Skip to main content
NCBI home page
ACS AuthorChoice logoLink to ACS AuthorChoice
. 2022 Mar 25;87(8):5158–5165. doi: 10.1021/acs.joc.1c03128

Counteranions at Peripheral Sites Tune Guest Affinity for a Protonated Hemicryptophane

Yannan Lin 1, Michael R Gau 1, Patrick J Carroll 1, Ivan J Dmochowski 1,*
PMCID: PMC9017572  PMID: 35333529

Abstract

graphic file with name jo1c03128_0008.jpg

The affinity of small molecules for biomolecular cavities is tuned through a combination of primary and secondary interactions. It has been challenging to mimic these features in organic synthetic host molecules, however, where the cavities tend to be highly symmetric and nonpolar, and less amenable to chemical manipulation. Here, a host molecule composed of a TREN ligand and cyclotriveratrylene moiety was investigated. Size-matched polar guests were encapsulated within the cavity via triple protonation of the TREN moiety with various sulfonic acids. X-ray crystallography confirmed guest encapsulation and identified three methanesulfonates, p-toluenesulfonates, or 2-naphthalenesulfonates hydrogen-bonded with H3TREN at the periphery of the cavity. These structurally diverse counteranions were shown by 1H NMR spectroscopy to differentially regulate guest access at the three portals, and to undergo competitive displacement in solution. This work reveals “counteranion tuning” to be a simple and powerful strategy for modulating host–guest affinity, as applied here in a TREN-hemicryptophane.

Introduction

Controlling the guest-binding behavior of synthetic hosts has been a central focus of supramolecular chemistry, as it provides fundamental insights into biomolecular recognition as well as new drug-delivery modules, catalysts, and sorbents. Considerable effort has been devoted to the development of responsive host molecules where molecular recognition is modulated by external stimuli such as oxidation/reduction,1−5 acid/base,6−10 or photochemistry.11−13 Guest recognition can also be regulated by the binding of effectors such as ions or small organic modules at peripheral sites.14−18 However, such stimuli-responsive systems are less explored and generally lack tunability. Methods are needed for the facile installation of effectors at host-molecule peripheral sites.

We and others have long investigated cryptophane host systems for encapsulating small molecules in organic and aqueous solutions.19−28 Cryptophanes are homotopic capsules built from two cyclotriveratrylene (CTV) units. Replacing one of the CTVs with another C3-symmetric capping moiety reduces the capsule symmetry and provides an opportunity to polarize the cavity. As a result, the molecule is converted to a heteroditopic cavitand that can encapsulate a wider range of polar molecules such as ammonium guests,29,30 ion pairs,31−33 zwitterions,34,35 and carbohydrates.36,37 Previously in our lab, an amine-terminated hemicryptophane was developed with three rotators that exhibited gyroscope-like behavior.38 However, this cavity was too small and rigid to engage in guest inclusion. Others have developed larger and more flexible hemicryptophanes.39 One particularly promising example is L, which has been reported to mimic the active sites of metalloenzymes when complexed with metals, and also catalyze the hydrolysis of activated alkyl carbonates40,41 and the selective oxidation of primary alcohols.42

Inspired by the host–guest properties of calix[6]arenes reported by Reinaud and Jabin,43,44 we sought to enhance the binding affinity of L for polar guests by protonating the TREN moiety and thus polarizing the cavity. In this process, we discovered serendipitously that the resulting conjugate base counteranions cap the apertures of the cavity and regulate small-molecule access and guest binding affinity. TREN protonation provides a versatile method for installing counteranions with widely varying stereoelectronic properties. This work highlights the opportunity to generate a diverse set of peripherally tuned, biomimetic cavities from H3TREN-hemicryptophane.

Experimental Section

General Consideration

Unless otherwise specified, chemicals and solvents were purchased from commercial vendors and used without purification. The starting material 1 was prepared according to a literature procedure.45 Deuterated solvents were purchased from Cambridge Isotope Laboratories. 1H NMR and 13C NMR spectra were recorded in deuterated chloroform (CDCl3) using Bruker AVIII400, AVIII500, or NEO600 NMR spectrometers.

Synthesis of L

In an oven-dried flask, 1 (300.0 mg, 416 μmol) was combined with tris(2-aminoethyl)amine (60.90 mg, 416 μmol) and glacial acetic acid (50.00 mg, 832 μmol) in a mixture of dry acetonitrile (80.0 mL) and dry methanol (160 mL). After stirring at reflux for 1 h under a dinitrogen atmosphere, sodium borohydride (158 mg, 4.16 mmol) was added to the solution on an ice bath. The mixture was warmed to ambient temperature and further stirred for 3 h. After the reaction was complete, the solution mixture was cooled to rt and evaporated to dryness. The crude material was redissolved with chloroform (60 mL) and washed thrice with 1.0 M sodium hydroxide (30 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The resulting residue was resuspended in acetone (4 mL) and added dropwise to diethyl ether (10 mL) to induce a white precipitate. The pure product was collected by filtration and dried in vacuo to give L as a white powder (287.4 mg, 84.3% yield). 1H NMR (CDCl3, 298 K, 600 MHz): δ 2.39–2.72 (m, 12H), 3.34 (s, 9H), 3.40–3.51 (m, 6H), 3.67 (d, 3H, J = 13.6 Hz), 4.78 (d, 3H, J = 13.5 Hz), 6.35 (d, 6H, J = 8.6 Hz), 6.86 (s, 3H), 6.88 (d, 6H, J = 8.6 Hz), 7.16 (s, 3H). 13C{1H} NMR (CDCl3, 298 K, 150 MHz) δ 35.6, 48.5, 53.9, 55.5, 55.9, 113.9, 114.6, 125.7, 129.1, 132.3, 133.6, 137.9, 142.3, 150.9, 159.2 ppm.

Synthesis of [3H-L][OTs]3

In a round-bottom flask, L (41.2 mg, 50.3 μmol) was combined with p-toluenesulfonic acid monohydrate (38.3 mg, 201 μmol) in a mixture of acetone (8 mL) and methanol (16 mL). The mixture was magnetically stirred under ambient conditions overnight. After the reaction was complete, the solvent was evaporated to dryness. The solid was redissolved by chloroform (30 mL) and washed twice with deionized (DI) water (15 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The pure product was obtained as a white solid (48.5 mg, 72.2% yield). 1H NMR (CDCl3, 298 K, 600 MHz): δ 2.34 (s, 9H), 3.22 (s, 9H), 3.34–4.25 (m, 12H), 3.69 (d, 3H, J = 13.7 Hz), 4.13–4.39 (m, 6H), 4.84 (d, 3H, J = 13.6 Hz), 6.41 (d, 6H, J = 8.6 Hz), 6.90 (d, 6H, J = 8.5 Hz), 6.93 (s, 3H), 6.94 (d, 6H, J = 7.1 Hz), 7.00 (d, 6H, J = 7.9 Hz), 7.19 (s, 3H). 13C{1H} NMR (CDCl3, 298 K, 125 MHz). δ 21.5, 36.0, 44.0, 51.1, 51.3, 55.7, 114.3, 115.2, 124.5, 125.6, 126.0, 127.8, 128.8, 132.2, 137.9, 140.4, 140.4, 142.2, 150.7, 159.1 ppm; HRMS (ESI-TOF): m/z calcd for C72H78N4O15S3, 1357.4524 ([M + Na]+); found, 1357.4553 [M + Na]+.

