A Bis-Acridinium Macrocycle as Multi-Responsive Receptor and Selective Phase Transfer Agent of Perylene

Supporting information for this article is given via a link at the end of the document. Abstract : A bis-acridinium cyclophane incorporating switchable acridinium moieties linked by a 3,5-dipyridylanisole spacer was studied as a multi-responsive host for polycyclic aromatic hydrocarbon guests. Complexation of perylene was proven to be the most effective and was characterized in particular by a charge transfer band as signal output. Effective catch and release of the guest was triggered by both chemical (proton/hydroxide) and redox stimuli. Moreover, the dicationic host was also easily switched between organic and perfluorocarbon phases for application related to the enrichment of perylene from a mixture of polycyclic aromatic hydrocarbons. experiments demonstrate the ability of fluorous solvents combined with supramolecular receptor for selective transportation processes.


Introduction
The past decades have seen the emergence of numerous covalent artificial receptors. [1] Supramolecular chemistry and selfassembly have also allowed the formation of sophisticated receptors incorporating several recognition units. [2] These receptors have gained in complexity with the integration of switching units allowing a control of the guest-binding properties. [3] However, multi-state systems responsive to different type of stimuli are still scarce in the literature and are based on the combination of molecular switches in either the host or the guests. Such systems were recently reported to control the association/dissociation process in host-guest complexes [4] and the motion in mechanically interlocked molecules. [5] In this context, 9-aryl-acridinium moieties are emerging building blocks [6] for the development of multi-responsive receptors of Polycyclic Aromatic Hydrocarbons (PAHs). Indeed, these building blocks are single components responsive to different stimuli (electron, light and nucleophile) thus avoiding the combination of several switches. Upon redox [7] or acid/nucleophile [8] stimulations, the acridinium fragments experience reversible and profound changes of their electronic properties and/or shape, two key parameters strongly affecting recognition processes (Scheme 1). Among the few studies reporting acridinium based switchable supramolecular systems, a family of [2]rotaxanes incorporating two acridinium stoppers was described by Abraham and coworkers. [9] The photochromic properties of the acridinium stoppers were used to trigger the shuttling of a tetracationic macrocycle. In a seminal work, Yoshizawa and coworkers recently reported the synthesis of the tetrakisacridinium receptor interacting with long hydrophilic molecules (e.g. coumarin and steroid derivatives). [10] Upon addition of nucleophiles, the formation of the corresponding tetrakisacridane macrocycle triggers the decomplexation of the guest molecules as the result of the modulation of the cavity size of the receptor. Scheme 1. Two possible mesomeric forms of the 9-aryl-N-methyl acridinium subunit highlighting the electronic and 2D to 3D structural changes occurring upon addition of redox and pH stimuli.
An additional interest of acridinium moieties resides in their ionic nature allowing their straightforward confinement in aqueous and organic phases according to the associated counterions. [10,11] This is of primary importance for applications in molecular separation/purification processes which mostly exploit aqueous/organic solvents biphasic systems. [12] Perfluorocarbons (PFCs) are the least polar liquids making them non-miscible at room temperature and ambient pressure with both water and organic solvents, hydrocarbons included. [13] In reason of their extremely poor solvation ability, PFCs are appealing phases for receptors confinement. [14] They do not compete with the hostguest interactions, thus increasing their strength, [15] but also potentially limit the number and amount of competing guests or hosts in the recognition phase. These unique properties have been exploited to develop potentiometric ion sensing assays exhibiting unequalled sensitivity and selectivity ranges, [15a-b, 16] as well as a few colorimetric/fluorogenic assays. [17] Rather surprisingly, application of PFCs and fluorous supramolecular receptors to selective separation/transportation processes have been much less explored. [18] It might be ascribed to the difficulty of getting receptors with enough fluorophilicity to impart high partitioning in the fluorous phase.
Herein, the four-step synthesis of the bis-acridinium cyclophane (1 2+ ) and its recognition properties towards PAHs is reported. The chemical and redox-controlled encapsulation/release properties of the cyclophane towards perylene (Per) is demonstrated. This dicationic host also showed its ability to switch between CH2Cl2 and perfluorocarbon phases using fluorophilic supramolecular anions. In addition, the confinement of the receptor in a fluorous phase was exploited to the selective extraction of Per from a mixture of PAHs.
