Synthesis of a highly strained deep cavitand

Abstract

Access to highly strained molecules remains a challenge. We report the synthesis of a bench-stable and highly strained (∼135 kcal mol⁻¹) deep cavitand (1). Synthesis of 1 follows a two-step protocol from known starting materials. The rigid structure of 1 contains four arch-shaped biphenyelenes with a large cavity (∼500 ų) to host fullerenes.

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Challenging Hückel's rule to discover new phenomena by bending aromatic systems from their stable planar geometry is an ongoing scientific endeavor.¹ Although the discovery of fullerenes brought to light spherical aromaticity,² the synthesis of discrete compounds with bent aromatic systems was considered a major challenge.³ Anthracene dimers and [n]cyclo-para-phenylacetylenes were the first molecular species with radial aromaticity.^4,5 Years later, the synthesis of [n]cyclo-para-phenylenes ([n]CPPs) was put forward by Jasti et al.⁶ To date, several methods have been developed to build highly-strained and contorted nanohoops⁷ revealing novel applications.⁸ The smallest [n]CPP reported to date is [5]CPP,^9,10 which has a strain energy (SE) of ∼120 kcal mol⁻¹ (Fig. 1a).¹¹ Other strained molecules close in SE to [5]CPP are known in the literature.^12–15 Further up on the SE scale are Stępień's carbazole-based bowls (Fig. 1b),¹⁶ and Kayahara and Yamago's doubly-annulated [10]cycloparaphenyelene (Fig. 1c),¹⁷ with 138/144 and ∼150 kcal mol⁻¹ of strain, respectively. Higher up on strain is a triple hoop compound with 24 aromatic rings at ∼153 kcal mol⁻¹ reported by Tian, Ye, and Sun (Fig. 1d).¹⁸ A similar, yet less strained, species was reported by Jasti et al.¹⁹ Last, and to the best of our knowledge, Tanaka's carbon cage (163 kcal mol⁻¹, Fig. 1e)²⁰ and Wang's molecular bowl (∼164 kcal mol⁻¹, Fig. 1f)²¹ display the largest SEs known to date. Here, we report 1 – a highly strained deep cavitand with SE of ∼135 kcal mol⁻¹ and unusually high host:guest binding affinity for fullerenes (Fig. 1g).

Fig. 1 Highly strained conjugated aromatic structures. (a)–(f) Previous examples reported in the literature. (g) This work, deep cavitand 1. Values shown correspond to the DFT-calculated strain energies. SE in (f) was calculated using StrainViz.²⁹

Our group and others have developed a synthetic approach towards contorted macrocycles based on macrocyclic arene species, e.g., resorcin[4]arenes.^22–25 In our work, the resulting tubular species develop a sizable strain in the last synthetic step reaching values of ca. 90 kcal mol⁻¹ at poor isolated yields of <1–3%. We hypothesized that low yields could be overcome by moving away from intermolecular reactions in exchange for intramolecular couplings. The success of this approach was demonstrated recently with the synthesis of 1m,²⁶ a non-strained analogue of 1, and has also been exemplified by others in recent reports.²⁷ Following an intramolecular Ni-mediated homocoupling reaction, and comparing it to our previous reports employing intermolecular cross couplings, led us to improve our yields by 20-fold in the strain-forming step.

The synthesis of 1 – a highly strained deep-cavity molecular container – consists on derivatizing 3²⁸ through a Suzuki – Miyaura cross coupling reaction with para-chlorophenyl boronic acid resulting in compound 2 in 75% yield (Fig. 2a). The yield obtained for 2 is remarkable as eight C–C bonds are formed. Subsequently, a Ni-mediated Yamamoto cross coupling leads to 1 as a white solid in 23% yield. In comparison, the intermolecular Suzuki–Miyaura cross coupling between 3 and 4,4′-biphenyldiboronic acid bis(pinacol) ester does not produce 1 in detectable quantities (Fig. 2a). Using meta-chlorophenyl boronic acid in this reaction sequence leads to 1m, which is substantially less rigid than 1 (SE = ∼9 kcal mol⁻¹, SI).²⁶

Fig. 2 (a) Templated synthesis of 1 indicating the intra- and intermolecular approach. (b) ¹H NMR of 1 in CDCl₃ collected at room temperature. Integration is provided considering one-fourth of 1. (c) Experimental MALDI MS molecular ion peaks of 1 (blue trace). Black trace represents the simulated [M]⁺ isotopic distribution. (d) Molecular crystal structure of 1 obtained at 100 K. Thermal ellipsoids are set at 50% probability level. The C and O atoms are colored grey and red, respectively. The H atoms and R groups are omitted for clarity. Inset: Chemdraw drawing indicating the torsional angle α. Maroon arrows indicate the distance of 1.6 nm from the midpoint of one distorted biphenyl to the opposing one.