Synthesis of [3H-L][OMs]3

In a round-bottom flask, L (40.3 mg, 49.2 μmol) was combined with methanesulfonic acid (18.9 mg, 196 μmol) in chloroform (80 mL). The mixture was magnetically stirred under ambient conditions overnight. After the reaction was complete, the solution was concentrated 2-fold, washed twice with DI water (6 mL), dried over anhydrous sodium sulfate, and evaporated to dryness. The pure product was obtained as a white solid (53.0 mg, 97.3% yield). 1H NMR (CDCl3, 298 K, 600 MHz): δ 1.90 (s, 9H), 2.08–3.82 (m, 12H), 3.47 (s, 9H), 3.73 (d, 3H, J = 13.7 Hz), 3.95–4.71 (m, 6H), 4.87 (d, 3H, J = 13.6 Hz), 6.54 (d, 6H, J = 8.5 Hz), 6.96 (s, 3H), 7.05 (d, 6H, J = 8.5 Hz), 7.26 (s, 3H). 13C{1H} NMR (CDCl3, 298 K, 125 MHz) δ 36.0, 38.0, 43.6, 50.8, 51.5, 55.9, 114.0, 114.9, 125.7, 126.5, 128.2, 132.2, 138.1, 141.9, 150.6, 159.8 ppm; HRMS (ESI-TOF): m/z calcd for C54H66N4O15S3, 1129.3585 ([M + Na]+); found, 1129.3577 [M + Na]+.

Synthesis of [3H-L][ONs]3

In a round-bottom flask, L (20.0 mg, 24.4 μmol) was combined with 2-naphthalenesulfonic acid (20.3 mg, 97.7 μmol) in a mixture of methanol (6 mL), acetone (3 mL), and chloroform (20 mL). The reaction was magnetically stirred under ambient conditions overnight. After the reaction was complete, the solution was evaporated to dryness. The crude material was redissolved by chloroform (30 mL) and washed thrice with DI water (120 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The pure product was obtained as a white solid (7.5 mg, 21.2% yield). 1H NMR (CDCl3, 298 K, 600 MHz): δ 2.36–4.32 (m, 12H), 2.69 (s, 9H), 3.67 (d, 3H, J = 13.7 Hz), 4.30–4.34 (m, 6H), 4.83 (d, 3H, J = 13.6 Hz), 6.30 (d, 6H, J = 4.3 Hz), 6.81 (s, 3H), 6.96 (d, 6H, J = 4.2 Hz), 7.09 (s, 3H), 7.17 (s, 3H), 7.49 (s, 3H), 7.52–7.55 (m, 3H), 7.58–7.60 (m, 3H), 7.60–7.61 (m, 3H), 7.67–7.69 (m, 3H), 7.79–7.81 (m, 3H). 13C{1H} NMR (CDCl3, 298 K, 125 MHz). δ 36.2, 43.9, 51.1, 51.2, 55.1, 114.1, 115.0, 122.6, 123.8, 125.5, 125.7, 126.6, 127.3, 127.6, 127.7, 128.1, 129.3, 132.3, 134.0, 137.8, 140.2, 142.2, 150.6, 158.7 ppm; HRMS (ESI-TOF): m/z calcd for free base C51H54N4O6, 819.4122 ([M + H]+); found, 819.4112 [M + H]+; m/z calcd for anion C10H7SO3, 207.0116; found, 207.0122.

Two-Dimensional Diffusion-Ordered Spectroscopy (2D DOSY) 1H NMR

The experiments for determining the diffusion coefficients were performed at 298 K on a Bruker AVIII500 spectrometer equipped with a 5 mm DUAL probe with a z-axis gradient coil. Maximum gradient strength was 5.35 G/cmA. The standard Bruker pulse program, ledbpgp2s, employing a stimulated echo and longitudinal eddy-current delay (LED) using bipolar gradient pulses for diffusion was utilized. Diffusion time was 50 ms, and the duration of the sine shaped gradient was 1.5 ms for all samples.

Two-Dimensional Exchange Spectroscopy (2D EXSY) 1H NMR

The experiment was performed at 298 K on a Bruker AVIII 500 spectrometer using a conventional NOESY sequence. 2048 and 128 data points were used in the t2 and t1 domain, respectively, where 64 scans were collected for each slice. tmix = 100 ms was applied as the mixing time.

Crystal Growth

Slow diffusion of diethyl ether into the chloroform solution of 4 mM L, [3H-L][OMs]3, [3H-L][OTs]3, or [3H-L][ONs]3, with or without the guest molecules, resulted in crystals suitable for X-ray diffraction (XRD) analysis that gave the crystal structures of L, [3H-L][OMs]3, [3H-L][OTs]3, acetamide·[3H-L][OTs]3, acrylamide·[3H-L][OTs]3, DMF·[3H-L][OTs]3, and [3H-L][ONs]3. Slow diffusion of diethyl ether into the DMF solution of 4 mM [3H-L][OMs]3 resulted in crystals suitable for X-ray diffraction analysis that gave the crystal structure of DMF·[3H-L][OMs]3. Slow diffusion of diethyl ether into the dichloromethane solution of 3 mM [3H-L][ONs]3 with DMF resulted in crystals suitable for X-ray diffraction analysis that gave the crystal structure of DMF·[3H-L][ONs]3.

Crystal Structure Determination

Single crystal X-ray diffraction data for compound L were collected on a Bruker D8QUEST CMOS area detector using graphite-monochromated Mo Kα radiation (λ = 0.71073 Å). All other data sets were collected on Rigaku XtaLAB Synergy-S diffractometers with HPC area detectors using confocal multilayer optic-monochromated Cu Kα radiation (λ = 1.54184 Å) for compounds [3H-L][OTs]3, acetamide·[3H-L][OTs]3, DMF·[3H-L][OTs]3, and DMF·[3H-L][ONs]3 and Mo Kα radiation (λ = 0.71073 Å) for acrylamide·[3H-L][OTs]3, [3H-L][OMs]3, DMF·[3H-L][OMs]3, and [3H-L][ONs]3. The Bruker data were integrated using SAINT46 and corrected for absorption using SADABS;47 the Rigaku data were integrated with CrysAlisPro(48) and corrected for absorption with SCALE3 ABSPACK.49 The structures were all solved by dual space methods – SHELXT.50 For [3H-L][OTs]3, acetamide·[3H-L][OTs]3, acrylamide·[3H-L][OTs]3, [3H-L][OMs]3, [3H-L][ONs]3, and DMF·[3H-L][ONs]3, there were regions of disordered solvent for which reliable disorder models could not be devised; the X-ray data were corrected for the presence of disordered solvent using SQUEEZE.51 Refinement was by full-matrix least-squares based on F2 using SHELXL.52 All reflections were used during refinement. Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were refined using a riding model. Detailed refinement data are listed in Tables S1–S9.

