Supramolecular “containers”: self-assembly and functionalization of thiacalix[4]arenes for recognition of amino- and dicarboxylic acids

Abstract

New p-tert-butylthiacalix[4]arenes containing amide, tertiary amine and ammonium fragments in cone conformation were synthesized and characterized. The interaction of the p-tert-butylthiacalix[4]arenes with amino-, dicarboxylic acids and EDTA was studied by electron spectroscopy. The ability of the synthesized thiacalix[4]arenes to form supermolecules and supramolecular associates with guests was shown by dynamic light scattering. The formation of commutative and cascade supramolecular systems based on amphiphilic macrocycles was studied by UV spectroscopy and dynamic light scattering. It was shown that thiacalix[4]arene containing quaternary ammonium fragments with three methyl groups at the nitrogen form associates – “containers” containing glutamic acid as a guest.

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Introduction

Molecular recognition of dicarboxylic and amino acids by synthetic receptors and self-assembled associates can be applied to mass transfer processes and various multicomponent industrial or biological separation systems.^1–6 As a rule, during the interaction of macrocycles with target compounds by van der Waals forces, hydrogen bonds, electrostatic, CH/π, π–π-stacking interactions, solvophobic and hydrophobic effects, host–guest complexes, dimer associates and supramolecular aggregates can be observed.^7–20 To construct these supramolecular structures, organic compounds (molecular building platform) should be modified with appropriate binding sites which are complementary to the guest structure.^3–33 The modification of a macrocyclic platform by polyfunctional reagents is one of the most effective approaches to the synthesis of receptors capable of supramolecular self-assembly.^3,4,34–38 Thiacalix[n]arenes and calix[n]arenes are currently used as molecular building blocks.^{15–20,22,32,35,38–42} The utility of thiacalix[4]arenes, analogs of classical calixarenes, is that they can be easily obtained in one-step synthesis and their upper and lower rims can be modified by various functional groups.^{22,35,39–47} It was shown recently that supermolecules and supramolecular assembles can be formed by interaction of p-tert-butylthiacalix[4]arenes with metal cations and dicarboxylic acids.^6,38,48–51 Besides, macrocycles can form cascade or commutative three-component systems depending on the sequence of binding of a number of substrates.^52,53 In commutative systems, the order of the substrate binding is arbitrary (Fig. 1). Contrary to that, the cascade systems assume binding multiple substrates to be realized in specific order (Fig. 1).

Fig. 1 Possible paths of the formation of cascade and commutative three-component systems.

A study of the formation of commutative and cascade supramolecular structures in water is necessary for development of the systems needed for separation of biological substrates from aqueous solutions and for drug delivery systems. The cascade systems seem most suitable for the synthesis of such supramolecular structures for extraction and separation of various biological components. Meanwhile, commutative system can be used for delivery systems adapted for biologically important substrates. Amphiphilic thiacalix[4]arenes able to form electrostatic interactions and hydrogen bonding are very attractive targets to study the formation of supermolecules and supramolecular assemblies in water.^{15–20,37,38,54–57} The development of appropriate supramolecular ensembles (dimeric capsules, micelles, or vesicles) by self-assembling in polar solvents can be achieved by introduction of amide, amine and quaternary ammonium fragments in the structure of the macrocycles. The formation of supermolecules and supramolecular assembles based on amphiphilic p-tert-butylthiacalix[4]arenes containing the cationic fragments can be realized by involvement of the anionic fragments, e.g., carboxylate, sulfate, sulfonate and phosphate groups. Disodium ethylenediaminetetraacetate (EDTA) was taken as a carboxylate group carrier. To study the ability of supermolecules and supramolecular assemblies based on cationic p-tert-butylthiacalix[4]arenes and EDTA to interact with a third component, dicarboxylic and amino acids were specified as substrates (Fig. 2).

Fig. 2 Possible types of supramolecular structures formed by tetrasubstituted p-tert-butylthiacalix[4]arenes with EDTA, dicarboxylic and amino acids.

In this work, the synthesis of p-tert-butylthiacalix[4]arenes tetrasubstituted by amine, amide, quaternary ammonium groups at the lower rim, the determination of structure of macrocycles by physical methods and the design of self-assembled supramolecular nanoparticles based on these macrocycles with EDTA, dicarboxylic and amino acids are described. Also, the mechanism of self-assembling and aggregation which led to the formation of supramolecular assemblies in solution is discussed.

Results and discussion

Synthesis of p-tert-butylthiacalix[4]arenes tetrasubstituted at the lower rim with amine, amide, quaternary ammonium fragments

To synthesize target products, i.e. p-tert-butylthiacalix[4]arenes containing quaternary ammonium groups, the introduction of amide fragments in the structure of macrocycles followed by the interaction of amine groups with the halogenoalkanes has been studied. Tetraester 1 based on p-tert-butylthiacalix[4]arene,⁵⁸ N,N-diethylethane-1,2-diamine and N,N-dimethylpropane-1,3-diamine were selected as initial reagents.

The interaction of the tetraester 1 in the cone conformation with N,N-diethylethane-1,2-diamine and N,N-dimethylpropane-1,3-diamine in toluene–methanol (1 : 1) under 10 h reflux resulted in formation of the compounds 2 and 3 containing amide and tertiary amine groups at the lower rim (Scheme 1). The formation of quaternary ammonium salts based on p-tert-butylthiacalix[4]arenes was achieved by the reactions of the amines 2 and 3 with iodomethane and benzyl bromide in methanol (Scheme 2). Macrocycles 4–6 containing quaternary ammonium fragments were obtained with excellent yields. It should be mentioned that the compounds 4–6 synthesized are soluble in water.

