Fluorinated [2]rotaxanes with spirofluorene motifs: a non-symmetric distribution of the ring component along the axle component

Abstract

Oxidative dimerization of terminal alkynes (Glaser coupling) triggered by spirofluorene derived macrocyclic phenanthroline–Cu complexes was implemented to synthesize a series of novel [2]rotaxanes. Size and structural variations among the components and their implications on the dynamic behaviour were investigated in detail through ¹H and ¹⁹F NMR spectroscopy. Strong perturbations in the NMR spectra of the rotaxanes with substituted macrocyclic components with low symmetry indicated the non-symmetric distribution of the ring component along the axle component. In some [2]rotaxanes, localization of the ring component in the proximity of the 1,3-diyne moiety was observed.

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Introduction

Mechanical entrapping of otherwise disparate constituents has played a quintessential role in broadening the canvas of modern supramolecular chemistry. This restricted positioning of dissimilar molecules eventually led to the development of mechanically interlocked molecules (MIMs) like rotaxanes, catenanes, knots, etc.^1,2 The potential applications of these MIMs in general and rotaxanes in particular in various fields like nanoelectronics, polymer chemistry, catalysis and medical science are continuously increasing their traction.^3–7 Accordingly, many synthetic methodologies like template synthesis, self-assembly, or metal mediated coupling reactions were developed to access these attractive targets through efficient ways.⁸

In addition to their alluring structural and physio-chemical attributes, control of the distribution of components in rotaxanes has been studied thoroughly to understand their dynamic behavior and elaborated further to develop stimuli-responsive molecular systems.⁹ A localized distribution of the ring component along the axle has been achieved by introducing functional groups so that two components could interact (Fig. 1a).^1,2 Alternatively, introduction of a bulky substituent in the axle component that acts as a kinetic barrier resulted in the restricted movement of the ring component (Fig. 1b).¹⁰ This restricted movement may have far reaching consequences on the properties and applications of these rotaxanes and represents an important area for further investigations.

Fig. 1 Control of the distribution of the ring component in [2]rotaxanes.

We have been using resorcinol–stitched macrocyclic phenanthroline–Cu complexes for the synthesis of rotaxanes and catenanes by effectively harnessing the catalytic activity of these complexes.¹¹ We envisioned that the introduction of a substituted spiro structure with low symmetry into the ring component could also help to control the distribution of the ring component (Fig. 1c). In this article we report the synthesis of a series of novel spirofluorene-based [2]rotaxanes (Fig. 2). A non-symmetric distribution of the ring component was observed by introducing a spirofluorene motif with low symmetry into the ring component.

Fig. 2 [2]rotaxanes with a spirofluorene moiety.

Our quest for the synthesis of spirofluorene based [2]rotaxanes commenced with the syntheses of fluorinated axle precursors (3a–d, Scheme 1). Fluorine atoms were introduced to utilize ¹⁹F NMR spectroscopy for the conformational analysis of rotaxanes. Mitsunobu reaction was set up between alcohols (1a–d) bearing preinstalled terminal dumbbell moieties and TMS protected difluorophenol 2. After the removal of the TMS group, the axle precursors (3a–d) with different alkyl chain lengths were isolated (Scheme 1).

Scheme 1 Synthesis of axle precursors.

With required axle precursors in hand, our next target was the design and synthesis of macrocyclic components based upon the spirofluorene motif. 2-iodospiro[fluorene-9,9′-xanthene]-3′,6′-diol 4A, which acted as a common starting substrate, was synthesized from fluorene using a reported protocol.¹² Treatment of 4A with various dibromides resulted in the formation of the corresponding dialkylated precursors 5A–D in 73–94% yields (Table 1). To introduce bromoethyl groups, it was necessary to use an excess amount of 1,2-dibromoethane in the presence of K₂CO₃ and 18-crown-6 (entry 1).¹³ The synthesis of other compounds proceeded under standard conditions devised for the alkylation of phenols (entries 2–4).¹⁴