Measuring the Association Constant KA

A solution of [3H-L][OTs]3 (4 mM in CDCl3, 600 μL) or [3H-L][ONs]3 (2 mM in CDCl3, 600 μL) was titrated in NMR tubes with aliquots of a guest solution (300 mM formamide, 300 mM acetamide, 300 mM acrylamide, or 1.2 M DMF in CDCl3). After each addition, the chemical shifts (δ) of the methylene axial protons Ha on the CTV unit resonating at 4.84 ppm ([3H-L][OTs]3) or 4.83 ppm ([3H-L][ONs]3) were measured by 1H NMR spectroscopy at 298 K and plotted as a function of the guest-to-host molar ratio. Association constant KA was extracted by nonlinear least-squares fitting of these plots using the Bindfit program.53 All titrations were performed in triplicate.

Modulating the Affinity of DMF to the Cationic Cryptand

To lower the guest affinity, a solution of [3H-L][OTs]3 (4 mM in CDCl3, 600 μL) and 20 equiv of DMF were titrated in an NMR tube with aliquots of a solution of n-tetrabutylammonium methanesulfonate [Bu4N][OMs] (300 mM in CDCl3). After each addition, the bound DMF signals resonating at 0.00 ppm and −0.71 ppm were recorded by 1H NMR spectroscopy at 278 K. The relative integration of the encapsulated DMF peaks in each spectrum was plotted as a function of the molar ratio of [Bu4N][OMs] to [3H-L][OTs]3. To enhance the guest affinity, a solution of [3H-L][OMs]3 (4 mM in CDCl3, 600 μL) and 20 equiv of DMF were titrated in another NMR tube with aliquots of a solution of n-tetrabutylammonium tosylate [Bu4N][OTs] (600 mM in CDCl3). After each addition, the bound DMF signals resonating at 0.00 ppm and −0.71 ppm were recorded by 1H NMR spectroscopy at 278 K. The relative integration of the encapsulated DMF peaks in each spectrum was plotted as a function of the molar ratio of [Bu4N][OTs] to [3H-L][OMs]3.

Results and Discussion

The hemicryptophane L was prepared via a column-free protocol that was optimized based on a reported method.40 To fully protonate the capsule, excess tosylic acid (TsOH, 4 equiv) was reacted with L (Scheme 1). When the reaction was completed, extraction with DI water removed the unreacted acid and yielded pure [3H-L][OTs]3 (72% yield) with three tosylate counteranions as confirmed by 1H NMR spectroscopy (Figure 1a) and mass spectrometry (Figure S1). This is different from Reinaud’s more open calix[6]tren system, where all four TREN amines were protonated.43 Although the proton signals of this new hemicryptophane species were notably shifted when compared with the neutral cage L, the 1H NMR profile of [3H-L][OTs]3 is characteristic of a C3-symmetric conformation.

Scheme 1. Synthesis of L, [3H-L][OTs]3, [3H-L][OMs]3, and [3H-L][ONs]3.

Scheme 1

Open in a new tab

Conditions: (a) tris(2-aminoethyl)amine, acetic acid, methanol/acetonitrile, reflux, 1 h; then sodium borohydride, 25 °C, 3 h, 84%; (b) p-toluenesulfonic acid monohydrate, methanol/acetone, overnight, 72%; (c) 2-naphthalenesulfonic acid, methanol/acetone/chloroform, overnight, 21%; (d) methanesulfonic acid, chloroform, overnight, 97%.

Figure 1.

Figure 1

Open in a new tab

1H NMR spectra (600 MHz, 298 K, CDCl3) of 6 mM [3H-L][OTs]3 (a) before and (b) after the addition of 10 equiv of DMF. (●) Free DMF; (▼) encapsulated DMF; (◆) −OCH3; (■) methylene proton Ha on CTV unit; (★) H2O.

Slow diffusion of diethyl ether into a chloroform solution of L or [3H-L][OTs]3 resulted in single crystals suitable for X-ray analysis (Figures 2a–b and S3). To quantify the conformational changes associated with the protonated capsule in the solid state, we defined the distances between the centroids of the benzene rings on the CTV unit as d1, the distances between the centroids of the phenylene rotators as d2, and the distances between the N atoms of the TREN moiety as d3 (Figure 3). Despite the significant solution 1H NMR spectral changes upon protonation, the hemicryptophane underwent a moderate conformational change in the crystal structure comparing L to [3H-L][OTs]3 (Table 1). Except for a small and consistent increase of d2 indicating slight cavity expansion, the CTV unit and the TREN moiety remained relatively unchanged. Furthermore, the interactions between the tosylate anions and the cationic cryptand were observed in the solid state, which revealed that each of the tosylates is stacked between two neighboring phenylene groups of the capsule, thereby impeding guest exchange at the three portals. The distances between the protonated N atoms and two of their closest tosylate O atoms were both less than 2.8 Å, which are well within hydrogen-bonding distance. As a result, each O atom on the tosylate is bridging two H atoms from the protonated TREN, forming a total of six hydrogen bonds. These intermolecular hydrogen bonds were also observed in CDCl3 solution by 1H DOSY NMR spectroscopy (Figure S4). Resonances from the anionic tosylates and the cationic cryptand showed identical diffusion coefficients, log(D/m2 s–1) = −9.06 at 298 K.

Figure 2.

Figure 2

Open in a new tab

Crystal structure of [3H-L][OTs]3: (a) side view showing the empty cavity; (b) bottom view showing the hydrogen-bonding network formed between [3H-L]3+ and the three –OTs anions. (c, d) Crystal structure of DMF·[3H-L][OTs]3: (c) side view showing the encapsulation of DMF; (d) bottom view showing the hydrogen-bonding network formed between [3H-L]3+ and the three –OTs anions. (e, f) Crystal structure of [3H-L][OMs]3: (e) side view showing the empty cavity; (f) bottom view showing the hydrogen-bonding network formed between [3H-L]3+ and the three –OMs anions. Gray, light-green, blue, red, and yellow spheres represent the C, H, N, O, and S atoms, respectively. Solvent molecules and H atoms are omitted for clarity, except for those highlighted in the hydrogen bonds as light-green spheres.

Figure 3.

Figure 3

Open in a new tab

Cross section of the hemicryptophane structure. The yellow broken lines indicate the distances between the centroids of the benzene rings on the CTV unit (d1), the green broken lines indicate the distances between the centroids of the phenylene rotators (d2), and the blue broken lines indicate the distances between the N atoms of the TREN moiety (d3).

Table 1. Comparison of the Structural Parametersa Related to the Conformation of the Hemicryptophanes Investigated in This Study.

