Bis-resorcin[4]arene Selectively Forms Hexameric Capsules in Apolar

Letter Cite This: Org. Lett. 2018, 20, 3958−3961

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Bis-resorcin[4]arene Selectively Forms Hexameric Capsules in Apolar Solvents: Evidence from Diffusion NMR Inbar Horin,† Tal Adiri,† Yossi Zafrani,†,‡ and Yoram Cohen*,† †

School of Chemistry, The Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv 69978, Tel Aviv, Israel Department of Organic Chemistry, Israel Institute for Biological Research, Ness-Ziona 74000, Israel

‡

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S Supporting Information *

ABSTRACT: Bis-resorcin[4]arene 2 connected by its lower rims was synthesized via click chemistry and found, by diffusion NMR, to self-assemble quantitatively, despite the different alternatives, into hexameric capsules reminiscent of the well-characterized hexameric capsule of resorcin[4]arene 1. The hexameric capsules of the flexible bis-resorcin[4]arene 2 prevail in apolar organic solvents and can, as expected, encapsulate quite well ammonium salts, demonstrating that spontaneous self-assembly into hexameric capsules is a general characteristic of such systems.

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solvents.14,15 Interestingly, very recently it was shown that the respective hexamers of pyrogallol[4]arene are not suitable for carrying many of those reactions.14e Ditopic hosts extend the functionality of their monotopic counterparts to afford systems that enable one to study, for example, cooperativity, ion-pair binding and provide a means for the preparation of supramolecular polymers.16 Indeed, in the last decades, some bis-calixarenes and bis-resorcin[4]arenes were prepared and used to construct supramolecular systems and supramolecular oligomers and polymers.17 Very recently, feet-to-feet rigid bis-resorcin[4]arenes were prepared and found to self-assemble into supramolecular polymers.18 Because of the growing interest in supramolecular polymers and their applications,16,19 we decided to prepare a flexible bisresorcin [4]arene such as 2 (Figure 1) and study first its selfassembly in apolar solvents with the aim of determining which of the possible self-assembled supramolecular structures that this system can adopt (see Figure 2 for some possible options) actually prevail in solution.

esorcin[4]arenes, known to the chemical community for decades,1 have become an important building block in supramolecular chemistry2 since the first covalent container molecules were prepared by Cram and co-workers in 1985.3 Since that time, different resorcin[4]arene derivatives have been prepared and used to construct noncovalent capsules through the use of various noncovalent interactions ranging from metal−ligand and electrostatic interactions to hydrogen bonds and, more recently, halogen bonds.4,5,2c In this context, however, the crystal structure of the hexameric capsule of resorcin[4]arene, based on hydrogen bonds, introduced by MacGillivray and Atwood in 1997, represents a milestone.6 Mattay and co-workers demonstrated thereafter that pyrogallol[4]arenes also form hexameric capsules in the solid state,7 and Shivanyuk and Rebek showed that the hexameric capsules of resorcin[4]arene can be observed in apolar solutions in the presence of the appropriate guests.8 Diffusion NMR,9 which has been shown to be an effective analytical tool for studying encapsulation and molecular capsules,10 showed that resorcin[4]arenes self-assemble, spontaneously, into hexameric capsules with eight water molecules,11 while pyrogallol[4]arenes form hexameric capsules without the mediation of water molecules.12 Diffusion NMR and later fluorescence resonance energy transfer (FRET), demonstrated that the self-assembly of mixtures of resorcin[4]arenes and pyrogallol[4]arenes proceeds with self-sorting to afford only homohexamers,13 suggesting that the two hexamers are probably more different than one can assume a priori. Tiefenbacher realized that resorcin[4]arene hexamers can in fact act as Brönsted acids because of the water molecules embedded in their hexameric structures.14a Since then, Tiefenbacher, Scarso, and others have used the hexameric capsules of the lipophilic resrocin[4]arene 1 as nanoreactors and enzyme mimics of several reactions in organic © 2018 American Chemical Society

Figure 1. Molecular structures of mono- and ditopic-resorcin[4]arenes 1 and 2, respectively. Received: May 15, 2018 Published: June 20, 2018 3958

DOI: 10.1021/acs.orglett.8b01526 Org. Lett. 2018, 20, 3958−3961

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compounds, sharp and well-defined sets of peaks are observed. However, in the apolar chloroform solutions, much broader peaks were observed in the 1H NMR spectra of these systems. These figures also show that the peaks of 2 are in fact broader than those of 1. In addition, we measured the diffusion coefficients (D) of 1 and 2 in acetone-d6 and CDCl3 solutions. Figure 3 shows the signal decay of one representative peak of

Figure 2. Some of the supramolecular structures that compound 2 can form (A) linear supramolecular polymers, (B) hexameric species, (C) fused hexamers, and (D) multidimensional network.