Scheme 1

Scheme 2

In MALDI-TOF mass spectra of quaternary ammonium salts 4 and 6 based on p-tert-butylthiacalix[4]arenes, the molecular ions [M–I⁻]⁺ and [M–Br⁻]⁺ formed by subtracting halogen anion were detected. In the mass spectra, molecular ion peaks corresponding to Hofmann elimination products of the synthesized compounds were detected. Fig. 3 shows the MALDI-TOF mass spectrum of quaternary ammonium salt 4 based on p-tert-butylthiacalix[4]arene as an example. Fig. 4 shows the Hofmann elimination of quaternary ammonium salts 4 in cone conformation.

Fig. 3 MALDI-TOF mass spectrum of the compound 4 (4-nitroaniline was used as a matrix).

Fig. 4 Scheme of the Hofmann elimination of the compound 4.

The structure and composition of the synthesized p-tert-butylthiacalix[4]arenes 2–6 tetrasubstituted at the lower rim were determined by physical methods: ¹H and ¹³C NMR, IR spectroscopy, mass spectrometry and elemental analysis. The purity of the compounds was monitored by TLC. It was shown that the proton NMR chemical shifts, spin multiplicities and integrals (peak area) correspond to the structures of the macrocycles 2–6.

The interaction of p-tert-butylthiacalix[4]arenes tetrasubstituted at the lower rim with EDTA, amino and dicarboxylic acids

p-tert-Butylthiacalix[4]arenes 4–6 containing amide and quaternary ammonium groups (Scheme 3) were selected for molecular recognition of dicarboxylic acids (oxalic, malonic, and succinic acid), amino acids (DL-alanine, DL-valine, DL-leucine, DL-aspartic acid and DL-glutamic acid), and EDTA.

Scheme 3

The UV spectroscopy is a universal tool for studying complexation properties of the p-tert-butylthiacalix[4]arene derivatives. Changes in the absorbance spectrum of the p-tert-butylthiacalix[4]arenes 4–6 after addition of the amino and dicarboxylic acids indicated the formation of their complexes with the substrates. The appropriate changes were found to be quite high in some cases. Thus, increased absorption at 190–300 nm (hyperchromic effect) was found for the complexes of the p-tert-butylthiacalix[4]arenes 4–6 in cone conformation with some substrates indicating effective interaction between reactants.

To quantify molecular recognition of the EDTA, amino and dicarboxylic acids by p-tert-butylthiacalix[4]arenes 4–6, the stability constants and the stoichiometry of the “macrocycle – substrate” complex formed in the water phase were established. It was shown that the interaction of p-tert-butylthiacalix[4]arenes 4–6 in cone conformation with the substrates led to formation of the 1 : 1 complexes (Table 1).

Table 1 Logarithms of the association constants (log K_ass) of the complexes of p-tert-butylthiacalix[4]arenes 4–6 with EDTA, amino and dicarboxylic acids

	4	5	6
EDTA	2.69 ± 0.06	2.56 ± 0.04	2.61 ± 0.21
Oxalic acid	3.17 ± 0.07	3.40 ± 0.07	3.38 ± 0.10
Malonic acid	2.67 ± 0.13	2.54 ± 0.12	2.74 ± 0.16
Succinic acid	2.60 ± 0.19	2.37 ± 0.22	2.53 ± 0.15
Alanine	2.67 ± 0.06	2.81 ± 0.07	2.51 ± 0.17
Valine	2.46 ± 0.06	2.88 ± 0.05	3.04 ± 0.14
Leucine	2.27 ± 0.05	3.03 ± 0.05	3.10 ± 0.21
Aspartic acid	2.38 ± 0.04	2.55 ± 0.09	2.54 ± 0.07
Glutamic acid	2.42 ± 0.06	2.79 ± 0.05	2.52 ± 0.09

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The macrocycle 4 with quaternary ammonium fragments with three methyl groups at the nitrogen atom interacted more efficiently with dicarboxylic acids and EDTA (Table 1). The efficiency of the interaction decreases in the range: oxalic, malonic, succinic acid (Table 1). The logarithms of the association constant changed by transition from oxalic to malonic and succinic acids due to the increasing size of the substrates and their decreasing acidity. It was shown that the efficiency of interaction of the compound 4 with EDTA (log K_ass = 2.69) is the same as in the case of the macrocycle 4 with malonic acid (log K_ass = 2.67). For the complexes with amino acids, the efficiency of the interaction depended on the side chain group of the amino acid. Least effective interaction (log K_ass = 2.27) was observed for “bigger” amino acid (leucine) containing isobutyl fragment. The presence of additional binding sites (carboxyl group in case of aspartic and glutamic acid) in the structure of an amino acid has negligible influence on the efficiency of interaction (Table 1).

In the interaction of p-tert-butylthiacalix[4]arenes 5 and 6 with dicarboxylic acids, the tendency observed was similar to that for the macrocycle 4. The efficiency of interaction decreases in the range: oxalic > malonic > succinic acids (Table 1). In case of the macrocycles 5 and 6 in contrast to compound 4, the opposite tendency was observed in comparison with the complexation of dicarboxylic and amino acids. During the interaction of p-tert-butylthiacalix[4]arene 5 with amino acids, decreasing substrate size led decreasing logarithms of the association constants for amino acids with hydrophobic side chain in the range: leucine > valine > alanine and for amino acids with negative side chain in the range: glutamic > asparagine acid (Table 1). The efficiency of the interaction of p-tert-butylthiacalix[4]arene 6 with α-amino acids decreased in the range: leucine > valine > alanine, glutamic and aspartic acids (Table 1). In the case of macrocycle 6, the logarithm of the association constant with EDTA is equal to 2.61. This is as effective as the interaction of the macrocycle 5 with malonic and aspartic acids (log K_ass = 2.25).