  L [3H-L][OTs]3 [3H-L][OMs]3 [3H-L][ONs]3
d1̅ (Å) 4.65 4.76 4.76 4.75
d2̅ (Å) 6.33 7.14 7.41 7.23
d3̅ (Å) 4.24 4.42 4.53 4.48
Open in a new tab
a

Distances reported here are all taken as the average of d1, d2, or d3.

We hypothesized that the protonated capsule [3H-L][OTs]3 should encapsulate polar guest molecules more effectively than the neutral cage L. To test this possibility, we examined the inclusion of several different amides, including formamide, DMF, acetamide, and acrylamide. In contrast to L that showed negligible binding affinity, the addition of these polar molecules to [3H-L][OTs]3 induced 1H NMR spectral changes that were consistent with guest encapsulation (Figures 1b and S5). Structural analysis further confirmed the binding of the cationic cryptand with each guest (Figures 2c–d and S6–S7). The orientation of the guests complemented the polarity of the cavity. In the crystal structure of DMF·[3H-L][OTs]3, for example, the electron-rich oxygen atom points toward the protonated TREN pocket whereas the methyl groups on the nitrogen point toward the CTV unit. The distances between the carbonyl O atom of the encapsulated DMF and the protonated N atoms of the capsule were 3.02(3), 3.10(3), and 3.15(4) Å, all of which suggested weak hydrogen-bonding interactions. These three relatively long hydrogen bonds enhance the dispersion interactions between the guest and the CTV unit. It is also worth noting that the hydrogen bonds between the tosylate anions and the cationic cryptand were preserved after guest encapsulation in the solid state. However, these interactions were weaker than those formed in the “apo” cages because the protonated TREN moiety was also hydrogen-bonded with the included guest.

Examination of the 1H NMR spectra revealed that the resonance at 3.22 ppm corresponding to the three methoxy groups on the CTV was shifted downfield upon guest encapsulation, consistent with their expulsion from the cavity. A similar downfield-shifting effect was observed for guest binding in Reinaud’s calix[6]tren and other hemicryptophane systems.31,33,43,54,55 As the three methylene axial protons Ha on the CTV unit displayed well-defined signals during the entire guest titration experiment, their chemical shift was plotted as a function of the host–guest ratio (Figures S8–S15). The Bindfit program was used to model experimental titration curves, and an optimal fit was found for a 1:1 host–guest stoichiometry.53 On this basis, the association constant, KA, was calculated for the binding of [3H-L][OTs]3 with four different polar guests at 298 K (Table 2). Acrylamide exhibited an almost 20-fold higher affinity compared to formamide. As the guest size increased from DMF to DEF (N,N-diethylformamide), guest encapsulation was no longer observed (Figure S16). Thus, the protonated capsule showed good selectivity for encapsulating amides of different sizes and shapes.

Table 2. Comparison of the Association Constants KA (M–1) for the 1:1 Complexes Formed between [3H-L][OTs]3 and the Amide Guests That Are Investigated in This Study at 298 K.

graphic file with name jo1c03128_0007.jpg

Open in a new tab

Notably, the exchange of DMF with the protonated capsule [3H-L][OTs]3 is much slower than the other three amides because the signals of the included DMF (inside) and free DMF (outside) were observed separately in the 1H NMR spectrum. The free DMF resonates at 8.01 ppm (aldehydic proton), 2.95 ppm, and 2.87 ppm (methyl protons) whereas the encapsulated DMF resonates at 5.36 ppm (aldehydic proton), 0.05 ppm, and −0.66 ppm (methyl protons), which was confirmed by 2D 1H EXSY NMR (Figure S17). However, the fast spin–lattice relaxation of the entrapped DMF prevented us from getting an actual exchange rate via a quantitative 2D EXSY experiment.56 Consistent with the observation in the solid state, the DMF-bound cationic cryptand was also hydrogen-bonded with the tosylate anions in solution. 1H DOSY NMR measurement in CDCl3 clearly showed that the cationic cage and the anionic tosylates had the same diffusion coefficient, log(D/m2 s–1) = −9.06 at 298 K (Figure S18).

Considering the robustness of the peripheral hydrogen-bonding interactions observed for [3H-L][OTs]3 in both the solid and solution states, we sought to tune the hosting properties of the cationic cryptand by varying the capping anions. We examined methanesulfonate because it has the same sulfonate moiety as the tosylate and should similarly “cap” the cage. This was confirmed by 1H DOSY NMR measurement in CDCl3 (Figure S21) as well as the crystal structure of [3H-L][OMs]3 (Figure 2e–f) which was prepared by reacting L with excess methanesulfonic acid (MsOH) and crystallized by diffusing ether vapor into its chloroform solution. Despite the fact that the methanesulfonate has the right size for the cavity and shares the 3-fold symmetry of the cationic cryptand, no anion encapsulation was observed in the solid state. Instead, [3H-L][OMs]3 adopted a similar structural conformation to [3H-L][OTs]3, and the portals of the cavity were also capped with three individual methanesulfonates through hydrogen bonds. The distances between the bridging O atoms on the methanesulfonates and their closest N atoms ranged from 2.727(3) to 2.825(3) Å, which indicated similar hydrogen-bonding interactions to those in [3H-L][OTs]3. When the crystals of [3H-L][OMs]3 were redissolved in CDCl3 and characterized by NMR again, the recorded 1H NMR spectrum was identical to the one collected as it was synthesized. This observation suggested that no anion was entrapped by the hemicryptophane in solution, which also held true for [3H-L][OTs]3. Although these two capsules share many similarities in the solid state, their binding properties were found to be dramatically different in solution. For example, when DMF (10 equiv) was added to a CDCl3 solution of [3H-L][OMs]3, none of the 1H signals from the cationic cryptand were shifted in the NMR spectrum (Figure 4a–b). This observation was in sharp contrast to what we saw, as the same equivalents of DMF were added to the solution of [3H-L][OTs]3. Further addition of DMF induced some observable 1H NMR spectral changes that were consistent with guest encapsulation (Figure 4c–d). For example, the doublet that belongs to the methylene protons Ha on the CTV unit was shifted upfield. In addition, the singlet that belongs to the protons on the methoxy groups was significantly broadened and marginally shifted downfield. Although no bound DMF signals were observed during the entire experiment, we confirmed the capability of [3H-L][OMs]3 to encapsulate DMF in the solid state (Figure S22). The single crystals were obtained by diffusing diethyl ether into a DMF solution of [3H-L][OMs]3, a condition in which the concentration of the guest molecule was maximized. Likewise, introducing the other three guests to [3H-L][OMs]3 resulted in minor but consistent 1H NMR spectral changes (Figures S23–S25), all of which suggested that the affinity of these polar molecules for [3H-L][OMs]3 was significantly lower than that for [3H-L][OTs]3. This confirmed our initial hypothesis that the binding property of the cationic cryptand [3H-L]3+ can be tuned through secondary interactions with the capping anions.

Figure 4.

