Redox-Responsive Artificial Molecular Muscles: Reversible Radical

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Redox-responsive Artificial Molecular Muscles: Reversible Radical-based Self-assembly for Actuating Hydrogels Angelique F. Greene, Mary Danielson, Abigail O. Delawder, Kevin P. Liles, Xuesong Li, Anusree Natraj, Andrew Wellen, and Jonathan C. Barnes Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.7b03635 • Publication Date (Web): 16 Oct 2017 Downloaded from http://pubs.acs.org on October 16, 2017

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Chemistry of Materials

Redox-responsive Artificial Molecular Muscles: Reversible Radicalbased Self-assembly for Actuating Hydrogels Angelique F. Greene, Mary Danielson, Abigail O. Delawder, Kevin P. Liles, Xuesong Li, Anusree Natraj, Andrew Wellen, Jonathan C. Barnes* Department of Chemistry, Washington University, St. Louis, MO 63130, USA

ABSTRACT Interest in the design and development of artificial molecular muscles has inspired scientists to pursue new stimuli-responsive systems capable of exhibiting a physical and mechanical change in a material in response to one or more external environmental cues. Over the past few decades, many different types of stimuli have been investigated as a means to actuate materials. In particular, materials that respond to reduction and oxidation of their constituent molecular components have shown great promise on account of their ability to be activated either chemically or electrochemically. Here, we introduce a novel redox-responsive mechanism of actuation in hydrogels by describing a systematic investigation into the radical-based selfassembly of a series of unimolecular viologen-based oligomeric links, present at only 5 mol % of the polymer linkers in a three-dimensional network; a process which results in an overall reversible contraction of a family of hydrogels – down to 35% of their original volume in the first 25 minutes and ultimately to 9% after a few hours – even whilst remaining submerged in water. This actuation process starts with a decrease in electrostatic repulsion upon chemical reduction leading to a loss of counterions and intramolecular self-assembly of the main-chain viologen subunits – an overall mode of actuation which takes place relatively quickly in comparison to hydrogels of similar size, and where the rate of contraction is accelerated as higher molecular weight oligoviologen links are implemented. The contraction process ultimately leads to a two-fold increase in elasticity of the material, and, upon exposure to oxygen and water, the hydrogels quickly oxidize and regain their original size and mechanical properties, thus resulting in a reversible actuation process that is capable of lifting objects which are five to six times heavier than the contracted hydrogel itself. INTRODUCTION Artificial molecular muscles12 range in scale from nanometer-sized molecular machines3,4 all the way up to larger macromolecular-based systems.5,6,7 In common with human skeletal muscle8 – which is called into action via an electrochemical signal that ultimately results in the release of Ca2+ and activation of actin and myosin filaments – artificial molecular systems are designed to respond to external stimuli. Thus, interest in the design and development of new stimuliresponsive materials9–13 has surged over the last few decades; typically with an eye towards creating self-healing materials14–17 or polymer actuators18–24 that possess novel properties. The

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more commonly employed modes of inducing mechanical responses in a material include i) electrochemical activation19,25,26 that initiates ion mobility between two electrodes,27,28 ii) changing pH29–31 or temperature32–34 that results in electrostatic repulsion or entropically-driven desolvation, respectively, or iii) irradiation with light, which may isomerize an azobenzenecontaining polymer,35–37 or initiate unidirectional rotation about an overcrowded olefin in a molecular motor.38,39 Capitalizing on the redox chemistry associated with electroactive moieties – either chemically or electrochemically – to induce a mechanical response in a material is also an area of great interest in the design of electroactive polymer- and gel-based actuators.19,40,41 The more commonly utilized platforms in this area involve conjugated polymers,42,43 such as polyaniline44,45 and polypyrrole.46–48 The mechanism for these redox-based systems typically involves oxidation of a portion of the subunits along the conjugated polymer backbone, which results in an influx of counterions to balance the newly formed charges, thus resulting in the swelling (and eventual deswelling) of the material, and hence actuation.19 Redox-responsive ferrocene (Fc)-based systems49–51 have also been investigated as either side-chain52,53 or main-chain54,55 polymer gels56 and follow a similar mechanism of ion flux and electrostatic repulsion, however, they also have the added benefit of functioning as self-healing materials16 and actuators57 through the use of host–guest interactions58,59 that can be switched between on (neutral Fc) or off (oxidized Fc+) states, resulting in further swelling and disruption of non-covalent cross-linking. Here, we report the synthesis (Figure 1a–b) and application (Figure 1c) of a series of watersoluble, unimolecular main-chain oligoviologens as a cheap, robust, and redox-responsive means of reversibly contracting cubic-centimeter-sized hydrogels down to 35% of their starting volumes within the first 25 minutes and ultimately down to 9% after approximately three hours. This novel redox-based mechanism of actuation (Figure 1c) involves the generation of viologen radical-cations (i.e., V2+ to V•+) at each subunit upon chemical reduction, which results in a decrease in electrostatic repulsion and corresponding number of counteranions, followed by the intramolecular collapse of the redox-active oligomer through the non-covalent, radical-based self-assembly of reduced main-chain viologen subunits. This self-assembly mechanism is analogous to that of an accordion, whereby the thermodynamically favorable pairing60 of radical electrons between viologen subunits in the same network link results in a decrease in its length and mass and ultimately leads to a reduction in the overall mesh size of the three-dimensional network. The radical-pairing effect also reorganizes the network and the material contracts down to 9% of its original volume in the case of the higher molecular weight oligoviologen linkers. Thus, even while sitting in salt-containing water, the redox-based driving force for network reorganization in a viologen-containing hydrogel is capable of reducing electrostatic repulsion and excluding water and counteranions from the material. RESULTS & DISCUSSION Viologens61,62 – or more specifically 4,4'- and 2,2'-dialkyl-bipyridiniums – are electroactive molecules whose redox chemistry was initially reported63,64 by Michaelis over 85 years ago. Since then, they have been used as herbicides,65 electrochromic materials in gel-based 2 ACS Paragon Plus Environment

