Synthesis of a [2]catenane by ring closing metathesis of a [2]rotaxane prepared by crown ether active templation

Abstract

The high yielding synthesis and spectral characterization of a [2]catenane prepared by Grubbs catalyzed ring closing metathesis of a [2]rotaxane prepared by crown ether active template synthesis is described.

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Introduction

[2]Catenanes¹ – molecules consisting of two interlocked macrocyclic rings – are typically synthesized by templated self-assembly followed by covalent bond formation. Classic examples of templates/templating interactions used in the self-assembled synthesis of [2]catenanes include metal cations,² π–π stacking³ and hydrogen bonding.⁴ Considering the emerging functional applications of [2]catenanes (e.g. receptors in host–guest chemistry⁵ and as catalysts in chemical reactions⁶) – the ready access to such species is paramount.

As part of investigations aiming to achieve post-synthetic modification of mechanically interlocked molecules⁷ – we wished to prepare a [2]catenane possessing amide N–H functionality not sterically blocked by the interlocked architecture. Our attention was caught by the recently disclosed crown ether active templation methodology for the synthesis of rotaxanes.⁸ Conversion of a [2]rotaxane into a [2]catenane is possible by cyclizing an appropriately functionalized axle component.⁹ We therefore proposed that by attaching terminal vinyl groups to the axle of a [2]rotaxane prepared by crown ether active template synthesis (CEATS), that cyclization to a [2]catenane could be achieved by Grubbs catalyzed ring closing metathesis (RCM) (Fig. 1).¹⁰ This communication details the successful execution of this proposed strategy, hence demonstrating that CEATS may be used to prepare [2]rotaxane precursors to [2]catenanes.¹¹

Fig. 1 Schematic retrosynthetic analysis of target [2]catenane.

Results and discussion

Our successful route, used the amide-forming CEATS (rather than our original plan to use the nucleophilic aromatic substitution variant), requiring synthesis of amine (HA-1) and activated ester (HA-2) half-axles (Schemes 1 and 2).¹¹ Trifluoromethyl and tert-butyl groups were included in HA-1 and HA-2 respectively to act as steric blocking groups to ensure capture of crown ether macrocycle upon axle formation.¹² Rigid aromatic spacers to the terminal vinyl groups were also included to entropically aid the final RCM cyclization step.

Scheme 1 Synthesis of amine half axle HA-1.

Scheme 2 Synthesis of activated ester half axle HA-2.

The synthetic route to amine half-axle HA-1 is presented in Scheme 1. Phenol 2¹³ was alkylated with the mesylate of compound 1¹⁴ to afford compound 3. Subsequent hydrolysis of the ester generated carboxylic acid 4. This was then converted to its acid chloride (using oxalyl chloride and catalytic DMF) and reacted with amine 5.¹⁵ The isolated amide 6 was subjected to Boc-deprotection using TFA to afford the amine half axle HA-1.

The synthesis of the activated ester half axle HA-2 is shown in Scheme 2. Installation of the tertiary amide was accomplished via an acid chloride mediated amide formation of mono-methyl ester 7¹⁶ with secondary amine 8.¹⁷ Hydrolysis of the ester in 9 was then carried out to afford carboxylic acid 10. Finally, to generate the target activated ester HA-2, carboxylic acid 10 was reacted with p-nitrophenol via EDC-mediated ester formation.

With the half axles now in hand, rotaxane synthesis could be attempted (Scheme 3). Half axle HA-1 and 24-crown-8 (24-c-8)¹⁸ were dissolved in dry toluene and stirred for 10 minutes. Then, Et₃N was added followed by slow addition of a solution of 1.3 equivalents of activated ester HA-2 in dry toluene. The reaction was left to stir at room temperature for four days. The reaction mixture was then concentrated to dryness and purified by column chromatography. Target [2]rotaxane R was isolated in a 50% yield.

Scheme 3 Synthesis of [2]rotaxane R and [2]catenane C.

