Synthesis and anion binding studies of tris(3-aminopropyl)amine-based tripodal urea and thiourea receptors: proton transfer-induced selectivity for hydrogen sulfate over sulfate

Tris(3-aminopropyl)amine-based tripodal urea and thiourea receptors, tris([(4-cyanophenyl)amino]propyl)urea (L1) and tris([(4-cyanophenyl)amino]propyl)thiourea (L2), have been synthesized and their anion binding properties have been investigated for halides and oxoanions. As investigated by H NMR titrations, each receptor binds an anion with a 1 : 1 stoichiometry via hydrogen-bonding interactions (NH/anion), showing the binding trend in the order of F > H2PO4 > HCO3 > HSO4 > CH3COO > SO4 2 > Cl > Br > I in DMSO-d6. The interactions of the receptors were further studied by 2D NOESY, showing the loss of NOESY contacts of two NH resonances for the complexes of F , H2PO4 , HCO3 , HSO4 or CH3COO due to the strong NH/anion interactions. The observed higher binding affinity for HSO4 than SO4 2 is attributed to the proton transfer from HSO4 to the central nitrogen of L1 or L2 which was also supported by the DFT calculations, leading to the secondary acid–base interactions. The thiourea receptor L2 has a general trend to show a higher affinity for an anion as compared to the urea receptor L1 for the corresponding anion in DMSO-d6. In addition, the compound L2 has been exploited for its extraction properties for fluoride in water using a liquid–liquid extraction technique, and the results indicate that the receptor effectively extracts fluoride from water showing ca. 99% efficiency (based on L2).


Introduction
Anion coordination chemistry is a major area of research in supramolecular chemistry, since anions play critical roles in many biological, chemical and environmental applications. [1][2][3][4][5][6][7] As learned from nature, hydrogen-bonding interactions are key factors in controlling many important functions of biomolecules, e.g. information storage, signal transfer, replication and catalysis. 8 In order to understand and mimic the natural interactions involved in complex living systems, several types of neutral synthetic molecules including amides, 9 thioamides, 10 ureas, 11 thioureas, 12 pyrroles, 13 and indoles 14 have been broadly employed as effective receptors for a variety of anions in solution and solid state.
Among these various receptors that possess hydrogen bonding capabilities in anion binding via NH/anion interactions, urea-based receptors have received much attention recently, due to the acidic nature and directional properties of NH groups for anionic guests. 11a,15 An early example reported by Hamilton et al. demonstrated that a simple acyclic urea containing a single urea functionality showed an affinity for acetate (K ¼ 45 M À1 ) in DMSO. 16 Fabbrizzi et al. synthesized a bis(4nitrophenyl) urea receptor that formed a strong complex with uoride (K ¼ 2.40 Â 10 7 M À1 ) in CH 3 CN. 17 Gale et al. developed a urea-based receptor linked with indole groups that formed a carbonate complex stabilized by NH donor groups from both indole and urea functional groups. 18 Johnson et al. reported a rigid dipodal urea linked with acetylene groups, which was shown to form a ve-coordinate chloride complex. 19 Recently, a number of urea-and thiourea-based receptors have been developed based on the use of tris(2-aminoethyl)amine (tren) as a framework appended with different aromatic groups. 20,21 For example, a m-cyanophenyl-based tripodal urea reported by Custelcean et al. was shown to form a silver-based MOF that encapsulated sulfate by a total of twelve hydrogen bonds. 20a Wu et al. reported a 3-pyridyl-based tripodal urea that also showed strong affinity for sulfate. 20b Ghosh et al.
reported a pentauorophenyl-based tripodal urea for the selective binding of phosphate. 20c A m-nitrophenyl substituted tripodal urea synthesized by Das et al. was found to form capsular complexes with carbonate and sulfate. 20h The progression from urea to thiourea leads to an enhanced acidity of a NH group in the later, thereby a thiourea could have a stronger affinity for an anion than its urea analogue. 22 3 ]. 21a The compound was able to transport bicarbonate across lipid membranes. While uorinated tripodal ureas and thioureas were shown to transport chloride anions through a lipid bilayer. 21b In the case of p-uorophenyl tripodal thiourea, an encapsulated chloride complex and a sulfate capsular complex were structurally characterized. 21b A tren-based tris-(thiourea) receptor substituted with p-nitrophenyl groups was shown to form a rigid dimeric capsule with trivalent phosphate. 21c Our group has recently reported a p-cyanophenyl tripodal urea for sulfate forming a seven coordinate sulfate complex. 23a Further work on this receptor for halides has demonstrated the binding trend in the order of uoride > chloride > bromide > iodide in solution. 23b Ghosh et al. has recently reported that the thiourea analogue p-cyanophenyl tripodal receptor is capable of forming a 1 : 1 complex with uoride and 2 : 1 complex with sulfate, showing moderate extraction efficiencies for uoride and sulfate from aqueous solutions. 21d Our continued interests in the development of urea/ thiourea-based anion receptors 24 have led us to use a slightly larger tripodal framework as tris(3-aminopropyl)amine linked with three p-cyanophenyl groups. Because of the longer chain in the propylene group as compared to the ethylene chain analogue, such receptors are expected to provide larger and exible cavities; which could affect their selectivity patterns for an anion. The choice of cyanophenyl-substituted spacers was derived from their ability to act as electron-withdrawing groups, which was further supported by DFT calculations, showing the highest electron potential on cyano-groups. In particular, recent studies showed that the structural manipulation of simple receptors with variable lengths, sizes, functional groups and spacers can lead to selective binding of a particular anion. 15 Herein, we report the synthesis of two propylene-linked new receptors L1 and L2 (Scheme 1), and their comparative anion binding studies by 1 H NMR titrations and 2D NOESY experiments in DMSO-d 6 , showing the unusual selectivity for hydrogen sulfate than sulfate. In addition, L2 was further used for the extraction of uoride in water using a liquid-liquid extraction technique.

