High affinity of p-sulfonatothiacalix[4]arene with phenanthroline-diium in aqueous solution

Abstract

The molecular binding behavior of three sulfonated calixarene hosts, p-sulfonatocalix[4]arene (SC4A), p-sulfonatocalix[5]arene (SC5A), and p-sulfonatothiacalix[4]arene (STC4A), with two phenanthroline-diium guests, 5,6-dihydropyrazion[1,2,3,4-lmn][1,10]phenanthroline-4,7-diium (DP²⁺) and 6,7-dihydro-5H-[1,4]diazepino[1,2,3,4-lmn][1,10]phenanthroline-4,8-diium (PPQ²⁺), were systemically investigated in neutral phosphate buffer solutions by microcalorimetry, cyclic voltammetry, NMR spectroscopy, and molecular mechanics calculation. We found that the phenanthroline-diium guests were captured by SC4A, SC5A, and STC4A from their aromatic moieties. Furthermore, STC4A displays a high affinity with phenanthroline-diium guests in the order of magnitude of 10⁵ M⁻¹. It is the reported highest binding order of magnitude for STC4A up to now, although the binding constants of SC4A and SC5A with phenanthroline-diium guests are still a little larger.

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Introduction

p-Sulfonatothiacalix[4]arene (STC4A), the analogue of p-sulfonatocalix[n]arenes (SCnAs, n = 4–8), was first prepared by Miyano et al.¹ Rather than a simple substitution for conventional calixarenes, thiacalix[4]arene should be regarded as a unique molecular framework because replacement of the methylene linkages of calix[4]arenes by sulfur atoms provides various intrinsic characteristics of thiacalix[4]arene,² such as a wider cavity, lower electron density, more flexibility, additional coordination sites of sulfur, and so on. As anticipated, STC4A shows much different inclusion behavior toward some organic molecules and metal ions in water as compared with SCnAs.³ Therefore, STC4A should have been widely used as an important supramolecular building block. However, unlike SCnAs, which have been popularly applied in many fields,^4–6 such as amphiphile,⁷ polymer,⁸ enzyme mimic/enzyme assay,⁹ and biomedicine,¹⁰ in the past three decades due to their robust inclusion properties with numerous guest molecules,^11–18 STC4A is by far less explored owing to its much weaker affinity with model guest.

We previously studied the structures and thermodynamics for the intermolecular complexation of p-sulfonatocalix[4]arene (SC4A), p-sulfonatocalix[5]arene (SC5A), and STC4A with methyl viologen (MV²⁺) and diquat (DQ²⁺) in neutral phosphate buffer solutions on account of the biological environment of serum (pH ca. 7.3). We found that MV²⁺ displayed the high affinities with SC4A and SC5A around 10⁵ M⁻¹,^15e which have been applied in the MV²⁺ detoxification.^10b,d However, the binding constant of STC4A + MV²⁺ complex is only in the order of magnitude of 10³ M⁻¹ under the same condition.^10b We also found that the position of the nitrogen atoms in guests also exerted dramatic influence on the complex stabilities, and upon complexation with the same host, the binding constants of DQ²⁺ were always larger than those of MV²⁺.^10b However, we noted that the DQ²⁺/MV²⁺ selectivity for STC4A was much lower than that for SC4A and SC5A. Therefore, the affinity of STC4A + DQ²⁺ complex is still moderate.