[2]Rotaxane R was characterized by NMR and IR spectroscopies, and high-resolution mass spectrometry. Evidence for rotaxane formation is clearly visible upon comparison of the ¹H NMR spectra of [2]rotaxane R and free axle Ax (Fig. 2). The crown ether protons a are split as the two faces of the ring experience different chemical environments. There are also downfield shifts for the newly formed axle amide N–H β, along with axle protons 23, 25, 26, 29 and 35, arising from hydrogen bonding to oxygen atoms of the crown ether ring. Further evidence to support isolation of [2]rotaxane R was provided by detection of the molecular ion peak, [M + H]⁺, at m/z = 1242.6509 Da, in the high resolution mass spectrum (see ESI†).

Fig. 2 Partial ¹H NMR spectra of (a) the free axle Ax, (b) [2]rotaxane R and (c) [2]catenane C (CDCl₃, 400 MHz, 298 K). See Scheme 3 for atom labels.

With [2]rotaxane R afforded in sufficient quantity, synthesis of target [2]catenane C was undertaken. To generate the catenane, a ring closing metathesis using Grubbs first-generation catalyst (Grubbs I) under high dilution conditions was selected (Scheme 3). The synthesis began by dissolving [2]rotaxane R in dry CH₂Cl₂ to afford a 1.2 μM solution. Grubbs I catalyst (20 mol%) was added portion wise over 30 minutes, then the reaction was stirred in the dark for 16 hours. The reaction mixture was then concentrated to dryness and the crude material chromatographically purified, with [2]catenane C isolated in a yield of 86%.¹⁹

Evidence for the formation of [2]catenane C can be observed when comparing its ¹H NMR spectrum to that of [2]rotaxane R (Fig. 2). Despite broadening of axle peaks, successful cross metathesis is clearly identifiable by loss of terminal alkene protons 1 and 45 and simplification of the multiplet for protons 2 and 44 to two broad singlets (indicating formation of both olefinic geometric isomers).^20,21 Once again, isolation of the target interlocked molecule was provided by detection of the molecular ion peak, [M + H]⁺, at m/z = 1214.6211 Da, in the high resolution mass spectrum (see ESI†).

Conclusions

The synthesis of a [2]catenane by adaptation of the recently disclosed CEATS of [2]rotaxanes has been demonstrated. The combination of good and excellent yields for, respectively, [2]rotaxane and [2]catenane formation steps makes the synthetic route described above appealing for the preparation of [2]catenanes.²² The synthesis of further [2]catenanes, and their subsequent post-synthetic modification to allow for deployment in a range of host–guest applications, is ongoing in our laboratories and will be reported in due course.

Author contributions

NHE proposed the study. SRB conducted the synthesis and characterization of materials. NHE supervised the work, and completed further synthesis and characterization in response to the comments of the reviewers. NHE (with assistance from SRB) wrote the manuscript. SRB (with assistance from NHE) complied the ESI.†

Data availability

Underlying data for this paper are provided in the ESI.† Electronic copies of NMR spectra (including fid files) will be available upon publication from: https://doi.org/10.17635/lancaster/researchdata/671 and https://doi.org/10.17635/lancaster/researchdata/685.

Conflicts of interest

There are no conflicts of interest to declare.

Acknowledgements

SRB is grateful for provision of EPSRC DTP PhD funding from the Engineering and Physical Sciences Research Council [EP/T518037/1] and a Sydney Andrew Scholarship from the Society of Chemical Industry. Mass spectrometry data were recorded by Karl Heaton of the mass spectrometry service at the University of York and Peter Bentley of the mass spectrometry service at Lancaster University.