The receptor 1•2PF6 and all precursors were characterized by NMR, UV-vis spectroscopies and MS spectrometry (see SI). The 1 H NMR spectrum of 1•2PF6 (CD3CN, 298K) revealed characteristic triplets at 5.47 and 5.44 ppm ( 3 Jgem = 1.0 Hz) corresponding to the olefin protons of both expected diastereomers of the cyclophane, namely trans and cis in a 9:1 ratio (Fig. 2a). Crystals of the inclusion complex C6H6 ⊂ 1•2PF6 were grown by vapor diffusion of C6H6 into an CH3CN solution of 1•2PF6, and its structure was solved by X-ray diffraction analysis ( Fig. 1b-c). [24] The preorganization of both acridinium moieties was clearly evidenced by the optimum distance for -stacking interactions (dC9-C9 = 7.198 Å and dN-N = 7.676 Å). Overall, the cavity size (7.2  15.6 Å) is well-adapted to PAHs such as Per. Recognition Properties. NMR and UV-vis studies were employed to probe the recognition properties of 1•2PF6 toward PAHs, namely Per, anthracene (Ant) and naphthalene (Naph). The 1 H NMR (CD3CN, 298 K) of the 1:1 mixture (c = 1.5  10 -3 mol L -1 ) of 1•2PF6 and Per revealed a chemical shift of all protons in comparison to the individual host and guest (Fig. 2). More especially, upfield shifts of the acridinium protons ((H1/8) = -0.42, (H3/6) = -0.41, and (H4/5) = -0.57 ppm) of 1•2PF6 for the trans isomer as well as of the Per protons ((H1/6/7/12) = -0.58, (H2/5/8/11) = -0.52 and (H3/4/9/10) = -0.44 ppm) suggested - interactions between the guest and the acridinium subunits. The inclusion complex Per ⊂ 1•2PF6 was confirmed by the downfield shifts of the inner proton Ho' of the 1,3-dipyridylanisyl spacer ( (Ho') = 0.42 ppm) and the olefin protons ((Htrans) = 0.22 and (Hcis) = 0.08 ppm). In addition, the existence of the inclusion complex was confirmed by control experiments using the 9pyridyl-N-acridinium moiety as host (see SI, Figure S4.1). Indeed, the 1 H NMR spectrum (CD3CN, 298 K) of the 1:1 mixture of 9pyridyl-N-acridinium and Per showed no chemical shifts of any proton signals suggesting a macrocyclic effect and the cooperative assistance between both acridinium moieties in 1•2PF6. Of particular interest, complex formation gave rise to a new electronic transition in the visible region (max = 606 nm; 606 ~ 670 L mol -1 cm -1 ) [25] attributed to a charge transfer band from Per to the acridinium units of the receptor, responsible for the color change from yellow to green (Fig. 2-3). This optical output was only observed for the complexation of Per and account of its higher -donor character in comparison to Ant and Naph. The poor solubility of Per did not allow NMR or UV-Vis titration experiments in CH3CN. In order to get higher solubility of both 1 2+ and Per in a common solvent, namely CH2Cl2, 1•2PF6 was converted to the corresponding tetrakis[3,5bis(trifluoromethyl)phenyl]borate (BArF) salt, 1•2BArF (see SI). Monitored by UV-Vis spectroscopy, titration experiments in CH2Cl2 allowed the estimation of an association constant of 1200 ± 38 L mol -1 between Per and 1•2BArF (fitted to a 1:1 binding model, see SI, Fig. S4.3). [26] Remarkably, this binding constant is 18 and 400 times higher than the binding constant determined between 1•2BArF and Ant (Ka = 66 ± 3 L mol -1 , see SI Fig. S4. [5][6] and Naph (Ka = 3 ± 0.08 L mol -1 , see SI Fig. S4.7-4.8) respectively. [27] Classical molecular dynamics simulation shed light on the dynamic behavior of the Per ⊂ 1 2+ complex in CH2Cl2. In the course of the calculated trajectory (10 µs), Per exchanges eleven times between the center of the cavity of host 1 2+ and bulk CH2Cl2 (see SI, Fig. S8.1-2) with an average residence time of about 650 ns (from 23 ns to 2151 ns). The calculated free energy difference of -26.8 kJ mol -1 between the associated and dissociated complex is in good agreement with the experimental value of -17.6 kJ mol -1 .
Multi-Switching Properties. To demonstrate the chemical switching from the bis-acridinium macrocycle, the macrocyclic bis-acridane 5 was prepared in quantitative yield by addition of a solution of KOH (1 mol L -1 ) to a solution of 1•2PF6 in CH3CN (see structure in Fig. 3). [28] Compound 5 exhibited no binding ability for Per in CD2Cl2 as demonstrated by 1 H NMR spectroscopy (see SI, Fig. S5.3-S5.4). This behavior can be rationalized by the drastic geometrical change of the acridane units and by the loss of aromaticity of the recognition units in 5 in comparison to its bisacridinium precursor 1•2PF6 (see SI). [29] The reversible conversion between 5 and the receptor 1•2PF6 upon addition of protons (trifluoroacetic acid, TFA) or hydroxides (KOH) was evidenced by 1 H NMR and UV-vis studies (see SI, Fig. S5.1-2 and S5.6-7).