Figure 4

Open in a new tab

1H NMR spectra (600 MHz, 298 K, CDCl3) of 6 mM [3H-L][OMs]3 (a) before and (b) after the addition of 10 equiv of DMF; (c) 40 equiv of DMF; (d) 80 equiv of DMF. (◆) −OCH3; (■) methylene proton Ha on CTV unit.

To further explore the versatility of this capping strategy, a third protonated hemicryptophane [3H-L][ONs]3 was synthesized with three 2-naphthalenesulfonates as the counteranions. XRD analysis revealed that the cationic cryptand adopted a similar structural conformation to the other two capsules and was capped with hydrogen-bonded anions at the three portals (Figure S29). After the addition of 20 equiv of DMF to [3H-L][ONs]3, the entrapped DMF signals were clearly observed by 1H NMR spectroscopy at 5.34 ppm (aldehydic proton), 0.03 ppm, and −0.72 ppm (methyl protons) (Figure S30). The encapsulation of DMF was also confirmed in the solid state (Figure S31). Further investigation by NMR titration disclosed an association constant of DMF with [3H-L][ONs]3 to be (1.5 ± 0.1) × 102 M–1 (Figures S32–S33), which was almost twice as high as that with [3H-L][OTs]3 and infinitely higher than with [3H-L][OMs]3. Such a dramatic difference in the measured binding affinity exhibited by the same cationic cryptand can be attributed to two main factors: one is the size of the anions, and the other is the strength of the hydrogen-bonding network, which is estimated by the pKa of the conjugate acid of the anions. As the 2-naphthalenesulfonate is more sterically bulky than the other two sulfonates, the portals of [3H-L][ONs]3 are blocked most effectively. At the same time, 2-naphthalenesulfonic acid is less acidic than the conjugate acid of the other two sulfonates (pKa of methanesulfonic acid is −1.2, pKa of tosylic acid is −1.34,57 pKa of 2-naphthalenesulfonic acid is 0.6158), and –ONs should bind more tightly to the peripheral sites than the other two anions according to the pKa slide rule.59 By taking advantage of both factors, [3H-L][ONs]3 therefore exhibits the highest affinity for DMF in this series. On the other hand, –OMs binds more tightly to the portals than –OTs but has a smaller size than –OTs. These factors counteract, and the net result is that [3H-L][OTs]3 exhibits a higher affinity to DMF than [3H-L][OMs]3. Because the methanesulfonic acid is minimally more acidic than the tosylic acid, the size of the anions is believed to play a more significant role than the acidity of the conjugate acid in this type of counteranion-dependent guest binding modulation. It is also important to mention, owing to some degree of conformational differences among the capsules with different counteranions, the distinct guest complementarity to the binding pocket brought by ion pairing could be relevant to the different binding affinity exhibited by the protonated hemicryptophane.

Finally, we applied our “counteranion tuning” strategy to modulate the binding properties of the protonated capsule via the interconversion between two capping states (Figure 5a). We chose to monitor the inclusion of DMF by 1H NMR spectroscopy because the relative integration of the entrapped DMF peak can precisely report the percentage of guest encapsulation. Due to the broadness of the peak at rt, the NMR spectra were collected at 278 K to improve quantitation of the signals. [Bu4N][OMs] was titrated into a mixture of 4 mM [3H-L][OTs]3 and 20 equiv of DMF, a condition where the cavity was saturated with one DMF molecule (Figure 5b). Upon the addition of [Bu4N][OMs], the intensity of the encapsulated DMF peaks gradually decreased (Figure S34). After the addition of 3 equiv of [Bu4N][OMs], the included DMF signals entirely disappeared from the 1H NMR spectrum (Figure 5c), consistent with complete guest release from the capsule. The relative integration of this bound DMF peak was plotted as a function of the molar ratio of [Bu4N][OMs] to [3H-L][OTs]3 (Figure 5d), and this gave a linear relationship with R2 = 0.996. Further addition of [Bu4N][OMs] did not induce any noticeable peak shifting for the proton signals of the cationic cryptand [3H-L]3+, indicating that the three capping tosylate anions were completely substituted with the methanesulfonate anions. Inversely, when [Bu4N][OTs] was added stepwise to a mixture of 4 mM [3H-L][OMs]3 and 20 equiv of DMF (Figure 5e), the included DMF signals were gradually restored (Figure S35). Addition of 36 equiv of [Bu4N][OTs] fully recovered the signals (Figure 5f), as expected for the saturation of the cavity with one DMF molecule. A control experiment ruled out that this effect could be due to changes in the ionic strength (Figure S36). A linear relationship was found for the relative integration of the encapsulated DMF peak and the molar ratio of [Bu4N][OTs] to [3H-L][OMs]3 with R2 = 0.980 (Figure 5g). With additional [Bu4N][OTs] being introduced, the chemical shifts of the protons on the cationic cryptand [3H-L]3+ no longer changed. This is indicative of the complete replacement of the capping methanesulfonates with the tosylates. These data reveal the competition between tosylates and methanesulfonates to bind at the three portals of the cationic cryptand. Stepwise displacement of either capping anion makes it possible to modulate the affinity of DMF for the protonated capsule. As the strength of the hydrogen-bonding network in [3H-L][OMs]3 is marginally stronger than that in [3H-L][OTs]3, more [Bu4N][OTs] is required to fully resaturate the three anion binding sites of [3H-L][OMs]3. Anion binding at the peripheral sites provides control over a wide range of molecules that can occupy the cavity.

Figure 5.

Figure 5

Open in a new tab

(a) Schematic representation of the interconversion between [3H-L][OTs]3 and [3H-L][OMs]3. (b, c) 1H NMR spectra (500 MHz, 278 K, CDCl3) of a mixture of 4 mM [3H-L][OTs]3 and 20 equiv of DMF (b) before and (c) after the addition of 3 equiv of [Bu4N][OMs]. (d) Relative integration of the encapsulated DMF peaks as a function of the molar ratio of [Bu4N][OMs] to [3H-L][OTs]3. (e, f,) 1H NMR spectra (500 MHz, 278 K, CDCl3) of a mixture of 4 mM [3H-L][OMs]3 and 20 equiv of DMF (e) before and (f) after the addition of 36 equiv of [Bu4N][OTs]. (g) Relative integration of the encapsulated DMF peak as a function of the molar ratio of [Bu4N][OTs] to [3H-L][OMs]3.

Conclusions

In conclusion, we have demonstrated a model TREN-hemicryptophane host with enhanced binding properties that result from triply protonating the cavity with sulfonic acids. Various size-matched amide molecules were encapsulated with good selectivity. In the process of protonating the TREN moiety, we discovered a versatile class of counteranions that stably hydrogen bond at the periphery of the capsule and modulate the affinity of the encapsulated guest. This work highlights “counteranion tuning” as a simple but powerful methodology to control guest binding in a synthetic organic host. The examples here illustrate a modular system that can be expanded to generate a large number of host molecules by varying the size and acidity of the capping anions that occupy the peripheral sites. The ability to modulate guest binding at a primary site by varying the occupancy of anions at well-defined secondary sites mimics important features of molecular recognition found in many biomolecular systems.