Analysis of 2 via ¹H NMR displays six aromatic resonances indicating an ideal C₄-symmetric structure in solution (Fig. S1). Formation of 1 results in eight aromatic resonances suggesting that a species of similar symmetry to 2 is formed yet with additional intricacies (Fig. 2b). This observation led us to propose that phenylene ring “P” cannot freely rotate making resonances “a” and “c” no longer equivalent as in 2; similarly, “b” and “d” are unique resonances in 1. COSY and NOESY NMR supports the assignment of 1 (Fig. S5–S7). Note that MALDI-MS of 1 match perfectly the simulated pattern of its cationic molecular ion peak, [M]⁺ (Fig. 2c). Variable temperature ¹H NMR of 1 in 1,1,2,2-tetrachloroethane-d₂ (TeCA-d₂) from 25 to 115 °C showcases non-coalescing resonances confirming the rigid nature of “P” (Fig. S8). DFT calculations indicate a rotational barrier of ∼25 kcal mol⁻¹ for “P”, similar to other rigid systems.³⁰

The top-rim of 1 contains twelve phenylenes connected in a unique and alternating 2 : 1 para : meta fashion. We did not observe decomposition, color change, or the formation of new products during the purification of 1 using silica gel or after prolonged time on the benchtop, as shown through MALDI-MS and ¹H NMR. In contrast, other strained systems are known to decompose over time.^9,16 We grew colorless crystals by slow diffusion of MeCN into a chlorobenzene solution of 1. The structure of 1 is shown in Fig. 2d providing a clear view of the biphenyl contortion with an average displacement angle of 12.4(3) degrees, similar to [6]CPP (12.6 deg.),¹² and a torsional angle (α) of 10(3) deg. which is smaller than [5]CPP and [6]CPP at 12(2)⁹ and 26.4(7) deg.,³¹ respectively. Last, biphenyl contortion produces a large and unexpected shielding of the “g” resonance as it shifts from 6.74 ppm in 2 to 4.82 ppm in 1, suggesting an anisotropic effect is induced by the biphenyl moieties despite the distance of ∼5.2 Å to the centroid of “P”.

The SE of 1′ (R = Me) was calculated considering two different homodesmotic reactions (Fig. S9) and six different DFT functionals (Table S2). From all twelve calculations, the SE of 1′ ranges from 128 to 147 kcal mol⁻¹. Data obtained using B3LYP/6-31G(d) provides a SE for 1′ of ∼135 kcal mol⁻¹, which allow us to compare with literature values. For instance, the SE of [6]CPP is 97 kcal mol⁻¹ making an average strain of ∼16 kcal mol⁻¹ per aryl ring.¹² In comparison, the same metric for 1′ is ∼17 kcal mol⁻¹ considering only the aromatic rings within the four distorted biphenyls. In stark contrast, the meta-connected species 1m′ has a minor contortion of ∼9 kcal mol⁻¹ of SE or 1.1 kcal mol⁻¹ per aryl ring in the connecting biphenyls (Fig. S10).

We examined the electronic properties of 1 via UV-vis absorption, fluorescence emission, and supported our findings through TD-DFT calculations. Its lowest energy absorption band is observed at λ_max of 331 nm in CH₂Cl₂ at room temperature, which is red shifted by ∼80 nm relative to 1m (Fig. 3a). A fluorescence red shift of 81 nm is seen between 1 (λ_em = 425 nm) and 1m (λ_em = 344 nm). A visual comparison of the fluorescence shift is shown in Fig. S11. We attribute these differences to greater π conjugation in 1. The fluorescence quantum yield (ϕ_f) of 1 is 0.06 as determined by the relative method described by Williams et al.³² using anthracene as standard. For reference, [5]CPP and [6]CPP are not emissive.^9,10,31 The smallest member in the [n]CPP family with measurable fluorescence is [7]CPP with ϕ_f of 0.0007.³³ Based on TD-DFT calculations, we attribute the major absorption band in 1 at λ_max of 331 nm to H → L + 1 and H → L + 2 transitions, where H and L stands for HOMO and LUMO, respectively. The H → L transition is forbidden (Table S3), similar to [n]CPPs.¹¹ Despite heavy contortion of 1, its HOMO displays an overall benzenoid structure distributed over all twelve phenylenes atop the resorcin[4]arene (Fig. 3b). DFT results on 1′ indicate a HOMO–LUMO gap of 3.99 eV, while the unstrained analogue 1m′ has a larger gap of 4.73 eV, which is similar to the trend in [n]CPPs where the HOMO–LUMO gap increases as strain decreases.³⁴

Fig. 3 (a) UV-vis absorption and emission spectra of 1 (blue traces) and 1m (black traces) collected in CH₂Cl₂ at room temperature. (b) HOMO and LUMO density plots of 1 (±0.02 au).

