Promoting Mechanochemistry of Covalent Bonds by Noncovalent

Letter pubs.acs.org/macroletters

Promoting Mechanochemistry of Covalent Bonds by Noncovalent Micellar Aggregation Hui Li,† Robert Göstl,‡ Marie Delgove,‡ Joren Sweeck,‡ Qiuyu Zhang,† Rint P. Sijbesma,*,‡ and Johan P. A. Heuts*,‡ †

Key Laboratory of Applied Physics and Chemistry in Space of Ministry of Education, School of Science, Northwestern Polytechnical University, 710072 Xi’an, Shaanxi, China ‡ Laboratory of Supramolecular Polymer Chemistry, Institute for Complex Molecular Systems, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands S Supporting Information *

ABSTRACT: Optical reporting of covalent bond scission in self-assembled structures in water is an important step toward the detection of forces in biological systems. Here we show that micelles of a diblock copolymer comprising hydrophobic poly(butyl acrylate) and hydrophilic poly(acrylic acid) blocks connected by an off-center mechanoresponsive moiety are mechanochemically active when sonicated in aqueous solution. Facile optical read-out of the force-activation is warranted by formation of a blue-fluorescent anthracene cleavage from the mechanophore, an anthracene-maleimide Diels−Alder adduct. In contrast to the efficient bond scission when the block copolymers are noncovalently anchored in liquid-like micellar cores, isolated unimers in solution are not activated by ultrasonication because the dimensions and viscous drag are drastically lower. These results demonstrate that covalent mechanochemistry can be enabled by noncovalent interactions.

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feedback signal when subjected to mechanical stress in the form of ultrasound. Our work was inspired by the approach reported by Moore and co-workers23 in which mechanophoreanchored poly(methyl acrylate) (PMA) chains are grafted on the surface of silica nanoparticles and the high capability of the anthracene-maleimide Diels−Alder adduct for optical report over covalent bond scission.24 We synthesized block copolymers comprising of a long hydrophilic poly(acrylic acid) (PAA) and a short hydrophobic poly(butyl acrylate) (PBA) block connected by the anthracene-maleimide Diels−Alder adduct (Figure 1a). From these nonsymmetric block copolymers, micelles were prepared by self-assembly in water (Figure 1b). Subsequently, the mechanical activation of these polymers was studied by ultrasonication in solution; we studied aqueous micellar and homogeneous solution. Parallel to our own efforts, an example of mechanochemistry involving micelles has been reported by Du, Zhang, and coworkers.20 They fabricated micelles of an ABA-type amphiphilic block copolymer with a spiropyran moiety at the chain center in a THF/water solvent mixture. It has been demonstrated that the degree of mechanical activation of these micelles increased with increasing water content in the solvent mixture. However,

mart materials designed to respond to different external stimuli, such as electric and magnetic fields, heat, light, or mechanical stress, are broadly sought-after candidates for a wide range of potential applications.1−6 Especially polymers comprising of tailor-made molecular moieties responding to mechanical stress (mechanophores) garner significant research interest in modern materials science as they allow for sensing of material failure, a macroscopic process, on a nanoscopic scale.1,5,6 Above and beyond optical force sensing,7−10 many impressive mechanoresponsive systems have been fabricated for various purposes including the release of small molecules,11−13 self-healing and -repair,14−17 or mechanocatalysis.18,19 However, though molecular stress-sensing in biologically relevant, advanced polymeric architectures and assemblies, such as micelles, vesicles, or polymersomes, requires the compatibility to aqueous media, functional mechanochemistry in water has only rarely been investigated.20−22 Furthermore, mechanochemical activation usually relies on the transfer of force through covalent bonds alone, limiting its use in biological systems which are almost always formed by self-assembly. It is therefore highly relevant to explore the use of noncovalent interactions, such as micellar aggregation, in mechanochemistry. Here we report on the self-assembly of mechanochemically inactive block copolymers into mechanochemically active micelles in aqueous solution resulting in a fluorescence © XXXX American Chemical Society

Received: July 28, 2016 Accepted: August 2, 2016

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DOI: 10.1021/acsmacrolett.6b00579 ACS Macro Lett. 2016, 5, 995−998

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ACS Macro Letters

Scheme 1. Synthetic Route Towards PBA32-b-PAA214 5 Containing the Maleimide-Anthracene Diels-Alder Adduct Mechanophore

Figure 1. (a) Illustration of the force-induced scission of the anthracene-maleimide mechanophore when (b) embedded in block copolymer micelles, but not in homogeneous solution.