The ability of the macrocycles 4–6 to interact with amino and dicarboxylic acids was shown using electron spectroscopy. The interaction of the p-tert-butylthiacalix[4]arenes 4–6 with oxalic acid was found to be most effective. In the case of the macrocycle 4, less effective interaction was observed for “bigger” amino acid (leucine). However, in the case of p-tert-butylthiacalix[4]arenes 5 and 6, the interaction with leucine was most effective. It was shown that the presence of additional binding sites in the structure of amino acids did not affect the efficiency of interaction of the substrates with the macrocycles 4–6.

Self-assembly of aggregates based on p-tert-butylthiacalix[4]arene derivatives with EDTA, amino and dicarboxylic acids in aqueous phase

According to the UV spectroscopy, the p-tert-butylthiacalix[4]arenes 4–6 interact with EDTA, dicarboxylic and amino acids with 1 : 1 stoichiometry. The logarithms of the association constants changed from 2.27 to 3.40. The substrates (EDTA, and dicarboxylic amino acids) can interact with multiple molecules of p-tert-butylthiacalix[4]arenes, because the guest molecules contain several potential binding sites. However, according to the UV spectroscopy, one receptor molecule binds one substrate molecule with 1 : 1 stoichiometry. This indicates the formation of 1 : 1 complexes or supramolecular structures formed by alternating host and guest molecules. The dynamic light scattering (DLS) is one of the methods to study the formation of supermolecules and supramolecular assemblies in solution. Self-association and aggregation of the compounds 4–6 in cone conformation were studied in water. Dicarboxylic acids (oxalic, malonic, succinic acids), amino acids (DL-alanine, DL-valine, DL-leucine, DL-aspartic acid and DL-glutamic acid) and EDTA were selected as substrates.

The study of self-association of the macrocycles 4–6 in water at 1 × 10⁻⁶ M concentration showed that only p-tert-butylthiacalix[4]arene 5 formed nanosized particles of about 180 nm (Table 2). However, in the case of compounds 4 and 6 taken in the same concentration, no self-associates was observed in water. According to the UV spectroscopy results obtained with this concentration, the formation of supramolecular associates in water requires the presence of quaternary ammonium fragments with bulk alkyl or aryl substituents at the nitrogen in the structure of a receptor.

Table 2 Size of aggregates (average hydrodynamic diameters, d₁, d₂, (nm)), peak area intensity, S₁, S₂, (%), for peaks 1 and 2, obtained with p-tert-butylthiacalix[4]arene derivatives and EDTA, dicarboxylic and amino acids in H₂O at 20 °C, and polydispersity index (PDI)

System	d1, nm/S1, %	d2, nm/S2, %	PDI
4 + EDTA	188.3 ± 26.6/100	—	0.19 ± 0.05
4 + oxalic acid	199.6 ± 24.4/100	—	0.25 ± 0.03
4 + malonic acid	191.2 ± 28.7/93.2	3808.3 ± 295.5/6.8	0.34 ± 0.03
4 + succinic acid	130.8 ± 8.1/100	—	0.28 ± 0.06
4 + leucine	189.6 ± 14.5/100	—	0.17 ± 0.06
4 + glutamic acid	170.5 ± 17.8/97.3	4488.0 ± 1039.2/2.7	0.24 ± 0.04
5	180.9 ± 22.9/100	—	0.26 ± 0.04
5 + EDTA	151.7 ± 19.8/97.3	3575.4 ± 1278.2/2.7	0.26 ± 0.01
5 + oxalic acid	174.9 ± 23.9/98.2	4868.5 ± 593.2/1.8	0.27 ± 0.02
5 + malonic acid	166.5 ± 15.6/98.5	4430.3 ± 1333.1/1.5	0.29 ± 0.03
5 + succinic acid	184.8 ± 3.4/100	—	0.31 ± 0.02
5 + alanine	171.4 ± 21.7/96.5	4253.7 ± 1431.9/3.6	0.34 ± 0.04
5 + valine	151.2 ± 42.5/97.8	3633.0 ± 870.3/2.3	0.28 ± 0.03
5 + leucine	211.3 ± 7.6/97.1	31.8 ± 15.4/3.0	0.29 ± 0.02
5 + aspartic acid	133.3 ± 21.1/94.9	4631.8 ± 414.1/5.1	0.31 ± 0.06
5 + glutamic acid	208.5 ± 33.2/100	—	0.28 ± 0.01
6 + alanine	255.3 ± 27.0/100	—	0.16 ± 0.07
6 + valine	229.6 ± 25.4/98.4	4471.0 ± 402.6/1.6	0.26 ± 0.06
6 + leucine	182.9 ± 25.2/100	—	0.24 ± 0.04
6 + aspartic acid	186.1 ± 12.2/100	—	0.29 ± 0.02
6 + glutamic acid	185.5 ± 61.3/96.1	3616.5 ± 362.5/3.9	0.34 ± 0.05

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The study of the interaction of the macrocycles 4–6 in cone conformation in water with dicarboxylic, amino acids and EDTA by dynamic light scattering showed that p-tert-butylthiacalix[4]arene 6 did not form associates with dicarboxylic acids and EDTA. However, according to the UV spectroscopy, during the introduction of dicarboxylic acids and EDTA into the system containing the macrocycle 6, significant absorbance changes were observed, hence, the guest–host complexes were formed. The sizes of the complexes are very small to determine it by DLS. During the interaction of compound 6 with amino acids, the supramolecular aggregates were formed. The hydrodynamic diameters of these associates decreased in the range from valine and alanine to “bigger” amino acids–leucine, aspartic and glutamic acids (Table 2).