Acknowledgments

This research was supported by NIH Grant R35-GM-131907 to I.J.D.; Y.L. was supported by the UPenn Mitchell Fellowship. We thank Drs. Jun Gu and Chad W. Lawrence for assistance with NMR spectroscopy. We thank Dr. Charles W. Ross for mass spectrometry expertise.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.1c03128.

  • Experimental and characterization details; NMR analysis; and XRD data for L (CCDC-2115517), [3H-L][OTs]3 (CCDC-2115515), acetamide·[3H-L][OTs]3 (CCDC-2115518), acrylamide·[3H-L][OTs]3 (CCDC-2115514), DMF·[3H-L][OTs]3 (CCDC-2115519), [3H-L][OMs]3 (CCDC-2115516), DMF·[3H-L][OMs]3 (CCDC-2125947), [3H-L][ONs]3 (CCDC-2125946), and DMF·[3H-L][ONs]3 (CCDC-2130025) (PDF)

Accession Codes

CCDC 2115514–2115519, 2125946–2125947, and 2130025 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

The authors declare no competing financial interest.

Supplementary Material

jo1c03128_si_002.pdf (4.1MB, pdf)

References

  1. Helgeson R. C.; Hayden A. E.; Houk K. N. Controlled Gating of a Hemicarcerand by Disulfide-Dithiol Interchange. J. Org. Chem. 2010, 75 (3), 570–575. 10.1021/jo9012496. [DOI] [PubMed] [Google Scholar]
  2. Pochorovski I.; Diederich F. Development of Redox-Switchable Resorcin[4]Arene Cavitands. Acc. Chem. Res. 2014, 47 (7), 2096–2105. 10.1021/ar500104k. [DOI] [PubMed] [Google Scholar]
  3. Frasconi M.; Fernando I. R.; Wu Y.; Liu Z.; Liu W. G.; Dyar S. M.; Barin G.; Wasielewski M. R.; Goddard W. A.; Stoddart J. F. Redox Control of the Binding Modes of an Organic Receptor. J. Am. Chem. Soc. 2015, 137 (34), 11057–11068. 10.1021/jacs.5b05618. [DOI] [PubMed] [Google Scholar]
  4. Jia F.; Schröder H. V.; Yang L. P.; Von Essen C.; Sobottka S.; Sarkar B.; Rissanen K.; Jiang W.; Schalley C. A. Redox-Responsive Host-Guest Chemistry of a Flexible Cage with Naphthalene Walls. J. Am. Chem. Soc. 2020, 142 (7), 3306–3310. 10.1021/jacs.9b11685. [DOI] [PubMed] [Google Scholar]
  5. Mansoor I. F.; Dutton K. G.; Rothschild D. A.; Remsing R. C.; Lipke M. C. Uptake, Trapping, and Release of Organometallic Cations by Redox-Active Cationic Hosts. J. Am. Chem. Soc. 2021, 143 (41), 16993–17003. 10.1021/jacs.1c06121. [DOI] [PubMed] [Google Scholar]
  6. Branda N.; Grotzfeld R. M.; Valdes C.; Rebek J. Control of Self-Assembly and Reversible Encapsulation of Xenon in a Self-Assembling Dimer by Acid-Base Chemistry. J. Am. Chem. Soc. 1995, 117 (1), 85–88. 10.1021/ja00106a010. [DOI] [Google Scholar]
  7. Hu W. B.; Hu W. J.; Zhao X. L.; Liu Y. A.; Li J. S.; Jiang B.; Wen K. A1/A2-Diamino-Substituted Pillar[5]Arene-Based Acid-Base-Responsive Host-Guest System. J. Org. Chem. 2016, 81 (9), 3877–3881. 10.1021/acs.joc.6b00617. [DOI] [PubMed] [Google Scholar]
  8. Lascaux A.; Leener G. De; Fusaro L.; Topić F.; Rissanen K.; Luhmer M.; Jabin I. Selective Recognition of Neutral Guests in an Aqueous Medium by a Biomimetic Calix[6]Cryptamide Receptor. Org. Biomol. Chem. 2016, 14 (2), 738–746. 10.1039/C5OB02067K. [DOI] [PubMed] [Google Scholar]
  9. Kurihara K.; Yazaki K.; Akita M.; Yoshizawa M. A Switchable Open/Closed Polyaromatic Macrocycle That Shows Reversible Binding of Long Hydrophilic Molecules. Angew. Chem., Int. Ed. 2017, 129 (38), 11518–11522. 10.1002/ange.201703357. [DOI] [PubMed] [Google Scholar]
  10. Zhiquan L.; Xie H.; Border S. E.; Gallucci J.; Pavlović R. Z.; Badjić J. D. A Stimuli-Responsive Molecular Capsule with Switchable Dynamics, Chirality, and Encapsulation Characteristics. J. Am. Chem. Soc. 2018, 140 (35), 11091–11100. 10.1021/jacs.8b06190. [DOI] [PubMed] [Google Scholar]
  11. Shinkai S.; Nakaji T.; Ogawa T.; Shigematsu K.; Manabe O. Photoresponsive Crown Ethers. 2. Photocontrol of Ion Extraction and Ion Transport by a Bis(Crown Ether) with a Butterfly-like Motion. J. Am. Chem. Soc. 1981, 103 (1), 111–115. 10.1021/ja00391a021. [DOI] [Google Scholar]
  12. Wang H.; Liu F.; Helgeson R. C.; Houk K. N. Reversible Photochemically Gated Transformation of a Hemicarcerand to a Carcerand. Angew. Chem., Int. Ed. 2013, 52 (2), 655–659. 10.1002/anie.201205376. [DOI] [PubMed] [Google Scholar]
  13. Qu D. H.; Wang Q. C.; Zhang Q. W.; Ma X.; Tian H. Photoresponsive Host-Guest Functional Systems. Chem. Rev. 2015, 115 (15), 7543–7588. 10.1021/cr5006342. [DOI] [PubMed] [Google Scholar]
  14. Davis A. V.; Fiedler D.; Seeber G.; Zahl A.; Van Eldik R.; Raymond K. N. Guest Exchange Dynamics in an M4L6 Tetrahedral Host. J. Am. Chem. Soc. 2006, 128 (4), 1324–1333. 10.1021/ja056556+. [DOI] [PubMed] [Google Scholar]
  15. Durola F.; Rebek J. The Ouroborand: A Cavitand with a Coordination-Driven Switching Device. Angew. Chem., Int. Ed. 2010, 49 (18), 3189–3191. 10.1002/anie.200906753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Zarra S.; Smulders M. M. J.; Lefebvre Q.; Clegg J. K.; Nitschke J. R. Guanidinium Binding Modulates Guest Exchange within an [M4L6] Capsule. Angew. Chem., Int. Ed. 2012, 51 (28), 6882–6885. 10.1002/anie.201202665. [DOI] [PubMed] [Google Scholar]
  17. Kremer C.; Lützen A. Artificial Allosteric Receptors. Chem. - Eur. J. 2013, 19 (20), 6162–6196. 10.1002/chem.201203814. [DOI] [PubMed] [Google Scholar]