Table 1 Synthesis of 5A–D from 4A

Entry	Dibromide	Cond.	Compd.		Yield (%)
1	BrCH2CH2Br (excess)	K2CO3 18-crown-6 80 °C, 36 h	5A	CH2CH2	94
2	BrCH2CH2CH2Br (10 equiv.)	K2CO3 CH3CN reflux, 4 h	5B	CH2CH2CH2	73
3	BrCH2CH2CH2CH2Br (10 equiv.)	K2CO3 CH3CN reflux, 4 h	5C	CH2CH2CH2CH2	81
4		K2CO3 CH3CN reflux, 4 h	5D		86

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The macrocyclic complexes 9A–D were synthesized from 5A–D in three steps (Scheme 2). Williamson's etherification of 5A–D with 6¹⁵ produced the macrocycles 7A–D bearing iodo functionality. Sonogashira reaction of 7A–D with (tert-butyldimethylsilyl)acetylene (TBS acetylene) gave the macrocycles 8A–D with a spiro structure. Reaction of 8A–D with CuI produced the spirofluorene based macrocyclic copper complexes 9A–D.

Scheme 2 Synthesis of macrocyclic phenanthroline–Cu complexes 9A–D. Reagents and conditions, (a) K₂CO₃, DMSO : H₂O (99 : 1, v/v), 65 °C, 4 h, 59–68%; (b) Pd(PPh₃)₄, CuI, TBS acetylene, NEt₃ : DMF (dry, 1 : 2, v/v), rt, 18 h, 85–93%; (c) CuI, CH₂Cl₂ : CH₃CN (2.5 : 1, v/v), rt, 4 h, 90–95%.

Copper complexes 9A–D and the axle precursor 3c having a 12 carbon alkylene chain were used for the synthesis of rotaxanes incorporating different sizes of macrocyclic components (Scheme 3). A mixture of 9A–D (1 equiv.), terminal alkyne 3c (2.5 equiv.), I₂ (1.3 equiv.), and K₂CO₃ (3.8 equiv.) in dry xylene was heated at 130 °C for 24–36 h in a sealed tube. The oxidative dimerization of the terminal alkyne proceeded and metal complexed rotaxanes were formed. Demetallation was carried out by the addition of aqueous ammonia¹⁶ to yield rotaxanes 10Ac–10Dc along with the dimerized axle component 11c as a minor product. The influence of the structure of macrocycle on the yields of rotaxanes (76–82%) was small.

Scheme 3 Synthesis of rotaxanes with different macrocycles.

The ¹H NMR spectrum of the rotaxane 10Ac was recorded in CDCl₃¹⁷ and the spectrum was compared with those of the corresponding axle (11c) and ring (8A) components (Fig. 3). A notable difference between the spectra of the rotaxane 10Ac and axle component 11c is the splitting of some signals. In the spectrum of 11c, a doublet integrating to 4 protons was observed at 7.03 ppm and this signal was assigned to H^fg (Scheme 3). In the spectrum of rotaxane, splitting of this signal was observed and the two signals corresponding to H^f and H^g appeared at 6.68 and 7.50 ppm, respectively (Fig. 3).¹⁸ A similar splitting pattern was observed in the 3.7–4.2 ppm region. A triplet was observed at 4.15 ppm in the spectrum of the axle component 11c which was assigned as H^hi (Scheme 3). This signal appeared as two separate signals (H^h and Hⁱ) in the NMR spectrum of rotaxane 10Ac which were observed at 4.03 and 3.83 ppm, repectively (Fig. 3). This large separation was induced by the presence of the ring component with a less symmetric spiro structure. The signals of the ring component 8A above 7.5 ppm showed a slight upfield shift in rotaxane 10Ac. For instance, the two doublets at 8.37 and 8.24 ppm in 8A shifted to 8.20 ppm in 10Ac. This small upfield shift was frequently observed in other rotaxanes we synthesized.

Fig. 3 Comparison of ¹H NMR spectra of rotaxane 10Ac, axle component 11c and ring component 8A (CDCl₃, 500 MHz).

To gain further insights, ¹⁹F NMR spectra of the rotaxane 10Ac and the axle component 11c were compared (Fig. 4). Two separate signals for the fluorine atoms on the two aromatic rings of 10Ac were observed at −127.1 and −127.9 ppm, while a signal at −127.0 ppm was observed for 11c. The emergence of these two distinct signals reconfirmed the loss of symmetry of the system.

