Charge-assisted hydrogen bonding in a bicyclic amide cage: an effective approach to anion recognition and catalysis in water

Abstract

Hydrogen bonding is prevalent in biological systems, dictating a myriad of life-sustaining functions in aqueous environments. Leveraging hydrogen bonding for molecular recognition in water encounters significant challenges in synthetic receptors on account of the hydration of their functional groups. Herein, we introduce a water-soluble hydrogen bonding cage, synthesized via a dynamic approach, exhibiting remarkable affinities and selectivities for strongly hydrated anions, including sulfate and oxalate, in water. We illustrate the use of charge-assisted hydrogen bonding in amide-type synthetic receptors, offering a general molecular design principle that applies to a wide range of amide receptors for molecular recognition in water. This strategy not only revalidates the functions of hydrogen bonding but also facilitates the effective recognition of hydrophilic anions in water. We further demonstrate an unconventional catalytic mechanism through the encapsulation of the anionic oxalate substrate by the cationic cage, which effectively inverts the charges associated with the substrate and overcomes electrostatic repulsions to facilitate its oxidation by the anionic MnO₄⁻. Technical applications using this receptor are envisioned across various technical applications, including anion sensing, separation, catalysis, medical interventions, and molecular nanotechnology.

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Introduction

Hydrogen bonding plays a crucial role in nature, enabling biological receptors to recognize hydrated substrates. This mechanism underpins numerous vital functions in aqueous environments.^1–5 However, replicating this process with synthetic analogs poses significant challenges, particularly in using hydrogen bonds for substrate recognition in water.^6–9 One major hurdle is the strong hydration of both receptor and substrate, creating high energetic barriers due to the need for desolvation during the binding process. Additionally, most organic building blocks used to synthesize hydrogen bonding receptors are poorly soluble in water, complicating the design and synthesis of water-soluble receptors. The pursuit of water-soluble hydrogen bonding receptors capable of effectively recognizing strongly hydrated substrates marks a cutting-edge frontier in supramolecular chemistry. Achieving this functionality could have profound impacts across various fields, including catalytic chemical transformations, biology, healthcare, environmental science, and molecular nanotechnology.^10–16

Current approaches to revalidating hydrogen bonding in water mainly focus on two strategies: hydrophobicity-assisted and charge-assisted hydrogen bonding. Hydrophobicity-assisted hydrogen bonding, in particular, involves the design of receptors that mimic the structure of protein-binding pockets.^17–20 These receptors feature hydrogen bonding residues buried within a hydrophobic binding pocket. This design leverages the hydrophobic effect to offset the energy cost of dehydration, thus serving as the primary driving force. At the same time, hydrogen bonding ensures the selectivity in the binding process. This approach has successfully been applied in a variety of hydrogen bonding receptors, such as molecular temples,^21–27 tetralactam macrocycles,^{19,20,28–31} naphthotubes,^32–40 and cyclopeptides,^41–43 demonstrating its viability and effectiveness.

Charge-assisted hydrogen bonding is another critical strategy for the binding of anionic substrates in water, leveraging electrostatic interactions to offset hydration energy. However, this strategy is predominantly confined to polyammonium and guanidinium receptors. Polyammonium receptors exhibit^44,45 (Fig. 1a, left) high effectiveness in acidic conditions but lose their anion-binding efficiency and water solubility under neutral or basic pH, thereby restricting their applications. Guanidinium-based receptors can maintain^8,9,46–48 (Fig. 1a, right) their charge in neutral environments but face challenges in conformational flexibility and strong solvation. For instance, a single guanidinium ion's binding with carbonate or phosphate in water is negligible, with a binding constant (K_a) of less than 5 M⁻¹.⁹ This limitation narrows the charge-assisted hydrogen bonding application in guanidinium receptors to specific molecular frameworks that either incorporate constrained amino imidazoline, bicyclic guanidinium residues, or use multiple guanidinium groups for anion binding.^11,46–50 This restriction significantly limits the diversity of molecular scaffolds available for receptor design. Consequently, despite the effectiveness of leveraging electrostatic interactions in enhancing hydrogen bonds in water, there is a pressing need for a broader molecular design strategy to fully exploit the power of charge-assisted hydrogen bonding.