For the macrocycles 4 and 5 in cone conformation, the formation of supramolecular aggregates was observed not only for amino acids as in the case of the compound 6, but also for dicarboxylic acids and EDTA (Fig. 5A). It is interesting to note that for p-tert-butylthiacalix[4]arene 4, the hydrodynamic size of supramolecular aggregates decreased in the range from oxalic and malonic acids to succinic acid. For amino acids, the particle sizes also decreased in the range from leucine to glutamic acid (Table 2). Thus, the increased size of substrate led to decreased size of the supramolecular particles. However, the size of supramolecular aggregates of the macrocycle 4 with EDTA was the same as that of particles based on p-tert-butylthiacalix[4]arene 4 with malonic acid and leucine (Table 2).

Fig. 5 Possible paths of the formation of supramolecular aggregates.

For p-tert-butylthiacalix[4]arene 5, changes in the size of substrates did not lead to any changes of the particle size. The hydrodynamic diameters of supramolecular aggregates with oxalic, malonic, succinic acids and alanine were equal to 175, 167, 185 and 171 nm, respectively. The size of supramolecular particles was close to that (180 nm) observed for self-association products of p-tert-butylthiacalix[4]arene 5. However, it was shown by UV spectroscopy, that the introduction of dicarboxylic and amino acids into the system containing macrocycle 5, the significant absorbance changes took place. This indicates interaction of the p-tert-butylthiacalix[4]arene 5 with the substrates. The UV spectroscopy and DLS data confirm the ability of the self-associates based on p-tert-butylthiacalix[4]arene 5 to recognize the substrates. However, the interaction of the macrocycle 5 with EDTA, valine and aspartic acid resulted in the size of aggregates equal to 152, 151 and 133 nm, respectively. This is significantly smaller than the size of self-associates (180 nm). The interaction of the macrocycle 5 with leucine and glutamic acid led to the formation of particles with the sizes of about 211 and 208 nm, respectively. This is also significantly different from that obtained for the self-associates based on p-tert-butylthiacalix[4]arene 5. However, the efficiency of the interaction of the macrocycle 5 with amino, dicarboxylic acids and EDTA did not significantly change. According to UV spectroscopy and DLS, we suggested that the self-associates formed by p-tert-butylthiacalix[4]arene 5 are able to interact with substrates with no respect of their structure (Fig. 5B).

The ability of the macrocycles 4–6 to form supramolecular associates with dicarboxylic, amino acids and EDTA was shown with DLS. The presence of quaternary ammonium fragments with bulk alkyl or aryl substituents at the nitrogen atom in the structure of receptors was found to be required for self-association. In the case of the macrocycle 5, increasing size of a substrate decreased the size of supramolecular particles.

The spatial structures of p-tert-butylthiacalix[4]arene 4 (Fig. 6) and complex of p-tert-butylthiacalix[4]arene 4 with malonic acid (Fig. 7) were studied by two-dimensional ¹H–¹H NMR NOESY spectroscopy.

Fig. 6 ¹H–¹H NOESY NMR spectra of the compound 4 (in D₂O, 25 °C, 400 MHz).

Fig. 7 ¹H–¹H NOESY NMR spectra of the compound 4 with malonic acid (ratio 1 : 100, corespondingly) (in D₂O, 25 °C, 400 MHz).

The cross-peaks between protons of tert-butyl groups and ArH were observed for cone 4 (Fig. 6). In addition to it we also observed cross-peaks between the protons of CH₂CH₂CH₂N⁺(CH₃)₃ with protons of tert-butyl groups and ArH for the cone stereoisomer 4 due to dipole–dipole interactions. The observed cross peaks indicate the close proximity of the quaternary ammonium fragments to hydrophobic tert-butyl groups and the aryl fragments of the macrocycle as well. These arrangement of positively charged substituents of p-tert-butylthiacalix[4]arene 4 protect hydrophobic tert-butyl groups, aryl fragments and increase molecular solubility of the macrocycle 4 in a polar solvent like water.

It has been shown by UV spectroscopy earlier that the macrocycle 4 are able to interact with malonic acid with 1 : 1 stoichiometry ratio, also it has been shown by DLS that p-tert-butylthiacalix[4]arene 4 with malonic acid are able to form supramolecular aggregates. The significant changes in the ¹H–¹H NMR NOESY spectrum were observed due to the adding of malonic acid to the macrocycle 4 (Fig. 7).

The cross peaks between protons of tert-butyl groups and CH₂–CH₂–CH₂ groups and between ArH and –N(CH₃)₃ fragments were disappeared. However, the cross-peaks between oxymethylene fragments and tert-butyl groups are appeared. According to the ¹H–¹H NOESY NMR spectrum (Fig. 7), and literature,⁵⁹ we assumed that the repulsion of positively charged quaternary ammonium nitrogen atoms leads to transfer tert-butyl group into the cavity of the macrocycle (Fig. 8). As a result such distortion leads to appear some cross-peaks and disappear of others.