Fig. 4 ¹⁹F NMR spectra of rotaxane 10Ac and axle component 11c (CDCl₃, 377 MHz).

Encouraged by these findings, a comparative study of ¹H NMR spectra of rotaxanes 10Ac–10Dc was carried out and the reduced symmetry of the axle component in the rotaxanes was reflected in the NMR spectra, although to different extent (Fig. 5). In the ¹H NMR spectra, overlapping of the signals was observed in 10Cc and the analysis of the data was difficult (Fig. 5a). In other rotaxanes, a clear tendency was observed: the emergence of two separate signals and an upfield shift of one of the methylene groups was encountered in the spectra of rotaxanes 10Ac and 10Bc. Although we expected that the introduction of an aromatic ring in the linker would influence the chemical shifts of the methylene group, the observed difference in the chemical shifts was smallest for 10Dc, which can be attributed to the increased size of the macrocycle.

Fig. 5 Comparison of (a) ¹H and (b) ¹⁹F NMR spectra of rotaxanes 10Ac–10Dc and the axle component 11c (CDCl₃, 500 MHz for ¹H and 377 MHz for ¹⁹F). The signals of H^h and Hⁱ (Fig. 3) are marked with an asterisk.

As compared to the ¹H NMR spectra, the ¹⁹F NMR spectra could be analyzed with ease. The overlap of the signals did not occur, and two well separated signals were observed in rotaxanes 10Ac–10Dc (Fig. 5b). The observed values for ¹⁹F signals are summarized in Table 2. These signals mostly appeared between −127 to −128 ppm and a maximum difference of 0.75 ppm was observed between the two signals in case of 10Ac. As expected, the difference in the chemical shifts between two ¹⁹F signals decreased (from 0.75 ppm in the case of 10Ac to 0.07 ppm in the case of 10Dc) as the size of the ring component increased.

Table 2 ¹⁹F NMR chemical shifts (ppm, CDCl₃, 377 MHz) of the rotaxanes 10Ac–10Dc and the axle component 11c

Entry	Linker	Compound	δF		ΔδF^a
a ΔδF = δF (low field) − δF (high field).
1		10Ac	−127.12	−127.87	0.75
2		10Bc	−127.31	−127.65	0.34
3		10Cc	−127.00	−127.18	0.18
4		10Dc	−126.98	−127.05	0.07
5	(Axle component)	11c	−127.03		—

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Based on the observed upfield shifts of the signals of the methylene groups in the ¹H NMR spectra (Fig. 5a) and the fluorine signals in the ¹⁹F NMR spectra (Fig. 5b) of 10Ac–10Dc compared to those of the corresponding axle component 11c, we assumed that the upfield shifts were induced by the presence of the ring component in the proximity of the axle component. The splitting of the signals of the axle component in rotaxanes 10Ac–10Dc could be explained in two ways (Fig. 6). A simple “substituent effect” may be responsible for the observed spectra. The distribution of the ring component along the axle moiety would not be significantly affected by the spiro structure with low symmetry and the difference in the substituents attached to the spiro moiety (alkynyl group vs hydrogen atom) induced the difference in the observed chemical shifts (Fig. 6a). Alternatively, the distribution of the ring component could be modulated by the low symmetry of the spiro moiety (Fig. 6b). The presence of the bulky alkynyl group might induce a non-symmetric distribution of the ring component along the axle component, and a difference in the chemical shifts would be observed.

Fig. 6 Possible explanations for the difference in the NMR chemical shifts of 10Ac. (a) “Substituent effect”: the influence of (different) substituents on the ¹H and ¹⁹F NMR chemical shifts of the rotaxanes. (b) Difference in the distribution of the ring component induced by the presence of different substituents.

To understand the observed chemical shifts in the NMR spectra in depth, we synthesized symmetric spirofluorene based rotaxanes and observed their NMR spectra. Once again, the synthesis commenced from spirofluorene based diols 4B and 4C, readily accessible from a reaction of parent fluorenone or diiodofluorenone with resorcinol (Scheme 4).¹³ Compounds 4B and 4C upon dialkylation furnished 12 and 13. Solubility issues associated with 4C prompted us to slightly change the reaction sequence and a sequential dialkylation followed by a Sonogashira reaction was implemented (to install the two silylacetylene functionalities) prior to Williamson's etherification to yield 13. Williamson's etherification of 12 and 13 with 6 resulted in the formation of macrocyclic complexes 14 and 15. Treatment of these macrocycles with CuI produced the copper complexes 16 and 17.