Fig. 1 (a) Representative anion receptors with charge-assisted hydrogen bonding functionalities. (b) The structural formula of TPPC³⁺·3Cl⁻ and a summary of its structural features.

Hydrogen-bonding receptors, especially those utilizing amide functionalities, have been the subject of extensive research in the field of anion recognition. However, the majority of this research has focused^51–67 on anion binding in organic solvents. Given the significant number of hydrogen bonding receptors that either cannot bind anions in water due to solubility issues or lose their effectiveness because of strong solvation, there is a crucial need for a universal molecular design strategy that revalidates the hydrogen bonding capability of these receptors through the principle of charge-assisted hydrogen bonding. Such a strategy promises to have a far-reaching impact on the field of anion recognition in water.

In this research, we showcase a general approach to revalidate the hydrogen bonding capability of amide receptors for anion recognition in water. We demonstrate a water-soluble tripodal tricationic cage-type receptor TPPC³⁺·3Cl⁻ under the principle of charge-assisted hydrogen bonding. The receptor utilizes (Fig. 1b) pyridinium moieties both as charge carriers and for water solubilization groups.^68–71 The introduction of positive charges creates electrostatic attractions with anions, which serve as the driving force to overcome their dehydration energy barrier, while hydrogen bonding patterns within the binding pocket provide substrate selectivity. This receptor is synthesized through a dynamic process, beginning with an imine condensation reaction, followed by a crucial imine-to-amide oxidation step to complete the cyclization. TPPC³⁺·3Cl⁻ exhibits remarkable affinities and selectivities for hydrophilic anions such as C₂O₄²⁻, SO₄²⁻, and NO₃⁻. The binding to these hydrophilic anions is primarily driven by a favorable entropic effect resulting from the anion desolvation upon their associations by the cage. Additionally, the encapsulation of HC₂O₄⁻ by TPPC³⁺ inverts its overall charge, forming the [HC₂O₄⁻⊂TPPC³⁺]²⁺ complex. This charge inversion overcomes the electrostatic repulsion and increases the reactivity between HC₂O₄⁻ and MnO₄⁻. As a result, TPPC³⁺·3Cl⁻ shows a catalyst activity for the oxidation of HC₂O₄⁻ by MnO₄⁻, illustrating its practical application in catalytic chemical transformation in water.

Results and discussion

Molecular design and synthesis

The 3,5-dicarboxamide pyridinium building block has been extensively explored by the Beer group in mechanically interlocked structures, leveraging the charge and hydrogen bonds for anion recognition in organic solvents.^72–79 As a proof of principle for charge-assisted hydrogen bonding in amide-based receptors, we have introduced (Fig. 1b) this pyridinium moiety as the charge carrier into a rigid, preorganized bicyclic molecular cage developed by Anslyn and Mastalerz.^59,80–82 The trimethyl pinwheel-shaped pyridinium cage, TPPC³⁺·3Cl⁻, is equipped with six hydrogen bond donors converging towards its binding cavity. The C–H bonds at the para position of the pyridinium rings are polarized, creating three additional hydrogen bond donors pointing toward the cavity.^69,71 Additionally, the three pyridinium residues serve as charge carriers, assisting the hydrogen bonding by providing electrostatic attractions with anions in water. When associated with the hydrophilic counter-anion Cl⁻, the receptor maintains good water solubility.⁸³ This molecular design strategy exemplifies a general approach that could be extended to other amide-based hydrogen bonding receptors for binding hydrophilic substrates in water.^54,55

The TPPC³⁺·3Cl⁻ cage can be synthesized (Fig. 2) through two distinct methods. The first method involves a traditional approach, where acyl chloride 2 is reacted with the pinwheel-shaped triamine 1 under high dilution conditions. This process results in the critical intermediate, amide cage 5, at a low yield of 9%, which is common for irreversible macrocyclization reactions not relying on the use of a template.^84–88 An alternative and more effective method employs^68,81,82,89 dynamic imine chemistry followed by the Pinnick oxidation reaction. The triamine 1 is condensed with bisaldehyde 3, leading to a quantitative formation of the bicyclic imine skeleton. The resulting imine cage 4 can then be converted into the key intermediate amide cage 5 through Pinnick oxidation, achieving a much higher yield of 61%. The final steps involve alkylating the pyridine moiety to form a pyridinium salt, followed by standard anion exchange with a yield of 76%. These three steps produce the water-soluble amide cage TPPC³⁺·3Cl⁻ with an overall yield of 46% from easily accessible starting materials.