In this study, to further enhance the affinities of sulfonated calixarene hosts with model guests, we synthesized two phenanthroline-diium guests, 5,6-dihydropyrazion[1,2,3,4-lmn][1,10]phenanthroline-4,7-diium (DP²⁺) and 6,7-dihydro-5H-[1,4]diazepino[1,2,3,4-lmn][1,10]phenanthroline-4,8-diium (PPQ²⁺), because they have much more conjugated structures as compared with DQ²⁺. Then we studied the molecular binding behaviors between sulfonated calixarene hosts and phenanthroline-diium guests in neutral phosphate buffer solutions by microcalorimetry, cyclic voltammetry, NMR spectroscopy, and molecular mechanics calculation. We found that the phenanthroline-diium guests were captured by SC4A, SC5A and STC4A from their aromatic moieties. Furthermore, in contrast to the higher DQ²⁺/MV²⁺ selectivity for SC4A and SC5A, we excitingly note that the DP²⁺ (or PPQ²⁺)/DQ²⁺ selectivity for STC4A is much higher. As a result, STC4A displays the high affinities with phenanthroline-diium guests in the order of magnitude of 10⁵ M⁻¹. To the best of our knowledge, it is the reported highest binding order of magnitude for STC4A complex up to now. The high affinity of STC4A with phenanthroline-diium would be beneficial to explore the supramolecular application of STC4A by designing suitable guest. For example: the high affinity between STC4A and phenanthroline-diium is highly desirable as the reporter pair of supramolecular tandem assay, particularly for potential application in high-throughput screening for drug discovery;^9i,19 modifying hydrophilic phenanthroline-diium with a hydrophobic group may lead to the formation of a supramolecular amphiphile upon complexation with STC4A;⁷ synthesizing bis-phenanthroline-diium may lead to the formation of a supramolecular polymer upon complexation with lower-rim-linked bis-STC4A;^8b and so on.

Results and discussion

Binding ability and thermodynamics

To compare quantitatively the selective binding behaviors of sulfonated calixarenes with diquaternary salts (Scheme 1), the microcalorimetric experiments for the intermolecular complexation of SC4A, SC5A, and STC4A with DP²⁺ and PPQ²⁺ were performed in pH 7.2 phosphate buffer solutions, which could not only give the binding affinities (K_s) between hosts and guests, but also show the accompanied enthalpy (ΔH°) and entropy (TΔS°) changes. The obtained results are listed in Table 1 together with our previous thermodynamic results for the intermolecular complexation of MV²⁺ and DQ²⁺ with the three sulfonated calixarenes under the same conditions.^10b,15e All the stoichiometric ratios (N values) that we observed from curve-fitting results of the binding isotherm fell within the range of 0.90–1.10 : 1. This clearly indicates that all the inclusion complexes have a 1 : 1 stoichiometry.

Scheme 1 Structural illustration of sulfonated calixarenes (SC4A, SC5A, and STC4A) and diquaternary salts (MV²⁺, DQ²⁺, DP²⁺, and PPQ²⁺).

Table 1 Complex stability constants (K_s/M⁻¹), enthalpy (ΔH°/(kJ mol⁻¹)), and entropy (TΔS°/(kJ mol⁻¹)) changes for 1 : 1 intermolecular complexations of sulfonated calixarenes with diquaternary salts in pH 7.2 phosphate buffer solutions at 298.15 K

Hosts	Guests	Ks	ΔH°	TΔS°
a Ref. 15e.b Ref. 10b.
SC4A^a	MV^2+	9.33 × 10^4	−31.98	−3.62
SC5A^a		2.51 × 10^5	−31.52	−0.67
STC4A^b		8.68 × 10^3	−31.01	−8.53
SC4A^b	DQ^2+	7.95 × 10^5	−33.90	−0.21
SC5A^b		3.23 × 10^6	−32.78	4.39
STC4A^b		4.57 × 10^4	−32.26	−5.65
SC4A	DP^2+	(1.55 ± 0.07) × 10^6	−36.94 ± 0.21	−1.59 ± 0.10
SC5A		(2.43 ± 0.18) × 10^6	−31.85 ± 0.10	4.61 ± 0.09
STC4A		(1.86 ± 0.01) × 10^5	−36.15 ± 0.01	−6.05 ± 0.01
SC4A	PPQ^2+	(1.59 ± 0.02) × 10^6	−38.05 ± 0.07	−2.64 ± 0.10
SC5A		(3.60 ± 0.33) × 10^6	−32.57 ± 0.05	4.86 ± 0.28
STC4A		(2.81 ± 0.01) × 10^5	−38.02 ± 0.03	−6.91 ± 0.04