Bis-rsorcin[4]arene 2 was prepared by click chemistry according to the synthetic route presented in Scheme 1 (see also Scheme S1 in the Supporting Information (SI) for the entire synthetic path). Scheme 1. Synthetic Route for the Preparation of 2

Figure 3. 1H NMR signal decay as a function of the gradient strength (G) for 10 mM solution, along the diffusion coefficients extracted for (A) 1 in CDCl3, (B) 2 in CDCl3, (C) 1 in acetone-d6, and (D) 2 in acetone-d6.

each of the two compounds in CDCl3 and acetone-d6 as a function of the gradient strength (G). The ln of the normalized signal intensities (ln I/I0) for both compounds in the two solvents are presented in Figure S7 (see SI). Interestingly, these experiments showed that the diffusion coefficients of 1 and 2 in acetone are 0.79 ± 0.01 × 10−5 cm2 s−1 and 0.58 ± 0.01 × 10−5 cm2 s−1, respectively, while in chloroform these values were found to be 0.24 ± 0.01 × 10−5 cm2 s−1 and 0.18 ± 0.01 × 10−5 cm2 s−1, respectively. Note that these values, in CDCl3, correspond to Stokes radii of 1.64 and 2.26 nm for the aggregates of 1 and 2, respectively (see the SI for details of calculations). In addition, the diffusion coefficients of 2 and 1 were found to be smaller in CDCl3 as compared to acetone-d6, but those of 2 were smaller than that of 1 in both solvents. Interestingly we found that the diffusion coefficients of 1 and 2, in CDCl3, remain constant upon dilution (see Figure S10 in the SI). All of these results suggest that both 1 and 2 are in fact monomers in acetone. However, in the chloroform solutions it appears that both 1 and 2 are higher aggregates. Since it is well-known that 1 forms hexameric capsules in chloroform solution8,11 it may well be that 2 also forms hexameric aggregates or even hexameric capsules like 1 despite the fact that 2 can, in principle, form

First, we prepared 1-bromoundecanal (4), 1-yne-undecanal (5), and dodecanal (6) by oxidation of the appropriate alcohols with pyridinium chlorochromate (PCC).20 Then resorcin[4]arenes 1b and 1c were prepared by reacting resorcinol with a 3:1 mixture of 6 and 4 followed by reaction with sodium azide or with a 3:1 mixture of 6 and 5, respectively (see also Scheme S1 and Figures S1−S3 in the SI). Finally, copper-catalyzed click reaction between 1b and 1c afforded the bis-resocrcin[4]arene 2 after tedious purification by column chromatography, and its spectroscopic data are given in the SI (see Figure S4). To explore the self-assembly of compound 2, we decided to use diffusion NMR relying on the well-characterized hexamers of resorcin[4]arene 1 as a reference. We first studied these systems in acetone and methanol, where monomers of 1 and 2 should prevail, and then in chloroform, both in the absence and presence of guests, where higher H-bonded aggregates should dominate. The aim was to determine which, if any, of the options shown in Figure 2 is indeed adopted by 2 in chloroform solution. Figures S5 and S6 show the 1H NMR spectra of 1 and 2 in CDCl3 and acetone-d6, respectively, demonstrating the difference in the line-shape in the two solvents. In acetone, for both 3959

DOI: 10.1021/acs.orglett.8b01526 Org. Lett. 2018, 20, 3958−3961

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which are characteristic of encapsulated ammonium salts in such capsules, are observed.8a,11a Integration clearly demonstrate that 2 forms, in this case, hexameric capsules which encapsulate one THABr molecule. To further support the above conclusion and to characterize the relative stability of the formed hexameric capsules of 2, we studied the effect of CD3OD titration on the diffusion coefficient of the hexameric capsules of 2 and 1 (as a reference) in the presence of THABr. The results are summarized in Figure 5. Figure 5 shows that addition of

other supramolecular structures such as those presented in Figure 2. To shed further light on the nature of the aggregate that 2 forms in chloroform, we decided to titrate the CDCl3 solutions of both 2 and 1 (as a reference) with CD3OD, which should break the hydrogen bounds and afford the monomeric species in each case. The results presented in Figure 4 show, as