Fig. 2 Synthesis of TPPC³⁺·3Cl⁻ using a conventional high dilution approach (method I) and a dynamic approach (method II).

Anions binding in water

The anion-binding properties of TPPC³⁺·3Cl⁻ in water were analyzed through ¹H NMR titration experiments. Our findings (Fig. S45†) show that the chemical shift of the inward-facing C–H proton B depends on the concentration of TPPC³⁺·3Cl⁻, indicating that the cage is partially occupied by Cl⁻ counter anions and exists as a mixture of TPPC³⁺ and Cl⁻⊂TPPC³⁺. Therefore, the anion binding affinities measured should be considered as apparent binding affinities, reflecting the displacement of chloride ions from the binding cavity by the target anions. To avoid D/H exchange between the protons from the cage and D₂O and to obtain direct evidence of the hydrogen bonding between the anions and TPPC³⁺·3Cl⁻, we performed the experiments in a solution of 10% D₂O and 90% H₂O. The broad peak around 8.84 pm represents the NH proton signals. Upon the addition of Na₂SO₄, this peak showed dramatic downfield shifts (Δδ = +0.69 ppm), suggesting the hydrogen bonds formation between SO₄²⁻ and the NH protons from TPPC³⁺·3Cl⁻ in water. The inward-facing C–H protons, labeled (Fig. 1b) as proton B, are polarized, making them effective hydrogen bond donors. The binding of SO₄²⁻ by TPPC³⁺·3Cl⁻ results (Fig. 3a) in a notable upfield shift (Δδ = −0.15 ppm) of proton B. This observed shift in proton B indicates a change in the hydrogen bonding state of these protons, likely transitioning from bonding with H₂O or Cl⁻ to SO₄²⁻. Nonlinear fitting of the chemical shift changes of proton B against the concentration of SO₄²⁻, based on a 1 : 1 binding model, yielded an apparent binding constant (K_a) of (1.7 ± 0.1) × 10⁴ M⁻¹. In a separate experiment, where the titration was performed in D₂O, the same trend in the changes of the chemical shifts was observed (Fig. S37†). The nonlinear fitting of the changes in the chemical shift of proton B in D₂O yielded (Fig. S38†) a similar apparent binding affinity of (2.5 ± 0.3) × 10⁴ M⁻¹.

Fig. 3 (a) ¹H NMR spectra (400 MHz, 10% D₂O + 90% H₂O) of TPPC³⁺·3Cl⁻ (0.1 mM) titrated with Na₂SO₄. (b) ITC profile of TPPC³⁺·3Cl⁻ (0.5 mM) titrated with Na₂SO₄ in H₂O.

The binding of SO₄²⁻ by TPPC³⁺·3Cl⁻ was further confirmed using isothermal titration calorimetry (ITC). A solution of Na₂SO₄ in H₂O was incrementally added to a 0.5 mM solution of TPPC³⁺·3Cl⁻, and the heat change in the system was monitored over time. The ITC data revealed (Fig. 3b) an endothermic binding process mainly assigned to the interaction between SO₄²⁻ and TPPC³⁺. Analyzing the binding isotherm with a 1 : 1 binding model yielded an apparent binding affinity similar to our previous findings at a K_a of (2.0 ± 0.6) × 10⁴ M⁻¹. The ITC results indicated that the binding is primarily driven by favorable entropy (−TΔS = −6.35 kcal mol⁻¹), with only a minor enthalpic penalty (ΔH = +0.48 kcal mol⁻¹). This outcome aligns with our hypothesis that the dehydration of the highly hydrophilic SO₄²⁻ demands significant enthalpic energy. The combined hydrogen bonding and electrostatic interactions between SO₄²⁻ and TPPC³⁺·3Cl⁻ do not completely offset this high enthalpic requirement, resulting in a small net enthalpic penalty of +0.48 kcal mol⁻¹. At the same time, the dehydration process releases water molecules from both the hydration shell of SO₄²⁻ and the binding cavity of the cage into the bulk solution, providing a substantial entropic driving force for the molecular recognition of this hydrophilic anion. Such an entropically driven binding mechanism, commonly observed in the association of hydrophobic molecules in water (known as the hydrophobic effect), is rare for hydrophilic substrates as it typically requires significant enthalpic compensation for dehydration.^8,90 In this case, charge-assisted hydrogen bonding proves to be a unique and effective strategy to facilitate the dehydration of hydrophilic anions in water.