The rigidity of 1 produces a large shape-persistent cavity. The crystal structure of 1 showcases cofacial packing producing a shared cavity space for twelve MeCN molecules. Using the molecular volume of MeCN (87.8 ų)³⁵ and the void space calculator of Olex2,³⁶ we determine the size of this cavity to be between 465 and 527 ų (Fig. S13). Molecular containers display cavities from ∼90 to ∼400 ų,^37–44 except for a recent report describing a species with a cavity of ∼800 ų.⁴⁵ Despite these reports, hosts with large pseudospherical cavities are rare.⁴⁶

We hypothesized 1 can host fullerenes, similar to 1m.^{26 1}H NMR titration experiments showed that addition of C₆₀ or C₇₀ to 1 generates a new set of resonances that co-exist with those of free host 1 (Fig. 4) suggesting a large association constant (K_a) for adduct formation. No further spectral changes are observed after addition of 1 equivalent of C₆₀. The benzal proton in 1, resonance “i”, experiences an upfield shift from 5.96 to 5.87 ppm and points directly at the π surface of C₆₀. Computational data demonstrates that shielding effects occur above the hexagonal rings in C₆₀ and C₇₀, and deshielding over the pentagons.⁴⁷ We conclude that on average the benzal proton in C₆₀ ⊂ 1 points at hexagons in C₆₀. Titration of C₇₀ to 1 also results in an upfield shift of the benzal proton to 5.87 ppm (Fig. S15); thus, nesting of C₆₀ and C₇₀ within 1 occurs in a similar fashion. Last, the diffusion properties of 1 and its fullerene adducts were probed via DOSY NMR. We expect 1 to have a larger diffusion coefficient (D) than its fullerene adducts (D = 1.34(1) × 10⁻¹⁰ m² s⁻¹, Fig. S16); however, it was surprising to find that adducts C₆₀ ⊂ 1 and C₇₀ ⊂ 1 also differ in its D from 1.26(1) × 10⁻¹⁰ to 1.10(1) × 10⁻¹⁰ m² s⁻¹ (Fig. S17 and S18), respectively.

Fig. 4 ¹H NMR titration of C₆₀ into 1 in TeCA-d₂ at room temperature.

Binding data for fullerene ⊂ 1 was obtained from fluorescence quenching experiments. Titration of C₆₀/C₇₀ into 1 were performed in TeCA (Fig. S19 and S20). Fitting of the data using Bindfit⁴⁸ reveals K_as of 5.7(13) × 10⁵ and 5.5(19) × 10⁵ M⁻¹ for C₆₀ ⊂ 1 and C₇₀ ⊂ 1, respectively, which are lower than the non-strained analogues C₆₀ ⊂ 1m and C₇₀ ⊂ 1m.²⁶ These K_as are medium-to-large,⁴⁹ with the exception of a few examples displaying higher binding affinities.^50,51 Last, we calculated the non-covalent interaction surface through the Hirshfeld partition of molecular density (IGMH) to visualize the nesting between C₆₀ or C₇₀ and 1.⁵² The IGMH isosurface shows the interaction between the contorted biphenyls, π contacts, and the benzal protons of 1 with fullerene's π surface (Fig. S21).

In summary, we developed the synthesis of 1 – a highly strained deep cavitand built atop an alkyl resorcin[4]arene scaffold. The final product contains four highly contorted arch-shaped biphenylenes. The overall strain energy of 1 is ∼135 kcal mol⁻¹. The rigid structure of 1 produces a large internal void space enough to accommodate fullerenes. Our approach will allow the synthesis of other highly strained molecules pushing the known boundaries in contorted aromatic chemistry.

This research was partially supported by NSF CAREER CHE-2302628 and funds by Rice University. R. H. S. acknowledges the support of the Robert A. Welch Foundation Young Investigator Award and Welch Foundation grant C-2142-20230405. We thank Dr Christopher L. Pennington for assistance with HRMS. S. M. acknowledges the support from the Dietrich School of Arts & Sciences Graduate Fellowship and the Andrew Mellon Pre-doctoral Fellowship. We thank the support from the CRC and instrumentation made available through SEA at Rice University.