  18. Takezawa H.; Tabuchi R.; Sunohara H.; Fujita M. Confinement of Water-Soluble Cationic Substrates in a Cationic Molecular Cage by Capping the Portals with Tripodal Anions. J. Am. Chem. Soc. 2020, 142 (42), 17919–17922. 10.1021/jacs.0c08835. [DOI] [PubMed] [Google Scholar]
  19. Bartik K.; Luhmer M.; Dutasta J.-P.; Collet A.; Reisse J. 129Xe and 1H NMR Study of the Reversible Trapping of Xenon by Cryptophane-A in Organic Solution. J. Am. Chem. Soc. 1998, 120 (4), 784–791. 10.1021/ja972377j. [DOI] [Google Scholar]
  20. Hill P. A.; Wei Q.; Eckenhoff R. G.; Dmochowski I. J. Thermodynamics of Xenon Binding to Cryptophane in Water and Human Plasma. J. Am. Chem. Soc. 2007, 129 (30), 9262–9263. 10.1021/ja072965p. [DOI] [PubMed] [Google Scholar]
  21. Chambers J. M.; Hill P. A.; Aaron J. A.; Han Z.; Christianson D. W.; Kuzma N. N.; Dmochowski I. J. Cryptophane Xenon-129 Nuclear Magnetic Resonance Biosensors Targeting Human Carbonic Anhydrase. J. Am. Chem. Soc. 2009, 131 (2), 563–569. 10.1021/ja806092w. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hill P. A.; Wei Q.; Troxler T.; Dmochowski I. J. Substituent Effects on Xenon Binding Affinity and Solution Behavior of Water-Soluble Cryptophanes. J. Am. Chem. Soc. 2009, 131 (8), 3069–3077. 10.1021/ja8100566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Taratula O.; Hill P. A.; Khan N. S.; Carroll P. J.; Dmochowski I. J. Crystallographic Observation of “Induced Fit” in a Cryptophane Host-Guest Model System. Nat. Commun. 2010, 1 (1), 148. 10.1038/ncomms1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jacobson D. R.; Khan N. S.; Colle R.; Fitzgerald R.; Laureano-Perez L.; Bai Y.; Dmochowski I. J. Measurement of Radon and Xenon Binding to a Cryptophane Molecular Host. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (27), 10969–10973. 10.1073/pnas.1105227108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Riggle B. A.; Wang Y.; Dmochowski I. J. A “Smart” 129Xe NMR Biosensor for pH-Dependent Cell Labeling. J. Am. Chem. Soc. 2015, 137 (16), 5542–5548. 10.1021/jacs.5b01938. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Brotin T.; Martinez A.; Dutasta J.-P.. Water-Soluble Cryptophanes: Design and Properties. In Calixarenes and Beyond; Springer: Cham, 2016; pp 525–557. [Google Scholar]
  27. El-Ayle G.; Holman K. T.. Cryptophanes. In Comprehensive Supramolecular Chemistry II; Elsevier: Oxford, 2017; pp 199–249. [Google Scholar]
  28. Zemerov S. D.; Lin Y.; Dmochowski I. J. Monomeric Cryptophane with Record-High Xe Affinity Gives Insights into Aggregation-Dependent Sensing. Anal. Chem. 2021, 93 (3), 1507–1514. 10.1021/acs.analchem.0c03776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Canceill J.; Collet A.; Gabard J.; Kotzyba-Hibert F.; Lehn J. Speleands. Macropolycyclic Receptor Cages Based on Binding and Shaping Sub-units. Synthesis and Properties of Macrocycle Cyclotriveratrylene Combinations. Preliminary Communication. Helv. Chim. Acta 1982, 65 (6), 1894–1897. 10.1002/hlca.19820650623. [DOI] [Google Scholar]
  30. Perraud O.; Lefevre S.; Robert V.; Martinez A.; Dutasta J.-P. Hemicryptophane Host as Efficient Primary Alkylammonium Ion Receptor. Org. Biomol. Chem. 2012, 10 (5), 1056–1059. 10.1039/C1OB06657A. [DOI] [PubMed] [Google Scholar]
  31. Le Gac S.; Jabin I. Synthesis and Study of Calix[6]Cryptamides: A New Class of Heteroditopic Receptors That Display Versatile Host-Guest Properties toward Neutral Species and Organic Associated Ion-Pair Salts. Chem. - Eur. J. 2008, 14 (2), 548–557. 10.1002/chem.200701051. [DOI] [PubMed] [Google Scholar]
  32. Perraud O.; Robert V.; Martinez A.; Dutasta J.-P. The Cooperative Effect in Ion-Pair Recognition by a Ditopic Hemicryptophane Host. Chem. - Eur. J. 2011, 17 (15), 4177–4182. 10.1002/chem.201002116. [DOI] [PubMed] [Google Scholar]
  33. Delecluse M.; Colomban C.; Moraleda D.; de Riggi I.; Duprat F.; Michaud-Chevallier S.; Dutasta J.-P.; Robert V.; Chatelet B.; Martinez A. Positive Cooperative Effect in Ion-Pair Recognition by a Tris-Urea Hemicryptophane Cage. Chem. - Eur. J. 2018, 25 (13), 3337–3342. 10.1002/chem.201805534. [DOI] [PubMed] [Google Scholar]
  34. Perraud O.; Robert V.; Gornitzka H.; Martinez A.; Dutasta J.-P. Combined Cation-π and Anion-π Interactions for Zwitterion Recognition. Angew. Chem., Int. Ed. 2012, 51 (2), 504–508. 10.1002/anie.201106934. [DOI] [PubMed] [Google Scholar]
  35. Cochrane J. R.; Schmitt A.; Wille U.; Hutton C. A. Synthesis of Cyclic Peptide Hemicryptophanes: Enantioselective Recognition of a Chiral Zwitterionic Guest. Chem. Commun. 2013, 49 (76), 8504–8506. 10.1039/c3cc44784g. [DOI] [PubMed] [Google Scholar]
  36. Perraud O.; Martinez A.; Dutasta J.-P. Exclusive Enantioselective Recognition of Glucopyranosides by Inherently Chiral Hemicryptophanes. Chem. Commun. 2011, 47 (20), 5861–5863. 10.1039/c1cc10964b. [DOI] [PubMed] [Google Scholar]
  37. Long A.; Perraud O.; Albalat M.; Robert V.; Dutasta J.-P.; Martinez A. Helical Chirality Induces a Substrate-Selectivity Switch in Carbohydrates Recognitions. J. Org. Chem. 2018, 83 (12), 6301–6306. 10.1021/acs.joc.8b00276. [DOI] [PubMed] [Google Scholar]
