Self-Assembled Cagelike Receptor That Binds Biologically Relevant Dicarboxylic Acids via Proton-Coupled Anion Recognition

Abstract

We report here a fully organic, self-assembled dimeric receptor, constructed from acyclic naphthyridyl-polypyrrolic building blocks. The cagelike dimer is stable in the solid state, in solution, and in gas phase, as inferred from X-ray diffraction and spectroscopic analyses. This system acts as a receptor for oxalic acid, maleic acid, and malonic acid in the solid state and in THF solution. In contrast, acetic acid, propionic acid, adipic acid, and succinic acid, with pK_a values > ca. 2.8, were not bound effectively within the cagelike cavity. It is speculated that oxalic acid, maleic acid, and malonic acid serve to protonate the naphthyridine moieties of the host, which then favors binding of the corresponding carboxylate anions via hydrogen-bonding to the pyrrolic NH protons. The present naphthyridine-polypyrrole dimer is stable under acidic conditions, including in the presence of 100 equiv trifluoroacetic acid (TFA), p-toluenesulfonic acid (PTSA), H₂SO₄, and HCl. However, disassembly may be achieved by exposure to tetrabutylammonium fluoride (TBAF). Washing with water then regenerates the cage. This process of assembly and disassembly could be repeated >20 times with little evidence of degradation. The reversible nature of the present system, coupled with its dicarboxylic acid recognition features, leads us to suggest it could have a role to play in effecting the controlled "capture" and "release" of biologically relevant dicarboxylic acids.

Figure 1.

Single crystal X-ray structures of the acyclic polypyrrolic synthon (7•7)_1/2, along with its corresponding supramolecular macrocyclic receptor, 7•7. (a) Ball and stick model of a single unit of 7, as present in 7•7. (b, c) Two different views of the hydrogen-bonded supramolecular dimer 7•7. (d) Space-filling model of the self-assembled cage 7•7 showing the potential substrate-accessible void. Solvent molecules (CHCl₃) are omitted for clarity. (e) Ball and stick model of a single unit of 3. (f) Truncated view along the crystallographic z axis of the infinite hydrogen-bonded “zigzag” supramolecular construct formed by 3 in the solid state, i.e., (3)_n. Green lines denote presumed hydrogen-bond interactions between the pyrrolic ester groups and the pyrrole NH protons.

Figure 2.

Single crystal X-ray structures of the hydrogen-bonded dimeric receptor 7•7 and its various host–guest complexes. (a) The illustrative example of host–guest complex between supramolecular receptor 7•7 and CHCl₃ with empirical chemical formula [7•7⊂(CHCl₃)₄]. (b–d) The host–guest complexes between supramolecular receptor 7•7 and maleic acid, oxalic acid, and malonic acid, with empirical chemical formulas [(7•7H₂)²⁺⊂(Hmaleate⁻)₂], [(7•7₂)²⁺⊂(Hoxalate⁻)₂], and [(7•7H₂)²⁺⊂(Hmalonate⁻)₂], respectively. Encapsulated THF solvent molecules are omitted for clarity. (e) A representative example of 3D packing of maleic acid guests within the cavities of 7•7 along the crystallographic x axis. Note: The entrapped guests within the cavity are shown in space-filling form in (e).

Figure 3.

(a, b) Single crystal X-ray structure of the hydrogen-bonded receptor 7•7 with H₂SO₄, having the empirical chemical formula [(7•7H₂)²⁺⊂(H₂SO₄⁻)₂]. (c) Space-filling model of the host–guest complex.

Figure 4.

(a) Changes in the ¹H NMR spectrum (partial views) seen when host 7•7 is subject to titration with increasing quantities of PTSA (up to 10 equiv) and after aqueous washing. (b) Changes in the ¹H NMR spectrum (partial views) seen when host 7•7 is treated with increasing quantities of TBAF (up to 20 equiv). (c) Changes in the ¹H NMR spectrum (partial views) seen when host 7•7 is treated with increasing quantities of TBACl (up to 50 equiv) followed by treatment with AgNO₃ (50 equiv). All ¹H NMR spectroscopic experiments were performed at 600 MHz in THF-d₈ at 298 K under otherwise identical conditions.

Figure 5.

(a–d) Representative UV–vis spectroscopic titrations showing the changes in the spectral features observed when receptor 7•7 is titrated with increasing quantities of (up to 600 equiv) oxalic acid, maleic acid, malonic acid, and TBAF (100 equiv), respectively. All experiments were carried out with [7•7] = 1.00 × 10⁻⁵ M in anhydrous THF at 298 K. Insets: Photographs under ambient light of the initial host solution and the corresponding solutions obtained after the addition of the indicated titrants.

Figure 6.

Emission spectroscopic titrations of 7•7 (1.00 × 10⁻⁶ M in anhydrous THF) involving the incremental addition of up to 600 equiv of oxalic acid (a), maleic acid (b), and malonic acid (c), and 100 equiv of TBAF (d) at 298 K. An excitation wavelength (λ_ex) of 320 nm was used in all cases. Insets: Photographs of the host-based emission as seen in the presence of the indicated guests with irradiation provided by a 365 nm UV lamp.

Scheme 1.. Synthesis of the Naphthyridine-Containing Tetrapyrrole 7a

aReagents, conditions, and yields: (a) Pd(OAc)₂, PPh₃, K₂CO₃, DMF/H₂O, N₂, reflux, 24 h (yield: 70%); (b) NaOH, EtOH/H₂O, 85 °C, 5 h (yield 95%); (c) ethylene glycol, 185 °C, 50 min (yield: 91%); (d) I₂/KI, NaHCO₃, CH₂Cl₂/H₂O, rt, 1 h, Na₂S₂O₃ (yield: 65%); (e) Pd(PPh₃)₄, K₂CO₃, DMF/H₂O, reflux, 16 h (yield: 45%).