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devices,66,67 redox mediators in energy storage applications,68,69 and as either π-electrondeficient70 moieties or as a source of persistent71 or stable72 radicals, which can function as molecular recognition units that are used to template the synthesis of oligomeric mechanically interlocked molecules,73 as well as catenanes,74 rotaxanes,75 and artificial molecular pumps.76 However, the use of oligoviologens – consisting of main-chain subunits spaced on either side by flexible and water-soluble ethylene glycol tethers – has yet to be investigated as an actuating platform in three-dimensional polymer-based gels and materials. We therefore sought to incorporate oligoviologen linkers into a hydrogel in order to determine what effect the role of changing the oligomeric chain length would play in actuating the material – in terms of the magnitude, or degree, that it can be contracted and expanded, as well as how quickly this process can be completed. To investigate the role that chain length (i.e., total viologen concentration in each oligomeric linker) plays in this process, an iterative synthesis was carried out (Figure 1a, Schemes S1–S11) that is akin to a sequential chain-growth polymerization at each termini. Beginning with a bipyridine (BIPY) end-capped hexaethylene glycol (HEG) precursor, (HEGBIPY2+), a viologen-containing dimer was synthesized in the presence of 20 equiv of tosyl endcapped HEG (HEG-Tos)77 in MeCN, heated to 130 ⁰C in a sealed high-pressure flask. After 12–16 h, the HEG-BIPY2+ is converted to 2V4+ (Figure 1a, top chemical structure) and the product was isolated through precipitation in a 1:1 mixture of PhMe and MeCN, followed by centrifugation. Similarly, the BIPY end-capped compound 4V6+ was prepared by treating 2V4+ with 20 equiv of 4,4'-bipyridine in MeCN, heated to 130 ⁰C for 12–16 h, followed by precipitation and material recovery after centrifugation. At any point in the synthesis, the BIPY end-capped compound can be terminally functionalized by treating it with 35 equiv of TosDEG-N378 at 130 ⁰C for 20–24 h (Scheme S12). This iterative synthetic protocol has been repeated several times, resulting in the synthesis of several grams of the shorter oligomers (i.e., n = 2–4) and 100’s of milligrams of the higher molecular weight ones (n = 6–10), resulting in a series of unimolecular and even-numbered oligoviologens, where n = 2, 4, 6, 8, or 10 for nV(2n)+. (See Supporting Information for more detailed procedures for the synthesis and nuclear magnetic resonance (NMR) characterization – Figures S1 and S2 – for each oligoviologen). Confirmation of the radical-pairing-induced intramolecular self-assembly, or collapse, at the macromolecular level (i.e., pre-hydrogel) was carried out separately in MeCN and H2O, whereby each nV(2n)+ compound (at 0.2 mM) was reduced to the corresponding nV(n)•+ radical cation by the excessive addition of zinc dust (Zn0) or 1 M sodium dithionite (Na2S2O4), respectively. Absorption spectroscopy (UV-vis-NIR) was then performed (Figure 2) on each of the dark purple colored oligoviologen solutions. In MeCN, two intense bands were observed with absorptions at approx. 520 and 850 nm, with only mild bathochromic shifting observed as more viologen subunits were added in the higher molecular weight oligoviologens. In contrast, the study carried out in H2O not only showed two intense absorption bands centered around 520 and 850 nm, but as the oligoviologens increased in molecular weight and degree of polymerization (DP), a strong bathochromic shift was observed (Figure 2A), where the absorption peak centered about 850 nm for 2V4+ red-shifted up to 899 nm in the case of 10V20+ and produced a broad shoulder that carried over into the 1000–1100 nm range. These trends associated with the absorption profiles of each oligoviologen have been investigated previously in other viologen3 ACS Paragon Plus Environment


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containing systems60, and are an indication that while radical-radical dimerization is occurring in both solutions, there is some percent population in H2O that forms intramolecular tris(radical) stacks, as evidenced by the large amount of red-shifting that occurs as more viologen subunits are added to the oligomeric compound. To corroborate these results, an electron paramagnetic resonance (EPR) experiment was performed (Figure 3) at room temperature on a 0.2 mM solution of 4V8+ dissolved in dry, degassed DMF (see Supporting Information for experimental parameters). Since the radical pairing between reduced viologens is weaker in DMF, we were able to observe a signal possessing hyperfine splitting, similar to what Winter and co-workers reported previously79 for polydispersed main-chain viologens possessing aliphatic spacers in between each viologen subunit. Upon addition of H2O to the DMF solution containing 4V4(•+), the EPR signal was lost, a trend which may be attributed to an increase in radical pairing between the four V•+ subunits along the backbone of the oligomer. Moreover, this phenomenon is aided by the hydrophobic effect,80 which entails aggregation of less polar π-systems upon exposure to H2O. To fabricate the hydrogels, an azide end-capped polyethylene glycol (PEG-N3, Mn = 2000)81 was prepared (see Supporting Information) and combined with only 5 mol % of azide end-capped nV(2n)+ (i.e., nV(2n)+–N3), and this mixture was dissolved in DMF along with 0.5 equiv of a tetraalkyne cross-linker (TAXL)82 (Figure 1c; see Supporting Information for its preparation). In a separate solution, 0.5 equiv of copper sulfate (CuSO4) and 0.5 equiv of sodium ascorbate were dissolved in H2O and added to the DMF mixture in a 3:1 DMF:H2O ratio. This mixture of starting materials was vortexed for approx. 10 s before being deposited as a semi-viscous liquid into a cubic silicone mold, wherein the final cross-linking goes to completion, and the hydrogel was thus formed (Figure S4). The copper was mostly removed by soaking the hydrogel for 12– 16 h in an aqueous Versene solution that contains 0.2 M ethylenediaminetetraacetic acid (EDTA) ligand in phosphate buffered saline (PBS), followed by washing in pure H2O solutions for an additional 4–6 h to remove any excess EDTA ligand. This process was repeated for all values of n noted above, such that three hydrogels containing 5 mol % of each oligoviologen chain could be prepared, totaling 15 cubic hydrogels in all. Additionally, this protocol was also adapted to other molds, such as LC/MS vial caps and rubber septa, thus allowing for the preparation of disklike hydrogels that were used for assessing the mechanical properties of the hydrogels (vide infra). With each hydrogel now in hand, a systematic investigation was carried out where the number of available oligoviologen chains in the network was kept constant (i.e., identical mol % for all hydrogels), and instead only the length and molecular weight (thus, wt %) were varied as the different oligoviologens (n = 2 – 10 subunits) were incorporated into the corresponding hydrogels. The contraction of each viologen-containing hydrogel (prepared in triplicate) was initiated by submerging each in a 1 M solution of Na2S2O4 – which is known to be a one-electron reductant for viologens in water83 (see Figure S3 for cyclic voltammograms of oligoviologens in H2O) – in an N2-filled glovebox. It is important to note that the reduction can also be carried out on the bench top, with the caveat that fresh Na2S2O4 solution is used since it degrades within a few hours upon exposure to atmospheric O2. Placement of the hydrogels in the reducing solution 4 ACS Paragon Plus Environment