Fig. 8 Representation of p-tert-butylthiacalix[4]arene 4 conformations.

Thus, the formation of supramolecular particles due to the adding of malonic acid to the macrocycle 4 leads to substantial convergence quaternary ammonium fragments of macrocycles. The convergence of quaternary ammonium fragments of macrocycles leads to repulsion them from each other, as a result p-tert-butylthiacalix[4]arene 4 takes a distorted cone conformation, i.e. when one of the aromatic rings is partially take macrocyclic cavity.

Three-component systems based nanoscale aggregates formed by p-tert-butylthiacalix[4]arenes tetrasubstituted at the lower rim with dicarboxylic, amino acids and EDTA

According to the UV spectroscopy and DLS, p-tert-butylthiacalix[4]arenes 4–6 containing amide and quaternary ammonium groups can be used to create three-component cascade or commutative supramolecular systems. For the formation of a three-component systems, dicarboxylic and amino acids were chosen as guests and EDTA as a “cap” of a supramolecular container. It was shown by UV-spectroscopy, that the macrocycles 4–6 can effectively interact with EDTA, dicarboxylic and amino acids (Table 1). DLS recorded the formation of supramolecular associates – two-component systems (p-tert-butylthiacalix[4]arene 4–6 – EDTA or p-tert-butylthiacalix[4]arene 4–6 – dicarboxylic, amino acids) in aqueous phase (Table 2). The ability of nanoscale particles (two-component systems) to interact with a third component for the development of three-component cascade or commutative systems was studied. Changes in the hydrodynamic particle size caused by introduction of a third component into the supramolecular assembles (p-tert-butylthiacalix[4]arene – EDTA or p-tert-butylthiacalix[4]arene – dicarboxylic, amino acids) were discovered by DLS to confirm the formation of three-component systems.

The type of a three-component system (cascade or commutative) can be determined following changes in the hydrodynamic size of particles resulted from the interaction of two-component systems with a third component. It should be noted that the order of a substrate binding depends on the efficiency of interaction of p-tert-butylthiacalix[4]arene with substrates. According to the UV spectroscopy, the efficiency of interaction of the macrocycles 4–6 with EDTA, dicarboxylic and amino acids negligibly changed (Table 1). Hence, the formation of commutative supramolecular systems is mostly typical for the p-tert-butylthiacalix[4]arenes 4–6 irrespective of the substrate bonded first.

It was shown by DLS that the introduction of a third component into the supramolecular assemble (two-component system) resulted in the formation of commutative supramolecular systems only in the case of p-tert-butylthiacalix[4]arene 6 (Table 3). The macrocycle 4 is only one able to form cascade supramolecular system (Table 3). No three-component systems were observed for the p-tert-butylthiacalix[4]arene 5.

Table 3 Size of aggregates (average hydrodynamic diameters, d₁, d₂, d₃, (nm)), peak area intensity, S₁, S₂, S₃, (%), for peaks 1, 2 and 3, obtained with p-tert-butylthiacalix[4]arene derivatives and EDTA, dicarboxylic and amino acids in H₂O at 20 °C, and polydispersity index (PDI)

System	d1, nm/S1, %	d2, nm/S2, %	d3, nm/S3, %	PDI
Cascade system
[4 + glutamic acid]agr. + EDTA	0.7 ± 0.1/8.5	155.6 ± 17.9/86.5	4355.6 ± 627.4/5.0	0.35 ± 0.06
Commutative system
[6 + EDTA] + oxalic acid	171.6 ± 41.8/100	—	—	0.17 ± 0.04
[6 + oxalic acid] + EDTA	177.4 ± 9.0/100	—	—	0.19 ± 0.07
[6 + EDTA] + malonic acid	187.4 ± 13.6/100	—	—	0.17 ± 0.04
[6+ malonic acid] + EDTA	189.6 ± 37.5/82.6	4446.3 ± 265.1/17.4	—	0.40 ± 0.09
[6 + EDTA] + succinic acid	193.4 ± 19.8/89.4	4235.4 ± 540.0/10.6	—	0.38 ± 0.12
[6+ succinic acid] + EDTA	193.3 ± 45.6/96.7	4327.3 ± 1777.0/3.3	—	0.26 ± 0.01

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Among commutative system, the p-tert-butylthiacalix[4]arene 6 did not form nanoparticles with oxalic, malonic, succinic acids and EDTA but could form nanoscale aggregates (three-component system) by introduction of a third component into the system based on a macrocycle and a substrate (Table 3). The formation of three-component nanoscale particles with the same size was shown by DLS. Thus, the hydrodynamic diameter of supramolecular assemblies ([macrocycle 6 + oxalic acid] + EDTA) and ([the macrocycle 6 + EDTA] + oxalic acid) did not depend on the sequence of substrate binding (177 and 171 nm, respectively).

For cascade system formed by the macrocycle 4, EDTA and glutamic acid, nanoscale particles with hydrodynamic size of about 188 and 170 nm, respectively, were formed. The interaction of supramolecular associates (the compound 4 and glutamic acid) with EDTA led to decrease of the particle size to 1 nm (Fig. 9). However, no changes of the hydrodynamic diameter occurred during the interaction of supramolecular assemblies [the compound 4 and EDTA] with glutamic acid. It is interesting to note that the size of three-component cascade system [the compound 4 + glutamic acid] + EDTA is about 1 nm. This corresponds to the capsules containing glutamic acid as a guest in the cavity.