Synthesis
The synthesis of L1 (urea) and L2 (thiourea) was accomplished from the reaction of tris(3-aminopropyl)amine (1) with three equivalents of 4-cyanophenyl isocyanate/isothiocyanate (2) in CH 2 Cl 2 (Scheme 2), following the similar method as reported before for ethylene chain analogues. 23,24 In general, a higher yield was achieved for urea-based receptor (90%) than the thiourea-based receptor (73%). Attempts to obtain X-ray quality crystals of free receptors or anion complexes were unsuccessful.

NMR titration studies
The binding properties of the new receptors (L1 and L2) for a number of anions including F À , Cl À , Br À , I À , ClO 4 À , NO 3 À , HSO 4 À , H 2 PO 4 À , CH 3 COO À , HCO 3 À and SO 4 2À were investigated by 1 H NMR studies in DMSO-d 6 . Initially, the anion binding abilities of L1 and L2 were screened by the addition of one equivalent of the respective anion to a host solution. As shown in Fig. 1, two NH protons of urea group of L1 appeared at 8.94 ppm (H1) and 6.37 ppm (H2). These protons shied downeld aer the addition of oxoanions including HSO 4 À , H 2 PO 4 À , CH 3 COO À , HCO 3 À and SO 4

2À
. However, no appreciable shi was observed in the presence of ClO 4 À , NO 3 À , Br À and I À . Among the all anions, the highest shi of NH's was observed for uoride followed by H 2 PO 4 À and CH 3 COO À . The addition of F À or H 2 PO 4 À to L1 resulted in the broadening of NH peaks. 25 Such a signicant downeld shi of both NH resonances for an anion is attributed to the direct involvement of the NH groups in anion binding via NH/anion interactions. For the thiourea-based receptor L2, two corresponding NH protons that appeared at 9.86 ppm (H1) and 8.17 ppm (H2) were also found to respond with different anions exhibiting the similar trend ( Fig. 2) as observed for L1 (Fig. 1). However, a higher downeld shi was observed for L2 with oxoanions and halides as compared to L1 with the corresponding anions. In the case of F À and H 2 PO 4 À and HCO 3 À with L2, peak broadening of NHs occurred similar to that observed for L1. The binding constants of L1 and L2 for different anions were measured by 1 H NMR titration experiments in DMSO-d 6 . Fig. 3 shows a representative example of 1 H NMR titration spectra obtained from the incremental addition of hydrogen sulfate to L2, displaying a gradual shi change in both NH's resonances. The changes in the chemical shis of NH's of L1 or L2 were plotted with an increasing amount of an anion, providing the best t for a 1 : 1 binding model for the anions, 26 as shown in Because of the peak broadening of NH's aer the addition of F À to both receptors, the binding constants for uoride were determined from shi changes of aromatic CH protons (Fig. 6).
The binding constants of L1 and L2 for different anions determined from nonlinear regression analyses of chemical shi changes are listed in Table 1. An inspection of the binding data suggests that both receptors show a similar trend of binding for the investigated anions exhibiting the highest affinity for F À . In general, the thiourea-based receptor L2 exhibits higher affinity for an anion as compared to L1, which is due to the enhanced acidity of NHs in L2 incorporated with thiourea groups, as expected. 12b Both receptors, however, show negligible affinity for other halides. For oxoanions, the highest binding was achieved for H 2 PO 4 À , followed by HSO 4 À , HCO 3 À , CH 3 COO À and SO 4 2À . The observed binding constants broadly reect the inuence of relative basicity of the anions. 27 However,    the higher binding constants of both receptors for HSO 4  , showing greater selectivity for HSO 4 À . As compared to ethylenechain analogues, 20h,23a,b the propylene chains in L1 and L2 might result in the higher basicity of the central nitrogen, which could be due to the weaker inductive effect 29 of urea/thiourea groups through the longer propylene chains. Thus the central nitrogen can act as a base to transfer a proton from HSO 4 À . Both receptors showed higher binding for HCO 3 À as well, supporting this assumption. For highly basic acetate anion, the noncompliment shape of CH 3 COO À with the tripodal binding pocket might be a probable reason lowering the binding constant than that of H 2 PO 4 À . In general, the propylene-based receptors showed lower binding affinity for anions as compared to ethylene-based analogues, which could be due to the exible nature of the cavity and enhanced basicity of the central nitrogen in L1 or L2.

