Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis and Anion Recognition Features of a Molecular Cage Containing Both Hydrogen Bond Donors and Acceptors Ju Hyun Oh,†,§ Jeong Hyeon Kim,†,§ Dong Sub Kim,‡ Hye Jin Han,† Vincent M. Lynch,‡ Jonathan L. Sessler,*,‡ and Sung Kuk Kim*,† †
Department of Chemistry and Research Institute of Natural Science, Gyeongsang National University, Jinju 660-701, Korea Department of Chemistry, The University of Texas at Austin, 105 East 24th Street, Stop A5300, Austin, Texas 78712-1224, United States
‡
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ABSTRACT: A molecular cage, macrobicycle 2, containing amide and pyrrole groups as hydrogen-bonding donors and imine groups as hydrogen-bonding acceptors has been synthesized. Compound 2 was found to recognize tetrahedral oxyanions with high affinities, such as H2PO4−, HSO4−, SO42−, and HP2O73−, as well as the spherical halide anions, in chloroform. A single-crystal X-ray diffraction analysis revealed that compound 2 formed a 1:1 complex with H2PO4− in the solid state.
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appropriately arranged hydrogen-bonding donors and acceptors.29 Here, we report the 1,3,5-trisubstituted benzene skeleton-based molecular cage (2). This system was designed to possess both a preorganized structure and a threedimensional cavity suitable for encapsulating anionic species. As described below, compound 2 contains amide and pyrrole groups as hydrogen-bonding donors and imine groups as hydrogen-bonding acceptors. It was found by 1H NMR and UV/vis spectroscopic analysis to have the ability to bind various oxyanions with high affinity in addition to the halide anions.
n increasing understanding of the roles played by anions in biology, chemistry, and the environment, is inspiring efforts to develop receptors possessing the capability to recognize, bind, and detect anions selectively.1−10 In the search for anion receptors displaying high selectivity and affinity for specific anions, systems benefiting from a high level of preorganization and possessing geometrical shapes optimized for anion encapsulation are attractive.2,3,11 Studies with the so-called calix[4]pyrroles have served to illustrate the benefits of preorganization in the context of anion recognition. For instance, the conformationally flexible parent form of calix[4]pyrrole 3 (octamethylporphyrinogen) binds the fluoride anion with high affinity and selectivity in apolar media.12−14 In contrast, the so-called strapped calix[4]pyrroles incorporating an additional linkage between the diametrical meso carbon atoms of the calix[4]pyrrole framework show remarkably enhanced affinities and selectivities for specific anions as compared with the parent calix[4]pyrrole.15−17 This modulation in binding behavior is attributed in part to the encapsulation of the targeted anions by the receptors, a feature that reduces competing solvation effects.10,18−24 Geometric effects can be no less important in terms of tuning the binding strength and selectivity of anion receptors.1−10 For instance, tren- or trisubstituted benzene-based tripodal receptors having an enforced three-dimensional structure have proved effective in recognizing tetrahedral oxyanions, such as the phosphate and the sulfate anions.18−27 Specifically, tripodal receptor 1 was reported to recognize the dihydrogen phosphate and the hydrogen pyrophosphate anion highly selectively over other anions, including halide anions.28 On the other hand, the protonated forms of these and other anions (e.g., hydrogen sulfate, dihydrogen phosphate, hydrogen pyrophosphate anion, etc.) are complexed well by receptors bearing both © XXXX American Chemical Society
Molecular cage 2 was synthesized following the procedure depicted in Scheme 1. Compound 4 was prepared as reported previously. 30 Coupling compound 4 with 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene 5 in the presence of EDCI (1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide), HOBt (hydroxybenzotriazole), and DIPEA (N,N-diisopropylethylamine) in DMF afforded the tripodal trisaldehyde (6) in 63% yield. The formyl groups of 4 were then condensed with trisamine 5 to give molecular cage 2 in quantitative yield. Cage 2 was characterized by standard spectroscopic techniques, such Received: April 30, 2019
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DOI: 10.1021/acs.orglett.9b01515 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
in the electron density of the imino pyrrole moiety. Particularly large downfield shifts in the amide NH proton resonances were seen in the presence of oxyanions (e.g., HSO4−, SO42−, and H2PO4−). Moreover, the signal of the proton (Ha) next to the amide NH was shifted slightly upfield, whereas that of Hc connected to the imine was shifted to lower field. Collectively, these findings are ascribed to anion binding within cage 2. Upon titrating cage 2 with TBAF in CDCl3, the proton signal (Hc) in the 1H NMR spectrum corresponding to the imines was gradually shifted upfield, while that of the amide NH proton experienced a drastic downfield shift. Saturation in the changes was observed upon the addition of 2.33 equiv of TBAF (Figure 2). The induced chemical shift changes at
Scheme 1. Synthesis of Cage 2
as 1H and 13C NMR spectroscopy and HRMS (high resolution mass spectrometry), as well as by means of a single-crystal Xray diffraction analysis. The ability of 2 to recognize certain anions in solution was evaluated via 1H NMR spectroscopy using CDCl3 as the solvent. The spectrum of cage 2 in its ion-free form is characterized by the presence of two singlets at δ = 8.36 and 5.82 ppm corresponding to the imine CH and the amide NH proton resonances, respectively (Figure 1). The pyrrolic NH
Figure 2. Partial 1H NMR spectra recorded during the titration of cage 2 (3 mM) with tetrabutylammonium fluoride (TBAF) in CDCl3.
