Mechanical Unfolding and Thermal Refolding of Single-Chain

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Mechanical Unfolding and Thermal Refolding of SingleChain Nanoparticles Using Ligand-Metal Bonds Avishai Levy, Roi Feinstein, and Charles E. Diesendruck J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01960 • Publication Date (Web): 24 Apr 2019 Downloaded from http://pubs.acs.org on April 24, 2019

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Journal of the American Chemical Society

Mechanical Unfolding and Thermal Refolding of Single-Chain Nanoparticles Using Ligand-Metal Bonds Avishai Levy, Roi Feinstein and Charles E. Diesendruck* Schulich Faculty of Chemistry, Technion – Israel Institute of Technology, Haifa, 3200008, Israel.

Supporting Information Placeholder ABSTRACT: Covalent macromolecules tend to fragment

under mechanical stress through the mechanochemical scission of covalent bonds in the backbone. However, linear polymers that have been intramolecularly collapsed by covalent bonds show greater mechanochemical stability compared to other thermoplastics. Here, Rhodium-π bonds are used for intramolecular collapse in order to show that mechanical stress can be removed from the polymer backbone and focused on weaker intramolecular cross-links, leading to polymer unfolding instead of mechanochemical events at the backbone. Moreover, given Rhodium-π bonds form spontaneously, by changing the time interval between ultrasound pulses, we demonstrate that entropic spring effects can lead to polymer refolding and reformation of the previously cleaved metal-ligand bonds, effectively repairing the intramolecular non-covalent cross-links. These findings provide the first example of an intramolecular repairing mechanism in synthetic molecules in solution, allowing for restoration of chemical bonds after mechanochemical events.

Single-chain polymer nanoparticles (SCPNs) are thermoplastics made by intramolecular collapse of linear polymers, in a process analogous to protein folding.1–4 Several similarities have been shown between SCPN and disordered proteins’ properties.5 SCPNs can be folded and unfolded chemically6–8 or even mechanically.9,10 When atomic-force microscopy is used, a protein-like step-wise unfolding is observed.11 More recently, we have shown that folding thermoplastics with covalent intramolecular cross-links (IM-CLs), improve their mechanochemical stability even at high strain rates.10,12 When SCPNs are mechanically stressed, each chain acts as a tiny network with mechanochemical events not necessarily leading to chain fragmentation; i.e., covalent bonds are cleaved, but the molecular weight of the chain, and, as a consequence, the polymer properties, remain unchanged. In our initial studies, intramolecular collapse was done though the formation of C-C bonds10 in order to not affect the solvent-polymer polar interactions,13 but, consequently, there was no differentiation between IM-CL and backbone bonds.14

While SCPN unfolding through the scission of C-C bonds requires significant amounts of energy,15,16 it does not include two of the most attractive characteristics of protein mechanical unfolding: regioselectivity and thermal refolding. In Nature, the biomaterials that need to withstand the greatest strains are made from very large proteins such as titin,17 elastin,18 fibronectin19 etc. Despite their size, these proteins absorb energy through orderly mechanochemical scission of IM-CLs.20,21 When stress is released, the proteins refold22 driven by entropic spring effects.23 Here, we describe a simple SCPN system capable of achieving both mechanochemical regioselectivity and autonomous refolding ability using non-covalent interactions as IM-CLs24–26 such as metal-ligand bonds, which can form quite non-polar (fitting the polymer polarity) organometallic complexes. The mechanochemical scission of metal-ligand bonds is endothermic,27 and if ligand and less-coordinated metal are stable enough, reversibility is possible. Metal-ligand bonds have been exploited as mechanophores in the context of mechanochemical activation of latent catalysts,28–30 as well as in mechanical energy dissipation and self-healing in metallopolymer networks.31–33 Using SCPNs containing numerous metal attachment points, mechanochemical scission of one ligand keeps the metal attached to the backbone, which, due to chain dynamics and high molarity, can lead to spontaneous ligand-metal bond reformation, restoring the IM-CL and refolding the chain. In order to assess regioselectivity and reformation34 of IM-CLs, an additional mechanophore16 is used to measure the rate of mechanochemical events at the polymer backbone. A facile pathway to induce intramolecular collapse was chosen based on rhodium-π-bond coordination.35–37 The procedure involves merely treating linear polybutadiene (PB) with a rhodium(I)-ethylene complex in high dilution and, within a short time, the ethylene ligands are substituted by the double bonds in the polymer backbone. An advantage to using PB is that it allows the incorporation