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Among several weak noncovalent interactions working between calixarene hosts and model guests, hydrogen bond, π-stacking, and van der Waals interactions mainly contribute to the enthalpy changes, while electrostatic interaction,^12a conformation change, and desolvation effect contribute to the entropy changes. As shown in Table 1, all the intermolecular complexations between sulfonated calixarenes and diquaternary salts are driven by the favorable enthalpy changes (ΔH° = −31.01 to −38.05 kJ mol⁻¹), accompanied by small positive (favorable) or negative (unfavorable) entropy changes (TΔS° = −8.53 to 4.86 kJ mol⁻¹), which indicates that the governing factor for these complexations is the inclusion of guests into the host cavity,^13f,g and hydrogen bond, π-stacking, and van der Waals interactions are the main driven forces.

As can be seen from Table 1, MV²⁺ displays the high affinities with SC4A and SC5A around 10⁵ M⁻¹, while the binding constant of STC4A + MV²⁺ complex is only in the order of magnitude of 10³ M⁻¹ under the same condition. The weaker binding ability of STC4A originates mainly from the more unfavorable entropy change. It indicates that the cavity size and preorganized structure of STC4A do not fit well with MV²⁺ guest, leading to a greater loss of conformational degrees of freedom and structure freezing upon complexation.^10b The position of the nitrogen atoms in guests also exerts dramatic influence on the complex stabilities, and upon complexation with the same host, the binding constants of DQ²⁺ are always larger than those of MV²⁺. Both the enthalpy changes and the entropy changes for the intermolecular complexations of DQ²⁺ with SC4A, SC5A, and STC4A are relatively more favorable than those of MV²⁺ with the three sulfonated calixarene hosts. It indicates that, on one hand, in comparison with MV²⁺, DQ²⁺ is more prone to form π-stacking and van der Waals interactions with sulfonated calixarenes and then shows the more favorable enthalpy changes; on the other hand, the complexation of DQ²⁺ with sulfonated calixarenes gives rise to smaller conformational loss and more favorable desolvation effect, and then shows the more relatively favorable entropy changes.^10b After careful analysis of the data, we can also see that the DQ²⁺/MV²⁺ selectivity for STC4A (K_{s(STC4A+DQ²⁺)}/K_{s(STC4A+MV²⁺)} = 5.3) is much lower than that for SC4A (K_{s(SC4A+DQ²⁺)}/K_{s(SC4A+MV²⁺)} = 8.5) and SC5A (K_{s(SC5A+DQ²⁺)}/K_{s(SC5A+MV²⁺)} = 12.9). It means that the binding constant of STC4A increases only a little upon complexation from MV²⁺ to DQ²⁺. Therefore, the affinity of STC4A + DQ²⁺ complex is still moderate. However, the K_s value of DQ²⁺ with SC5A has displayed a high affinity over 10⁶ M⁻¹ accompanied by a large increasement of the binding constant of SC5A upon complexation from MV²⁺ to DQ²⁺. The SC5A/STC4A selectivity for DQ²⁺ is as high as 70.7.