saturation amounted to Δδ = 2.06 ppm for the amide NH proton and Δδ = 0.26 ppm for the imine CH (Hc), respectively. Similar but relatively smaller chemical shift changes were seen in the 1H NMR spectra upon the titration of 2 with the TBA+ (tetrabutylammonium) salts of other halide anions (Figures S1−S3). In contrast to what was seen for the above anions, when cage 2 was subjected to titration with H2PO4−, HSO4−, and SO42− (as the respective TBA+ salts), two sets of distinguishable resonances were observed for all of the proton signals of 2 in the 1H NMR spectra recorded in CDCl3 until saturation was reached upon the addition of ∼1 equiv of the oxyanion in question (Figures 3, S4, and S5). These two sets of proton signals are attributable to the anion-free and anion-bound forms of cage 2, respectively. The inferred slow anion-exchange kinetics were taken as preliminary evidence for strong binding. This latter presumption was reinforced by the marked downfield shifts seen for the amide NH proton resonance induced upon exposure to an anion source (Δδ = 2.65 ppm for H2PO4−, Δδ = 2.48 ppm for SO42−, and Δδ = 2.43 ppm for HSO4−, respectively) as well as the fact that the addition of only 1 molar anion equiv was sufficient to induce saturation of the spectral changes. Noticeable chemical shift changes were also observed when cage 2 was subjected to an 1H NMR spectral titration with tetrabutylammonium hydrogen pyrophosphate ([TBA+]3· HP2O73−); again, this was taken as evidence that receptor 2 is able to bind this anion well (Figure S6). Cage 2 in its anion-free form displays two absorption peaks centered at 310 and 375 nm in its UV−vis spectrum (Figure
Figure 1. Partial 1H NMR spectra of (a) 2 (3 mM) only, (b) 2 + excess TBAF (tetrabutylammonium fluoride), (c) 2 + excess TBACl, (d) 2 + excess TBABr, (e) 2 + excess TBAI, (f) 2 + excess TBAH2PO4, (g) 2 + excess (TBA)3·HP2O7, (h) 2 + excess (TBA)2· SO4, and (i) 2 + excess TBAHSO4 in CDCl3.
proton resonance was not apparent in the 1H NMR spectrum, a finding attributed to intra- or intermolecular hydrogenbonding interactions that serve to broaden the signal beyond recognition (Figure 1). In contrast, in the relatively polar solvent DMSO-d6, the proton signal corresponding to the pyrrolic NHs was readily observed at δ = 10.95 ppm (see the SI). Upon exposure of cage 2 to various anions, including F−, Cl−, Br−, I−, HSO4−, SO42−, H2PO4−, and HP2O73− (as their tetrabutylammonium (TBA+) salts), in CDCl3, shifts in most of the proton signals of 2 were observed (Figure 1). Specifically, in the presence of anions, the proton signal of the amide NHs underwent a significant downfield shift, presumably as the result of forming hydrogen bonds with the anions. Concurrently, an upfield shift in the signals assigned to the imine CH protons was seen, presumably because of hydrogen-bonding interactions between the anions and the pyrrolic NHs, which would be expected to result in an increase B
DOI: 10.1021/acs.orglett.9b01515 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
with H2PO4− in the crystal exists in two different forms. In one form, a methylene group was found to be inserted between the nitrogen atoms of the amide with the pyrrole not participating in the anion binding to form a new five-membered ring (Figure S20).31 On the basis of the metric parameters for the second structure (Figure S21), it was inferred that the H2PO4− anion serves to protonate one of imines of the cage giving rise to what is formally a complex between HPO42− and [2·H]+. The proton-free oxygen atoms of the hydrogen phosphate anion are directly hydrogen bonded to two pyrrolic NH and two amide NH protons at N···O distances of between 2.78 and 2.84 Å. The OH and an oxygen atom of the HPO42− form hydrogen bonds with the imine nitrogen atom and the iminium NH of the receptor; these are characterized by distances of 2.79 and 2.94 Å (N···O interaction), respectively (Figure 4). Figure 3. 1H NMR spectra recorded during the titration of cage 2 (3 mM) with tetrabutylammonium dihydrogen phosphate (TBAH2PO4) in CDCl3.
S7). The absorption band appearing at lower energy undergoes a hyperchromic shift, while the absorption band at 310 nm shifts hypsochromically upon exposure to anions (Figures S7− S15). Job’s plot experiments performed in chloroform proved consistent with a 1:1 binding stoichiometry (Figures S16− S19). By fitting the UV/vis spectroscopic titration data from the various titrations to a standard 1:1 binding profile, association constant (Ka) values of between Ka = 1.56 × 104 and 4.53 × 106 M−1 in chloroform could be approximated (Table 1). As Table 1. Association Constants (Ka, M−1)a of Receptor 2 for Anions As Estimated by UV/vis Spectroscopic Titrations in CHCl3 at Room Temperature anions −
F Cl− Br− I− HSO4− SO42− H2PO4− HP2O73−
2b 1.57 2.25 3.84 2.07 4.53 2.66 1.56 1.76
× × × × × × × ×
Figure 4. View of one of the two structures seen in the single crystal structure of the complex obtained upon treating cage 2 with a H2PO4− anion source. This complex is formally the result of proton transfer (i.e., 2·H+·HPO42−). Thermal ellipsoids are scaled to the 30% probability level. Dashed lines are indicative of hydrogen bonds. The TBA+ cation located outside the cavity of 2 and most hydrogen atoms have been omitted for clarity.
3c,d 6
10 105 104 104 106 106 104 106
1.72 × 104 350 10