Conflicts of interest

There are no conflicts to declare.

Data availability

All the supporting data associated with this work are available in the SI. The SI includes general experimental procedures, characterization details, crystallographic information, ¹H NMR, ¹³C NMR, UV-vis, and fluorescence spectra of all compounds (PDF). See DOI: https://doi.org/10.1039/d5cc04263a

CCDC 2393731 contains the supplementary crystallographic data for this paper.⁵³

Notes and references

1. M. A. Majewski and M. Stepien, Angew. Chem., Int. Ed., 2019, 58, 86–116.
2. M. Bühl and A. Hirsch, Chem. Rev., 2001, 101, 1153–1184.
3. P. R. Ashton, N. S. Isaacs, F. H. Kohnke, A. M. Z. Slawin, C. M. Spencer, J. F. Stoddart and D. J. Williams, Angew. Chem., Int. Ed. Engl., 1988, 27, 966–969.
4. S. Kammermeier, P. G. Jones and R. Herges, Angew. Chem., Int. Ed. Engl., 1996, 35, 2669–2671.
5. T. Kawase, H. R. Darabi and M. Oda, Angew. Chem., Int. Ed. Engl., 1996, 35, 2664–2666.
6. R. Jasti, J. Bhattacharjee, J. B. Neaton and C. R. Bertozzi, J. Am. Chem. Soc., 2008, 130, 17646–17647.
7. S. Mirzaei, E. Castro and R. Hernández Sánchez, Chem. – Eur. J., 2021, 27, 8642–8655.
8. E. J. Leonhardt and R. Jasti, Nat. Rev. Chem., 2019, 3, 672–686.
9. P. J. Evans, E. R. Darzi and R. Jasti, Nat. Chem., 2014, 6, 404–408.
10. E. Kayahara, V. K. Patel and S. Yamago, J. Am. Chem. Soc., 2014, 136, 2284–2287.
11. T. Iwamoto, Y. Watanabe, Y. Sakamoto, T. Suzuki and S. Yamago, J. Am. Chem. Soc., 2011, 133, 8354–8361.
12. E. R. Darzi and R. Jasti, Chem. Soc. Rev., 2015, 44, 6401–6410.
13. L.-H. Wang, N. Hayase, H. Sugiyama, J. Nogami, H. Uekusa and K. Tanaka, Angew. Chem., Int. Ed., 2020, 59, 17951–17957.
14. X. Zhang, H. Shi, G. Zhuang, S. Wang, J. Wang, S. Yang, X. Shao and P. Du, Angew. Chem., Int. Ed., 2021, 60, 17368–17372.
15. C. Chi, Y. Han, S. Dong, J. Shao and W. Fan, Angew. Chem., Int. Ed., 2021, 60, 2658–2662.
16. D. Myśliwiec, M. Kondratowicz, T. Lis, P. J. Chmielewski and M. Stępień, J. Am. Chem. Soc., 2015, 137, 1643–1649.
17. L. Sun, E. Kayahara, T. Nishinaga, M. Ball, D. Paley, C. Nuckolls and S. Yamago, Bull. Chem. Soc. Jpn., 2024, 97, uoad011.
18. Q. Zhou, Z. Xu, K. Li, X. Tian, L. Ye and Z. Sun, Chem. – Asian J., 2024, 19, e202301131.
19. T. D. Clayton, J. M. Fehr, T. W. Price, L. N. Zakharov and R. Jasti, J. Am. Chem. Soc., 2024, 146, 30607–30614.
20. N. Hayase, J. Nogami, Y. Shibata and K. Tanaka, Angew. Chem., Int. Ed., 2019, 58, 9439–9442.
21. W. Zhang, Y. Ding, S. Yu, J. Lyu, J. Yu, J. Li, X. Zhao, L. Feng, J. Wang, Z. Zhou and Q. Wang, Angew. Chem., Int. Ed., 2025, 64, e202425355.
22. E. André, B. Boutonnet, P. Charles, C. Martini, J.-M. Aguiar-Hualde, S. Latil, V. Guérineau, K. Hammad, P. Ray, R. Guillot and V. Huc, Chem. – Eur. J., 2016, 22, 3105–3114.
23. S. Mirzaei, E. Castro and R. Hernández Sánchez, Chem. Sci., 2020, 11, 8089–8094.
24. E. Castro, S. Mirzaei and R. Hernández Sánchez, Org. Lett., 2021, 23, 87–92.
25. A. Nasser Moussa Bamba, A. Ben Saida, I. Abdellah, S. Latil, V. Guérineau, J.-F. Gallard and V. Huc, Eur. J. Org. Chem., 2024, e202400485.
