A tetrasulfate-resorcin[6]arene cavitand as the host for organic ammonium guests

Abstract

The first example of a resorcin[6]arene cavitand in which sulfate bridges are introduced between the OH groups is here reported. In addition to their structural role, sulfate bridges behave as functional supramolecular interacting groups thus favoring the complexation of suitable organic ammonium guests.

---

In the last two decades bowl-shaped macrocycles¹ have stimulated the imagination of chemists devoted to molecular recognition. In fact, thanks to the presence of a cavity, they are potentially able to accommodate appropriate guests. Among the bowl-shaped macrocycles, resorcin[4]arene-based cavitands² are a family of hosts in which bridging elements are introduced between adjacent phenolic OH groups.

In the last decade, the search for supramolecular applications of cavitand hosts has produced interesting examples of molecular recognition,³ sensing,⁴ and catalysis.⁵ Among them, peculiar recognition abilities have been shown by tetraphosphonate resorcin[4]arene cavitands⁶ in which phosphorus bridges were introduced at the upper rim of the macrocycle. The molecular recognition properties of tetraphosphonate cavitands have been exploited in gas sensing⁷ and cantilever-based chemical sensors have been obtained.⁸ In these cases, a particular affinity was evidenced by tetraphosphonate hosts toward N-methylated ammonium guests, thanks to H-bonding and dipole–dipole interactions between P=O bridging groups of the host and the ammonium moiety of the guest.⁸

Very recently, we have reported⁹ an improved procedure for the synthesis of the large resorcin[6]arene macrocycle 1 and we have shown that in the solid state it adopts a pinched cone conformation very similar to that reported for p-tert-butylcalix[6]arene.¹⁰ The interesting recognition abilities showed by tetraphosphonate resorcin[4]arene hosts, prompted us to investigate the synthesis of a large resorcin[6]arene cavitand¹¹ in which new interacting groups, such as sulfate, were used as bridging elements.

Our idea was inspired by a recent study by Shi¹² and coworkers in which it is shown that the treatment of phenol derivatives with N,N′-sulfuryldiimidazole, in the presence of Cs₂CO₃ as the base, afforded diaryl sulfates in good yields.

Prompted by these results, we attempted the formation of sulfate-bridges between the OH groups of 1 under conditions modified with respect to those of Shi and coworkers.^12,13 Thus, the treatment of 1 with 10 equiv. of N,N′-sulfuryldiimidazole [(Im)₂SO₂] (Scheme 1) and K₂CO₃ in dry DMA at 75 °C for 60 h, afforded derivative 2 in 30% yield, after column chromatography on silica gel.¹³

Scheme 1

High-resolution MALDI Fourier-Transform ion cyclotron resonance (MALDI-FT-ICR) mass spectrometry showed a molecular ion peak at 1087.0895 m/z for 2 in accordance, with the molecular formula [M + Na]⁺ of a tetrasulfate-bridged derivative (calcd 1087.0888).¹³ The structure assignment of (SO₄)₄-bridged 2 was based on the spectral ¹H and ¹³C NMR data. In fact, three possible (SO₄)₄-bridged derivatives are possible (Fig. 1), namely, 1,2,4,5-tetra-bridged, 1,2,3,4-tetra-bridged, and 1,2,3,5-tetra-bridged.

Fig. 1 The three possible regioisomers of a tetrasulfate-bridged resorcin[6]arene.

The ¹H NMR spectrum of 2 at 403 K (Fig. 2, 400 MHz, TCDE) reveals the presence of two broad ArCH₂Ar singlets at 4.05 and 3.94 ppm in a 2 : 1 ratio,¹³ two ArCH₃ singlets at 2.29 and 2.42 ppm (2 : 1 ratio),¹³ and finally two ArH signals in a 2 : 1 ratio at 7.30 and 7.33 ppm, which allowed the confidential assignment of the 1,2,4,5-bridging pattern (Fig. 1). In accordance, the ¹³C NMR spectrum¹³ of 2 in TCDE (75 MHz, 403 K) showed two ArCH₃ signals at 9.3 and 10.3 ppm, two ArCH₂Ar signals at 33.3 and 29.3 ppm, and 10 signals in the aromatic region.