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Journal of the American Chemical Society Scheme 1. Synthetic strategy for the preparation of the polymers used in this study. CHCl3 NaOH (1.25 eq) n

rt

Rh2Cl2(C2H4)4 m

l

THF, rt

p

Rh Cl

Cl Cl

m

o Cl Cl

Cl

Rh Cl Rh

Rh Cl

Rh2Cl2(C2H4)4

of gem-dichlorocyclopropane (gem-DCC) mechanophores to the backbone.38 gem-DCC works as an indicator of stress in the backbone providing a clear 1H-NMR signal upon mechanical activation,39–42 i.e., quantifiable information on the regioselectivity of the mechanochemical reaction. All cis-PB36 was initially functionalized by cycloaddition of dichlorocarbene to the double bonds using CHCl3 and KOH to incorporate gem-DCC mechanophores in the backbone. Base quantities were tuned to provide a conversion of 45%, which seemed adequate for this study, as a reasonable range of gem-DCC activation can be measured and compared, and enough alkenes are left for rhodium coordination. This modified PB copolymer was then intramolecularly collapsed at high dilution (1 mg/ml) by simple addition of a fresh solution of Rh2Cl2(C2H4)4 in dry THF at room temperature.35 The detailed synthetic route is depicted in Scheme 1 (polymers L and CL1-7). For detailed experimental procedures, see the supporting information (SI). Seven different SCPNs were prepared, each folded by different quantities of rhodium-dimer, connecting from 0.5 to 15 mol% of the monomers. The intramolecular collapse of the modified cis-PB copolymer L was monitored by gel permeation chromatography (GPC) and NMR spectroscopy, which indicated that gem-DCC was not affected by the presence of the Rh(I) complex. The polymer peak moved towards higher retention volumes (RV) in GPC, indicating reduction in hydrodynamic volume as a consequence of reaction progress.35 The reaction was continued for several hours, but after ca. 3 h, the RV stabilized, indicating that an equilibrium was reached (see the SI). The chromatograms obtained for the different polymers CL1-7, folded by increasing amounts of Rh, and linear polymer L are shown in Figure 1. Even small quantities of rhodium (0.5 mol%, CL1) induce a significant shift of the polymer peak. As expected, the RV moves in accordance to the amount of rhodium added.35 Using triple-detector GPC, all the molecular properties for each polymer could be measured (see the SI). The changes in average molecular weight, hydrodynamic radii and intrinsic viscosity are consistent with the trend in

Figure 1 and the expected changes for intramolecular collapse.35,43 Ultrasound induced solvodynamic shear was used to stress the polymers having different amounts of the rhodium additive in solution during mechanochemical competition experiments.44 A fresh CL polymer (CL1-7) was prepared for each sonication experiment: the required amount of rhodium was weighted, added to L in THF, stirred for 3 h (the required time for the CL reaction) and directly sonicated. Each SCPN and L polymer was sonicated three times for 45 minutes using pulsed ultrasound program (1s on, 2s off) in THF, at 9°C.10

1 0.8

Relative scale

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0.6 0.4 0.2 0 21

23

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27 29 Time (min)

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35

Figure 1. GPCs of polymers L (light blue), CL1 (orange), CL2 (grey), CL3 (yellow), CL4 (red), CL5 (green), CL6 (dark blue) and CL7 (brown) in THF. Signal shown from differential refractive-index detector.