The binding pattern of C₂O₄²⁻ anion with TPPC³⁺·3Cl⁻ presents distinct characteristics compared to that of SO₄²⁻. The ¹H NMR spectra of TPPC³⁺·3Cl⁻ obtained in a mixture of 10% D₂O and 90% H₂O show (Fig. 4a) notable downfield shifts for both the NH protons (Δδ = + 0.65 ppm) and protons B (Δδ = +0.35 ppm) with an increasing concentration of Na₂C₂O₄. This result serves as direct evidence of hydrogen bonding formation between TPPC³⁺ and C₂O₄²⁻ in water. Nonlinear fitting of changes in the chemical shift of proton B yielded a K_a higher than 10⁶ M⁻¹. This strong apparent binding affinity was independently corroborated by ITC, which indicated (Fig. 4b) a K_a of (2.0 ± 0.9) × 10⁶ M⁻¹. The ITC experiments revealed an exothermic process for this binding, with a favorable enthalpic contribution (ΔH) of −3.3 kcal mol⁻¹. Additionally, a substantial favorable entropic contribution (−TΔS = −5.3 kcal mol⁻¹) was identified as the primary driving force for the interaction between C₂O₄²⁻ and TPPC³⁺. These results suggest that the charge-assisted hydrogen bond not only overcomes the dehydration barrier of C₂O₄²⁻ but also provides additional binding enthalpy, serving as an additional driving force for the recognition of hydrophilic C₂O₄²⁻ anion in water. More importantly, the anion binding facilitated by charge-assisted hydrogen bonding significantly benefits from the release of constrained water molecules from both the hydration shell of the anions and the binding pocket of the cage. This entropic effect serves as the primary driving force behind the effective anion binding in water.

Fig. 4 (a) ¹H NMR spectra (400 MHz, 10% D₂O + 90% H₂O) of TPPC³⁺·3Cl⁻ (0.2 mM) titrated with Na₂C₂O₄. (b) ITC profile of TPPC³⁺·3Cl⁻ (0.1 mM) titrated with Na₂C₂O₄ in H₂O.

The binding affinities of TPPC³⁺·3Cl⁻ with various anions in water are detailed in Table 1. TPPC³⁺ shows a strong affinity for I⁻ and NO₃⁻, with similar binding strengths in the order of 10⁴ M⁻¹. AcO⁻ and NO₂⁻ exhibit comparable affinities, each around 1500 M⁻¹, while Br⁻ and Cl⁻ are both around 600 M⁻¹. In terms of selectivity for halide anions,⁹¹ we observed a trend of I⁻ > Br⁻ ≈ Cl⁻. The higher affinity for I⁻ compared to Br⁻ and Cl⁻ suggests that the hydrophobic effect is a predominant driving force in anion binding in water. Although Br⁻ is more hydrophobic than Cl⁻, Br⁻ has a lower charge density, resulting in similar apparent binding affinities for both anions. This observation indicates that electrostatic interactions may also play a significant role in binding. Generally, TPPC³⁺ demonstrates higher affinities for anions with more negative charges, as evident in the observed trend: C₂O₄²⁻ > SO₄²⁻ > NO₃⁻. Additionally, TPPC³⁺ shows notable shape selectivity in anion binding. More binding sites correlate with higher affinity, and anions with similar structures exhibit comparable affinities, as seen in the trend NO₃⁻ > AcO⁻ ≈ NO₂⁻. Further thermodynamic analysis indicates that the anion binding by TPPC³⁺ is consistently associated with a positive entropy change, which acts as a major driving force in the recognition process. Overall, TPPC³⁺·3Cl⁻ demonstrates effective selectivity in anion binding in water. This selectivity is influenced by a combination of factors, including electrostatic attraction, shape complementarity, and hydrophobicity.