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resulted in a rapid change in color of the swollen hydrogels in only a matter of seconds, where the hydrogel turned to a dark purple color. Although the majority of contraction occurs during the first 25–45 min (Figures S5–S6), the hydrogels were left in the reducing solution for several hours so the final contracted volume ratio could be measured (Figure 4a) as the percent ratio (final/initial) between the starting volume and mass of the swollen hydrogel and the corresponding volume and mass of the fully reduced and contracted hydrogel. A general trend becomes clear when looking at the contraction data across all oligoviologen samples in Figure 4a. Specifically, the degree of contraction grows larger as more viologen subunits are introduced into the oligoviologen links in the three-dimensional polymer network. This dramatic change in size and mass is partially attributed to the efficient collapse of the constituent oligoviologen chains as a consequence of radical pairing between subunits, but it is also mainly due to the fact that a decrease in electrostatic repulsion occurs, in addition to a greater number of counterions being lost as more dicationic viologens (V2+) are reduced to their corresponding radical cation (V•+). Evaluating the kinetics of each of the cubic hydrogels (Figure 4b) – particularly during the first 25 minutes – an increase in the rate of contraction (vol % min–1) is observed as higher DP oligoviologens are introduced into the network. Even though the longer oligoviologens constitute a slightly higher mass loading (i.e., more viologen subunits per link) the mol % – and therefore the number of oligomeric links – is kept constant across all hydrogels, so the hydrogels with longer oligoviologens present exhibit faster rates of reorganization upon reduction (Figure 4b). This behavior may be attributed to the fact that the higher molecular weight oligoviologens lose a greater number of positive charges after the diffusion-limited introduction of the chemical reductant, resulting in a loss of more anions after the fast reduction step when compared to the lower molecular weight oligoviologens. Thus, this charge reduction and ionic efflux, in combination with the intramolecular aggregation of the viologen subunits, results in greater rates of contraction for hydrogels containing the higher molecular weight oligoviologens. Similar kinetic behavior was observed for disk-like hydrogels containing oligoviologens (Figure S8), indicating a lack of shape dependence for the reduction and contraction process. In terms of the reversibility of each hydrogel, four cycles of contractions and expansions were performed in triplicate (Figure 4c, Figure S7) for each cubic redox-responsive hydrogel. The first cycle typically started from a slightly smaller initial volume than the starting point of the second cycle, however, this can be attributed to the fact that more free void space is created after the first contraction pushes out any residual catalyst, or salt. Thereafter, the reversibility of the hydrogel actuation has been demonstrated successfully, with little to no loss in size and mass recovery over the first four cycles. Generally speaking, the majority of the contraction of each of the swollen hydrogels occurs during the first 25–45 min (Figure S6). After a few hours, each hydrogel lost a few more millimeters in each dimension, resulting in the final contracted state. The images shown in Figure 4d illustrate the change in color of the hydrogels upon reduction during the first cycle – where the initial yellowish/greenish color results from the presence of residual copper that is expelled during contraction – as well as the dramatic size changes that occur for both cubic (top) and disk-like (bottom) hydrogels that contain 5 mol % of the oligoviologen linkers (nV(2n)+). Furthermore, it is important to note that the hydrogels are incapable of re-expansion when only O2 or H2O is present. In other words, if a 5 ACS Paragon Plus Environment