Fig. 9 Size distribution by number for the system consisting of (1) supramolecular particles ([the compound 4 – glutamic acid] – EDTA), (2) the macrocycle 4 and glutamic acid, (3) the macrocycle 4 and EDTA in the water.

The efficiency of the interaction of two-component systems with dicarboxylic, amino acids and EDTA was studied by UV spectroscopy (Table 4). It was shown that the interaction of two-component systems with substrates led to 1 : 1 stoichiometry, the logarithms of the association constants slightly changed by transition from macrocycles to two-component systems (Tables 1 and 4). The logarithms of the association constants for two- and three-component systems confirmed most preferable formation of commutative supramolecular systems based on the macrocycles synthesized.

Table 4 Logarithms of the association constants (log K_ass) of nanoscale aggregates based on compounds 4–6 with glutamic acid, dicarboxylic acids and EDTA

System	log Kass
a Cascade system.b Commutative systems.
[4 + glutamic acid]agr. + EDTA^a	2.53 ± 0.06
[6 + EDTA]agr. + oxalic acid^b	3.16 ± 0.06
[6 + oxalic acid]agr. + EDTA^b	2.42 ± 0.16
[6 + EDTA]agr. + malonic acid^b	2.30 ± 0.10
[6 + malonic acid]agr. + EDTA^b	2.55 ± 0.04
[6 + EDTA]agr. + succinic acid^b	2.05 ± 0.12
[6+ succinic acid]agr. + EDTA^b	2.24 ± 0.08

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Thus, the formation of commutative and cascade supramolecular systems was shown by UV spectroscopy and DLS. According to the UV spectroscopy, the formation of three-component commutative systems is most preferable for the p-tert-butylthiacalix[4]arenes synthesized. The formation of the capsules based on the p-tert-butylthiacalix[4]arene 4 and EDTA containing glutamic acid as a guest in the cavity was shown by DLS.

Conclusion

New p-tert-butylthiacalix[4]arenes containing amide, tertiary amine and ammonium fragments in the cone conformation were synthesized. The study of the interaction of the macrocycles 4–6 with EDTA, dicarboxylic and amino acids by UV-spectroscopy showed that the logarithms of the association constants varied from 2.27 to 3.40, and the stoichiometry was 1 : 1. Similar logarithms of the association constants indicate the formation of supramolecular assemblies and supermolecules by electrostatic interactions. It was shown by UV spectroscopy and DLS that the interaction of supermolecules and supramolecular assemblies with a third component (dicarboxylic and amino acids) led to the formation of commutative and cascade supramolecular systems. It was found that for the macrocycles able to interact with the substrates with the same efficiency, the formation of commutative supramolecular systems occurred. However, only in the case of p-tert-butylthiacalix[4]arene 4 the formation of cascade three-component system [the compound 4 + glutamic acid] + EDTA with the size of about 1 nm was observed. It corresponds to the dimeric capsules containing glutamic acid as a guest in the cavity.

Experimental

General

The ¹H NMR spectra of compounds (3–5% solution in CDCl₃, (CD₃)₂SO) were recorded on 400 MHz Bruker Avance 400 spectrometer using CDCl₃ and (CD₃)₂SO as internal standard. The ¹H–¹H NOESY NMR spectra of compound 4 (10⁻³ M in D₂O) and complex of compound 4 (10⁻³ M in D₂O) with malonic acid (10⁻¹ M in D₂O) were recorded on 400 MHz Bruker Avance 400 spectrometer using D₂O as internal standard.

The IR spectra (suspension in vaseline oil) were recorded on Tensor 27 (Bruker) IR spectrometer. The IR spectra from 4000 to 400 cm⁻¹ were considered in this analysis. The spectra were measured with 1 cm⁻¹ resolution and 64 scans co-addition. The time required for obtaining each specter under the conditions stated was approximately 16 s.

Elemental analysis was performed on Perkin-Elmer 2400 Series II instruments.

Mass spectra (MALDI-TOF) were recorded on Ultraflex III in the 4-nitroaniline matrix.

Melting points were determined using Boetius Block apparatus. The purity of the compounds was monitored by melting, boiling points, ¹H NMR and thin layer chromatography (TLC) on 200 μm UV 254 silica gel plate using UV-light (254 nm).

In this work, the following reagents and solvents were used: methanol (chemical pure), N,N-dimethylpropane-1,3-diamine (chemical pure), N,N-diethylethane-1,2-diamine (chemical pure), iodomethane (chemical pure), benzyl bromide (chemical pure), toluene (chemical pure), acetonitrile (chemical pure).

General procedure for the synthesis of the compound 2 and 3

In a round bottom flask equipped with magnetic stirrer and a reflux condenser, the compound 1 (0.50 g, 0.46 × 10⁻³ mol) in 30 mL of mixture of toluene and methanol was dissolved. N,N-Dimethylpropane-1,3-diamine or N,N-diethylethane-1,2-diamine (1.00 mL) was added. The reaction mixture was refluxed for 72 h. The solvent was removed under reduced pressure. The precipitate was washed with water and dried under reduced pressure over phosphorus pentoxide.