References

1. Q. Chen and K. Zhu, Chem. Soc. Rev., 2024, 53, 5677–5703.
2. (a) C.-O. Dietrich-Buchecker, J.-P. Sauvage and J.-P. Kintzinger, Tetrahedron Lett., 1983, 24, 5095–5098; (b) S. M. Goldup, D. A. Leigh, T. Long, P. R. McGonigal, M. D. Symes and J. Wu, J. Am. Chem. Soc., 2009, 131, 15924–15929; (c) S.-T. Tung, C.-C. Lai, Y.-H. Liu, S.-M. Peng and S.-H. Chiu, Angew. Chem., Int. Ed., 2013, 52, 13269–13272; (d) C. Lincheneau, B. Jean-Denis and T. Gunnlaugsson, Chem. Commun., 2014, 50, 2857–2860; (e) R. Mitra, M. Thiele, F. Octa-Smolin, M. C. Letzel and J. Niemeyer, Chem. Commun., 2016, 52, 5977–5980.
3. (a) P. R. Ashton, T. T. Goodnow, A. E. Kaifer, M. V. Reddington, A. M. Z. Slawin, N. Spencer, J. F. Stoddart, C. Vicent and D. J. Williams, Angew. Chem., Int. Ed. Engl., 1989, 28, 1396–1399; (b) D. G. Hamilton, J. K. M. Saunders, J. E. Davies, W. Clegg and S. J. Teat, Chem. Commun., 1997, 897–898.
4. (a) C. A. Hunter, J. Am. Chem. Soc., 1992, 114, 5303–5311; (b) F. Vögtle, S. Meier and R. Hoss, Angew. Chem., Int. Ed. Engl., 1992, 31, 1619–1622; (c) A. G. Johnston, D. A. Leigh, R. J. Pritchard and M. D. Deegan, Angew. Chem., Int. Ed. Engl., 1995, 34, 1209–1212; (d) C. N. Marrs and N. H. Evans, Org. Biomol. Chem., 2015, 13, 11021–11025; (e) J. E. M. Lewis, Org. Biomol. Chem., 2019, 17, 2442–2447.
5. J. T. Wilmore and P. D. Beer, Adv. Mater., 2024, 36, 2309098.
6. A. W. Heard, J. M. Suárez and S. M. Goldup, Nat. Rev. Chem., 2022, 6, 182–196.
7. P. Waelès, M. Gauthier and F. Coutrot, Angew. Chem., Int. Ed., 2020, 60, 16778–16799.
8. (a) S. D. P. Fielden, ChemSystemsChem, 2024, 6, e202300048; (b) S. D. P. Fielden, D. A. Leigh, C. T. McTernan, B. Pérez-Saavedra and I. J. Vitorica-Yrezabal, J. Am. Chem. Soc., 2018, 140, 6049–6052; (c) C. Tian, S. D. P. Fielden, G. F. S. Whitehead, I. J. Vitorica-Yrezabal and D. A. Leigh, Nat. Commun., 2020, 11, 744; (d) C. Tian, S. D. P. Fielden, B. Pérez-Saavedra, I. J. Vitorica-Yrezabal and D. A. Leigh, J. Am. Chem. Soc., 2020, 142, 9803–9808; (e) S. Amano, S. D. P. Fielden and D. A. Leigh, Nature, 2021, 594, 529–534; (f) L. Binks, C. Tian, S. D. P. Fielden, I. J. Vitorica-Yrezabal and D. A. Leigh, J. Am. Chem. Soc., 2022, 144, 15838–15844.
9. (a) A. Coskun, S. Saha, I. Aprahamian and J. F. Stoddart, Org. Lett., 2008, 10, 3187–3190; (b) A. Tron, H.-P. J. de Rouville, A. Ducrot, J. H. R. Tucker, M. Baroncini, A. Credi and N. D. McClenaghan, Chem. Commun., 2015, 51, 2810–2813; (c) M. Zhang and G. De Bo, J. Am. Chem. Soc., 2020, 142, 5029–5033.
10. Examples of using Grubbs RCM to synthesize [2]catenanes from self-assembled pseudorotaxanes or orthogonal complexes: (a) B. Mohr, J.-P. Sauvage, R. H. Grubbs and M. Weck, Angew. Chem., Int. Ed. Engl., 1997, 36, 1308–1310; (b) D. G. Hamilton, N. Feeder, S. J. Teat and J. K. M. Sanders, New J. Chem., 1998, 22, 1019–1021; (c) M. R. Sambrook, P. D. Beer, J. A. Wisner, R. L. Paul and A. R. Cowley, J. Am. Chem. Soc., 2004, 126, 15364–15365; (d) A.-M. L. Fuller, D. A. Leigh, P. J. Lusby, A. M. Z. Slawin and D. B. Walker, J. Am. Chem. Soc., 2005, 127, 12612–12619; (e) L. C. Gilday, T. Lang, A. Caballero, P. J. Costa, V. Félix and P. D. Beer, Angew. Chem., Int. Ed., 2013, 52, 4356–4360; (f) I. C. Gibbs-Hall, N. A. Vermeulen, E. J. Dale, J. J. Henkelis, A. K. Blackburn, J. C. Barnes and J. F. Stoddart, J. Am. Chem. Soc., 2015, 137, 15640–15643; (g) J. P. Byrne, S. Blasco, A. B. Aletti, G. Hessman and T. Gunnlaugsson, Angew. Chem., Int. Ed., 2016, 55, 8983–8943.