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reduced/contracted hydrogel is exposed to O2 on the benchtop (away from the chemically reducing solution), the color of the hydrogel will change from dark purple to yellow – an indication that the reduced viologen subunits have been oxidized – however the material cannot increase in size and mass since there is no H2O present. Likewise, the contracted hydrogel will remain dark purple in color and will not swell back to its original size when removed from the chemically reducing solution and placed in N2-saturated H2O in an inert glovebox environment. Thus, both O2 and H2O are required to activate the re-expansion of the material, a process where the latter usually results in 98.0–99.5 % recovery in size and mass of the hydrogel during the first four cycles (see images in Figure 4d and Figure S7). It is important to note, however, that although we have cycled several oligoviologen-containing hydrogels up to as many as seven times, we have observed early stages of degradation – loss of small outer gel fragments – of the hydrogel during and after the fifth cycle, presumably as a consequence of the soft PEG chains in the network. Thus, the loss of these small outer fragments makes it difficult to obtain completely accurate volume and mass data for the hydrogel beyond four cycles. In order to assess the contribution that intramolecular self-assembly, or chain folding/aggregation, plays during the contraction process, a batch of hydrogels containing the total oligomeric linker composition of 5 mol % of an azide-end-capped monoviologen (i.e., 1V2+–N3, Scheme S11) and 95 mol % of PEG-N3 were prepared. These monoviologencontaining hydrogels thus served as a control since the individual viologen subunits are incapable of intramolecular self-assembly and the likelihood of intermolecular radical pairing is diminished as a result of being diluted by PEG linkers in the three-dimensional polymer network. The decreased occurrence of pairing interactions resulted in gels that appear more blueish in color (in contrast to the dark purple/black color observed for the oligoviologen-containing hydrogels) upon treatment with Na2S2O4 (Figure S9). Moreover, these hydrogels showed a vastly decreased degree of contraction (Figure 4a) and a much slower contraction rate (Figure 4b) that do not fit into a simple linear correlation based on the number of viologen subunits or positive charges. In fact, a non-linear trend is observed for both metrics and strongly suggests that the intramolecular self-assembly process plays an important role in the contraction process, which cannot be explained by loss in electrostatic repulsion and counteranions alone. To further confirm the latter point, an additional series of monoviologen-containing hydrogels were prepared (see Supporting Information for details related to their synthesis), where the moles of viologen matched the moles of viologen subunits found in the oligoviologen-containing hydrogels. In other words, we prepared (Table S1) hydrogels that contained molar equivalents of 1V2+–N3 that matched exactly the number of moles of viologen subunits in the hydrogels that contained 5 mol % of the dimer, tetramer, hexamer, octamer, and decamer oligoviologens. Chemical reduction of the series of monoviologen-based hydrogels using 1 M Na2S2O4 resulted in contraction kinetics (Figure S10) that are three times slower (i.e., requiring ~75 minutes to achieve 60% contraction) than the oligoviologen-containing hydrogels, and which are only capable of maximum contracted volume ratios no lower than 32% (Figure S11). These control experiments demonstrate that intramolecular self-assembly of the constituent oligoviologens is critical for faster-actuating soft materials (by a factor of three) that are capable of contracting down to 9% of their original starting volume – thus representing a 23% increase in the overall 6 ACS Paragon Plus Environment

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degree of contraction that can be achieved. Furthermore, to rule out contributions to actuation that may arise from changes in osmotic pressure, a control experiment was carried out (Figure S12), where a PEG-only hydrogel was subjected to treatment in 1 M Na2S2O4 reductant for 7 h. This experiment yielded little to no change in the volume of the hydrogel. Once the protocol for controlling the contraction and expansion had been established, we then sought to quantify the change in mechanical properties of the hydrogel material as a function of the contracted state possessing decreased mesh sizes and a reorganized network. To characterize the dynamic viscoelastic behavior of the contracted and expanded hydrogels, an oscillatory shear rheometer was employed (Figure 5a) using a 20 mm flat geometry on disk-like 6V12+-containing hydrogels, which were 20 mm in diameter for both the contracted (6V6(•+)) and expanded states. The first experiment consisted of a frequency sweep (at 1% strain amplitude) from 0.1 to 100 rad s–1 on both the reduced and expanded hydrogels (performed in triplicate) in order to identify whether or not any viscous behavior could be observed at higher rates of shear torque. For both states, the material behaved as an elastic solid, where at no point a cross-over of G' and G'' was observed, even at higher frequencies. There was, however, a roughly 2.5-fold increase in the elastic moduli (G') observed for the contracted hydrogels (purple squares shown in Figure 5a) in comparison to the oxidized/expanded hydrogels (red squares in Figure 3a). Moreover, the storage moduli G' was an order of magnitude greater than that of the loss moduli G'' for both the reduced and oxidized states – i.e., ~5.4 vs. 0.5 kPa and 2.2 vs. 0.23 kPa, respectively. Additionally, a strain sweep experiment was performed in triplicate at 10 rad s–1 on both the contracted and expanded hydrogels. This investigation resulted in stress vs. strain curves (Figure 5b), which show a linear viscoelastic region (LVR) in response to low strain in the range of 0– 3%. The black arrows shown in Figure 5b indicate the yield stress points for the reduced/contracted (purple trace) and oxidized/expanded (red trace) states of the hydrogels. As expected, the contracted hydrogels can undergo 63 Pa of yield stress at slightly higher strain amplitude (3%) versus only 32 Pa of yield stress at approx. 1.5% strain amplitude. These data indicate that the decreased mesh size and corresponding reorganized network – resulting from the reduction of the oligoviologen chains and loss of positive charges and counteranions – affords a mechanically more robust material that can be handled more readily and even stretched farther before breaking (Figure S13). As an example of the scalability of our novel actuatable platform, we introduced only 5 mol % of the 2V4+ oligomer into a series of hydrogels of different shapes (e.g., a bear, a star, or a leaf) and sizes (centimeters). The different hydrogel morphologies were synthesized using commercial silicone baking molds (Figure S14) and their chemically-induced contraction demonstrates how the actuation process is uniformly distributed throughout the material regardless of the different contours and creases that exist overall in the hydrogel. Furthermore, to demonstrate the artificial molecular muscle’s ability to carry out work, a cubic 6V12+-containing hydrogel was placed into an N2-saturated glass jar and a 2.028 g dime was placed on top of it (Figure 6) at an initial height of 7.0 mm. Next, a 1M Na2S2O4 solution was added until the hydrogel was completely submerged. Within the first minute, the color of the hydrogel changed from pale yellow to dark purple, indicating that reduction of the individual viologen subunits was successful. The height 7 ACS Paragon Plus Environment