To further enhance the affinities of sulfonated calixarenes with model guests, we synthesized two phenanthroline-diium salts for the reason that they have much more conjugated structures with one more benzene ring in their molecules as compared with DQ²⁺. As can be seen from Table 1, upon complexation with SC4A and STC4A, the K_s values of DP²⁺ and PPQ²⁺ are indeed larger than those of DQ²⁺. However, differing from the DQ²⁺/MV²⁺ selectivity, the DP²⁺ (or PPQ²⁺)/DQ²⁺ selectivity for SC4A and STC4A is only governed by the favorable enthalpy changes, accompanied by the unfavorable entropy changes. In comparison with DQ²⁺, much more conjugated DP²⁺ and PPQ²⁺ are more prone to form π-stacking and van der Waals interactions with sulfonated calixarenes and then shows the more favorable enthalpy changes. However, the cavity size and preorganized structure of SC4A and STC4A do not fit with larger phenanthroline-diium guests, leading to a greater loss of conformational degrees of freedom and structure freezing upon complexation. Moreover, in contrast to the DQ²⁺/MV²⁺ selectivity, we excitingly find that the DP²⁺ (or PPQ²⁺)/DQ²⁺ selectivity for STC4A (K_{s(STC4A+DP²⁺)}/K_{s(STC4A+DQ²⁺)} = 4.1; K_{s(STC4A+PPQ²⁺)}/K_{s(STC4A+DQ²⁺)} = 6.1) is much higher than that for SC4A (K_{s(SC4A+DP²⁺)}/K_{s(SC4A+DQ²⁺)} = 1.9; K_{s(SC4A+PPQ²⁺)}/K_{s(SC4A+DQ²⁺)} = 2.0). Furthermore, SC5A even displays the comparable binding affinities with phenanthroline-diium guests and DQ²⁺ accompanied by the similar enthalpy and entropy changes. As a result, STC4A displays the high affinities with phenanthroline-diium guests in the order of magnitude of 10⁵ M⁻¹. To the best of our knowledge, it is the reported highest binding order of magnitude for STC4A complex up to now, although the binding constants of SC4A and SC5A with phenanthroline-diium guests are still a little larger. One possible explanation for this phenomenon is that STC4A has a much more flexible structure by replacement of the methylene linkages of calix[4]arenes by sulfur atoms, and then can bind larger conjugated guest well by adjusting its structure. The above results also reveal that stronger binding does not always mean higher selectivity.

Electrochemical behavior

We previously found that the shift values for the first reduction potential of MV²⁺ upon complexation with SC4A and SC5A were −52 mV and −66 mV, and those of DQ²⁺ increased dramatically to −87 mV and −100 mV upon complexation with SC4A and SC5A, respectively (SC4A: shift value (DQ²⁺) − shift value (MV²⁺) = −35 mV; SC5A: shift value (DQ²⁺) − shift value (MV²⁺) = −34 mV).^15e However, upon complexation with STC4A, that shift value only changes from −11 mV of MV²⁺ to −30 mV of DQ²⁺ (STC4A: shift value (DQ²⁺) − shift value (MV²⁺) = −19 mV).^10b Compared with the complexation of STC4A, the larger change of the shift value from MV²⁺ to DQ²⁺ upon complexation with SC4A and SC5A is well in accordance with the much higher DQ²⁺/MV²⁺ selectivity for SC4A and SC5A. The large shift values for the first reduction potential of MV²⁺ and DQ²⁺ upon complexation with SC4A and SC5A are also in accordance with the high affinities of SC4A and SC5A with MV²⁺ and DQ²⁺.

Herein, the electrochemical behaviors of DP²⁺ in the absence and presence of SC4A, SC5A, and STC4A were also investigated in pH 7.2 phosphate buffer solutions by cyclic voltammetry. To focus on the first reduction potentials, the selected partial cyclic voltammetric curves of DP²⁺ before and after complexation by SC4A, SC5A, and STC4A are shown in Fig. 1. We can see that the first reduction potential of DP²⁺ also shifts to more negative values upon complexation with these hosts, indicating that DP²⁺ is more difficult to be reduced after complexation by sulfonated calixarenes. Differently, the shift value for the first reduction potential of DP²⁺ increases dramatically to −77 mV from −30 mV of DQ²⁺ upon complexation with STC4A (STC4A: shift value (DP²⁺) − shift value (DQ²⁺) = −47 mV). However, these shift values of DP²⁺ only increase to −121 mV and −127 mV from −87 mV and −100 mV of DQ²⁺ upon complexation with SC4A and SC5A, respectively (SC4A: shift value (DP²⁺) − shift value (DQ²⁺) = −34 mV; SC5A: shift value (DP²⁺) − shift value (DQ²⁺) = −27 mV). The larger change of the shift value from DQ²⁺ to DP²⁺ upon complexation with STC4A is also well in accordance with the above thermodynamic results that, in contrast to the higher DQ²⁺/MV²⁺ selectivity for SC4A and SC5A, STC4A displays a much higher DP²⁺/DQ²⁺ selectivity. Meanwhile, the large shift value for the first reduction potential of DP²⁺ upon complexation with STC4A is also in accordance with the high affinity of STC4A with phenanthroline-diium guest.