Table 1 Summary of anions binding in water by TPPC³⁺·3Cl⁻

Anions^a	K a/M^−1 (NMR)^b	K a/M^−1 (ITC)^c	ΔH/kcal mol^−1	TΔS/kcal mol^−1
a All anions come with sodium as the counter cation. b The titration experiments were performed in D2O. c The titration experiments were performed in H2O. d Apparent binding affinity is too high to be accurately determined by direct ^1H NMR titration. e Apparent binding affinity is too low to be accurately determined by ITC.
C2O4^2−	>10^6^d	(2.0 ± 0.9) × 10^6	−3.3	5.3
SO4^2−	(2.5 ± 0.3) × 10^4	(2.0 ± 0.6) × 10^4	0.5	6.4
I^−	(1.6 ± 0.2) × 10^4	(0.9 ± 0.1) × 10^4	−1.4	4.0
NO3^−	(1.4 ± 0.1) × 10^4	(1.1 ± 0.4) × 10^4	−1.6	3.9
AcO^−	1614 ± 11	N.A.^e	N.A.^e	N.A.^e
NO2^−	1439 ± 33	N.A.^e	N.A.^e	N.A.^e
Br^−	643 ± 38	N.A.^e	N.A.^e	N.A.^e
Cl^−	589 ± 25	N.A.^e	N.A.^e	N.A.^e

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Structural analysis by X-ray single crystallography and DFT calculations

Three distinct single crystal structures of TPPC³⁺ were obtained (Fig. 5a–c), corresponding to its association with Cl⁻, I⁻, and CF₃CO₂⁻ as counter anions. In all these structures, TPPC³⁺ maintains a similar conformation, with all NH bonds converging toward the binding cavity. In the Cl⁻ complex (Fig. 5a), two Cl⁻ anions and one water molecule were found within the TPPC³⁺ binding pocket. Each Cl⁻ forms two [NH⋯O] and one [CH⋯O] hydrogen bonds with one of the three pyridinium panels. Additionally, a water molecule located in the cavity aligns its hydrogens toward the two Cl⁻ guests, forming [OH⋯Cl] hydrogen bonds. The I⁻ complex (Fig. 5b) is analogous to the Cl⁻ complex, with each TPPC³⁺ binding two I⁻ ions and one water molecule through hydrogen bonds in its binding pocket. In the case of the CF₃CO₂⁻ complex (Fig. 5c), three CF₃CO₂⁻ anions are associated with each TPPC³⁺. Each carboxylate group interacts with two of the three pyridinium units, with each oxygen in the carboxylate group forming one [NH⋯O] and one [CH⋯O] hydrogen bond with the pyridinium unit.

Fig. 5 X-ray single crystal structures of (a) 2Cl⁻·H₂O⊂TPPC³⁺, (b) 2I⁻·H₂O⊂TPPC³⁺, (c) 3CF₃CO₂⁻⊂TPPC³⁺.

Notably, the solid-state single-crystal structures were obtained from organic solvents and do not fully represent the binding states observed in water. One key difference lies in the binding stoichiometry. For example, a 2 : 1 binding stoichiometry is observed for binding I⁻ in the solid state. In contrast, a 1 : 1 binding stoichiometry between I⁻ and TPPC³⁺ was determined in solution using ¹H NMR titration, where the shift of the inward-facing C–H proton B stopped after adding 1.0 equivalent of I⁻. Complementary results supporting the 1 : 1 binding stoichiometry are also found in high-resolution mass spectrometry (HRMS), where the m/z peaks for the 1 : 1 complexes were observed as the major peaks for all anions investigated, indicating that the 1 : 1 complex is the primary species in solution. The absence of m/z peaks for 2 : 1 complexes suggests these species are much less stable and should exist minimally compared to the 1 : 1 complex. In water, anions primarily form 1 : 1 complexes with TPPC³⁺. Forming higher-order anion complexes would require dehydrating a second anion with weaker electrostatic interactions and overcoming strong electrostatic repulsion, making such binding unlikely. In contrast, TPPC³⁺ tends to bind multiple anions in solid-state structures to balance its charges within the crystal lattice. Despite this difference, these crystal structures are valuable as they reveal the conformation of TPPC³⁺ with its convergent functionalities and demonstrate its interactions with anions through hydrogen bonds.