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of the dime was monitored over the course of several hours, and although most of the contraction occurred in the first three hours, complete contraction (height of 4.0 mm) was achieved after 12 h and no further reduction in size was observed thereafter. At this stage, the mass of the fully contracted hydrogel was 377 mg. Under ambient conditions, the reducing solution was then removed and replaced with O2-saturated fresh H2O – such that ~85% of the hydrogel remained submerged, while the dime remained out of solution. Within 6 h, the dime’s height had reached nearly 6.0 mm (Figure 6), and after sitting for a full 24 h in the aqueous oxidizing conditions, the color in the hydrogel changed back to a pale yellow and the height of the dime returned to the initial height of 7.0 mm, thus completing the cycle that included the lifting of a load that is nearly six times the mass of the contracted oligoviologen-containing hydrogel. CONCLUSION In conclusion, we have demonstrated successfully the development and implementation of a novel redox-responsive actuation platform that is based on flexible, water-soluble, and unimolecular oligoviologens that can be incorporated in small molar amounts into a material for the purposes of reversibly controlling the contraction and expansion processes of different hydrogel morphologies. The redox-based actuation mechanism is driven by the reduction in electrostatic repulsion, loss of counteranions, and the thermodynamically favorable radical pairing that occurs intramolecularly between main-chain viologen radical cations present in a series of unimolecular oligoviologens that have been synthesized with DPs ranging from only 1 up to 2 – 10 viologen subunits. The rapid collapse of these oligoviologen chains within the confines of a three-dimensional cross-linked polymer network – even whilst still submerged in H2O – stems from an overall reorganization that decreases the network’s mesh size and largely results from a decrease in electrostatic repulsion, which excludes counteranions and H2O from the material. Moreover, the degree and rate of actuation is markedly improved as the degree of polymerization is increased (i.e., more viologen subunits in the oligomeric linker), and the material can only be returned to its original state upon exposure of the contracted hydrogels to water and an oxidant, which in this case was simply ambient O2. Additionally, it has been demonstrated that this process is completely reversible over four cycles and can be used to manipulate the mechanical properties of the material post-reorganization of the network, whereby a 2.5-fold increase in the elastic shear moduli (G') and 2-fold increase in the yield stress point was observed upon contraction of the material. Lastly, a demonstration of the artificial molecular muscle performing work was carried out, whereby a dime that was nearly six times the mass of the contracted hydrogel was lifted upon oxidation and expansion of the soft material. We envision this process may be adapted to other materials other than PEG and platforms outside of hydrogels – while at even larger scales – such that it may prove useful as a general platform for a number of potential real-world materials applications, such as soft robotics, prostheses, and micro/nanoelectromechanical systems. METHODS Preparation of HEG-BIPY2+. A 100 mL thick walled high pressure flask with Teflon screw cap and stir bar was charged with HEG-Tos (1.206 g, 2.3 mmol), 4,4′-bipyridine (6.5 g, 40 mmol), 8 ACS Paragon Plus Environment

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and MeCN (15 mL). The flask was capped tightly and the mixture was stirred at high-pressure at 130 °C for 12 h. After 12 h, the reaction mixture was cooled to room temperature (caution: do not open vessel until room temperature is achieved) and the crude golden brown mixture was transferred to a 50 mL plastic centrifuge tube and PhMe (30 mL) was added to precipitate the pure product as a sticky brown oil. To assist in the precipitation and purification of the product the MeCN/PhMe mixture was centrifuged twice at 4490 rpm at −10 °C for 35 min, replacing the supernatant with fresh PhMe between runs. To maximize yields the MeCN/PhMe supernatant should be concentrated under reduced pressure and centrifuged a third time at identical conditions (1.176 g, 63%). This protocol was also used to prepare the other BIPY-endcapped oligomers. 1H NMR (300 MHz, CD3CN) δ: 8.93 (d, J = 6.9 Hz, 4H), 8.80 (dd, J = 4.5, 1.7 Hz, 4H), 8.30 (d, J = 6.8 Hz, 4H), 7.86 – 7.67 (m, 4H), 7.59 (d, J = 8.1 Hz, 4H), 7.12 (d, J = 7.9 Hz, 4H), 4.83 – 4.69 (m, 4H), 4.03 – 3.86 (m, 4H), 3.63 – 3.38 (m, 16H), 2.29 (s, 6H); 13C NMR (75 MHz, CD3CN) δ 161.68, 152.17, 146.73, 129.29, 126.61, 126.34, 122.76, 71.06, 70.99, 70.99, 70.75, 69.66, 21.16, 21.13. Preparation of 2V•4Tos. A 100 mL thick walled high pressure flask with Teflon screw cap and stir bar was charged with HEG-BIPY2+ (1.206 g, 0.69 mmol), HEG-Tos (8.25 g, 13.9 mmol), and MeCN (20 mL). The flask was capped tightly and the mixture was stirred at high-pressure at 130 °C for 16 h. After 16 h, the reaction mixture was cooled to room temperature and the crude golden brown mixture was transferred in equal parts to two 50 mL plastic centrifuge tubes and PhMe (30 mL) was added to each tube to precipitate the pure product as a sticky brown oil. To assist in the precipitation and purification of the product the MeCN/PhMe mixture was centrifuged twice at 4490 rpm at −10 °C for 35 min, replacing the supernatant with fresh PhMe between runs. To maximize yields the MeCN/PhMe supernatant should be concentrated under reduced pressure and centrifuged a third time under identical conditions (1.238 g, 86%). This protocol was also used to prepare the other Tosyl-end-capped oligomers. HRMS-ESI For 2V•4Tos; calcd for C91H124N4O30S5+: m/z = 1912.6898 [M + H]+; Found: 1912.6921 [M + H]+. 1 H NMR (500 MHz, CD3CN) δ: 9.03 (s, broad, 8H), 8.48 (s, broad, 8H), 7.79 – 7.66 (m, 4H), 7.62 – 7.51 (m, 8H), 7.38 (m, 4H), 7.17 – 7.00 (m, 8H), 4.80 (s, broad, 8H), 4.12 – 3.77 (m, 8H), 3.63 – 3.30 (m, 56H), 2.43 – 2.33 (m, 6H), 2.30 – 2.16 (m, 12H). 13C NMR (125 MHz, CD3CN) δ: 149.29, 146.51, 145.45, 143.18, 140.06, 132.64, 130.15, 128.84, 127.79, 126.66, 125.88, 70.17, 70.14, 70.06, 69.92, 69.80, 68.82, 68.18, 61.36, 20.76, 20.47. Preparation of 2V-N3•4Tos. A 100 mL thick walled high pressure flask with Teflon screw cap and stir bar was charged with HEG-BIPY2+ (0.300 g, 0.330 mmol), Tos-DEG-N3 (3.98 g, 11.5 mmol), and MeCN (15 mL). The flask was capped tightly and the mixture was stirred at highpressure at 130 °C for 24 h. After 24 h, the reaction mixture was cooled to room temperature and the crude golden brown mixture was transferred to a 50 mL plastic centrifuge tube and PhMe (30 mL) was added to precipitate the pure product as a sticky brown oil. To assist in the precipitation and purification of the product the MeCN/PhMe mixture was centrifuged twice at 4490 rpm at −10 °C for 35 min, replacing the supernatant with fresh PhMe between runs. To maximize yields the MeCN/PhMe supernatant should be concentrated under reduced pressure and centrifuged a third time at identical conditions (0.30 g, 56%). This protocol was also employed in the 9 ACS Paragon Plus Environment