11. For subsequent investigations, we originally targeted a [2]catenane possessing a single amide N–H, anticipating RCM of a [2]rotaxane prepared by the nucleophilic aromatic substitution variant of CEATS. However, as detailed in the ESI,† the yields of rotaxane formation were very low. Hence attention turned to preparing a [2]rotaxane by use of the amide formation variant of CEATS. As a consequence, [2]rotaxane R and [2]catenane C possess two N–H amides – but the amide N–H (β) formed by CEATS is sterically blocked by the 24-c-8 macrocycle.
12. Leigh and co-workers have reported that using the electron withdrawing trifluoromethyl instead of tert-butyl group on the amine half-axle leads to higher yields of [2]rotaxane formation in amide- forming CEATS (see ref. 8c).
13. Details of our synthesis of 2 from commercially available materials is to be found in the ESI.†.
14. Details of our synthesis of 1 from commercially available materials is to be found in the ESI.†.
15. C. B. Lan and K. Auclair, Eur. J. Org. Chem., 2021, 5135–5146.
16. A. R. Sapala, G. P. Maurya, H. Singh, N. Mehta, T. Karmakar and V. Haridas, Org. Biomol. Chem., 2023, 21, 5372–5376.
17. W.-W. Wang, T. Liu, Y.-M. Lv, W.-Y. Zhang, Z.-G. Liu, J.-M. Gao and D. Li, ACS Chem. Neurosci., 2021, 12, 1593–1605.
18. V. S. Talanov and R. A. Bartsch, Synth. Commun., 1999, 29, 3555–3560.
19. Chromatographic separation of [2]rotaxane R and [2]catenane C proved challenging. As reported in the original manuscript submission, using column chromatography, SRB was able to collect two fractions containing predominantly [2]catenane C, one >99 : 1 C : R which was used for spectral characterization. In response to reviewer comments regarding how the yield of the reaction was being reported, NHE repeated the RCM reaction and using preparative TLC isolated pure [2]catenane C in the quoted yield of 86%.
20. Rotamers, arising from the presence of the N–Me amide, are observed in the ¹H NMR spectra recorded at room temperature in CDCl₃ of free axle Ax, [2]rotaxane R and [2]catenane C, as evidenced by splitting of proton 37 resonance in all three spectra. Notably, upon RCM to form [2]catenane C, the number of protons exhibiting rotameric behaviour increases, including splitting of the peak for macrocyclic proton a′.
21. Hydrogenation of the C=C bond (which may have simplified the ¹H NMR spectrum) was not attempted due to the likelihood of cleaving benzylic ether linkages.
22. As suggested by a reviewer, we are planning in future work to investigate the direct CEATS of a [2]catenane by use of a linked amine-activated ester precursor.

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Footnote

† Electronic supplementary information (ESI) available: Details of experimental procedures (including further synthetic investigations); copies of characterization spectra. See DOI: https://doi.org/10.1039/d4ob01028k

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