Relative contractile motion of the rings in a switchable palindromic [3]rotaxane in aqueous solution driven by radical-pairing interactions

Abstract

Artificial muscles are an essential component for the development of next-generation prosthetic devices, minimally invasive surgical tools, and robotics. This communication describes the design, synthesis, and characterisation of a mechanically interlocked molecule (MIM), capable of switchable and reversible linear molecular motion in aqueous solution that mimics muscular contraction and extension. Compatibility with aqueous solution was achieved in the doubly bistable palindromic [3]rotaxane design by using radical-based molecular recognition as the driving force to induce switching.

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The concept of controlling molecular motion at will is an inspiring call to chemists.¹ The design and synthesis of organic molecules that are capable of achieving movement is the first step towards translating that motion into a macroscopic effect through integration into larger systems.² Some of the most impressive evidence that molecular motion can be translated into macroscopic motion comes from biology, wherein proteins and assemblies of proteins – themselves large molecules and supermolecules – routinely achieve incredible feats, from kinesin pulling organelles along microtubules, to the rotary motion of ATP synthase, to the propulsion that results from bacterial flagellum.³ When we turn to the synthetic world, there are still rather few comparable systems.⁴ One class of organic compounds is particularly well suited, however, to containing and exercising moving parts – namely, mechanically interlocked molecules⁵ (MIMs). Since MIMs consist of two or more components that cannot be separated without breaking a covalent bond, the bond(s) holding the molecule together is (are) called a mechanical bond. In the case of a rotaxane, a dumbbell-shaped component is encircled by a ring, and the inclusion of functional groups on the dumbbell, for which the ring has an affinity, provides recognition sites. When the affinity for one recognition site is increased or decreased relative to another one by a stimulus, this bistability serves as the driving force for the ring moving relative to the dumbbell. A unique interpretation of this design has been reported⁶ previously wherein the dumbbell contains two sets of identical recognition sites, in a constitutionally symmetric, or palindromic, design. Thus, in this prototypical design of a palindromic [3]rotaxane, the two rings achieve a linear contractile motion as they are switched between the inner and outer recognition sites.⁷ This motion (Fig. 1) mimics the molecular motion present in actin and myosin proteins within muscle tissue.³ In order to facilitate the next transition of the doubly bistable [3]rotaxane switches – from isolated molecules to integrated systems – and to enable biocompatible applications, these switches must operate in aqueous solution, the major medium of life itself.

Fig. 1 (a) Graphical representation of the relative motion of the ring components, which undergo a redox-stimulated contraction and expansion in a doubly bistable palindromic [3]rotaxane. (b) The contraction of the sarcomere in biological muscle is achieved through the ATP-driven molecular motion of actin and myosin proteins sliding relative to each other.

Recently, we have discovered the potential of radical–radical pairing interactions⁸ in the context of MIMs. It has been found that 4,4′-bipyridinium (BIPY²⁺) units, upon reduction to their radical cationic state (BIPY⁺˙), form strong inclusion complexes with the reduced diradical, dicationic (CBPQT²⁽⁺˙⁾) form of cyclobis(paraquat-p-phenylene) (CBPQT⁴⁺). The radical-based pairing interaction in the reduced state is strong and represents the driving force for switching to the radical state co-conformation^8d (RSCC) in a MIM, a process that is eliminated in the oxidised state by electrostatic repulsions between the positive charges on both components. Thus, redox stimuli initiate rapid and readily reversible switching, but what's more, this radical-based switching mechanism has been shown to occur in aqueous solution. Here, we incorporate this new switching mechanism into a palindromic [3]rotaxane.

The design of a doubly bistable palindromic [3]rotaxane requires two sets of identical recognition sites on the dumbbell. Our design utilises 1,5-dioxynaphthalene (DNP) units as the outer recognition sites, which enter into donor–acceptor interactions with the CBPQT⁴⁺ rings in the oxidised ground state co-conformation (GSCC). After reduction, the diradical, dicationic CBPQT²⁽⁺˙⁾ ring has a strong preference for the inner BIPY⁺˙ recognition sites and a decreased affinity for the DNP units, resulting in a shuttling motion whose reversal is facilitated by the electrostatic repulsion between the positive charges on both the BIPY²⁺ units and the tetracationic ring upon re-oxidation.