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preparation of 4V-N3•8Tos, 6V-N3•12Tos, 8V-N3•16Tos, 10V-N3•20Tos. 1H NMR (500 MHz, CD3CN) δ: 9.04 (s, broad, 8H), 8.49 (s, broad, 8H), 7.56 (s, broad, 8H), 7.10 (s, broad, 8H), 4.80 (s, broad, 8H), 3.90 (s, broad, 8H), 3.51 – 3.44 (m, broad, 24H), 3.28 (s, broad, 4H), 2.24 (s, 12H). 13C NMR (125 MHz, CD3CN) δ: 150.29, 147.21, 144.77, 140.32, 129.54, 127.45 126.50, 70.98, 70.87, 70.77, 70.52, 70.29, 69.50, 62.15, 51.20, 21.15. General Procedure for the Preparation of Copper(I)-mediated “Click” Hydrogels at 95/5 mol % PEG/Oligoviologen – Monomer, Dimer, Tetramer, Hexamer, Octamer, & Decamer. PEG-N3 (100mg, 0.045 mmol), azide-capped oligoviologen (2.3 µmol), 95/5 mol% respectively, and TAXL (68 mg, 0.023 mmol) were added to a glass scintillation vial and 0.9 mL of DMF was added. The mixture was vortexed until all of the solid entered solution. Then, CuSO4 (4 mg, 0.023 mmol) and sodium ascorbate (5 mg, 0.053 mmol) were added to two separate 2-dram vials and dissolved in 0.3 mL of deionized water. The CuSO4/H2O solution was then added in its entirety via a syringe to the polymer/DMF solution and the viscous green colored solution was vortexed for 10 sec. to ensure homogeneity of the pre-hydrogel mixture. Then, using a syringe the sodium ascorbate/H2O solution was added to the pre-hydrogel mixture and then vortexed for an additional 10 sec. The hydrogel reaction mixture was then carefully and rapidly plated into three 1cm cubic silicone molds via a syringe. The gelation process was complete after 30 min. The resulting hydrogels were then swollen in Versene solution (EDTA at 0.2M in PBS) overnight to remove excess copper ions remaining in the hydrogel. After swelling in Versene solution, the hydrogels were then transferred to a fresh solution of deionized water to complete the swelling process. General Procedure for the Chemical Reduction of the Hydrogels. All hydrogels were soaked in pure deionized H2O until the hydrogel had achieved its maximum volume prior to chemical reduction. The swollen hydrogel was then placed in a glass petri dish under an inert atmosphere of UHP nitrogen gas inside of a glovebox, and 1M Na2S2O4 in H2O was added to the dish until the hydrogel was completely submerged. Note: The chemical reduction and actuation of hydrogels can be performed on the benchtop in air, however, inert conditions were utilized due to the sensitivity to oxygen (O2) of the chemical reductant Na2S2O4. Upon the addition of 1M Na2S2O4, an immediate color change to an intense purple color occurred, which is indicative of radical cation formation and self-assembly of the viologen subunits within the hydrogel. The hydrogel was then allowed to sit for a maximum of 12 h in the reducing solution. After 12h, the shrunken hydrogel was transferred to a beaker of fresh water in air to allow for reoxidation back to its original “pre-shrunken” volume. Oscillatory Shear Rheometry. Frequency sweep (1.0% strain, 0.1 to 100 rad s–1) and strain sweep (10 rad s–1, 0−200% strain) experiments were performed on a TA Instruments (Newcastle, DE) AR-G2 oscillatory shear rheometer using a 20 mm geometry. All experiments were performed in triplicate for both the contracted (reduced) and expanded (oxidized) hydrogels. General Procedure for the Dime-lifting Experiment. A 6V12+-containing hydrogel – containing 5 mol% the hexamer oligoviologen and 95 mol% PEG (with respect to amount of polymer) – was fabricated in the shape of a rectangular prism and soaked in fresh H2O until fully 10 ACS Paragon Plus Environment

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swollen (1.2 cm x 0.7 cm). The hydrogel was then placed in an N2-saturated glass jar and a dime (2.028 g) was centered on top of the hydrogel. Sodium dithionite (115 mL;1M in H2O) was then slowly added until the solution fully submerged the hydrogel and the dime. The hydrogel was then allowed to reduce and contract over a 12 h period wherein the sodium dithionite solution was removed and fresh H2O (5 mL) was added until the majority of the hydrogel was submerged, but leaving the dime above water level. The hydrogel was then allowed to oxidize and expand by reabsorbing the surrounding water until the original height (7.0 mm) was achieved.