  38. Khan N. S.; Perez-Aguilar J. M.; Kaufmann T.; Hill P. A.; Taratula O.; Lee O.-S.; Carroll P. J.; Saven J. G.; Dmochowski I. J. Multiple Hindered Rotators in a Gyroscope-Inspired Tribenzylamine Hemicryptophane. J. Org. Chem. 2011, 76 (5), 1418–1424. 10.1021/jo102480s. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Zhang D.; Martinez A.; Dutasta J.-P. Emergence of Hemicryptophanes: From Synthesis to Applications for Recognition, Molecular Machines, and Supramolecular Catalysis. Chem. Rev. 2017, 117 (6), 4900–4942. 10.1021/acs.chemrev.6b00847. [DOI] [PubMed] [Google Scholar]
  40. Makita Y.; Sugimoto K.; Furuyoshi K.; Ikeda K.; Fujiwara S.; Shin-ike T.; Ogawa A. A Zinc(II)-Included Hemicryptophane: Facile Synthesis, Characterization, and Catalytic Activity. Inorg. Chem. 2010, 49 (16), 7220–7222. 10.1021/ic100725j. [DOI] [PubMed] [Google Scholar]
  41. Makita Y.; Ikeda K.; Sugimoto K.; Fujita T.; Danno T.; Bobuatong K.; Ehara M.; Fujiwara S.; Ogawa A. Enhancement of Catalytic Reactivity of Zinc(II) Complex by a Cyclotriveratrylene-Capped Structure. J. Organomet. Chem. 2012, 706–707, 26–29. 10.1016/j.jorganchem.2012.01.006. [DOI] [Google Scholar]
  42. Makita Y.; Fujita T.; Danno T.; Inoue M.; Ueshima M.; Fujiwara S.; Ogawa A. Selective Oxidation of Alcohols Catalyzed by a Hemicryptophane-Ruthenium Complex. Supramol. Catal. 2012, 1, 11–13. 10.2478/supcat-2012-0002. [DOI] [Google Scholar]
  43. Darbost U.; Rager M. N.; Petit S.; Jabin I.; Reinaud O. Polarizing a Hydrophobic Cavity for the Efficient Binding of Organic Guests: The Case of Calix[6]Tren, a Highly Efficient and Versatile Receptor for Neutral or Cationic Species. J. Am. Chem. Soc. 2005, 127 (23), 8517–8525. 10.1021/ja051299u. [DOI] [PubMed] [Google Scholar]
  44. Le Gac S.; Zeng X.; Girardot C.; Jabin I. Efficient Synthesis and Host-Guest Properties of a New Class of Calix[6]Azacryptands. J. Org. Chem. 2006, 71 (24), 9233–9236. 10.1021/jo061616v. [DOI] [PubMed] [Google Scholar]
  45. Arduini A.; Calzavacca F.; Demuru D.; Pochini A.; Secchi A. Synthesis of Cavity Extended Cyclotriveratrylenes. J. Org. Chem. 2004, 69 (4), 1386–1388. 10.1021/jo035557m. [DOI] [PubMed] [Google Scholar]
  46. SAINT , v8.38A; Burker: Madison-AXS, Wisconsin, USA, 2014. [Google Scholar]
  47. Krause L.; Herbst-Irmer R.; Sheldrick G. M.; Stalke D. Comparison of Silver and Molybdenum Microfocus X-Ray Sources for Single-Crystal Structure Determination. J. Appl. Crystallogr. 2015, 48 (1), 3–10. 10.1107/S1600576714022985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. CrysAlisPro, version 1.171.40.104a; Rigaku Corporation: Oxford, UK, 2020. [Google Scholar]
  49. SCALE3 ABSPACK, version 1.0.7; Rigaku Corporation: Abingdon, UK, 2005. [Google Scholar]
  50. Sheldrick G. M. SHELXT - Integrated Space-Group and Crystal-Structure Determination. Acta Crystallogr. A 2015, 71, 3–8. 10.1107/S2053273314026370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Spek A. L. Structure Validation in Chemical Crystallography. Acta Crystallogr. D 2009, 65 (2), 148–155. 10.1107/S090744490804362X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sheldrick G. M. Crystal Structure Refinement with SHELXL. Acta Crystallogr. C 2015, 71, 3–8. 10.1107/S2053229614024218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Brynn Hibbert D.; Thordarson P. The Death of the Job Plot, Transparency, Open Science and Online Tools, Uncertainty Estimation Methods and Other Developments in Supramolecular Chemistry Data Analysis. Chem. Commun. 2016, 52 (87), 12792–12805. 10.1039/C6CC03888C. [DOI] [PubMed] [Google Scholar]
  54. Makita Y.; Katayama N.; Lee H. H.; Abe T.; Sogawa K.; Nomoto A.; Fujiwara S.; Ogawa A. A Tri-Aromatic Amide Hemicryptophane Host: Synthesis and Acetylcholine Binding. Tetrahedron Lett. 2016, 57 (46), 5112–5115. 10.1016/j.tetlet.2016.10.017. [DOI] [Google Scholar]
  55. Long A.; Lefevre S.; Guy L.; Robert V.; Dutasta J.-P.; Chevallier M. L.; Della-Negra O.; Saaidi P.-L.; Martinez A. Recognition of the Persistent Organic Pollutant Chlordecone by a Hemicryptophane Cage. New J. Chem. 2019, 43 (26), 10222–10226. 10.1039/C9NJ01674K. [DOI] [Google Scholar]
  56. Perrin C. L.; Dwyer T. J. Application of Two-Dimensional NMR to Kinetics of Chemical Exchange. Chem. Rev. 1990, 90 (6), 935–967. 10.1021/cr00104a002. [DOI] [Google Scholar]
  57. Kim H.; Gao J.; Burgess D. J. Evaluation of Solvent Effects on Protonation Using NMR Spectroscopy: Implication in Salt Formation. Int. J. Pharm. 2009, 377 (1–2), 105–111. 10.1016/j.ijpharm.2009.05.018. [DOI] [PubMed] [Google Scholar]
  58. McCalley D. V. Some Practical Comparisons of the Efficiency and Overloading Behaviour of Sub-2μm Porous and Sub-3μm Shell Particles in Reversed-Phase Liquid Chromatography. J. Chromatogr. A 2011, 1218 (20), 2887–2897. 10.1016/j.chroma.2011.02.068. [DOI] [PubMed] [Google Scholar]
  59. Gilli P.; Pretto L.; Bertolasi V.; Gilli G. Predicting Hydrogen-Bond Strengths from Acid-Base Molecular Properties. The pKa Slide Rule: Toward the Solution of a Long-Lasting Problem. Acc. Chem. Res. 2009, 42 (1), 33–44. 10.1021/ar800001k. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

jo1c03128_si_002.pdf (4.1MB, pdf)

Articles from The Journal of Organic Chemistry are provided here courtesy of American Chemical Society

RESOURCES