Fig. 2 Methylene region of the ¹H NMR spectrum (400 MHz, TCDE) of 2 at different temperatures.

Surprisingly, cooling at 298 K caused dramatic changes in the ¹H NMR spectrum of 2 (Fig. 2, TCDE, 400 MHz). In fact, two distinct sets of ArCH₂Ar AX systems were identified by a 2D COSY spectrum (Fig. S4†) which are corresponding to two conformational isomers 2a and 2b (Fig. 3 and 4). The first set (red in Fig. 2), composed of three AX systems in a 1 : 1 : 1 ratio, is attributable to conformer 2a (Fig. 3 and 4d–f), while the second one (two AX systems in a 2 : 1 ratio, blue in Fig. 2) is related to conformer 2b (Fig. 3, 4a and b). Integration of the corresponding ¹H NMR signals evidenced a 50/50 ratio for the two conformers 2a and 2b.

Fig. 3 Chemical drawing of the two conformers 2a and 2b and of the guests studied in the present work.

Fig. 4 Lowest energy conformations (Monte Carlo conformational search, MM3, CHCl₃ as solvent) of: (a) top view of 2b; (b) side view of 2b; (c) particularly of the boat-chair conformation of the 8-membered ring bearing the sulfate bridge; (d) top view of 2a; (e) side view of 2a; (f) particularly of the distorted boat conformation of the 8-membered rings bearing sulfate bridge in 2a.

Regarding conformer 2b, the presence of two ArCH₂Ar AX systems at 4.51/3.70 (8H) and 3.90/3.14 (4H) ppm in a 2 : 1 ratio (COSY spectrum,¹³Fig. 2 at 298 K, signals in blue), two ArH singlets in a 2 : 1 ratio, and two ArCH₃ singlets in a 2 : 1 ratio in its ¹H NMR spectrum (TCDE, 298 K) pointed to a structure characterized by two orthogonal symmetry planes bisecting the aromatic rings A and D (Fig. 3) and the ArCH₂Ar carbons 3 and 6. An insight into the conformation 2b was obtained by a Monte Carlo conformational search (MM3 force field, CHCl₃ as solvent).

A symmetrical lowest energy structure was found in which the resorcin[6]arene skeleton adopts a pinched cone conformation¹⁰ (Fig. 4a–c). Interestingly, in this structure the 8-membered rings (in magenta in Fig. 3) bearing the sulfate-bridge, adopt a boat-chair conformation (Fig. 4c), in analogy to the known 6H,12H-dibenzo[d,g][1,3]dioxocine ring.¹⁴

Regarding conformer 2a, the ¹H NMR spectrum (TCDE, 298 K) evidenced the presence of three ArCH₂Ar AX systems at 4.55/3.75, 3.62/4.22, and 4.14/3.28 ppm in a 1 : 1 : 1 ratio (COSY spectrum,¹³Fig. 2, 298 K, signals in red), three ArH singlets in a 1 : 1 : 1 ratio, and three 1 : 1 : 1 ArCH₃ singlets, corresponding to a less symmetrical structure with respect to 2b. A Monte Carlo conformational search (MM3 force field, CHCl₃ as solvent) gave the conformation 2a in Fig. 4d as the lowest energy structure compatible with these ¹H NMR signal patterns. In particular, the resorcin[6]arene skeleton adopts again a pinched cone conformation but, differently from 2b, two adjacent 8-membered rings (i.e.: 1 and 2 in blue in Fig. 3), adopt a distorted-boat conformation (Fig. 4f). Such distorted-boat conformation was already observed in macrocyclic compounds containing 6H,12H-dibenzo[d,g][1,3]dioxocine rings.^14,15 The above variable temperature ¹H NMR experiments (TCDE, 400 MHz) (Fig. 2) clearly indicated that, notwithstanding the presence of sulphate bridges, the resorcin[6]arene skeleton of 2 still shows a residual conformational mobility, likely due to the presence of the four free OH groups.

