A Fluorescent Ditopic Rotaxane Ion‐Pair Host

Abstract We report a rotaxane based on a simple urea motif that binds Cl− selectively as a separated ion pair with H+ and reports the anion binding event through a fluorescence switch‐on response. The host selectively binds Cl− over more basic anions, which deprotonate the framework, and less basic anions, which bind more weakly. The mechanical bond also imparts size selectivity to the ditopic host.

Threading molecules through one another to form an interlocked architecture creates aw ell-defined three-dimensional space in which functional groups can be displayed. These functional groups often mediate attractive intercomponent interactions.Manipulation of these interactions in the design of molecular machines has led to significant advances in molecular shuttles,m otors,r atchets,a nd pumps. [1] Less well-studied is the use of interlocked molecules as scaffolds for the development of hosts and sensors.I ndeed, the majority of reported interlocked molecules that do display auseful output in response to asmall-molecule binding event are relatively structurally complex molecular shuttles, [2] with the attendant limitations on their synthetic accessibility. Furthermore,t he response to confounding analytes is typically not reported.
Thes tand-out exception to this is the use of interlocked molecules to bind and detect anions.B eer and co-workers [3] have exploited anion binding extensively in the assembly of rotaxanes and catenanes by employing the anion to template formation of am echanical bond. Thei nteractions that assembled the host "live on" in the product, allowing these catenanes and rotaxanes to bind anions with as electivity determined in part by the size and shape complementarity of the host and guest. By tethering an electroactive or photoactive unit to the host, Beer and co-workers have developed asmall number of interlocked anion sensors. [4] Thea nion-responsive sensors reported by Beer and coworkers typically rely on the same interactions for anion binding that are used in the formation of the mechanical bond. [5] Although effective,t his can be limiting since only arrangements of anion-binding functionality that are productive in the formation of the interlocked molecule can be applied as hosts.Herein, we report an alternative approach to anion-responsive fluorescent rotaxanes,inwhich the mechanical bond is used to alter the properties of simple anionbinding unit that plays no role in the rotaxane synthesis.A s aconsequence of the mechanical bond, significant differences were observed in the anion binding behavior of the rotaxane, resulting in ahost that is selective for binding Cl À over more (F À )o rl ess (Br À )b asic anions.T he crowded environment of the mechanical bond presents other weak non-covalent interactions,i na ddition to au rea-based anion binding unit, and appears to impart restricted access to the binding pocket based on anion size.
Rotaxane 1 (Figure 1a)w as synthesized in 92 %y ield using our small-macrocycle modification [6] of Leighsa ctivetemplate [7] Cu-mediated alkyne-azide cycloaddition (AT-CuAAC) reaction [8,9] (see the Supporting Information). The design of rotaxane 1 is based on previous reports of the naphthalimide urea core for the binding and transport of anions. [10]1 HNMR analysis of rotaxane 1 provided evidence that the bipyridine unit H-bonds to the urea moiety;the NH proton H 1 resonates at ah igher chemical shift in rotaxane 1 (Figure 1b,s pectrum ii)t han axle 2 (spectrum i). [11] This is consistent with the solid-state structure of 1 found by singlecrystal X-ray diffraction (SCXRD;F igure 2a), in which the macrocycle encircles the urea moiety with N-H···N distances of 2.32, 2.58, 2.44, and 2.88 .T he UV/Vis spectra of 1 and 2 display absorbances at 402 nm and 386 nm in CHCl 3 /CH 3 CN (1:1), respectively,which are attributed to the naphthalimide fluorophore,t hus suggesting that H-bonding from the urea contributes to ared-shift of the absorbance.Incontrast, 1 and 2 exhibit emissions at 470 and 474 nm, respectively,t hus suggesting that the mechanical bond does not significantly affect the fluorescence of the urea naphthalimide unit.