Scheme 4 Synthesis of macrocyclic phenanthroline–Cu complexes with a symmetric spirofluorene moiety. Reagents and conditions, (a) K₂CO₃, 18-crown-6, BrCH₂CH₂Br, 80 °C, 36 h, 91% (for 12 from 4B); (b) Pd(PPh₃)₄, CuI, TBS acetylene, NEt₃ : DMF (dry, 1 : 2, v/v), rt, 18 h, 76% (for 13, over two steps from 4C); (c) 6, K₂CO₃, DMSO : H₂O (99 : 1, v/v), 65 °C, 4 h, 59–68%; (d) CuI, CH₂Cl₂ : CH₃CN (2.5 : 1, v/v), rt, 4 h, 89–92%.

With symmetrical macrocyclic copper complexes at our disposal, we synthesized corresponding rotaxanes using 3c as the axle precursor (Scheme 5). Oxidative dimerization was facilitated between the macrocyclic copper complexes (16 and 17) and the axle precursor 3c. The reaction of 16 was performed in THF at 75 °C and the rotaxane 18 was isolated in 66% yield. The reaction of 17 was performed in xylene at 130 °C and the yield of rotaxane 19 was 74%.

Scheme 5 Synthesis of rotaxanes with high symmetry.

The ¹H and ¹⁹F NMR spectra of 18 and 19 were compared with those of diyne 11c (Fig. 7). As expected, the symmetric nature of 18 and 19 was reflected in the NMR spectra, and only one signal was observed for the two-methylene proton sets as well as fluorine atoms on the axle component. High-field shifts were observed for H^hi (Scheme 5) in 18 and 19, and the difference in chemical shifts between the methylene protons (H^hi, Scheme 5) of 18 and 19 was very small (Fig. 7a). Similar results were observed in the ¹⁹F NMR spectra; the observed chemical shift was influenced by the presence of the ring component, but it was not essentially influenced by the presence (or the absence) of an alkynyl group in the ring component (Fig. 7b). The results strongly imply that a simple “substituent effect” (Fig. 6a) is not operating in the rotaxanes, since the observed difference in the spectra between 18 and 19 was very small. Therefore, the observed splitting of the signals in the NMR spectra of 10Ac should have been induced by a non-symmetric distribution of the ring component along the axle component (Fig. 6b).

Fig. 7 Comparison of (a) ¹H and (b) ¹⁹F NMR spectra of rotaxanes with symmetrical macrocycles (CDCl₃, 500 MHz for ¹H and 377 MHz for ¹⁹F). The signals of H^hi (Scheme 5) are marked with an asterisk.

The distribution of the ring component along the axle component in rotaxanes was further studied by comparing the NMR spectra of rotaxanes with different axle lengths. We assumed that the distribution of the ring component would be affected by the length of the axle if the ring component was not preferentially located at a specific position. The influence of the ring component would be more pronounced in rotaxanes with a shorter axle since the probability of its presence at a specific position on the axle component would increase. Accordingly, a larger effect of the ring component on the chemical shifts of the axle component could be observed in rotaxanes with a shorter axle component. To confirm this, macrocycle 9A and axle precursors with different alkylene chain lengths (3a,b,d) were used to synthesize the rotaxanes with various axle lengths (Scheme 6). Reaction of 3a,b,d with 9A gave rotaxanes 10Aa, 10Ab and 10Ad along with the dimers of the alkynes. The yields of 10Ab (73%) and 10Ad (78%) were satisfactory while the yield of 10Aa was low (44%). The decreased yield of 10Aa can be attributed to the increased steric bulk of the alkyne 3a, which slowed down the threading reaction. Although the reactive ethynyl moiety in 3a is far from the bulky triarylmethyl group, the presence of a vertically oriented TBS ethynyl group in 9A would retard the formation of the alkynylcopper intermediate.

Scheme 6 Synthesis of rotaxanes with different axle lengths.