NOESY NMR experiments
2D NOESY NMR experiments were performed to characterize the structures and conformational changes of the complexes in solution. Previous studies by us 23a,b and others 20h suggested that 2D NOESY NMR can effectively be used to evaluate the binding strength. In order to corroborate the data from NMR titrations, all 2D NOESY spectra were recorded for free L1 and L2 and their spectra were compared aer the addition of one equivalent of the respective anions in DMSO-d 6 at room temperature ( Fig. 7 and Fig. S36-55 in ESI †). The Fig. 7a and b show the NOESY NMR spectra of free L1 and L2, respectively, each displaying a strong NH1/NH2 NOESY contact. Aer the addition of one equivalent of hydrogen sulfate, the NOESY contacts for both receptors completely disappeared ( Fig. 7c and d 2À and [L2(HSO 4 )] À are À55.5 and À47.4 kcal mol À1 . It is obvious that the binding energies of L2 are higher for both anions than those of L1, agreeing with the trend of experimental binding constants obtained from 1 H NMR titrations ( Table 1).
As shown in Scheme 1b and c, a strong electrostatic positive potential is created inside the cavities due to the presence of cyano-groups on aromatic rings, making them potential to host an anion. Fig. 8a and b show the optimized structures of the free receptors L1 and L2 in the solvent phase. For both cases, one NH group of an arm is hydrogen-bonded to oxygen/sulfate of another arm via NH/O/S interactions, thus creating a suitable cavity for guest. We previously observed similar hydrogen bonding interactions in a free p-cyanophenyl tripodal urea. 23a The optimized structures of L1 and L2 complexes with SO 4 2À are shown in Fig. 9, while those with HSO 4 À are displayed in Fig. 10.
The corresponding hydrogen bonding distances are listed in Table 2. It is noteworthy to mention that both receptors are deformed in order to interact with SO 4 2À or HSO 4 À through NH binding sites. In the sulfate complexes of L1 and L2, one sulfate is encapsulated within the cavity via a total six NH/O bonds, exhibiting a 1 : 1 binding for each case. Such a binding mode is in consistence with that observed in solution binding studies in DMSO-d 6 . Interestingly, in the optimized complexes with HSO 4 À as shown in Fig. 10, one proton from HSO 4 À is  transferred to the bridgehead nitrogen of L1 or L2, providing an additional binding site as NH + to the receptor. Thus the anion is held via a total of seven NH/O bonds, supporting the higher binding for HSO 4 À determined in solution by 1 H NMR titrations. Such a proton transfer was previously observed experimentally 23a as well as theoretically. 34

Fluoride extraction studies
The uoride extraction studies of L2 were successfully performed by liquid-liquid extraction technique using tetrabutylammonium iodide as the anion exchanger and the phase transfer agent, following the methods reported previously. 21d,35 For a typical extraction experiment, distilled water solution (5 mL) of sodium uoride (44.9 mg, 1 mmol) was added to the mixture of L2 (66.89 mg, 0.1 mmol) and tetrabutylammonium iodide (36.94 mg, 0.1 mmol) in chloroform (5 mL). The biphasic solution was mixed for 3 hours, and the two layers formed were separated. Aer the evaporation of the organic phase, the white solid product was washed with diethyl ether to remove the remaining tetrabutylammonium iodide, and collected aer drying. The extraction efficiency was calculated gravimetrically as 99%. Fig. 11 represents the comparative 1 H NMR spectra of the free receptor, extracted uoride complex and L2 in presence of one equivalent of [n-Bu 4 N] + F À in DMSO-d 6 . The 1 H NMR spectra of the extracted uoride complex shows broadening and    The solid state FT-IR analysis was also performed to examine the interactions of the receptor with uoride in the extracted complex. The signicant downward shi (Dn (N-H) ¼ 37 cm À1 ) of broad NH's stretching frequency from 3301 cm À1 (L2) to 3264 cm À1 (extracted uoride complex) was observed, 36 suggesting the strong N-H/F À interactions between NH groups and the uoride and ultimately deprotonation of the receptor by highly basic uoride anion (Fig. 12).