Titration of axle 2 with the tetrabutylammonium (TBA) salt of AcO À led to increasing downfield shifts of the signals for the NH protons H 1 and H 2 ,ared shift of the absorbance at 386 nm to 400 nm, and quenching of the emission associated with the naphthalimide.Non-linear-regression analysis of the 1 HNMR, UV/Vis and fluorescence titration data (see the Supporting Information) fit well to 1:1b inding models, thereby allowing binding constants to be determined (Table 1). Similar effects were observed for ar ange of anions with the observed order of anion affinity found to be I À < Br À < HSO 4 À < TsO À < MsO À < Cl À < F À < AcO À ; at rend in keeping with their H-bond-acceptor strengths. [12] We anticipated that addition of H-bond-accepting anions to rotaxane 1 would lead to displacement of the bipyridineurea interaction and that this competition between inter-and intra-molecular H-bonding might impart selectivity to 1 that is different from axle 2.However,titration of 1 with apanel of anions led to no observable change by 1 HNMR, UV/Vis,o r fluorescence spectroscopy,t hus suggesting that the NH···anion interaction is unable to compete with the inter-component H-bonds.
Theinhibition of anion binding in 1 corresponds to Lewis basic inhibition of the receptor.W ehave previously observed inhibition of an interlocked Au I catalyst due to asimilar Lewis basic interaction of the bipyridine moiety with the metal ion. [13] In that case,c atalytic activity was restored through binding of cations into the cavity of the rotaxane,a nd we speculated that asimilar interaction between acation and the bipyridine ring might be used to turn on anion binding by 1.
As aproof of concept, we investigated whether protonation of the bipyridine moiety could lead to binding of exogenous anions by the urea moiety.Furthermore,binding of anions by [1H] + would correspond to ditopic binding of HX, which is relatively unusual; [14] although anion binding motifs are known in which the host requires protonation, the donated proton is typically part of the anion coordination sphere. [15] In contrast, we anticipated that the proton would be sequestered in the rotaxane cavity,l eading to separated ion-pair binding. [16,17] When 1 was treated with an aqueous solution of HBF 4 , anew species with asignificantly different 1 HNMR spectrum (Figure 1b,spectrum iii)was obtained, which was assigned as 1·HBF 4 .K ey changes include an upfield shift of the signals attributable to NH protons H 1 and H 2, which suggests that they are no longer involved in H-bonding to the bipyridine unit, and an upfield shift of the signal attributable to H l ,which is consistent with the presence of aC H···p contact in the protonated rotaxane.The UV/Vis spectrum of rotaxane 1 also changes upon protonation;anew absorbance appeared at 310 nm that was assigned to the protonated bipyridine moiety, [18] and the absorbance band attributable to the naphthalimide blue-shifted to 381 nm, which is consistent with the urea moiety no longer being involved in H-bonding interactions.
SCXRD analysis confirmed the formation of the HBF 4 salt and revealed interactions consistent with the solutionphase data;p rotonation causes large-scale structural rearrangement to a(co)conformation in which one bipyridine Nis protonated and engaged in ah ydrogen bond with N3 of the triazole and, as ar esult, H l is held in close proximity to the face of one of the macrocycle aromatic rings.T he naphthalamide residue of 1·HBF 4 was found to be disordered about two orientations,o ne of which exhibits as hort face-face contact between one of the bipyridine rings and the naphthalimide unit (Figure 2b). Thus,a tl east in the solid state, protonation also seems to induce p-stacking of the bipyridine moiety and the naphthalimide ring. [19] Furthermore,i nt he solid state,the BF 4 À anion interacts with the urea protons,H h of the naphthalimide,and one of H G (Figure 2b).
Thesolid-state structure of 1·HBF 4 suggests that the urea NHs are no longer encumbered by the bipyridine donors and are thus available to bind exogenous anions. [20] Titration of 1·HBF 4 with basic anions such as AcO À or F À led to deprotonation of the host to regenerate 1,a sd etermined by 1 HNMR and UV/Vis analysis,a nd thus no anion binding. [21] Conversely,when 1·HBF 4 was treated with TBACl, the signals attributable to NH protons H 1 and H 2 shift downfield upon addition of the anion (Figure 1b,s pectrum iv), which is consistent with H-bonding of Cl À to the urea moiety. Simultaneously, peri proton H h also shifts downfield, which is consistent with aC H···Cl À hydrogen bond, and triazole proton H l shifts upfield, thus suggesting that the CH···p contact becomes stronger.SCXRD analysis of crystals grown from as olution of 1·HBF 4 in CH 2 Cl 2 /MeCN (1:1 v/v) in the presence of TBACl( 10 equiv) revealed that Cl À is bound as Titration experiments were carried out in CDCl 3 /CD 3 CN (1:1). K a determined by non-linearregression analysis (RMS error < 15 %, see the SupportingInformation). Anions were added as TBA salts.

