1,3-Alternate Calix Tubes

Chapter 7 1,3-ALTERNATE CALIX TUBES Shuttling of cationr Buncha Pulpoka", Lassaad Baklouti“, long Seung Kim‘. and Jacques Vicens“ "Supmmnlecullzr Chemlxtry Rmarcn Um"! and Organic Synlhesis Research Unit, Depimmenl of chmnxwy, Faculty of Science, Chuhlrmgknm Unlvzrxity, Fhyalhar Road, E./zrigkok 10330, 77u1Ilund. E-mail: Buncha.P@rhubz.ar.Ih: "Fat-ulté der Sciencex de Hizerle, Labnmmire dz Chirme des Interactions Mnléculuires, 7021 Zarzmma, Turiml,‘ Email.’ bi1kloutlIn.r.mizd@yah0o.fr; ‘Department nf Chemistry, Dmiknok University, Senul, I40-714 Repablir (If Korea: E-mail: /‘ong.rkim@dankonk.ut,kr; “Esme Chimie Pnlymérer er Marériaux, labomloire de Canctptlmi Maléculaire, UMR 75I2. 25 me Becquerel, E67087 Slrasbrrurg, Fmncz. Email.- viarnr@chimi£.u-.rIra.rbgfi Abstract: Ca|ix[4]arenes in their 1,3-alternate confonnation are particularly convenient scaffolds for the construction of extended calix tubes. These molecules can act as pcilylopic canon receptors and have the fascinating property of allowing cation transport! (“shutIling"] along the tube by passing through the "1:-basic tube“ {on-ned by the macrocyclic rings of the calixarene units. Although calix tubes can also influence anion lrmsport, ll’llS does not appear to involve anion shuttling. Key words: Calixarenes, nanoiubes. cnlrx tubes. 1.3-allemate conformation. 1. INTRODUCTION The desire to mimic and thereby understand the functions of biological systems has been a powerful stimulus in many areas of chemistry. The inherently three-dimensional nature and nanoscale dimensions of biological systems‘ place enormous demands upon the ability of the synthetic chemist to create “supermolecules"2 of the appropriate stereochemistry and function. As described in the preceding chapter 6, tube-like molecules derived from calix[4]arenes in their cone confonnation have provided fascinating insights into the nature of selective ion binding and transport. There is, however. some difficulty in extending the syntheses used for such molecules to create 135 J Vvzerrrandl zlamwfieiaum ;, Culixurcnm m IheNarmwur/I/, 135449 E‘ 2007 Sprliiger. 136 Chapter 7 longer tubes of dimensions such that they might be considered analogues of membrane-spanning ionophores. This difficulty is much diminished by the use of calix[4]arenes in their l,3—alternate confomiation. where the basic functional groups are now oriented in a manner which facilitates oligomer and polymer fonnation. Thus, the following discussion is a survey of the exploitation of this approach to the production of synthetic ionophores. The mimicry of trans-membrane ion transport‘ using synthetic ion channels‘ has, of course, been explored in various ways, the earliest successful system being based on a functionalised cyclodextrin which in fact proved more efficient (for Co(II) transport) than its natural analogue’; 2. THE FIRST 1,3-ALTERNATE CALIX TUBES An essential feature of a membrane-spanning ion channel is the presence of ion-binding sites at both termini of the channel, These sites may be considered ponals to the membrane space and a relatively simple design.“ readily open to variation. of a molecule incorporating portals for cation binding (or. when protonated, for anion binding) is that shown in Fig. 1. Molecules of this type have been shown to function as cation transporters in phospholipid bi1ayers7 and their form, with multiple tails attached to a hollow central unit (relay). stnlcturally analogous to that of polyps of the genus Hydra, has led to them being referred to as “hydraphiles".X The design of hydraphiles may be said to embody a “three macrocycles“ concept,” with a central macrocyclic ligand serving to pass a cation from one macrocyclic portal to the other. Hydrophobic spacers linking the macrocycles provide a means of adjusting the channel length to the thickness of a given membrane. 0/—\ V ‘"l~—O-i gvy cu Entry portal and headgoup Cennl iehy Figure 7.1. ‘Hydraphiles'. designed cation-conducting channels. An idealised representation of a “tunnel" form of a tris(macrocyc1e) 1 based on the linking of three diaza-18-crowno units is shown below. Such a configuration should also be realisable with a calix[4]arene unit as the cen- tral macrocycle and the first such derivatives, 2a and 2b, in which the spacer chains and headgroups were those that had proved efficacious in the 7, 1,3-Alternate Calix Tubes 137 hydraphile family, were prepared with the calixarene in its cone and 1,3-altemate conformations, respectively.” Conductance measurements showed that while cone 2a appeared to be inactive as a cation transporter, 1.3- alternate 2b was active and remained so even with t-butyl substituents on the para positions of the phenyl rings. Since such substitution was expected to block passage of a cation through the calixarene annulus, the intriguing question arose as to how a cation might be transferred from one portal to the other. By analogy with a synthetic sterol-based ion channel” consisting a tartrate-derived crown ether supporting six steroids, the calix[4]arene—cholic acid conjugates 3-7, again incorporating both cone and 1,3-altemate confor- mers, were prepared recently.” Molecular modeling of the fully extended confomiations of these species indicated that the 1,3-altemate calix deriva— tives 3-5 should have the