The chemical switching of macrocycle 5 to 1•2PF6 to efficiently release/catch Per was then probed by UV-vis spectroscopy following the variation in intensity of the Per to acridinium chargetransfer band (Fig. 3). Quantitative restoration of the Per ⊂ 1 2+ complex was achieved upon addition of 4.8 eq. of TFA. In other words, the dihydroxylated macrocycle 5 behaves as a protonactivated latent receptor for Per. In addition, Per was reversibly released upon addition of 9 eq. of tetrabutylammonium hydroxide (TBAOH, Fig. 3 inset). The redox-switchable properties of 1•2PF6 were investigated by cyclic voltammetry experiments in C2H4Cl2 (Fig. 4). At 100 mV s -1 , 1•2PF6 exhibits a reduction wave at a potential (Ec1) of -0.946 V vs Fc+/Fc and a reoxidation wave at -0.828 V vs Fc+/Fc (Ea1). This observation is in agreement with two quasi reversible oneelectron injection processes (Ep = 118 mV) leading to the formation of the diradical 1 0 at E1/2 = -0.887 V vs Fc+/Fc. [30] This observation is supported by the scan rate study performed from 50 to 800 mV s -1 (see SI, Fig. S6.1). Indeed, the plot of the cathodic and anodic intensity as a function of the square root of the scan rate (Ic and Ia = f( 1/2 )) shows a perfect linear relationship (see SI, Fig. S6.2 and S6.4). Noteworthy, the slight shift of the cathodic potential (Ec1) corroborates a process under diffusion control. In addition, spectro-electrochemical experiments were undertaken to provide evidences of the reduction of both acridinium units at the same potential. Upon reduction, the original spectrum of 1•2PF6 was converted to the spectrum of 1 0 (see SI,  After addition of an excess of Per (10 eq.) corresponding to 74% complex formation, a cathodic shift of the reduction (Ec2 = -0.977 V vs Fc + /Fc) and re-oxidation processes (Ea2 = -0.875 V vs Fc + /Fc) were observed (E1/2 = -0.926 V vs Fc + /Fc). This observation corroborates the formation of the host-guest complex since the electron rich guest transfers some of its electronic density to the acridinium moieties making them more difficult to reduce. The half-wave potential difference (E1/2) was found to be -39 mV and allowed the estimation of a binding constant (Ka') of 54 L mol -1 between the reduced receptor 1 0 and Per. This 20 times lower association constant compared to the constant found between 1•2PF6 and Per (Ka = 1 200 ± 21 L mol -1 in C2H4Cl2 in the presence of 0.1 mol L -1 of TBAPF6; see SI, Fig. S4.9) clearly evidences the destabilization of the host-guest complex upon reduction. This binding constant corresponds to 34% complex formation between the 1 0 and Per showing that the host-guest association-dissociation can be controlled to a different extent using either a redox or a chemical stimulus. [31] Phase transfer in perfluorocarbons. Interested in applying the receptor in selective transportation processes, perfluorcarbons (PFCs) were envisioned as potential liquid phases for the receptor confinement. [32] In 2011, some of us reported the transfer of a [Ru(bipy)3] 2+ dication from CH2Cl2 to a perfluorodecalin (PFD) phase by a markedly increase of the fluorine content coming from the associated counter-ions (Scheme 3). [33] These counter-ions are heteromeric supramolecular fluorous carboxylates-carboxylic acid anions easily formed in PFCs by an ionic H-bond interaction thus doubling the number of fluorous chains. [34] The back transfer from the PFD to CH2Cl2 was achieved by adding a tiny amount of a H-bond competitor, namely CH3OH, to the biphasic system thus disrupting the supramolecular anion. Scheme 3. Concept of fluorophilicity amplification applied to the phaseswitching of the [Ru(bipy)3] 2+ dication between CH2Cl2 and PFD phases. [31] Based on these results, the easy confinement of 1 2+ in a fluorous phase was hypothesized using highly fluorophilic supramolecular anion (Fig. 5a-b). Accordingly, a stock solution of 1•2(RfCOO-H-OOCRf) (c = 0.55  10 -3 mol L -1 ) in perfluoromethylcyclohexane (PFMC, 6 mL) was conveniently prepared by stirring a solution of bis-acridane 5 (c = 1.88  10 -3 mol L -1 ) in CH2Cl2 (2 mL) with a solution of commercially available perfluoro-2,5,8,11-tetramethyl-3,6,9,12-tetraoxopentadecanoic acid (RfCOOH, Rf = CF3CF2CF2O[(CF3)CFCF2O]3(CF3)CF) in PFMC (c = 7.5  10 -3 mol L -1 , 6 mL). The formation of 1•2(RfCOO-H-OOCRf) and its phase transfer were followed by UV-Vis spectroscopy and a transfer of 90% of 1•2(RfCOO-H-OOCRf) into the fluorous phase was determined (see SI, Fig. S7.1-2). [35] The receptor 1•2(RfCOO-H-OOCRf) proved to be highly fluorophilic as revealed by a back extraction from the PFMC phase to a fresh CH2Cl2 solution of only 0.3 % (see SI, Fig. S7.3). Addition of a small amount of CH3OH (a volume of ~ 4% of CH3OH compared to that of PFMC) as a Hbond competitor led to the quantitative back transfer of the receptor from the PFMC to the CH2Cl2 phase, thus supporting the formation of supramolecular H-bonded anions in the fluorous phase. Finally, the ability of the fluorous system to selectively extract and release Per from a mixture of PAHs was evaluated (see SI, section 7.5). A biphasic system composed of a solution of 1•2(RfCOO-H-OOCRf) (c = 1.88  10 -3 mol L -1 ) in PFMC (1 mL) and an equimolar solution of Per, Ant and Naph (c = 2  10 -3 mol L -1 each) in CH2Cl2 (2 mL) was stirred for 60 min. After decantation, an aliquot of the greenish PFMC phase (0.5 mL) was transferred in a test tube and extracted with two aliquots of fresh CH2Cl2 (1 mL + 0.5 mL). Analysis of the combined CH2Cl2 phase by UV-vis spectroscopy and GC (see SI, Fig. S7.11-S7.13) revealed a Per concentration (c ~ 114  10 -6 mol L -1 ) far superior than Ant (c = 6.1  10 -6 mol L -1 ) and Naph (c = 9.4  10 -6 mol L -1 ). These concentrations correspond to concentrations in the PFMC phase before release of ~ 342  10 -6 mol L -1 , 18.3  10 -6 mol L -1 and ~ 28.2  10 -6 mol L -1 for Per, Ant and Naph, respectively. Under similar conditions without 1•2(RfCOO-H-OOCRf), the extraction of Per, Ant and Naph in the PFMC phase led to concentrations of ~ 1.1  10 -6 mol L -1 , 5.1  10 -6 mol L -1 and ~ 27.1  10 -6 mol L -1 , respectively. This observation confirms that the amount of Naph recovered in the CH2Cl2 phase with and without 1•2(RfCOO-H-OOCRf) is essentially due to its innate partitioning. In addition, the partition coefficient (K = cPFMC/cCH2Cl2) of Naph between CH2Cl2 and PFMC is higher than that of Ant and much higher than that of Per. The recyclability of the fluorous phase was also assessed by conducting three consecutive extraction/release experiments from a CH2Cl2 phase containing a 1/1/1 molar ratio of Per, Ant and Naph (see SI for detailed procedure, Fig. S7.19-22, Tables S7.4-5). Combined UV-Vis spectroscopy and GC analysis showed that the fluorous phase could be reused two times with the same efficiency, both in terms of yield of extracted/released Per (17.1%, 16.5% and 17.0% for the first, second and third extraction/release processes, respectively) and selectivity (Per/Ant/Naph molar ratios of 9.5/1/1.05, 8.7/1/1.1, 10.6/1/1.06 for the first, second and third extraction/release processes, respectively). Overall, these experiments demonstrate the ability of fluorous solvents combined with supramolecular receptor for selective transportation processes.

Conclusion
The efficient synthesis of a multi-responsive cyclophane incorporating two acridinium moieties as recognition units was described. Its ability to form host-guest complexes with perylene on account of -donor/-acceptor interactions was shown in solution. Upon addition of hydroxide anions, the chemical switching properties of this system lead to the formation of the corresponding bis-acridane derivative. This derivative is unable to interact with perylene thus demonstrating the ability of the cyclophane to work as an ON/OFF switch. The electrochemical switching properties of the bis-acridinium cyclophane clearly evidenced a decrease of the host-guest interactions upon reduction. Finally, the phase switching behavior of the macrocycle between a perfluorocarbon and an organic layer was explored and successfully applied to the straightforward enrichment of perylene from a mixture of polycyclic aromatic hydrocarbons. The multifunctional properties associated to the cyclophane receptor integrating multi-responsive acridiniums units are promising and will be further explored in the context of selective transportation processes and functional materials.