5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetrakis-[(N-(3′,3′-dimethylaminopropyl)carbamoylmethoxy)]-2,8,14,20-tetrathiacalix[4]arene (cone-2). White powder, yield: 0.54 g (90%). Mp: 180 °C. ¹H NMR (400 MHz, 298 K, CDCl₃) δ 1.12 (s, 36H, (CH₃)₃C), 1.76 (m, 8H, –NCH₂CH₂CH₂NH), 2.21 (s, 24H, (CH₃)₂N), 2.34 (m, 8H, –NCH₂CH₂CH₂NH), 3.44 (m, 8H, NCH₂CH₂CH₂NH), 4.83 (s, 8H, OCH₂CO), 7.35 (s, 8H, ArH), 8.21 (t, 4H, ³J_HH = 5.8 Hz, CONH). ¹³C NMR (125 MHz, CDCl₃) δ 168.34, 157.66, 147.42, 134.83, 128.10, 74.49, 57.41, 45.45, 37.90, 34.26, 31.10, 27.44. IR (vaseline oil)_νmax 1662 (C=O); 2950, 3318 (N–H). MALDI-TOF: calcd for [M + H]⁺ m/z = 1289.6, [M + Na]⁺ m/z = 1311.7, found m/z = 1287.8, 1311.9. El. Anal. calcd for C₆₈H₁₀₄N₈O₈S₄: C, 63.32; H, 8.13; N, 8.69; S, 9.94. Found: C, 62.12; H, 8.29; N, 7.03; S, 8.31.

5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetrakis-[(N-(2′,2′-diethylaminoethyl)carbamoylmethoxy)]-2,8,14,20-thiacalix[4]arene (cone-3). White powder, yield: 0.55 g (88%). Mp: 213 °C. ¹H NMR (400 MHz, 298 K, CDCl₃) δ 1.00 (t, 24H, ³J_HH = 7.1 Hz), (CH₃CH₂–), 1.12 (s, 36H, (CH₃)₃C), 2.57 (q, 16H, ³J_HH = 7.1 Hz, –CH₂CH₃), 2.65 (t, 8H, ³J_HH = 6.9 Hz, –NCH₂CH₂NH), 3.46 (m, 8H, NCH₂CH₂NH), 4.87 (s, 8H, OCH₂CO), 7.34 (s, 8H, ArH), 7.93 (t, 8H, ³J_HH = 5.1 Hz, CONH). ¹³C NMR (125 MHz, CDCl₃) δ 168.58, 157.40, 147.34, 134.69, 128.38, 74.53, 51.63, 46.73, 36.95, 34.40, 31.45, 11.91. IR (vaseline oil)_νmax 1649 (C=O); 2952, 3312 (N–H). MALDI-TOF: calcd for [M + Na]⁺ m/z = 1367.7, found m/z = 1366.9. El. Anal. calcd for C₇₂H₁₁₂N₈O₈S₄: C, 64.25; H, 8.39; N, 8.33; S, 9.53. Found: C, 63.41; H, 8.95; N, 7.52; S, 7.98.

General procedure for the synthesis of the compound 4–6

In a round bottom flask equipped with magnetic stirrer and a reflux condenser, compound 2 or 3 (0.10 g) in 2 mL of methanol was dissolved. Equimolar amount of the alkylating reagent (iodomethane, iodoethane, benzyl bromide) for each amino group was added. The reaction mixture was refluxed for 72 h. The solvent was removed under reduced pressure. The precipitate was dried under reduced pressure over phosphorus pentoxide.

5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetrakis-[(N-(3′,3′,3′-trimethylammoniumpropyl)carbamoylmethoxy)]-2,8,14,20-thiacalix[4]arene tetraiodide (cone-4). Yellow powder, yield: 0.13 g (95%). Mp: 192 °C. ¹H NMR (400 MHz, 298 K, CDCl₃) δ 1.11 (s, 36H, (CH₃)₃C), 2.22 (m, 8H, –NCH₂CH₂CH₂NH), 3.49 (s, 36H, (CH₃)₃N⁺), 3.52 (m, 8H, –NCH₂CH₂CH₂NH), 3.89 (m, 8H, NCH₂CH₂CH₂NH), 4.99 (s, 8H, OCH₂CO), 7.35 (s, 8H, ArH), 8.49 (t, 4H, ³J_HH = 5.8 Hz, CONH). ¹³C NMR (125 MHz, CDCl₃) δ 169.03, 157.27, 147.65, 134.91, 128.10, 74.48, 64.53, 54.14, 36.19, 34.26, 31.12, 23.46. IR (vaseline oil)_νmax 1663 (C=O); 2955, 3317 (N–H). MALDI-TOF: calcd for [M–I⁻]⁺ m/z = 1730.7, found m/z = 1731.9. El. Anal. calcd for C₇₂H₁₁₆I₄N₈O₈S₄: C, 46.55; H, 6.29; N, 6.03; S, 6.90. Found: C, 46.00; H, 5.91; N, 5.66; S, 6.35.