Angewandte Chemie
Communications 5316 www.angewandte.org expected by the urea moiety in the protonated host with an additional C À H···Cl À contact with H h (Figure 2c)and alonger contact with H G .T he CH···p contact between H l and the flanking aromatic is also shorter than in 1 (Dd = 0.15 ), which is consistent with the solution-state data.
Thetitration of 1·HBF 4 with anions could also be followed by UV/Vis and fluorescence spectroscopy.A ddition of Cl À resulted in ar ed shift (Dl = 15 nm) and increase in the absorbance at 380 nm, and a2 -fold increase in the naphthalimide emission. Titrations with Br À ,HSO 4 À ,MsO À ,orTsO À revealed similar, although less pronounced changes.Although I À showed similar changes by 1 HNMR and UV/Vis spectroscopy,t he emission was quenched, presumably due to Stern-Volmer collisional effects. [22] Comparison of the binding constants determined for 1·HBF 4 with those of 2 reveal an umber of clear differences. Firstly,t he potential for deprotonation of 1·HBF 4 ,w hich renders it insensitive to anions,ensures that, whereas 2 binds more basic anions more strongly,t his is not the case for 1·HBF 4 ,w hich fails to bind the more basic F À and AcO À guests.S econdly,b inding of the less basic anions is much stronger to 1·HBF 4 than to the neutral host 2.T his is unsurprising since charge-charge interactions are expected to stabilize the interlocked complex significantly. [23] Therelative order of binding strength is also different for 2 and 1·HBF 4 .W hereas binding runs in the order I À < Br À < HSO 4 À < TsO À < MsO À < Cl À for 2,t he relative preference for the sulfonate versus halide anions is lower for 1·HBF 4 , resulting in the order I À < HSO 4 À < TsO À < MsO À < Br À < Cl À .T he relative preference of 1·HBF 4 for MsO À over TsO À is also higher. These results suggest that the crowded environment resulting from the presence of the threaded macrocycle adjacent to the urea motif in 1·HBF 4 provides some size and shape selection;the spherical Br À anion (ionic radius = 168 pm) [24] is preferred over the tetrahedral HSO 4 À and the larger MsO À and TsO À anions.C omparison of the solid-state structure of 1·HCl and 1·HBr (Figure 2d)suggests that as the anionic radius increases,t he "fit" of the anion between the urea nitrogen protons, peri proton H h ,a nd macrocycle proton H G decreases,forcing the anion out of the plane of the four H-anion contacts.
Finally,itisnoteworthy that 1·HBF 4 exhibits afluorescent switch-on response upon anion binding,w hereas axle 2 exhibits as witch-off response.T he origin of this photophysical difference is not obvious;inboth cases binding of the anion is expected to increase the electron density in the naphthalimide fluorophore and, on simple charge transfer grounds,w ould be expected to enhance the stability of the excited state,whereas the proximity of anions has previously been reported to result in PET quenching. [25] Theexplanation probably lies in the naphthalimide-bipyridine p-p interaction observed in the solid-state structure of 1·HBF 4 ,w hich is necessarily absent in the case of 2.Anion binding may affect this interaction by rigidifying the framework in some way, thus reducing non-radiative decay linked to bond rotation.
In conclusion, we have demonstrated that the AT-CuAAC reaction can be used to synthesize interlocked hosts for anions in which functional groups used or generated during the method of synthesis are not involved in the binding of the guest, thereby opening up new targets for study.I nd oing so, we serendipitously discovered arotaxane framework in which anion binding is activated allosterically by protonation, leading to as ystem that acts as ad itopic host for an HX ion pair. Theb inding event is reported by ac lear fluorescence response,a nd anion selectivity is determined both by the strength of the H-bonding interaction between the host and anion, and the anion pK a .Furthermore,the mechanical bond introduces size selectivity into this receptor.