The ¹H and ¹⁹F NMR spectra of 10Aa–10Ad were recorded and the results are summarized in Fig. 8. Unexpectedly, the chemical shifts of H^h and Hⁱ (Scheme 6) remained almost constant in the ¹H NMR spectra (Fig. 8a). Similarly, in the ¹⁹F NMR spectra we did not encounter any large differences in the chemical shifts and the difference between the two signals was mostly around 0.7 ppm (Fig. 8b).¹⁹ We initially anticipated that the distribution of the ring component in rotaxanes should be described as shown in Fig. 9a. The ring component of 10Ac, for example, would be distributed throughout the axle component except for the bulky dumbbell moieties, and a non-symmetric distribution would be induced by the presence of a less symmetric spiro moiety. In this case, high-field shifts of the signals of the methylene groups as well as the fluorine atoms would be observed as the length of the axle component becomes short. This assumption is based on the result that the high-field shifts of the signals were observed when the signals of the rotaxane were compared with those of the axle component and on the postulation that the probability of the presence of the ring component at a specific position would increase in shorter rotaxanes such as 10Aa (Fig. 9a). The observed results, however, could not be explained by the abovementioned assumption, because the chemical shifts were hardly influenced by the length of the axle component (Fig. 8). Instead, the results strongly indicate that there is localization of the macrocycle near the diyne functionality, and the ring component is less distributed along the alkylene moiety (Fig. 9b).²⁰ The difference in the distribution in a limited area (diyne moiety) would be responsible for the observed difference in the chemical shifts.²¹ The observed result contrasts with our previous studies on rotaxanes with larger ring components.⁹ The localized distribution can be explained in terms of the possible weak C–H…π interactions between the diyne functionality and the ring component (Fig. 10). This type of interaction has been reported in the solid state by several groups including ours.²² The bulkiness of the alkylene chain compared to the diyne structure could also be a driving force for the localization of the ring component in the proximity of the diyne moiety.

Fig. 8 Comparison of (a) ¹H and (b) ¹⁹F NMR spectra of rotaxanes with various axle lengths (CDCl₃, 500 MHz for ¹H and 377 MHz for ¹⁹F). The signals of H^h and Hⁱ (Schemes 3 and 6) are marked with an asterisk.

Fig. 9 (a) Initially anticipated distribution (solid line for 10Ac and dashed line for 10Aa) of the ring component in rotaxanes. (b) Revised distribution of the ring component in rotaxane 10Ac. A localized, non-symmetric distribution was observed.

Fig. 10 Possible weak interactions which induced the localization of the ring component in 10Ac.

Conclusions

In conclusion, we have outlined a general synthetic strategy, amenable to diversity creation for assembling spirofluorene based novel [2]rotaxanes in a high yielding and efficient manner. Detailed analyses of the ¹⁹F and ¹H NMR spectra revealed that the distribution of the ring component in rotaxanes could be modulated by the introduction of a less symmetric spiro moiety into the ring component. Localization of the cyclic component in the proximity of the 1,3-diyne moiety was observed. This study would contribute to the understanding of the relationship between the structure and conformation of the rotaxanes.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by JSPS KAKENHI (grant number JP19K05442 and JP22K03071) and The Science Research Promotion Fund provided by The Promotion and Mutual Aid Corporation for Private Schools of Japan.

Notes and references

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17. All NMR spectra we discussed in this manuscript were recorded in CDCl₃.
18. The assignment is based on the H–F COSY experiment. See ESI† for details.
19. See ESI† (Table S1) for details.
20. A reviewer pointed out that the ring component could be localized in one end of the axle component, and the conformation is stabilized by C–H⋯π interactions. We assume that this is unlikely because in the NMR spectrum of 10Aa (Fig. 3), for example, the chemical shifts of the protons bound to the dumbbell moiety are similar to those of the axle component 11c. The chemical shifts of these signals would be affected significantly if the rotaxane adopted the conformation suggested by the reviewer. We thank the reviewer for the valuable suggestions.
21. We assume that the major conformer would be the structure described at the bottom in Fig. 6b, because of the large steric bulk of the TBS group.
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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization, and copies of NMR spectra. See DOI: https://doi.org/10.1039/d2nj05021h

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