The synthesis of the bistable palindromic [3]rotaxane was performed following the protocol outlined in Scheme 1. In order to achieve higher yields of the desired [3]rotaxane than had previously been possible with clipping-based rotaxanation approaches,^6b we sought to use a threading-followed-by-stoppering protocol for the rotaxane formation. Therefore, the first step was synthesising an axle component, A·4PF₆, with azide functionalities at each end to aid and abet the subsequent stoppering reaction. The synthesis of the axle begins with a DNP-tri(ethylene glycol) unit⁹1 which was subjected to a monotosylation to induce desymmetrisation.¹⁰ The monotosylate 2 was reacted with sodium azide in order to install an azide group¹¹ in 3. The remaining hydroxyl group on 3 was then tosylated in order to form 4 prior to its reaction with a bisviologen-based core¹²5·2PF₆ to form the axle A·4PF₆.

Scheme 1 Synthetic route to the palindromic [3]rotaxane 3R·12PF₆ using a threading-followed-by-stoppering approach.

Rotaxanation was achieved by a threading-followed-by-stoppering approach wherein an excess of CBPQT·4PF₆ was incubated with the axle in MeCN at room temperature for a week. An electron-deficient alkyne¹³6 was added to form the stoppers as a result of copper-free Huigsen cycloadditions.¹⁴ The desired [3]rotaxane 3R·12PF₆ was obtained in 46% yield, along with a small amount (8%) of a [2]rotaxane byproduct (2R·8PF₆). See synthetic procedures in the ESI.†

¹H NMR spectroscopy of 3R·12PF₆ confirmed the hypothesis that, in the non-reduced GSCC, the CBPQT⁴⁺ rings reside on the DNP recognition units. Fig. 2 shows partial ¹H NMR spectra comparing the dumbbell D·4PF₆, the [3]rotaxane 3R·12PF₆ and the [2]rotaxane 2R·8PF₆. An upfield shift was observed for the peaks corresponding to the DNP protons (labelled H_4/8, H_2/6, and H_3/7) in the [2]- and [3]rotaxane, indicating that the DNP units are encircled by CBPQT⁴⁺ rings. This co-conformation was confirmed by through-space interactions observed in the ¹H–¹H ROESY NMR spectrum, shown in Fig. S9 in the ESI.† Variable temperature ¹H NMR spectra, which were recorded on the [2]rotaxane 2R·8PF₆ demonstrate that, in the GSCC, the inner BIPY²⁺ recognition sites serve as electrostatic barriers preventing the shuttling of the ring from one DNP recognition site to the other. See Fig. S11 in the ESI.†

Fig. 2 Partial ¹H NMR spectra (500 MHz, CD₃CN, 298 K) comparing the dumbbell D·4PF₆, the [2]rotaxane 2R·8PF₆, and the [3]rotaxane 3R·12PF₆ reveal upfield shifts of the resonances for the DNP protons in the rotaxanes (see Scheme 1 for proton labelling), indicating that the CBPQT⁴⁺ rings encircle the DNP units in the oxidised GSCC.

Following the characterisation of the [3]rotaxane 3R·12PF₆, we were interested in investigating its switching properties, particularly in aqueous solution. The solubility of the [3]rotaxane can be modulated by counterion exchange, given the fact that the PF₆⁻ salt is highly soluble in organic solvents such as MeCN and Me₂CO, and the Cl⁻ salt is soluble in aqueous solution. Counterion exchanges were achieved using NH₄PF₆ and nBu₄NCl. The shuttling of the CBPQT⁴⁺ rings between the recognition sites, following reduction to the hexaradical hexacationic RSCC, was monitored electrochemically and also by UV-Vis-NIR spectroscopy since NMR characterisation of the paramagnetic species was not possible.