these ABA-type block copolymers are symmetric and can thus also be mechanically activated in the disassembled state in organic solvent. In addition, the increased spiropyran activation in the micelle is mainly attributed to a change in polarity of the microenvironment of the mechanophores. In contrast, we here report the assembly of block copolymers into micelles comprising liquid-like PBA cores changing the dimensions and drag of the polymer aggregates by noncovalent interactions. In order to obtain micelles with a mechanophore at the interface of the hydrophobic and hydrophilic part, an AB-type amphiphilic diblock copolymer PBA32-b-PAA214, linking hydrophilic and hydrophobic blocks via the anthracene-maleimide Diels−Alder adduct, was synthesized according to Scheme 1. First, the synthesis of initiators 1 and 2 was performed following modified procedures of Moore and co-workers23 and Haddleton and co-workers.25 Anthracene-PtBA214 3 (Mn = 27.8 kDa, Đ = 1.26)26 was synthesized by atom transfer radical polymerization (ATRP) employing 1 as the initiator (Figure 2).27 Subsequently, initiator 2 was used to prepare maleimidePBA32 4 (Mn = 4.5 kDa, Đ = 1.17)26 via Cu(0)-catalyzed living radical polymerization (SET-LRP).28,29 PBA32-b-PtBA214 diblock copolymer was obtained by Diels−Alder reaction between 3 and 4 (Mn = 39.1 kDa, Đ = 1.41).26 The molecular weight distribution of PBA 32-b-PtBA214 reveals two minor peaks besides the desired diblock (Figure 2). The first peak at M ≈ 4.5 kDa corresponds to maleimidePBA32 4 as this reagent was used in slight excess to maximize conversion of the anthracene moiety. We ascribe the shoulder at about 70 kDa to termination by combination that occurred in the synthesis process of anthracene-PtBA214 3 and maleimide-PBA32 4 leading to a small amount of multiblock copolymer in the final product. Eventually, the desired AB-type amphiphilic diblock copolymer, PBA32-b-PAA214 5 was obtained after selective acidic hydrolysis of the t-butyl groups. The experimental details for all steps can be found in the Supporting Information. A clear micellar solution of amphiphilic copolymer 5 was obtained by dissolution in water with 1 equiv NaOH per

Figure 2. Molecular weight distributions of anthracene-PtBA214 3, maleimide-PBA32 4, and PBA32-b-PtBA214.26

carboxylic acid group and heating to 80 °C for about 3 h, as confirmed by dynamic light scattering (DLS) measurements (d ≈ 78 nm, ĐDLS = 0.45, Figure 3). We then employed ultrasonication to investigate the effect of micellization on the application of force. Ultrasonication generates an elongational flow around collapsing cavitation bubbles, inducing the coil−stretch transition of polymer chains in solution and thus transduces mechanical force.6,30 The aggregation of the PBA chains of 5 into micelles is expected to enhance mechanochemical effects. Even though the PBA chains are well below their entanglement molecular weight,31 the viscosity of the micellar cores is much higher than that of water. For comparison, the zero shear viscosity of poly n-butyl acrylate with a molecular weight of 4000 is 10 Pa·s, 104 times higher than that of water.32 The micellar core is therefore expected to provide sufficient drag to effectively increase the dimensions of the species on which the elongational force field of ultrasound acts.33,34 Thus, the hydrophilic PAA chains substituted with anthracene should cleave and result in a fluorescence signal 996

DOI: 10.1021/acsmacrolett.6b00579 ACS Macro Lett. 2016, 5, 995−998

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ACS Macro Letters

detected (Figure S13). DLS measurements revealed that during the first 5 min of sonication micellar aggregates are disrupted to single micelles which is visualized by a sudden decrease of diameter and dispersity ĐDLS (Figure S9). After this induction period, covalent bond scission can be observed (Figure 4) and the micelle diameter fluctuates around 20−40 nm. To prove that the self-assembly into micelles is indeed the trigger rendering this system mechanochemically active, we performed two control experiments. Initially, we applied the same ultrasonication conditions to a homogeneous solution of PBA32-b-PAA214 5 in a CH3Cl/MeOH mixture. As the mechanophore is situated far off-center (at ca. 13% contour length), we expect the individual chains to not cleave at the anthracene-maleimide Diels−Alder adduct (Figure 1b). Indeed, fluorescence spectra collected over the course of the ultrasonication process confirm that only a negligible amount of free anthracene is generated during the irradiation process, which we attribute to the chain-terminated combination products formed during the Diels−Alder reaction (Figure S10). Plotting the fluorescence intensity at the emission maximum λem = 420 nm comparing it to the activation of the micellar solution reinforces this result (Figure 4b). However, as this result does not rule out the effect of solvent on the cavitation process and we reasoned that the detection of fluorescence in experiments carried out below the CMC could prove difficult, we synthesized the water-soluble derivative PAA28-b-PAA214. We expect this derivative not to assemble into micelles in water while exhibiting comparable contour length and relative mechanophore position with respect to 5 (Figure S8). Indeed, from Figures 4b and S11 it becomes clear that this polymer does not cleave at the Diels−Alder moiety when subjected to ultrasonication in aqueous solution, confirming the self-assembly into micelles as origin for the mechanochemical activation of 5. We attribute the decrease in fluorescence intensity upon prolonged sonication in water to decomposition of the fluorophore via the reaction of radical species formed from the solvent with anthracene (Figure 4b).36,37 For sonication in organic solvent, this effect is not observed (Figures 4b and S10). We here showed that the self-assembly of an amphiphilic block copolymer PBA32-b-PAA214 5 comprising an off-center anthracene-maleimide Diels−Alder adduct mechanophore into micelles in water renders the formerly mechanochemically inactive polymer unimers active by increasing the effective contour length and effective molecular weight through aggregation into a larger superstructure. The scope of polymer mechanochemistry is enlarged beyond polymers with high contour lengths when noncovalent aggregation is used to create anchor points to form mechanochemically larger species. The effectivity of relatively short PBA chains shows that these anchor points neither need to be glassy, nor do the chains have to be entangled, at least at the high elongational strain rates found in sonicated solutions. We believe that the ability to sensitively detect mechanical stress in the form of ultrasound by fluorescence in aqueous systems on biologically relevant polymeric architectures constitutes an important step toward the application of force probes in true biological environments.