In fact, by increasing the temperature (Fig. 2), a coalescence for ArCH₂Ar AX systems of 2a was observed at 323 K, which led to an energy barrier of 14.6 kcal mol⁻¹.¹⁶ In analogy with the data previously reported for calixarenes bearing 1,3-dioxocine moieties,^14,15 this energy barrier should be associated with an interconversion process between the distorted-boat and the boat-chair conformation of the 8-membered rings of 2a to give 2b. By increasing the temperature, a second coalescence was ascertained at 363 K (400 MHz), corresponding to an energy barrier of 16.5 kcal mol⁻¹, to give an averaged symmetrical spectrum (Fig. 2). This conformational interconversion is related to the pinched cone inversion of 2b to its inverted pinched-cone structure.

The conformer 2a/2b ratio is strongly influenced by the nature of the solvent. In fact, in CD₃CN the symmetrical pinched conformation 2b is favoured (Fig. 5) with respect to 2a (at 298 K) with a 98/2 ratio (measured by ¹H NMR signal integration). Probably, the regular pinched conformation 2b in solution is templated by acetonitrile solvent molecules, which, as shown by X-ray crystallography (see below, Fig. 6a and d), are able to occupy its two sub-cavities establishing C–H⋯π and C–H⋯O=S interactions (Fig. 6a and d).

Fig. 5 Significant portions of the ¹H NMR spectra of: (top) 2 in TCDE (298 K, 600 MHz); (bottom) 2 in CD₃CN (298 K, 600 MHz). Marked in blue and in red are the ¹H NMR signals of the conformer 2b and 2a respectively.

Fig. 6 X-ray structure of tetrasulfate-resorcin[6]arene cavitand 2.

Crystals of tetrasulfate-cavitand 2 were obtained by slow evaporation of a CH₃CN solution. The asymmetric unit of the monoclinic crystals of 2 consists of one resorcin[6]arene molecule and seven acetonitrile solvent molecules. In accordance with the results of MM3 calculations (structure 2b, Fig. 4a) in the solid state, 2 adopts a pinched cone conformation with a boat-chair conformation for all the sulfate 8-membered rings (Fig. 6). Interestingly, the free OH groups of 2, O18 and O19 (see ORTEP in the ESI†),¹³ acting as intramolecular H-bond acceptors from adjacent OH groups (Fig. 6b, O17 and O20 respectively, with an O⋯O distance of 2.7 Å), play the role of intermolecular H-bond donor groups toward acetonitrile solvent molecules (Fig. 6b, O⋯N distance of 2.7 Å). In the solid state the two three-membered sub-cavities of 2 are occupied by two acetonitrile molecules (Fig. 6a and d) in which the methyl groups are involved in C–H⋯π interactions with the aromatic rings of 2 (average distance C⋯π^centroid of 3.55 Å). In addition, weak C–H⋯O=S hydrogen bonding¹⁷ interactions were detected between methyl groups of the acetonitrile guests inside the cavities and SO₄ bridging groups of 2, with an average C–H⋯O=S distance of 3.32 Å and an average C–H⋯O=S angle of 147.5 Å.¹⁷

Surprisingly, the tetrasulfate-bridged 2 was the only isolated product even when 1 was reacted under more drastic conditions (20 equiv. of (Im)₂SO₂ for 120 h). In a similar way, a further treatment of 2 with (Im)₂SO₂ only gave an unreacted material. Probably, the introduction of further SO₄-bridging elements between the free OH groups of 2 could be disfavoured by a consequent distortion of the pinched structure of the resorcin[6]arene macrocycle. In fact, a close inspection of the X-ray structure of 2‡ (Fig. 6) reveals a O⋯O distance between the free OH groups of 2.71 Å, significantly higher than that of SO₄-bridged O-atoms (2.48 Å).