The reduction potential for 3R·12Cl in aqueous solution was determined (Fig. 3) by differential pulse voltammetry using Ag/AgCl as a reference. Compared to the free BIPY²⁺ units in the dumbbell structure (−615 mV) and in the ring (−410 mV), the reduction potential of the [3]rotaxane was significantly shifted (−368 mV). The shift of the BIPY⁺˙ signal in the [3]rotaxane toward more positive potential indicates the formation of the trisradical complex between the BIPY⁺˙ and CBPQT²⁽⁺˙⁾. Spectroelectrochemistry (SEC) performed (Fig. 4) at an applied potential of −750 mV showed evidence for the shuttling of the reduced diradical, dicationic CBPQT²⁽⁺˙⁾ rings from the DNP recognition sites to the inner BIPY⁺˙ sites. This was revealed by a change in the charge-transfer band corresponding to the interaction between the CBPQT⁴⁺ rings and the DNP units in the GSCC. A comparison of the spectra of the reduced [3]rotaxane species with those of the dumbbell D^2(+·) and ring CBPQT²⁽⁺˙⁾ in their reduced states showed an absorption band centred at 1125 nm characteristic of the trisradical interaction in the hexaradical, hexacationic [3]rotaxane 3R^6(+·). SEC also showed significantly different absorption profiles for the reduced versus oxidised states of the [3]rotaxane. See Fig. S2 in the ESI.† In addition to electrochemical stimuli, switching was also achieved by chemical means – Na₂S₂O₄ and Zn dust for reduction in H₂O and MeCN respectively, and O₂ (air) for oxidation. See Fig. S3 and S4 in the ESI.†

Fig. 3 (a) Differential pulse voltammetry (DPV) of the [3]rotaxane 3R¹²⁺ (purple curve), dumbbell D⁴⁺ (red curve) and CBPQT⁴⁺ (blue curve) performed at 0.2 mM sample at 298 K in H₂O–DMF (9 : 1, v/v) with 0.1 M KNO₃ as the supporting electrolyte.

Fig. 4 UV-Vis Spectra (60 μM, 298 K) of 3R⁶⁽⁺˙⁾ (purple curve), D²⁽⁺˙⁾ (red curve) and CBPQT²⁽⁺˙⁾ (blue curve) conducted in H₂O–DMF (9 : 1, v/v) with 0.1 M KNO₃ as the supporting electrolyte at an applied potential of −750 mV vs. Ag/AgCl show different absorbances between species in their reduced states.

In summary, by combining new advances in radical-based MIM motifs with a design that results in relative contractile motion of the rings, we have produced a ‘next generation’ palindromic [3]rotaxane capable of redox switching in aqueous solution. The radical-pairing recognition motif is incredibly versatile, since it is amenable to switching by electrochemical or chemical stimuli in different media, including aqueous solution. This system brings the dream of artificial muscles that function employing the same mechanism natural muscle uses – namely molecular motion – one step closer.¹⁵ Operating in aqueous solution enables the integration of this molecular muscle mimic with biological interfaces. Future work will focus on the preparation of derivatives that include conjugation handles for incorporating this molecular switch into micro- and macroscopic materials and biological systems.

Acknowledgements

The research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under Award Number F32GM105403. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This research is part (Project #34-949) of the Joint Center of Excellence in Integrated Nano-Systems (JCIN) at King Abdul-Aziz City for Science and Technology (KACST) and Northwestern University (NU). The authors would like to thank both KACST and NU for their continued support of this research. A.C.F. was and E.J.D. is supported by the National Science Foundation (NSF) Graduate Research Fellowship Program. L.S.W. acknowledges support from the International Institute for Nanotechnology (IIN) at NU. J.C.B. was supported by a National Defense Science and Engineering Graduate Fellowship from the Department of Defense and gratefully acknowledges receipt of a Ryan Fellowship from the IIN while at NU.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ob01228c

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