-1271.
Beer PD, Drew MGB, Hesek D, Nam KC: A new carboxylate anion selective cobaltocenium calixI4larene receptor. J Chem Sot Chem Commun 1997: 107-l 08. The technical achievement of bridging a calix[4larene with a redox-active cobaltocenium group in a very strained conformation confers a very high degree of rigidity and preorganization in this new host.
39. ..
Szemes F, Hesek D, Chen Z, Dent SW, Drew MGB, Goulden AJ, Graydon AR, Grieve A, Mortimer RJ, Wear T et al.: Synthesis and characterization of novel acyclic, macrocyclic, and calix[llarene ruthenium(ll)bipyridyl receptor molecules that recognize and sense anions. lnorg Chem 1996, 35:5868-5879. The authors present a family of anion receptors based on ruthenium(ll) bipyridyl units exhibiting dual optical and electrochemical sensing capabilities. 40.
Beer PD, Dent SW, Hobbs GS, Wear TJ: Novel anion binding selectivity trends exhibited by new dinuclear rhenium(l), ruthenium(ll) and osmium(ll)bipyridyl cleft-type receptors. J Chem Sot Chem Commun 1997:99-l 00.
41.
Beer PD, Mortimer RJ, Szemes F, Weightman JS: Selective fluorimetric recognition of dihydrogen phosphate over chloride anions by a novel ruthenium(ll) bipyridyl receptor complex. Anal Commun 1996, 33:365-366.
42. ..
Atwood JL, Holman KT, Steed JW: Laying traps for elusive preys: recent advances in the non-covalent binding of anions. J Chem Sot Chem Commun 1996:1401-l 407. By using the outer aromatic surfaces of concave building blocks to anchor organometallic charged centers, the authors built very original rigid receptors which perform shape and size selective anion recognition with remarkable efficiency. 43. ..
Holman KT, Haliban MM, Jurisson SS, Atwood JL, Burkhalter RS, Mitchell AR. Steed JW: Inclusion of neutral and anionic quests within the cavity of p-metalated cyclotriveratrylene. J Ai Chem Sot 1996, 118:9567-9576. The authors showed that even aromatic concave surfaces can be used to bind anions selectively provided that their electron density is partially withdrawn by yexternally complexed metal centers. 44.
De Santis G, Fabbrizzi L, Licchelli M, Poggi A, Taglietti A: Molecular recognition of carboxylate ions based on the metal-ligand interaction and signaled through fluorescence quenching. Angew Chem Int Ed 1996, 35:202-204.
45.
Koike T, Takashige M, Kimura E, Fujioka H, Shiro M: Bis(Znllcyclen) complex as a novel receptor of barbiturates aqueous solution. Angew Chem Inf Ed 1996, 2:617-623.
46.
Kimura E, Aoki S, Koike T, Shiro M: A tris(Zn”l,4,7,10tetraaracyclododecane) complex as a new receptor for phosphate dianions in aqueous solution. J Am Chem Sot 1997, 119:3068-3076.
47.
Beer PD, Dent SW, Fletcher NC: Anion and cation recognition by a new mono- and bis-ruthenium00 bipyridyl crown ether receptor molecules. Polyhedron 1996, 15:2983-2996.
31. .
32.
Morzherin Y, Rudkevich DM, Verboom W, Reinhoudt DN: Chlorosulfonated celix[4larenes: precursors for neutral anion receptors with a selectivity for hydrogen sulfate. I Org Chem 1993, 58:7602-7605.
33. .
Beer PD, Drew MGB, Hesek D, Shade M, Szemes F: Anion recognition properties of new upper-rim bis[rhenium(l)bipyridyl. ruthenium(ll)bis(bipyridyl). cobaltoceniumlcalix[4larene receptors dictated by lower-rim substituents. J Chem Sot Chem Commun 1996:2161-2162. A good illustration of hoave the triggering of one ligand binding capabilities can be induced by long-range topological perturbations.
34.
35.
36.
37.
38.
Beer PD, Drew MGB, Jagesaar R: Selective anion recognition by novel 5,10,15,20-tetrakis~o-ferrocenyl-carbonylaminophenylsubstituted) zinc metalloporphyrin receptors. J Chem Sot Dalton Trans 1997:881-886. Beer PD, Drew MGB, Hesek D, Jagessar R: Spectral and electrochemical anion sensing by a novel 5,10,15.20-tetrakis(Rsubstituted)porphyrin receptor (R~sH4NHC(0)C5H~+PF6-). J Chem Sot Chem Commun 1995:1187-l 189. Beer PD, Fletcher NC, Drew MGB, Wear TJ: Chloride anion recognition by neutral platinum(ll) and palladium(ll)5,5’-bisamide substituted bipyridyl receptor molecules. Polyhedron 1997, 16:815-823. Beer PD, Graydon AR, Sutton LR: Luminescent anion recognition: selective induced emission by binding of dihydrogenphosphate. Polyhedron 1996, 15:2457-2461. Beer PD, Dent SW, Wear TJ: Spectral and electrochemical recognition halide anions by acyclic mononuclear ruthenium(ll)bipyridyi receptor molecules. J Chem Sot Dalton pans 1996:2341-2346.
in
Scheerder J, van Duynhoven JPM, Engbersen JFJ, Reinhoudt DN: Solubilization of NaX salts in chloroform by bifunctional receptors. Angew Chem Int Ed 1996, 35:1090-l 093. . This paper describes a new class ot elegant heterotroplc receptors that combine the dual capabilities of binding both cations and anions in a cooperative fashion. 48. .
Magrans JO, Ortiz AR, Molins MA, Lebouille PHP, SanchezQuesada J, Prados P, Pons M, Gago F, de Mendoza J: A designed non-peptidic receptor that mimics the phosphocholine binding site of the &PC603 antibody. Angew Chem Int Ed 1996, 35:1712-l 715. A nice achievement in the biomimetic approach for studying antibodyantigen interactions. The authors report the synthesis of a sophisticated receptor able to perform the multitopic recognition of naturally occuring zwitterions such as phosphocholines.
49. .
50.
Xiao KP, Btihlman P, Nishizawa S, Amemiya S, Umezawa Y: A chloride ion-selective solvent polymeric membrane electrode based on a hydrogen forming ionophore. Anal Chem 1997, 69:1038-l 044.
51.
Hutchins R, Bansal P, Molina P, Alajarin M, Vidal A, Bachas LG: Salicylate-selective electrode based on a biomimetic guanidinium ionophore. Anal Chem 1997, 69:1273-l 278.
52.
Ahlers B, Cammann K, Warzeska S, Krgmer R: Molecular recognition of cyanide by a dicopper(lI)macrocyclic ionophore: construction of a cyanide-selective liquid-membrane electrode. Angew Chem Int Ed 1996, 35:2141-2143.
Aylott JW, Richardson DJ, Russel DA: Optical biosensing of nitrate ions using a sol-gel immobilized nitrate reductase. Analyst 1997, 122:77-80. A very selective and efficient system based on the immobilization of naturally occuring matrices is described which can serve as a reference for future synthetic biosensor applications. 53. .