ASSOCIATED CONTENT Supporting Information The Supporting Information (SI) is available free of charge on the ACS Publications website at DOI: _____. Details on chemical compound synthesis, spectroscopic and spectrometric characterization data for each small molecule and oligomer, as well as any additional data such as hydrogel cycling data can be found in the SI. AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Author Contributions J. C. B. conceived the idea and J. C. B. and A. F. G. designed the experiments. A. F. G., M. D., A. O. D., K. P. L., X. L., A. N., and A. W. synthesized and characterized all compounds and materials. A. F. G. carried out the optical absorption spectroscopy and electron paramagnetic resonance experiments. A. F. G., A. O. D., and K. P. L. performed the hydrogel actuation and cycling experiments. J. C. B., K. P. L., A. O. D., and X. L. performed the rheological experiments. J. C. B. and A. F. G. co-wrote the manuscript, and all authors contributed to the refinement of the manuscript and supplementary information files. Notes The authors declare no competing financial interests. ACKNOWLEDGMENTS We thank Washington University in St. Louis (WUSTL) for the generous startup funds, which supported this research. The mass spectrometry data was obtained using the NIH / NIGMS Biomedical Mass Spectrometry Resource at WUSTL, which is supported by a grant from the National Institutes of Health / National Institute of General Medical Sciences (#8P41 GM103422). The rheological data was obtained through the Department of Mechanical Engineering and Materials Science at WUSTL and we thank Dr. Ruth J. Okamoto for help with mechanical properties testing of the reported materials. Lastly, we would like to thank Professor John-Stephen Taylor for fruitful discussions and for proof-reading the manuscript. REFERENCES

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74 Gibbs-Hall, I. C.; Vermeulen, N. A.; Dale, E. J.; Henkelis, J. J.; Blackburn, A. K.; Barnes, J. C.; Stoddart, J. F. Catenation through a Combination of Radical Templation and Ring-Closing Metathesis. J. Am. Chem. Soc. 2015, 137, 15640–15643. 75 Li, H.; Fahrenbach, A. C.; Dey, S. K.; Basu, S.; Trabolsi, A.; Zhu, Z.; Botros, Y. Y.; Stoddart, J. F. Mechanical Bond Formation by Radical Templation. Angew. Chem. Int. Ed. 2010, 49, 8260–8265. 76 Cheng, C.; McGonigal, P. R.; Schneebeli, S. T.; Li, H.; Vermeulen, N. A.; Ke, C.; Stoddart, J. F. An artificial molecular pump. Nature Nanotech. 2015, 10, 547–553. 3+ 77 Balamurugan, A.; Reddy, M. L. P.; Jayakannan, M. π-Conjugated polymer–Eu complexes: versatile luminescent molecular probes for temperature sensing. J. Mater. Chem. A 2013, 1, 2256–2266. 78 Eising, S.; Lelivelt, F.; Bonger, K. M. Vinylboronic Acids as Fast Reacting, Synthetically Accessible, and Stable Bioorthogonal Reactants in the Carboni–Lindsey Reaction. Angew. Chem. Int. Ed. 2016, 55, 12243–12247. 79 Juetten, M. J.; Buck, A. T.; Winter, A. H. A radical spin on viologen polymers: organic spin crossover materials in water. Chem. Commun. 2015, 51, 5516–5519. 80 Chandler, D. Interfaces and the driving force of hydrophobic assembly. Nature 2005, 437, 640–647. 81 Zhou, C.; Truong, V. X.; Qu, Y.; Lithgow, T.; Fu, G.; Forsythe, J. S. Antibacterial poly(ethylene glycol) hydrogels from combined epoxy-amine and thiol-ene click reaction. Polym. Chem. 2016, 54, 656–667. 82 Yao, F.; Xu, L.; Fu, G.-D.; Lin, B. Sliding-Graft Interpenetrating Polymer Networks from Simultaneous “Click Chemistry” and Atom Transfer Radical Polymerization. Macromolecules 2010, 43, 9761–9770. − 83 Mayhew, S. G. The Redox Potential of Dithionite and SO 2 from Equilibrium Reactions with Flavodoxins, Methyl Viologen and Hydrogen plus Hydrogenase. Eur. J. Biochem. 1978, 85, 535–547.

FIGURE CAPTIONS Figure 1. (a) An iterative synthesis was used to prepare each even-numbered (n = 2, 4, 6, 8 and 10) oligoviologen by (i) alternating between the excessive addition (20 equiv) of tosyl-endcapped hexaethylene glycol (HEG-Tos) and 4,4'-bipyridine (BIPY) in MeCN at 130 ⁰C for 12– 16 h in a closed reaction vessel. (b) The synthetic cycle begins (green box) with a BIPY-endcapped HEG (HEG-BIPY2+) and the oligomer is grown iteratively, with only intermittent precipitations in MeCN:PhMe, followed by centrifugation in order to isolate each product. At any point in the cycle, the BIPY-end-capped precursor can be removed and (ii) functionalized with terminal azide groups (red box) through the excessive addition (35 equiv, MeCN, 130 ⁰C, 20 h) of a tosylated diethylene glycol possessing one azide at its terminus (Tos-DEG-N3). (c) Synthesis of the click-based hydrogel involves two equiv of bis-azide-terminated linkers – where 95 mol % of the two equiv is comprised of only polyethylene glycol (PEG-N3) and 5 mol % consists of the oligoviologen (nV(2n)+-N3) – to one equiv of the tetra-alkyne cross-linker (TAXL). Figure 2. UV-Vis-NIR spectra of oligoviologens (2V•4Tos, 4V•8Tos,6V•12Tos, 8V•16Tos, 10V•20Tos) recorded in (a) 0.2 mM in H2O reduced with excess Na2S2O4 and (b) 0.2 mM in MeCN reduced with excess Zn dust. Generation of the viologen radical cations in solution triggers self-assembly in the form of spin-paired π-stacked “pimers” along the oligomer backbone. The “pimers” show a characteristic low energy absorption in the near IR around 800−850 nm. In addition to dimer formation, tris(radical) π-stacks can also form, as evidenced by a characteristic broad absorption around 1000 nm. This spectroscopic study provides insight into how the self-assembly of the oligoviologens in solution is affected by the increase of viologen subunits in each oligomer. It is observed as the oligomers increase in length, the λ max in the near IR region shows a distinct red-shifting in the spectral profile in water, presumably on account of hydrophobic effects, which ultimately pushes the equilibrium towards a higher population of dimers and trimers, relative to mostly just dimers in MeCN. 15 ACS Paragon Plus Environment