Fig. 1 Selected partial cyclic voltammetric curves for the first reduction potentials of DP²⁺ (1.0 mM in pH 7.2 phosphate buffer solution) in the absence and presence of 1 equiv. of SC4A, SC5A, and STC4A. The scan rate is 100 mV s⁻¹.

Binding mode

¹H NMR spectroscopy is a powerful tool that can be used to determine the structures of calixarene complexes.^13a Herein, to obtain the binding modes of DP²⁺ with SC4A, SC5A, and STC4A under neutral conditions, ¹H NMR spectra of DP²⁺ in the absence and presence of these hosts were measured in pD 7.2 phosphate buffer solutions. To ensure a fully complexation between sulfonated calixarenes and DP²⁺, the concentrations of host and guest were employed as 10 mM according to the measured binding constants above between host and guest. As can be seen from Fig. 2, all DP²⁺ protons exhibit visible upfield shifts upon complexation due to the ring current effect of the aromatic nuclei of sulfonated calixarene hosts, which suggests that the DP²⁺ guests are included into the cavities of the three hosts. Moreover, the DP²⁺ protons are still observed as a single resonance after complexation, indicating a fast exchange between a free DP²⁺ guest and a calixarene-complexed one on the NMR time scale. The corresponding chemical shift changes (Δδ) of guest protons in the presence of the three sulfonated calixarene hosts are listed in Table 2. We can see that the Δδ values differ from each other, which can be used to deduce the binding modes of host–guest complexes because the proton with the largest Δδ value would be affected mostly by the ring current effect of the aromatic nuclei of sulfonated calixarene hosts. As shown in Table 2, upon complexation with SC4A, SC5A, and STC4A, the Δδ values of DP²⁺ protons are in the similar order of H2, H3, and H4 > H1 > H5. The Δδ values of H5 are even negligible. Moreover, the DP²⁺ solutions changed from colorless to yellow upon addition of sulfonated calixarenes (Fig. S13†), suggesting the formation of charge-transfer complexes. All these results indicate that DP²⁺ is encapsulated into the cavities of the three sulfonated calixarene hosts from its aromatic moiety accompanied by the favorable π-stacking and van der Waals interactions. The deduced binding modes of phenanthroline-diium guest with sulfonated calixarene hosts are also stable by taking the expected electrostatic interactions between positively charged N⁺ in guest and negatively charged SO₃⁻ in host into account. The ¹H NMR spectra of DP²⁺ in the presence of these hosts were further measured at a reduced temperature as low as possible (Fig. S14†). Compared with the NMR signals at room temperature, the signals at a reduced temperature only become a little broaden, especially for SC5A + DP²⁺ complex. No other differences were observed. These results imply that DP²⁺ guest may prefer to be included into the host cavities only with one minimum-energy structure. Next, preliminary molecular modeling studies were performed to give the computational minimum-energy structures between sulfonated calixarene hosts and DP²⁺ guest. The results show that the cavities of sulfonated calixarenes prefer binding the aromatic moiety of DP²⁺ guest (Fig. 3), which is in accordance with the deduced binding modes above by ¹H NMR spectroscopy. The above thermodynamic results show that there are no significant differences for the binding affinities and accompanied enthalpy and entropy changes for the intermolecular complexation of DP²⁺ and PPQ²⁺ with the same sulfonated calixerene host, although PPQ²⁺ has one more methylene in its structure as compared with DP²⁺. The binding structures of phenanthroline-diium guest with sulfonated calixerene hosts can also explain this phenomenon well: the methylene moieties of the phenanthroline-diium guest are not included into the cavities of the sulfonated calixerene hosts, and they are directed to the solvent. Therefore, the one more methylene in PPQ²⁺ could not affect its binding properties with sulfonated calixerene hosts essentially.