Figure 4. Effect of CD3OD titration on the diffusion coefficients (D) of 10 mM CDCl3 solutions 1 and 2 at 298 K. Figure 5. Effect of CD3OD titrations on the diffusion coefficients (D) of hexamers 2 and 1 and the encapsulated THABr in CDCl3 solutions at 298 K.

expected, an increase in the D values upon addition of CD3OD until a plateau is reached. Indeed, a similar behavior is observed for both 1 and 2. Compound 2 shows a similar isotherm as 1, albeit at lower D values, because of its higher molecular weight compared to 1. These results make it reasonable to assume that 2 forms aggregates which are similar to those of 1 in chloroform solution, aggregates which may well be hexameric capsules. Note that a trimeric aggregate of 2 can be ruled out since such a system would have a similar diffusion coefficient as the hexamer of 1, which is clearly not the case. This is in sharp contrast to the behavior of the rigid feet-to-feet bis-resorcin[4]arenes, reported by Haino et al., which were found to self-assemble into supramolecular polymers of the type presented in Figure 2A.18 To rule out the presence of polymeric 1D, 2D, or 3D supramolecular structures in the CDCl3 solution of 2, which may be NMRinvisible, we analyzed the 1H NMR spectrum of the very same sample of 2 in acetone-d6 and CDCl3 against the same external standard (see Figure S8). By integrating the 1H NMR signals of the monomers (in acetone) and the hexamers (in chloroform) against the same capillary of external standard (10% H2O in D2O), it was clearly found that the hexameric capsules of 2 are obtained quantitatively. Thus, the supramolecular polymeric structures as those presented in Figure 2 A, D do not exist in observable quantities in the chloroform solution. Next, since we concluded that the bis-resorcin[4]arene 2 forms, in chloroform, aggregates which are reminiscent of the hexameric capsules of 1, we decided to study the interaction of 2 with tetrahexylammonium bromide (THABr), known to be an excellent guest for the hexamer of 1.8a,11a The 1H NMR spectra of 2 and 1 with THABr in CDCl3 solutions are presented in Figure S9 (see SI), which shows that the 1H NMR spectra of both types of hexameric capsules are similar in the presence of THABr but display somewhat broader peaks in the case of 2. Interestingly, in Figure S9A, as in Figure S9B, additional new and broad upfield signals, at negative ppm,

CD3OD to the CDCl3 solutions of 2 and 1 in the presence of THABr cause an increase in the diffusion coefficient of 2 and 1 until a plateau is reached. In addition, the diffusion coefficient of the encapsulated THABr is similar to that of 1 and 2. However, after addition of CD3OD, the peaks of the encapsulated THABr disappear from the spectrum. Interestingly, the disappearance of the peaks of the encapsulated THABr occurs before a significant disruption of the hexameric capsules is recorded. The addition of CD3OD to the chloroform solution of 2 and THABr also results in an increase in the diffusion of the nonencapsulated THABr, which is, as expected, much higher than that of 2 and the encapsulated THABr. These observations suggest that, in CDCl3 solution, the nonencapsulated THABr interact, to some extent, with the formed hexamers of 2, probably, from the outside. All these observations are reminiscent to those previously observed for the hexamers of the monotopic resorcin[4]arene 1 in the presence of THABr and other ammonium salts.11a,13a,21 In conclusion, click chemistry was used to synthesize the lipophilic and flexible bis-resorcin[4]arene 2 in order to study its self-assembly in apolar solvents. Diffusion NMR showed that despite the many possibilities of supramolecular assemblies that the ditopic compound 2 may adopt, it selfassembles in chloroform quantitatively into hexameric capsules of the type shown in Figure 2B, encapsulating ammonium salts like the hexamers of the monotopic counterpart 1. Note that the hexameric capsules of 2 have in fact two types of host sites. This study demonstrates that indeed spontaneous formation of hydrogen-bond hexameric capsules is much more common in systems such as resorcin[4]arenes,6,8,11,14,15 pyrogallol[4]arenes,8,12,13 calixpyridine[4]arenes22 and now in the flexible ditopic bis-resorcin[4]arenes. 3960

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01526. Synthesis and chemical characterization of compounds 1a, 1b, 1c, and 2 and diffusion NMR data of 1 and 2 in different solutions (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yossi Zafrani: 0000-0001-5977-528X Yoram Cohen: 0000-0002-9442-8547 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by the Israel Science Foundation (ISF, Grant No. 2013-155). REFERENCES

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DOI: 10.1021/acs.orglett.8b01526 Org. Lett. 2018, 20, 3958−3961