Macrocyclic squaramides: anion receptors with high sulfate binding affinity and selectivity in aqueous media

Abstract

A number of macrocyclic squaramide-containing receptors (MSQs) have been designed and synthesised and their interaction with a range of inorganic anions was studied in solution by ¹H NMR spectroscopy and ESI-HRMS. The binding data revealed remarkable binding of sulfate in aqueous mixtures from 0.5 to 50% v/v H₂O/DMSO-d₆. The larger [3]-MSQs were found to better match the size and shape of the sulfate ion than the [2]-MSQs, providing high affinity and selectivity for sulfate while other tetrahedral divalent anions such as selenate, phosphate species and chromate have substantially lower binding affinities. In mixtures of anions mimicking the composition of either nuclear waste or plasma, the [3]-MSQs were still able to bind sulfate ions with high affinity.

Fig. 1. Macrocyclic squaramides (MSQs) 1–6.

Scheme 1. Synthesis of the desired macrocyclic squaramide based receptor frameworks 1–4. Synthesis: (i) Et₃N, EtOH; (ii) 1 equiv. 8 or 9, high dilution, Et₃N, EtOH, heat. (iii) TFA/DCM (1 : 1); (iv) 1 equiv. 10 or 11, high dilution, Et₃N, EtOH, heat.

Fig. 2. Single crystal X-ray diffraction structures of (A) 1, (B) 3 and the solid state intermolecular hydrogen bond interactions of (C) 1 and (D) 3 in the presence of DMSO; hydrogen atoms not shown.

Fig. 3. (A): ¹H NMR titration of compound 1 with (TBA)₂SO₄ in DMSO-d₆ with 0.5% water at 300 K. (B): ¹H NMR titration of compound 2 with (TBA)₂SO₄ in DMSO-d₆ with 0.5% water at 300 K. (C): Comparison isotherms of squaramide NH, aromatic protons (Ar-H_a, H_b, H_c) for 2 in the presence of increasing concentrations of SO₄^2–.

Fig. 4. (A) The dominant binding mode of the complex formed between 1 and SO₄^2– viewed from the side and (B) from below clearly showing the interaction of SO₄^2– with the squaramide NH protons inside the macrocyclic cavity. The structure was obtained by single crystal X-ray diffraction. (C) Energy minimised molecular model of the complex formed between 1 and AcO^– viewed from the side and (D) from above.

Fig. 5. Energy minimised molecular model of the complex formed between 2 and sulfate.

Scheme 2. Synthesis of the desired macrocyclic squaramide based receptor frameworks 5 and 6. Synthesis: (i) Ph₃P (2 equiv.), THF/H₂O, RT, 8 h, 71%; (ii) 7 (2 equiv.), EtOH, Et₃N, overnight, RT, 80%; (iii) 17 (1 equiv.) EtOH, Et₃N, overnight, RT, 32%; (iv) Ph₃P (1 equiv.), THF/H₂O, RT, 8 h, 52%; (v) 7 (0.5 equiv.) EtOH, Et₃N, overnight, RT, 77%; (vi) Ph₃P, THF/H₂O, RT, 8 h; (vii) 18 (1 equiv.) EtOH, Et₃N, overnight, RT, 35%.

Fig. 6. X-ray crystallography determined structure of 5 (A) side view; (B) hydrogen bonds link adjacent molecules to form an approximately rectangular channel parallel to the a axis and centred on (0, 1/2, 0); (C) view down the a axis of the unit cell showing the pseudo-rectangular channels arising from hydrogen bonds between adjacent squaramides. Disorder at the end of the pendant TEG chains is not shown.

Fig. 7. Calculated space filling model of [TEG-MSQ 6·SO₄]^2– complex.

Fig. 8. (A): ¹H NMR titration of compound 6 with (TBA)₂SO₄ in 1 : 1 (v/v) H₂O–DMSO-d₆ mixture (pH 3.2) with 2.5 mM phosphates, 10 mM TBACl, 250 mM TBANO₃ at 300 K. (B): Comparison isotherms of squaramide NH, aromatic protons (Ar-H_a, H_b) in the presence of increasing concentrations of SO₄^2–. Estimated error in K_a < 15%.