To visualize the potential binding modes of TPPC³⁺ with anions in solution, we carried out structural optimization by DFT calculations at the BLYP-D3/SVP level in implicit water solvent for complexes with Cl⁻, Br⁻, I⁻, NO₃⁻, SO₄²⁻, and C₂O₄²⁻. All halide anions form (Fig. 6a–c and S72–S74†) hydrogen bonds with two of the three pyridinium units, establishing four [NH⋯O] and two [CH⋯O] hydrogen bonds. The NO₃⁻ anion associates (Fig. 6d and S76†) with two pyridinium units of TPPC³⁺ through two [NH⋯O] and two [CH⋯O] hydrogen bonds. The SO₄²⁻ anion can interact (Fig. 6e and S77†) with all three pyridinium units of TPPC³⁺. Of its four oxygen atoms of the SO₄²⁻ anion, three of them engage in a total of three [NH⋯O] and three [CH⋯O] hydrogen bonds, while the fourth oxygen forms one additional [NH⋯O] bond. This binding pattern results in a total of seven hydrogen bonds stabilizing the SO₄²⁻⊂TPPC³⁺ complex. The distances between the oxygen atoms on SO₄²⁻ and the pyridinium nitrogens on TPPC³⁺ range from 5.4 to 6.0 Å, indicating strong electrostatic interactions that stabilize the complex. The larger C₂O₄²⁻ anion fits (Fig. 6f and S78†) better within the TPPC³⁺ cavity. Two of its oxygen atoms form three [NH⋯O] and three [CH⋯O] hydrogen bonds with two of the pyridinium units, while the remaining two oxygens form one [NH⋯O] and two [CH⋯O] hydrogen bonds with the third unit. This binding pattern results in a total of nine hydrogen bonds, stabilizing the C₂O₄²⁻⊂TPPC³⁺ complex. The distances between the oxygen atoms on C₂O₄²⁻ and the pyridinium nitrogens on TPPC³⁺ are measured at 5.8 to 5.9 Å, suggesting strong electrostatic interactions that stabilize the C₂O₄²⁻⊂TPPC³⁺ complex.

Fig. 6 DFT optimized structure of (a) Cl⁻⊂TPPC³⁺, (b) Br⁻⊂TPPC³⁺, (c) I⁻⊂TPPC³⁺, (d) NO₃⁻⊂TPPC³⁺, (e) SO₄²⁻⊂TPPC³⁺, and (f) C₂O₄²⁻⊂TPPC³⁺.

Catalysis for oxalate oxidation

We next explored how oxalate encapsulation in water with TPPC³⁺·3Cl⁻ affects its reactivity in the oxidation process by the permanganate anion. This reaction between permanganate and oxalate is a well-known example of redox reactions exhibiting autocatalytic kinetics.^92–96 The reaction involves (Fig. 7a) C₂O₄²⁻ or HC₂O₄⁻ (depending on the pH) and MnO₄⁻, yielding Mn²⁺ and CO₂. Initially, the electrostatic repulsion between HC₂O₄⁻ and MnO₄⁻ results in a sluggish reaction rate. The reaction product, Mn²⁺, acts as a catalyst by forming a neutral complex with C₂O₄²⁻ as MnC₂O₄, which can be more efficiently oxidized by MnO₄⁻ to produce CO₂ and more Mn²⁺. This newly formed Mn²⁺ further catalyzes the reaction, leading to a characteristic reaction kinetics with an initial induction period needed to generate sufficient Mn²⁺ catalyst, followed by a rapid reaction rate acceleration.⁹⁴ We hypothesize (Fig. 7b) that TPPC³⁺·3Cl⁻ can act as a catalyst to bypass the initial electrostatic repulsion between HC₂O₄⁻ and MnO₄⁻, thereby speeding up the reaction by eliminating the induction period.