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Figure 3. Electron paramagnetic resonance (EPR) spectra of a 0.2 mM solution of 4V•8Tos with 0.25 eq. of sodium dithionite (0.05 M solution) added to generate the radical cation. Experimental parameters are as follows: Modulation Frequency = 100 kHz, Modulation Amplitude = 1.0 G, Sweep Time = 4 min, Time Constant = 0.03 s, Center Field = 337.160 mT, Sweep Width = 2.5 mT, and Microwave Power = 2 mW. Dimethyl formamide (DMF) was chosen as a solvent to disrupt hydrophobic π-stacking interactions between diamagnetic viologen cation-radicals to produce a small population of paramagnetic species in solution. In water, the reduced oligoviologen is EPR silent. Figure 4. (a) The maximum degree of contraction (i.e., the percent ratio of the final contracted volume to the initial swollen state volumes) for each hydrogel is plotted as a histogram, thus measuring (in triplicate) the change in volume (open rectangles) and mass (dashed rectangles) that was observed during the first part of cycle 2 after 12 h. The hydrogels contracted to the following percentages of the starting values (volume, mass): 1V2+ (65.7%, 74.7%), 2V4+ (35.0%, 46.5%), 4V8+ (25.1%, 30.9%), 6V12+ (16.8%, 24.0%), 8V16+ (8.8%, 15.0%), and 10V20+ (8.8%, 20.4%). (b) The volume of each hydrogel was measured (in triplicate) every 25 minutes during the second cycle of contraction in order to characterize the kinetics of the actuation process. The initial rates are reported from the initial 0–25 min portion of the curve. (c, d) The cycling ability of each hydrogel was also assessed (only 2V4+ and 6V12+ are shown for clarity; see Supporting Information for the other hydrogel cycling data). Cycle 1 began with the Versene-soaked and H2O-swollen hydrogels, which were soaked in 1M Na2S2O4 solution in an N2-filled glovebox for a few hours (the reduction can be carried out on the bench top as well). Next, the oxidation and expansion was performed by soaking the contracted gels in O2-saturated H2O, a step which requires 20–24 h to completely remove all color associated with reduced viologen subunits. The second cycle exhibits the largest possible degree of actuation for each hydrogel and upon oxidation and expansion, the hydrogels recover 98–99.5% of their original volume. This process was repeated over four cycles and the degree of actuation remains consistent throughout. (d) Both cubic and disk morphologies were examined. The first image of each shows the state of a representative hydrogel that was treated with Versene solution and swollen in pure H2O. The second image is of the reduced and contracted hydrogels, whereas the third image shows the oxidized and expanded hydrogels, which lost the initial yellowish/greenish color on account of copper expulsion during the contraction step. The error bars for each data point represent the standard error of the mean (SEM) for experiments that were carried out with a minimum value of n = 3 samples. Figure 5. (a) The dynamic viscoelastic behavior of a 6V12+-containing hydrogel – both in its contracted (purple) and expanded (red) states – was assessed by oscillatory rheometry by first synthesizing three samples in a 4.5 cm (diameter) petri dish, followed by reduction/contraction to approximately 2.5 cm and using a punch-out tool to obtain 2.0 cm diameter samples (see inset picture) that matched the instrument geometry. A frequency sweep from 0.1 to 100 rad s–1 was then carried out while keeping the strain amplitude constant at 1%. At no point during the course of the experiment is a cross-over point observed between the storage (G') and loss (G'') moduli; an outcome which indicates elastic behavior at all angular frequencies. (b) Analysis of the stress versus strain plots for the contracted (purple) and expanded (red) states – obtained from a strain sweep at 10 rad s–1 – reveals a nearly 2-fold increase in the yield stress point (arrows point to 63 16 ACS Paragon Plus Environment

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vs 32 Pa at 3.0 vs 1.5% strain amplitude, respectively) for the contracted vs the expanded state. The error bars for each data point represent the standard error of the mean (SEM) for experiments that were carried out with a minimum value of n = 3 samples. Figure 6. Demonstration of an artificial molecular muscle at work. A dime weighing 2.028 g was placed on top of a 6V12+-containing hydrogel (at an initial height of 7.0 mm), followed by the addition of a 1M Na2S2O4 solution in an N2-saturated glass jar, which completely submerged the hydrogel. Within the first minute, the color of the hydrogel changed from pale yellow to dark purple, indicating that the viologen subunits in the material had been reduced to the radicalcation (V●+). Although most of the contraction occurs within the first few hours, the hydrogel was allowed to contract fully over the course of 12 h, resulting in a final contracted height of 4.0 mm. At this stage, the hydrogel mass was 377 mg. Next, the reducing solution was removed and fresh O2-saturated H2O was added to the jar in the presence of ambient O2, and the increase in height was monitored as the viologen subunits oxidized and the hydrogel expanded. After 24 h, the height of the dime returned to its original point of 7.0 mm. Note: The small dark colored band at the top of the hydrogel after complete expansion resulted presumably from a small amount of the outer cupronickel layer of the dime having ‘plated’ onto the hydrogel while sitting in the reducing solution.



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Figure 1


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Redox-Responsive Artificial Molecular Muscles: Reversible Radical

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