26. S. Mirzaei, H. Khosravi, X. Hu, M. S. Mirzaei, V. M. E. Castro, X. Wang, N. A. Figueroa, T. Chang, Y.-P. Chen, G. P. Ríos, N. I. Gonzalez-Pech, Y.-S. Chen and R. Hernández Sánchez, Angew. Chem., Int. Ed., 2025, 64, e202505083.
27. Z. Sun, K. Ikemoto, T. M. Fukunaga, T. Koretsune, R. Arita, S. Sato and H. Isobe, Science, 2019, 363, 151–155.
28. K. Srinivasan and B. C. Gibb, Org. Lett., 2007, 9, 745–748.
29. C. E. Colwell, T. W. Price, T. Stauch and R. Jasti, Chem. Sci., 2020, 11, 3923–3930.
30. Z. Sun, T. Suenaga, P. Sarkar, S. Sato, M. Kotani and H. Isobe, Proc. Natl. Acad. Sci. U. S. A., 2016, 113, 8109.
31. J. Xia and R. Jasti, Angew. Chem., Int. Ed., 2012, 51, 2474–2476.
32. A. T. R. Williams, S. A. Winfield and J. N. Miller, Analyst, 1983, 108, 1067–1071.
33. T. J. Sisto, M. R. Golder, E. S. Hirst and R. Jasti, J. Am. Chem. Soc., 2011, 133, 15800–15802.
34. K. Kanai, T. Inoue, T. Furuichi, K. Shinoda, T. Iwahashi and Y. Ouchi, Phys. Chem. Chem. Phys., 2021, 23, 8361–8367.
35. M. Sakurai, J. Chem. Eng. Data, 1992, 37, 358–362.
36. O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard and H. Puschmann, J. Appl. Cryst., 2009, 42, 339–341.
37. J. R. Moran, S. Karbach and D. J. Cram, J. Am. Chem. Soc., 1982, 104, 5826–5828.
38. D. M. Rudkevich, G. Hilmersson and J. Rebek, J. Am. Chem. Soc., 1997, 119, 9911–9912.
39. H. Xi and C. L. D. Gibb, Chem. Commun., 1998, 1743–1744.
40. F. C. Tucci, D. M. Rudkevich and J. Rebek, J. Org. Chem., 1999, 64, 4555–4559.
41. E. Botana, K. Nättinen, P. Prados, K. Rissanen and J. de Mendoza, Org. Lett., 2004, 6, 1091–1094.
42. I. Pochorovski, C. Boudon, J.-P. Gisselbrecht, M.-O. Ebert, W. B. Schweizer and F. Diederich, Angew. Chem., Int. Ed., 2012, 51, 262–266.
43. F. Bertani, N. Riboni, F. Bianchi, G. Brancatelli, E. S. Sterner, R. Pinalli, S. Geremia, T. M. Swager and E. Dalcanale, Chem. – Eur. J., 2016, 22, 3312–3319.
44. J. Pfeuffer-Rooschüz, L. Schmid, A. Prescimone and K. Tiefenbacher, JACS Au, 2021, 1, 1885–1891.
45. J. Pfeuffer-Rooschüz, S. Heim, A. Prescimone and K. Tiefenbacher, Angew. Chem., Int. Ed., 2022, 61, e202209885.
46. B. Chen, J. J. Holstein, S. Horiuchi, W. G. Hiller and G. H. Clever, J. Am. Chem. Soc., 2019, 141, 8907–8913.
47. E. Kleinpeter, S. Klod and A. Koch, J. Org. Chem., 2008, 73, 1498–1507.
48. https://supramolecular.org.
49. X. Chang, Y. Xu and M. von Delius, Chem. Soc. Rev., 2024, 53, 47–83.
50. H. Isobe, S. Hitosugi, T. Yamasakia and R. Iizukaa, Chem. Sci., 2013, 4, 1293–1297.
51. M. Takeda, S. Hiroto, H. Yokoi, S. Lee, D. Kim and H. Shinokubo, J. Am. Chem. Soc., 2018, 140, 6336–6342.
52. T. Lu and Q. Chen, J. Comput. Chem., 2022, 43, 539–555.
53. M. S. Mirzaei, S. Mirzaei, H. Khosravi, R. Hernández Sánchez, CCDC 2393731: Experimental Crystal Structure Determination, 2024 DOI:10.5517/ccdc.csd.cc2lbw4z.

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Footnote

† These authors contributed equally.

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