The presence of sulfate bridges should make the resorcin[6]arene cavitand 2 a host able to bind suitable guests by means of H-bonding and/or dipole–dipole interactions. Therefore, we undertook complexation studies by means of ¹H NMR titrations¹⁸ with cationic guests (Fig. 3) such as 1,4-DiammoniumButane (1,4-DB²⁺), 1,8-DiammoniumOctane (1,8-DO²⁺), 1,10-DiammoniumDecane (1,10-DD²⁺), and DiMethylViologen (DMV²⁺). In order to minimize the ion-pairing effects, we decided to use the weakly-coordinating Tetrakis[3,5-bis(triFluoromethyl)Phenyl]Borate TFPB⁻ (Fig. 3) as the counter-anion.¹⁹ In fact, in the last years, we have shown that the TFPB anion is able to induce the recognition of ammonium guests by scarcely preorganized calixarene hosts.²⁰

¹H NMR titrations were carried out in CD₃CN, where the regular pinched 2b was the most abundant (98/2 ratio 2b/2a, see Fig. 5), by increasing the [guest]/[host] ratio while keeping constant the host concentration at about 0.001 mol L⁻¹.¹⁸ In all cases, the host signals were observed as averaged single resonances because of the fast exchange on the NMR timescale between the free and bound states. The addition of TFPB salt of 1,8-diammoniumoctane 1,8-DO²⁺ to a solution of host 2 caused a downfield shift¹³ of the ArCH₂Ar NMR signals of 2. The Job plot for 2 and 1,8-DO²⁺ showed a maximum at a mole fraction of 0.5, thus indicating a 1 : 1 binding stoichiometry. The titration data¹³ were analyzed by a nonlinear regression analysis¹⁸ and a value of 600 M⁻¹ was calculated for the formation of a 1,8-DO²⁺ ⊂ 2 complex. Molecular mechanics calculations suggest that in the 1,8-DO²⁺ ⊂ 2 complex (Fig. 7, top) the bis-ammonium guests are linked to 2via a two-point double-hydrogen bonding between NH₃⁺ and SO₄ groups, while the host assumes a regular pinched cone conformation. When 1,10-DD²⁺·2TFPB⁻ was added to a CD₃CN solution of 2 no appreciable interaction has been detected by NMR spectroscopy, and analogous results were observed during the complexation experiments between 2 and 1,4-DB²⁺. Probably, in this case the C_n-chains (n = 10 and 4) are respectively too long and too short to allow the two-point double-hydrogen bonding between terminal ammonium groups and sulfate bridges as proposed for the 1,8-DO²⁺ ⊂ 2 complex (Fig. 7). ¹H NMR spectroscopy and high-resolution MS evidenced¹³ that tetrasulfate cavitand 2 is able to interact with the DMV²⁺ guest (Fig. 8) with a 1 : 1 stoichiometry.¹³ A value of 1200 M⁻¹ was found by ¹H NMR titration for the association constant of the DMV²⁺ ⊂ 2 complex. A close inspection of the energy-minimized (OPLS force field) structure of the DMV²⁺ ⊂ 2 complex (Fig. 8, bottom) suggests that the positive N-atoms of the guest are in close contact with SO₄ bridges of 2 (average distance N⁺⋯O=S of 3.5 Å) to establish ion–dipole interactions. The formation of the DMV²⁺ ⊂ 2 complex was unequivocally confirmed by the base peak at 625.1068 m/z (calcd 625.1070) in the MALDI-FT-ICR mass spectrum (Fig. 8) in accordance with the molecular formula of the complex.

Fig. 7 Minimized structures (molecular mechanics calculations, OPLS force field) of: (bottom) DMV²⁺ ⊂ 2; (top) 1,8-DO²⁺ ⊂ 2.