Figure 3. Average size distribution by number (ρ = 0.5 mg·mL−1) as obtained by DLS measurements of a micellar solution of block copolymer 5.

after sonication of micellar 5, but not 5 in homogeneous solution (Figure 1b). Indeed, an unambiguous increase in fluorescence was detected over the course of the sonication of an aqueous micellar solution of PBA32-b-PAA214 5 (Figure 4a). Moreover,

Figure 4. Fluorescence measurements during ultrasonication. (a) Evolution of the emission (λexc = 260 nm) and excitation spectra (λem = 420 nm) of an aqueous micellar solution of 5. (b) Evolution of the emission intensity at λem = 420 nm as a function of sonication time.

the emission and excitation spectra (the latter resembling the features of the fluorophore’s absorption spectrum) identify the fluorophore as anthracene confirming that chain scission occurs on the desired mechanophore. The considerable red shift of both the absorption and fluorescence of anthracene in water is well-known and generally attributed to the formation of anthracene aggregates.35 Employing a rough concentration calibration performed via fluorescence of small molecule anthracene in aqueous sodium dodecyl sulfate solution, we estimate that about 40% of the Diels−Alder adducts are cleaved after 120 min sonication (Figure S12). Further, MALDI-TOF mass spectrometry and GPC measurements on the sonicated solution indicate that scission takes place predominantly at the mechanophore as only signals corresponding to the PBA32 fragment can be

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.6b00579. 997

DOI: 10.1021/acsmacrolett.6b00579 ACS Macro Lett. 2016, 5, 995−998

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(23) Li, J.; Shiraki, T.; Hu, B.; Wright, R. A. E.; Zhao, B.; Moore, J. S. J. Am. Chem. Soc. 2014, 136 (45), 15925−15928. (24) Göstl, R.; Sijbesma, R. P. Chem. Sci. 2016, 7 (1), 370−375. (25) Syrett, J. A.; Mantovani, G.; Barton, W. R. S.; Price, D.; Haddleton, D. M. Polym. Chem. 2010, 1 (1), 102. (26) Note that molecular weights were determined by GPC in THF at 40 °C and values are reported relative to narrow polystyrene standards. (27) Subramanian, S. H.; Dhamodharan, R. Polym. Int. 2008, 57 (3), 479−487. (28) Samanta, S. R.; Levere, M. E.; Percec, V. Polym. Chem. 2013, 4 (11), 3212. (29) Anastasaki, A.; Waldron, C.; Wilson, P.; Boyer, C.; Zetterlund, P. B.; Whittaker, M. R.; Haddleton, D. ACS Macro Lett. 2013, 2 (10), 896−900. (30) Cravotto, G.; Gaudino, E. C.; Cintas, P. Chem. Soc. Rev. 2013, 42 (18), 7521−7534. (31) Ahn, D.; Shull, K. R. Langmuir 1998, 14 (13), 3637−3645. (32) Herbst, F.; Binder, W. H. Polym. Chem. 2013, 4 (12), 3602− 3609. (33) Schaefer, M.; Icli, B.; Weder, C.; Lattuada, M.; Kilbinger, A. F. M.; Simon, Y. C. Macromolecules 2016, 49 (5), 1630−1636. (34) May, P. A.; Munaretto, N. F.; Hamoy, M. B.; Robb, M. J.; Moore, J. S. ACS Macro Lett. 2016, 5, 177−180. (35) Nakajima, A. J. Lumin. 1977, 15 (3), 277−282. (36) Ananthula, R.; Yamada, T.; Taylor, P. H. J. Phys. Chem. A 2006, 110 (10), 3559−3566. (37) Makino, K.; Mossoba, M. M.; Riesz, P. J. Phys. Chem. 1983, 87 (8), 1369−1377.

Experimental details and characterization data (PDF).

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS H.L. was supported by the National Natural Science Foundation of China (No. 51433008) and Graduate School of Northwestern Polytechnical University. R.G. was supported by the Deutsche Forschungsgemeinschaft (DFG) through a research fellowship, GO 2634/1-2. This work is supported by the Dutch Ministry of Education, Culture, and Science (Gravity Program 024.001.035).

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DOI: 10.1021/acsmacrolett.6b00579 ACS Macro Lett. 2016, 5, 995−998