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Scheme 2. Non-chain scissile mechanochemical events of folded polymer during sonication.

The mechanical energy from the ultrasound is transduced within the polymer by three possible mechanochemical transformations: backbone (C-C bond) fragmentation, unfolding (Rh-π scission), and gem-DCC activation. Previously, we followed SCPN unfolding and fragmentation indirectly, using a spin trap that differentiates between sonoradicals and macroradicals,45 but this spin-trap was not able to differentiate between the backbone and IM-CL. Here, gem-DCC is used to provide a direct measure of mechanical stress on the polymer backbone. Given all SCPNs are made from L, with the same quantity of gem-DCC randomly distributed, comparing polymers CL1-7 and measuring gem-DCC activation provides information on the deflection of stress from the backbone and into the IM-CL (Scheme 2). In L, before sonication, the gem-DCC and adjacent hydrogens provide 1H-NMR peaks at δ=1.6 ppm.38 Upon mechanochemical activation, the mechanophore undergoes electrocyclic ring-opening,46,47 producing new 1H-NMR signals for the chloroolefin protons at 5.8 and 4.5 ppm. Mechanophore activation can be quantified by comparing between these peaks and butadiene hydrogens’ peak at 5.4 ppm (see the SI). In order to obtain clear NMRs, after each sonication the polymer solution was treated with 2-(diphenylphosphino) benzaldehyde to remove the rhodium from the polymer chain, allowing for solvent evaporation without crosslinking.35 The activation of gem-DCC was calculated for each sample and averaged (Figure 2). About 60% of the gem-DCC present in the backbone of the linear polymer (L) and the lightly cross-linked polymers (CL1 and CL2 with 0.5% and 1% IM-CL density, respectively) were activated during sonication. This value is reduced as the amount of rhodium IM-CL increases, following a clear trend up to polymers CL6-7 (10 and 15 mol% IM-CL), in which only 10% of gem-DCC is activated. As gem-DCC activation is mechanochemical in nature (and not thermal),38 and, given that all polymers were exposed to identical ultrasonication conditions, clearly the binding of rhodium to the double bonds are reducing

the amount of stress in the polymer backbone.10 Importantly, scission of Rh-π bonds lead to polymer unfolding, as opposed to chain fragmentation when stress concentrates in the backbone. This process is similar to the mechanically induced scission of IM-CLs in proteins such as Titin, which absorb mechanical energy as it undergoes stepwise unfolding. As the Rh-π bond formation is spontaneous, mechanochemical unfolding of SCPNs through scission of these bonds lead to the interesting possibility of their autonomous reversibility. Each Rh2Cl2 bridge is connected to four double bonds in the polymer backbone. Therefore, if one (or up to three) of the Rh-π bonds breaks, the bridge is still attached to the chain, presenting relatively high effective concentration towards recoordination of a free alkene. While the exact mechanism by which cavitation leads to mechanochemistry in macromolecules is still in debate, it is expected to occur through some sort of chain unfolding (coil-to-stretch).48 Therefore, upon stress release (decay of cavitation bubbles), entropic spring effects should lead to a reduction in hydrodynamic volume, bringing the Rh into close contact with free alkenes in the backbone, leading to spontaneous reformation of the Rh-π IM-CL. Given our initial bimolecular reaction took ca. 3 h to reach equilibrium, the intramolecular reaction should occur much faster, perhaps in the order of seconds or minutes. If the time interval given between ultrasound pulses is increased, the chance of IM-CL reformation rises, and therefore, in the next pulse, the amount of IM-CL should be larger, leading to a reduction in the overall amount of activated gemDCC after a defined sonication time. CL4 was chosen to look for evidence of refolding, since it showed a significant inhibition of gem-DCC mechanochemical activation but not to the extent of the highest IM-CL polymers, in which improvement might not be seen. CL4 was subjected to sonications with different intervals between ultrasound pulses, which varied from 1 to 16 sec, up until 15 min net sonication time was applied. Each pulse program was tested in three independently prepared CL4 solutions. At the end of the sonication, the