Fig. 8 Significant portion of the HR MALDI FT-ICR mass spectrum of the DMV²⁺ ⊂ 2 complex (calcd 625.1070), showing the isotopic envelop with a Δ spacing of 0.5 m/z.

In fact, the Δ spacing of 0.5 m/z between the peaks in the isotopic envelop (Fig. 8) solely accounts for a doubly charged species of 1,8-DO²⁺ ⊂ 2, excluding the supramolecular structure with higher charges.

Conclusions

In conclusion, we have reported here the first example of a resorcin[6]arene cavitand in which sulfate bridges were introduced between the OH groups. Such bridging elements have the double role of structural scaffolds and of functional supramolecular interacting groups. Consequently, the obtained tetrasulfate cavitand is able to interact in solution with the 1,8-diammoniumoctane cation via a two-point double-hydrogen bonding between the ammonium groups and the sulfate bridges. The resorcin[6]arene cavitand is also able to complex the dimethylviologen cation by means of ion–dipole interactions. The resorcin[6]arene cavitand described here can be considered one the first examples of supramolecular application of larger resorcinarene macrocycles which could show further intriguing supramolecular properties.

Notes and references

1. K. Rissanen, Angew. Chem., Int. Ed., 2005, 44, 3652.
2. D. J. Cram, Science, 1983, 38, 456; D. J. Cram and J. M. Cram, in Container Molecules and Their Guests, Monographs in Supramolecular Chemistry, ed. J. F. Stoddart, Royal Society of Chemistry, Cambridge, 1994, ch. 5; L. M. Tunstad, J. A. Tucker, E. Dalcanale, J. Weiser, J. A. Bryant, J. C. Sherman, R. C. Helgeson, C. B. Knobler and D. J. Cram, J. Org. Chem., 1989, 54, 1305.
3. I. Pochorovski and F. Driedrich, Acc. Chem. Res., 2014, 47, 2096; S. M. Biros and J. Rebek Jr., Chem. Soc. Rev., 2007, 36, 93; S. Mosca, D. Ajami and J. Rebek Jr., Proc. Natl. Acad. Sci. U. S. A., 2015, 112, 11181; N. K. Beyeh, M. Cetina and K. Rissanen, Chem. Commun., 2014, 50, 1959; R. Pinalli, G. Brancatelli, A. Pedrini, D. Menozzi, D. Hernandez, P. Ballester, S. Geremia and E. Dalcanale, J. Am. Chem. Soc., 2016, 138, 8569; N. K. Beyeh, M. Cetina and K. Rissanen, Chem. Commun., 2014, 50, 1959; E. Busseron, J. Lux, M. Degardin and J. Rebek Jr., Chem. Commun., 2013, 49, 4842–4844; O. Perraud, V. Robert, A. Martinez and J.-P. Dutasta, Chem. – Eur. J., 2011, 17, 13405.
4. R. Pinalli and E. Dalcanale, Acc. Chem. Res., 2013, 46, 399; M. R. Ams, D. Ajami, S. L. Craig, J.-S. Yang and J. Rebek Jr., J. Am. Chem. Soc., 2009, 131, 13190; I. Alessandri, E. Biavardi, A. Gianoncelli, P. Bergese and E. Dalcanale, ACS Appl. Mater. Interfaces, 2016, 22, 14944; J. Ampurdanes, G. A. Crespo, A. Maroto, M. A. Sarmentero, P. Ballester and F. X. Rius, Biosens. Bioelectron., 2009, 25, 344; S. Neri, R. Pinalli, E. Dalcanale and L. J. Prins, ChemNanoMat, 2016, 2, 489; D. Masseroni, E. Biavardi, D. Genovese, E. Rampazzo, L. Prodi and E. Dalcanale, Chem. Commun., 2015, 51, 12799.