Fig. 7 Reaction formula showing (a) the slow oxidation of oxalate by MnO₄⁻ and (b) its rate acceleration by TPPC³⁺·3Cl⁻. (c) Changes of the UV-vis spectra in a KMnO₄ solution (0.2 mM) over 95 minutes after adding H₂C₂O₄ (1 mM). (d) Changes of the UV-vis spectra in a KMnO₄ (0.2 mM) solution in the presence of 5% TPPC³⁺·3Cl⁻ (0.01 mM) over 95 minutes following H₂C₂O₄ addition (1 mM). (e) The changes in absorbance at 525 nm for a KMnO₄ solution (0.2 mM) over 95 minutes, demonstrating the effects of different loadings of TPPC³⁺·3Cl⁻ as a catalyst on the reaction rate post H₂C₂O₄ (1 mM) addition.

To test our hypothesis, we mixed a solution of KMnO₄ (0.2 mM) with H₂C₂O₄ (1 mM) and monitored (Fig. 7c) the reaction by observing the decrease in the KMnO₄ absorbance band at 400–700 nm. Initially, the reaction progressed slowly, with only 20% of the KMnO₄ reduced (Fig. 7e) by H₂C₂O₄ in the first 60 minutes, marking the induction period. From 60 to 95 minutes, the reaction rate significantly increased, resulting in an 80% overall reduction of KMnO₄. Introducing 5% TPPC³⁺·3Cl⁻ (0.01 mM) into the KMnO₄ and H₂C₂O₄ mixture drastically accelerated (Fig. 7d) the reaction, with the KMnO₄ absorbance band dropping (Fig. 7e) to zero within 30 minutes, indicating a remarkable catalytic effect of TPPC³⁺·3Cl⁻. Monitoring the absorbance at 525 nm over time showed the absence of an induction period with the addition of 5% TPPC³⁺·3Cl⁻. The catalysis of oxalate oxidation by KMnO₄ with TPPC³⁺·3Cl⁻ is efficient even at a catalyst load (Fig. 7e) as low as 1%, attributed to the strong affinity between HC₂O₄⁻ and TPPC³⁺ in water.⁹⁷ With 10% TPPC³⁺·3Cl⁻ as the catalyst, the reaction achieved an 80% MnO₄⁻ reduction in just 20 minutes, which is 4.8 times faster than the autocatalytic reaction without TPPC³⁺·3Cl⁻ as the catalyst. The catalytic turnover number was estimated at 70 when 1% of the TPPC³⁺ was used as the catalyst.