ability to span a membrane 35 2 2 A thick, whereas cone-form derivatives 6 and 7 could span only 25 1 2 A. 138 Chapter 7 Measurements of both the H‘ and Na‘ transporting abilities of these compounds showed that. once again, the l.3—alternate calixarene derivatives were more efficient. The crucial factor in these cases may be the difference in the length of the channel possibly formed by the ion0phore.'Z While the activity of these synthetic ionophores is comparable to that of natural systems. the exact mechanism of their ion transport remains to be established, 3. METAL OSCILLATION THROUGH THE II-BASE TUNNEL OF THE 1,3-ALTERNATE CONFORMATION The l,3—altemate conformation of calix[4]arene can be considered a ‘smart’ building block for constructing original structures directed towards designed properties," Its utility stems from its ditopic form, with two divergent binding sites connected by orthogonal pairs of parallel phenyl rings foiming a “it-base tunnel”. The development of a facile synthesis of tetra—O—alkylated l.3»a|ternatc calixarenes 8 based on the use of Cs;CO« as a base catalyst in dimethylformamide (dmf)” led to extensive studies of their metal-ion binding capacity and the early discovery” that stability constant values for many metal ions exceeded those for the analogous cone 7. 1,3-Alternate Calix Tube: 139 conformer complexes. This enhanced ionophoricity was attributed to the involvement of the It electrons of the phenyl groups as donor centres,” various crystallographic studies. e.g. '7. providing evidence in support of this proposal. 10 E,“ Q'i;n Bu’ 8 Thus, a possible solution to the enigma of the means of passage of a cation via the central calixarene unit of a hydraphile was to propose that the “It-base tunnel” could function as a temporary binding site to allow transit of the cation through the macrocyclic cavity (Fig. 2), Figure 7.2. Representation of (a) the two metal-binding sites of a 1.3-alternate calix[4]arene and (b) cation oscillation through me 1t—base tunnel connecting these sites, as detected by NMR spectroscopy. Substantial support for this notion was provided by detailed studies of the complexation of Ag(l) by l,3-altemate ca|ix[4]arenes.” ‘H VTNMR spectroscopy provided evidence that exchange of the metal ion between the two binding sites can be imramalecular and thus must involve passage through the macrocyclic ring. In the case of the unsymmetrical 1,3-alternate 140 Chapter 7 calix[4]arene 9, this passage is involved in the establishment of an equili- brium where. at 188 K, 8.1% of Ag(I) resides in the cavity associated with the propyloxy substituents and 91.9% in the cavity with ethoxyethyloxy substituents (Fig. 3). lmramuleeular metal oscillation (fast process) 8.] ‘Z; 9].‘) '7: Figurc 7—3. Different proportions of Ag’ in the two different cavities of 9. Similar observations were made with Na’ and K‘. Much more sophist.i— cated exploitation of this behaviour has been applied in the development of a photocontrolled “molecular syringe“ 10.” Photoactivated cycloaddition reactions of the pendent anthracenyl lead to the conversion of a cavity where Ag(I) binding is preferred to one where this is less favoured than in the opposing cavity with propoxy of ethoxyelhyloxy suhslituents. Thus, irradiation of the Aga) Complex of 10 leads to the forced tunneling of the metal through to the other cavity (Fig. 4). A similar molecular syringe 12 has been based on a 1,3-altemate calix[4]arene bridged by an azacrown unit.” Agtl) is preferentially bound to the azacrown unit but protonalion of the nitrogen centre leads to ejection of the metal ion through the calixarene ring and into the ethoxyethyloxy site. 7. 1,3-Alternate Calix Tuber 141 E. D f. .1 (ii I J (O) t‘ 3 H; II Figure 7-4. The cycluaddition reaction uf L3-alternate cal|x[4]arenc dlanlhracenc-based IighI—switch molecular syringes lo. Thus. the nitrogen atom can be considered as a plunger, activated by protonation, which can drive the metal through the “syringe barrel" 1:-base tube of the calixarene (Fig. 5). protomlkm rid rim is J o It ,.» T tlqtouwulxm Figure 7-5. Molecular syringe 12 derived from a |,3—a|Iemate ca||x[4]arene azacrown. 142 Chapter 7 4. DOUBLY-BRIDGED 1,3-ALTERNATE CALIX[4]AREN ES Further investigations of cation tunnelling or "shuttling" in calixarenes were based on the 1,3-altemate calix[4]bl's(crown-5) 13?“ Again. VTNMR experiments with 1:1 complexes of K‘, Rb’, Cs’ and NH.’ provided evidence, from signal coalescences, for two exchange processes, one of which could be attributed to intramolecular cation transfer (TL.,.,,.m 125°C, 105°C, 45°C and 55°C. respectively. in 5:2 (CDCl3)3:DMF). Similar studies of complexes of the analogous thiacalix[4]arene derivative 14 in CDClr:CDJ0D (4:1) provided evidence that shuttling here was more rapid. For K(I), for example, T.._,,..,_, = 281 K, k._,,,,,‘ = 26.7 s” and AGic,Inlnt = 61.5 kl mol", whereas for the simple calix[4]arene complex in the same solvent, shuttling was not detected. Similarly, Cs‘ was observed to shuttle from one side to the other of 1,3~alternate /hiacalix[4]biscrown-6 (15). Interestingly, metal shuttling was observed in the 1:1 complex of K’ with non-symmetrical 1,3-alternate lhiacalix[4]crown-5.crown—6 (16) while it was not in the 1:1 Cs’ complex. 13 14 I5 16 17 I8 pxxxxx >§l| rgppop Z‘ -