70 60 50

for the first time, the intramolecular autonomous repair of chemical bonds after mechanochemical events. The cycle demonstrated here in solution is similar to the function of proteins like Titin, which unfold due to mechanical stress and then refold thermally by the reformation of non-covalent interactions. This strategy, now repeated in a simpler synthetic polymer, can be adapted as a new strategy for intramolecular self-healing, which may be used to address chain separation issues and complementary chemical group finding, which retards property restoration in polymers. While many metallopolymers have shown self-healing ability,31–33 these results are a proof of concept towards a bioinspired design in which unentangled chains49 are folded through strong intramolecular non-covalent interactions.50 Studies on these materials are ongoing in our group. 50.0

% gem-DCC activation

polymer was worked-up as previously and analyzed by 1HNMR spectroscopy to calculate the amount of gem-DCC activation (Figure 3). Clearly, increasing the interval time has a significant effect on the amount of gem-DCC activation. Longer times allow for polymer refolding and increase the chance of IM-CL reformation, which, in the following pulse, are capable of absorbing additional mechanical energy and remove stress from the polymer backbone. For example, while CL4 has a lower IM-CL ratio than CL5, if given enough time for refolding, it can reduce the amount of gem-DCC activation to comparable values. Similar trends were seen using CL3 and CL5; in contrast, when L, CL2 and CL7 are sonicated with a delay of 16 s, no significant changes in gem-DCC activation are seen (see the SI). These controls, respectively, indicate that: a) reduced gem-DCC activation only occurs when both polymer and Rh bridges are present; b) low Rh content does not improve mechanochemical stability, independently of delay time – a minimum IM-CL density is required; and, c) there is a minimal gem-DCC activation due to backbone stress that cannot be addressed by IMCLs, i.e., saturation is reached between 8-10 mol% Rh.

% gem-DCC activation

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45.0 40.0 35.0 30.0 25.0 20.0

40

0

5

10

15

20

Interval (s) 30

Figure 3. Gem-DCC activation in CL4 after 15 min net sonication with different interval times between ultrasound pulses; calculated from 1H-NMR spectroscopy.

20 10

ASSOCIATED CONTENT

0 0

5

10

15

%CL (mol) Figure 2. gem-DCC activation as a function of the polymers' rhodium IM-CL density after 15 min net sonication; calculated from 1H-NMR spectroscopy.

To conclude, we have demonstrated that synthetic polymers folded via non-covalent IM-CLs have the ability to remove the stress from the polymer backbone, transferring it to the weaker bonds, leading to controlled unfolding of the polymer under stress in solution. Incorporation of force-sensitive mechanophores into the polymer's backbone and IM-CL allowed for their differentiation and comparison, with most of the mechanical energy being absorbed at the weakest link, in this case, Rh2Cl2-π bridges. In addition, given enough time, these Rh-π bonds reform spontaneously, effectively restoring the polymer IM-CLs. The reformed Rh-π IM-CLs are capable of absorbing mechanical energy additional times, further reducing the amount of mechanochemical events in the polymer backbone. This work demonstrates,

Supporting Information. The supporting Information is available free of charge at http://pubs.acs.org. General information, experimental procedures, additional figures, NMRs, Statistics (PDF)

AUTHOR INFORMATION Corresponding Author * email: [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This material is based upon work supported by the Israel Science Foundation (Grant No. 920/15). The authors are grateful to Dr. Yasmin Rosen and Prof. Maya DavidovichPinhas for their help with statistic analysis.

REFERENCES (1) Altintas, O.; Barner-Kowollik, C. Single-Chain Folding of Synthetic Polymers: A Critical Update. Macromol. Rapid Commun.


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Cl p Cl

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Mechanical Unfolding and Thermal Refolding of Single-Chain

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