5. A. Galan and P. Ballester, Chem. Soc. Rev., 2016, 45, 1720; L. Marchetti and M. Mevine, ACS Catal., 2011, 1, 362; A. Mirabaud, J.-C. Mulatier, A. Martinez, J.-P. Dutasta and V. Dufaud, Catal. Today, 2016 DOI:10.1016/j.cattod.2016.03.050; R. J. Hooley, J. Richard and J. Rebek Jr., Chem. Biol., 2009, 16, 255; D. Masseroni, S. Mosca, M. P. Mower, D. G. Blackmond and J. Rebek Jr., Angew. Chem., Int. Ed., 2016, 55, 8290; W. Nai-Wei and J. Rebek Jr., J. Am. Chem. Soc., 2016, 138, 7512; A. Mirabaud, J.-C. Mulatier, A. Martinez, J.-P. Dutasta and V. Dufaud, ACS Catal., 2015, 5, 6748; J. Hong, K. E. Djernes, I. Lee, R. J. Hooley and F. Zaera, ACS Catal., 2013, 3, 2154.
6. P. Delangle and J.-P. Dutasta, Tetrahedron Lett., 1995, 36, 9325.
7. C. Tudisco, P. Betti, A. Motta, R. Pinalli, L. Bombaci, E. Dalcanale and G. G. Condorelli, Langumir, 2012, 28, 1782.
8. M. Dionisio, G. Oliviero, D. Menozzi, S. Federici, R. M. Yebeutchou, F. P. Schmidtchen, E. Dalcanale and P. Borgese, J. Am. Chem. Soc., 2012, 134, 2392.
9. P. Della Sala, C. Gaeta, W. Navarra, C. Talotta, M. De Rosa, G. Brancatelli, S. Geremia and P. Neri, J. Org. Chem., 2016, 81, 5726.
10. G. Brancatelli, S. Geremia, C. Gaeta, P. Della Sala, C. Talotta, M. De Rosa and P. Neri, CrystEngComm, 2016, 18, 5045.
11. For an example of a resorcin[6]arene-based cavitand in which methylene bridges were introduced between the OH groups, see: C. Naumann, E. Román, C. Peinador, T. Ren, B. O. Patrick, A. E. Kaifer and J. C. Sherman, Chem. – Eur. J., 2001, 7, 1637.
12. B.-T. Guan, X.-Y. Lu, Y. Zheng, D.-G. Yu, T. Wu, K.-L. Li, B.-J. Li and Z.-J. Shi, Org. Lett., 2010, 12, 396.
13. See ESI† for further details.
14. J. Wöhnert, J. Brenn, M. Stoldt, O. Aleksiuk, F. Grynszpan, I. Thondorf and S. E. Biali, J. Org. Chem., 1998, 63, 3866.
15. F. Troisi, C. Gaeta and P. Neri, Tetrahedron Lett., 2005, 46, 8041.
16. R. J. Kurland, M. B. Rubin and M. B. Wise, J. Chem. Phys., 1964, 40, 2426.
17. T. Steiner, Angew. Chem., Int. Ed., 2002, 41, 48.
18. K. Hirose, in Analytical Methods in Supramolecular Chemistry, ed. C. A. Schalley, Wiley-VCH, Weinheim, 2007, pp. 17–54.
19. S. H. Strauss, Chem. Rev., 1993, 93, 927.
20. C. Talotta, C. Gaeta and P. Neri, Org. Lett., 2012, 14, 3104; C. Gaeta, C. Talotta, F. Farina, M. Camalli, G. Campi and P. Neri, Chem. – Eur. J., 2012, 18, 1219.

---

Footnotes

† Electronic supplementary information (ESI) available. CCDC 1485235. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00336b

‡ Diffraction data were collected at the XRD1 beam-line of the Elettra synchrotron (Trieste, Italy). Crystallographic information. CCDC 1485235.¹³ Crystal data for 2: monoclinic, P21/n, Z = 4, a = 13.909(4) Å, b = 20.264(2) Å, c = 22.762(2) Å, α = 90, β = 91.41(3)°, V = 6414(2) ų, T = 100 K, D_x = 1.173 g cm⁻³, μ_calc = 0.217 mm⁻¹.

---