Fig. 2 ¹H NMR spectra of DP²⁺ in the absence and presence of SC4A, SC5A, and STC4A at pD 7.2. The host and guest were mixed in a 1 : 1 stoichiometry at 10 mM.

Table 2 Chemical shift changes (Δδ, ppm) of DP²⁺ protons in the presence of SC4A, SC5A, and STC4A at pD 7.2^a,b

Host	H1	H2	H3	H4	H5
a Δδ = δ(presence of 1 equiv. of host) − δ(free guest). Negative values indicate upfield shift.b The host and guest were mixed in a 1 : 1 stoichiometry at 10 mM.
SC4A	−1.39	−1.68	−1.96	−1.44	−0.40
SC5A	−0.76	−1.59	−1.76	−0.84	−0.40
STC4A	−0.43	−0.78	−1.94	−2.66	−0.19

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Fig. 3 Energy-minimized structures of SC4A + DP²⁺ complex (a), STC4A + DP²⁺ complex (b), and SC5A + DP²⁺ complex (c), which were optimized by the molecular mechanics method with a Dreiding force field.

Conclusions

In conclusion, the molecular binding behaviors of sulfonated calixerene hosts (SC4A, SC5A, and STC4A) with phenanthroline-diium guests (DP²⁺ and PPQ²⁺) were systemically investigated in neutral phosphate buffer solutions. Phenanthroline-diium guests are encapsulated into the cavities of the sulfonated calixarene hosts from their aromatic moieties. Furthermore, in contrast to the higher DQ²⁺/MV²⁺ selectivity for SC4A and SC5A, STC4A displays a much higher DP²⁺ (or PPQ²⁺)/DQ²⁺ selectivity. As a result, STC4A shows the high affinities with phenanthroline-diium guests in the order of magnitude of 10⁵ M⁻¹. It is the reported highest binding order of magnitude for STC4A complex up to now. The present results will help us to understand the inclusion phenomena, recognition mechanisms, and thermodynamic origins of sulfonated calixarenes in aqueous solution more systematically and comprehensively. Moreover, the high affinity of STC4A with phenanthroline-diium would be beneficial to explore the supramolecular application of STC4A by designing suitable guest, particularly in the fields of supramolecular tandem assays, supramolecular amphiphile, and supramolecular polymer.

Conflict of interest

The authors declare no competing financial interest.

Acknowledgements

This work was supported by the Foundation of Talent Introduction in Tianjin Normal University (5RL122), the Doctoral Foundation of Tianjin Normal University (52XB1111), the 973 Program (2011CB932502), and NSFC (91227107, 21432004, 21402141), which are gratefully acknowledged.

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Footnote

† Electronic supplementary information (ESI) available: Experimental section; ¹H and ¹³C NMR spectra of SC4A, SC5A, STC4A, DP²⁺, and PPQ²⁺ in D₂O; elemental analysis data of SC4A, SC5A, STC4A, DP²⁺, and PPQ²⁺; pictures showing the color of DP²⁺ solutions upon complexation with 1 equiv. of sulfonated calixarenes; ¹H NMR spectra of DP²⁺ guest in the presence of sulfonated calixarene hosts at different temperatures; “Net” heat effects of complexation of DP²⁺ and PPQ²⁺ with SC4A, SC5A, and STC4A for each injection, obtained by subtracting the dilution heat from the reaction heat, which was fitted by computer simulation using the “one set of binding sites” model. See DOI: 10.1039/c4ra15047c.

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