The catalytic mechanism facilitated by TPPC³⁺·3Cl⁻ is illustrated in Fig. 8 and is relatively straightforward. The encapsulation of HC₂O₄⁻ by TPPC³⁺ forms a complex (HC₂O₄⁻⊂TPPC³⁺) carrying a net charge of +2. This electrostatic attraction between the encapsulated complex and MnO₄⁻ enhances the oxidation of HC₂O₄⁻ into CO₂, subsequently releasing the free TPPC³⁺ cage to capture another HC₂O₄⁻ molecule, thereby perpetuating the catalytic cycle. To validate the effect of molecular recognition between TPPC³⁺ and HC₂O₄⁻ on the observed catalytic effect, we synthesized (Scheme S2†) a TPy³⁺·3Cl⁻ molecule as a control compound. This control compound carries identical charges to TPPC³⁺ but shows no binding with Na₂C₂O₄ in water (Fig. S44†). When we introduced 10% TPy³⁺·3Cl⁻ as a catalyst, we observed a slight rate acceleration for the oxidation of HC₂O₄⁻ by KMnO₄, indicating that charge neutralization from electrostatic interactions is a critical factor for the rate acceleration. In comparison, we achieved an even faster rate of acceleration using only 1% of TPPC³⁺·3Cl⁻, suggesting that molecular recognition mediated by charge-assisted hydrogen bonding enhances the catalytic effect by more than tenfold. To further confirm that the rate acceleration of the reaction was directly attributable to the binding between HC₂O₄⁻ and TPPC³⁺, we performed (Fig. S63†) an additional control experiment by adding Na₂SO₄ (10 mM) as a competitive binding agent into a reaction mixture of TPPC³⁺·3Cl⁻ (0.01 mM), KMnO₄ (0.2 mM) and H₂C₂O₄ (1.0 mM). The consequent oxidation rate of HC₂O₄⁻ decreased by 30% as a result of the competitive binding of SO₄²⁻ with TPPC³⁺, serving as compelling evidence that the specific interaction between HC₂O₄⁻ and TPPC³⁺ is a pivotal factor in accelerating the reaction. To rule out the possibility of encapsulation of the anionic MnO₄⁻ by TPPC³⁺, we examined a 1 : 1 mixture of KMnO₄ and TPPC³⁺·3Cl⁻ by ¹H NMR spectroscopy and observed (Fig. S43†) no change in chemical shift of TPPC³⁺·3Cl⁻, suggesting a lack of appreciable binding between MnO₄⁻ and TPPC³⁺. HRMS analysis of a mixture of KMnO₄ and TPPC³⁺·3Cl⁻ confirmed (Fig. S11†) the absence of binding, as it only displayed peaks corresponding to the free TPPC³⁺. Conversely, the HRMS spectra of a mixture containing KMnO₄, H₂C₂O₄, and TPPC³⁺·3Cl⁻ showed (Fig. S11†) a distinct peak at m/z 512.7495, pointing to the selective formation of the HC₂O₄⁻⊂TPPC³⁺ complex in the presence of the MnO₄⁻ anion.

Fig. 8 Schematic illustration of the catalytic cycle of oxalate oxidation catalyzed by TPPC³⁺.

Conclusions

In conclusion, a tangible outcome of this study is the development of the water-soluble amide cage, TPPC³⁺·3Cl⁻, which can be readily synthesized by a dynamic approach. This cage demonstrates strong affinities and excellent selectivities for hydrophilic anions in water. Notably, TPPC³⁺·3Cl⁻ exhibits remarkable binding affinities towards divalent anions such as C₂O₄²⁻ and SO₄²⁻, which play crucial roles in conditions like kidney stone formation^98,99 and the management of radioactive nuclear waste,¹⁰⁰ respectively. These findings are poised to advance efforts in oxalate removal during hemodialysis and enhance sulfate separation processes in the treatment of nuclear waste. Moreover, this research introduces the encapsulation of an anionic substrate by a cationic cage as a new mechanism for catalysis in water. This molecular recognition approach effectively inverts the charges of the substrate and facilitates reactions by overcoming electrostatic repulsions, showcasing an innovative strategy for developing catalysts in water.

From a fundamental standpoint, our work broadened the scope of charge-assisted hydrogen bonding by illustrating its utility in an amide-type synthetic receptor, offering a general molecular design principle that applies to a wide range of amide receptors. This principle not only revalidates their hydrogen bonding capabilities but also opens avenues for the efficient molecular recognition of hydrophilic substrates in water. These findings will pave the way for the development of synthetic receptors for medical intervention,^101–105 anion sensing,^106–112 separation and sequestration,^{10,100,113–115} and catalysis in biologically and environmentally relevant aqueous media.^116–120

Data availability

The data supporting this article have been included as part of the ESI.†

Author contributions

C. X. and W. L. conceived and designed the project and wrote the manuscript. X. C., Q. T., D. L., C. Z. and W. L. performed the experiments and analyzed the results. L. W. solved the crystal structures.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support for this work was provided by the National Science Foundation (CHE-2337419) and the University of South Florida start-up funding. This research made use of the XRAY and CPAS Core facilities at the University of South Florida. The research was supported in part by the computational resources provided by the CIRCE research cluster facility at the University of South Florida.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2334098 and 2334101–2334103. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4sc05236f

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