5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetrakis-[(N-(3′,3′-dimethyl-3′-benzylammoniumpropyl) carbamoylmethoxy)]-2,8,14 20-thiacalix[4]arene tetrabromide (cone-5). White powder, yield: 0.12 g (90%). Mp: 135 °C. ¹H NMR (400 MHz, 298 K, CDCl₃) δ 1.10 (s, 36H, (CH₃)₃C), 2.43 (m, 8H, –NCH₂CH₂CH₂NH), 3.26 (s, 24H, (CH₃)₂N⁺), 3.63 (m, 8H, –NCH₂CH₂CH₂NH), 3.97 (m, 8H, NCH₂CH₂CH₂NH), 4.91 (s, 8H, N⁺CH₂Ph), 5.17 (s, 8H, OCH₂CO), 7.34 (s, 8H, Ar′H), 7.38 (s, 8H, ArH), 7.63 (s, 12H, Ar′H), 9.13 (br. t, 4H, CONH). ¹³C NMR (125 MHz, CDCl₃) δ 169.32, 157.38, 147.70, 134.85, 133.27, 130.61, 129.17, 128.17, 127.37, 74.42, 67.55, 62.57, 49.80, 36.42, 34.19, 31.09, 23.16. IR (vaseline oil)_νmax 1664 (C=O); 2958, 3334 (N–H). MALDI-TOF: calcd for [M–Br⁻]⁺ m/z = 1794.6, found m/z = 1795.7. El. Anal. calcd for C₉₆H₁₃₂Br₄N₈O₈S₄: C, 58.41; H, 6.74; N, 5.68; S, 6.93. Found: C, 52.65; H, 6.56; N, 4.13; S, 6.50.

5,11,17,23-Tetra-tert-butyl-25,26,27,28-tetrakis-[(N-(2′-methyl-2′,2′-diethylammoniumethyl) carbamoylmethoxy)]-2,8,14 20-thiacalix[4]arene tetraiodide (cone-6). Yellow powder, yield: 0.13 g (92%). Mp: 165 °C. ¹H NMR (400 MHz, 298 K, CDCl₃) δ 1.11 (s, 36H, (CH₃)₃C), 1.43 (t, 24H, ³J_HH = 7.1 Hz, –CH₂CH₃), 3.35 (s, 12H, (CH₃)N⁺), 3.68 (q, 16H, ³J_HH = 7.1 Hz, –CH₂CH₃), 3.77 (br. t, 8H, –NCH₂CH₂NH), 3.97 (m, 8H, NCH₂CH₂NH), 4.97 (s, 8H, OCH₂CO), 7.34 (s, 8H, ArH), 8.74 (t, 8H, ³J_HH = 5.1 Hz, CONH). ¹³C NMR (125 MHz, CDCl₃) δ 169.65, 157.06, 147.82, 134.95, 128.11, 74.07, 59.36, 57.48, 48.72, 34.38, 33.92, 31.10, 8.64. IR (vaseline oil)_νmax 1664 (C=O); 2956, 3316 (N–H). MALDI-TOF: calcd for [M–I⁻]⁺ m/z = 1787.3, found m/z = 1787.1. El. Anal. calcd for C₇₆H₁₂₄I₄N₈O₈S₄: C, 47.70; H, 6.53; N, 5.86; S, 6.70. Found: C, 47.17; H, 6.00; N, 5.49; S, 5.96.

Determination of the association constant and stoichiometry of the complex by UV titration

UV-vis spectra were recorded by using a “Shimadzu UV-3600” spectrometer; the cell thickness was 1 cm. A 1 × 10⁻¹ M aqueous solution of dicarboxylic acids (oxalic, malonic, succinic acids), amino acids (DL-alanine, DL-valine, DL-leucine, DL-aspartic acid and DL-glutamic acid), and EDTA (0.5 × 10⁻³, 1 × 10⁻³, 1.5 × 10⁻³, 2.0 × 10⁻³, 2.5 × 10⁻³, 3.0 × 10⁻³, 3.5 × 10⁻³, 4.0 × 10⁻³, 4.5 × 10⁻³, 5.0 × 10⁻³ mL) was added to 1 mL of aqueous solution of the receptor 4–6 (3 × 10⁻⁶ M) or nanoparticles based on the macrocycles 4–6 (3 × 10⁻⁶ M) and substrates. The volume was brought to 3 mL with water, while the concentration of p-tert-butylthiacalix[4]arenes tetrasubstituted with the amidopyridine fragment (10⁻⁶ M) remained constant. The UV spectra of the obtained solutions were then recorded. The stability constant and stoichiometry of complexes were calculated as described elsewhere.⁵³ Three independent experiments were carried out for each series. Student's t test was used in statistical data processing.

Determination of the hydrodynamic size of the particles by DLS

The particle size was determined by Zetasizer Nano ZS instrument at 20 °C. The instrument contains a 4 mW He–Ne laser operating at a wavelength of 633 nm and incorporates noninvasive backscatter optics (NIBS). The measurements were performed at detection angle of 173°, and the measurement position within the quartz cuvette was automatically determined by the software. The results were processed with the DTS (Dispersion Technology Software 4.20) software package. A 1 mL aqueous solution of dicarboxylic acids (oxalic, malonic, succinic acids), amino acids (DL-alanine, DL-valine, DL-leucine, DL-aspartic acid and DL-glutamic acid), and EDTA (3 × 10⁻⁶ M) was added to 1 mL of the aqueous solution of the receptor 4–6 (3 × 10⁻⁶ M) or nanoparticles based on the macrocycles 4–6 (3 × 10⁻⁶ M) and substrates. The volume was brought to 3 mL with water. The mixture was mechanically shaken for 3 h and then magnetically stirred in a thermostated water bath at 20 °C for 1 h. Three independent experiments were carried out for each combination of a ligand and substrates. Student's t test was used in statistical data processing.

Acknowledgements

The financial support of RFBR (12-03-31137 mol_a, 12-03-00252-a) and the Program of the President of the Russian Federation for the State support of young Russian scientists – scholarships of the President of the Russian Federation (CP-1753.2012.4) is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H NMR, ¹³C NMR, UV-vis and MALDI-TOF mass spectres. Determination of the association constants between the hosts and the guests by UV titration. See DOI: 10.1039/c3ra44052d

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