Dynamic Chemistry of Selenium: Se–N and Se–Se Dynamic Covalent

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Dynamic Chemistry of Selenium: Se−N and Se−Se Dynamic Covalent Bonds in Polymeric Systems Shaobo Ji, Jiahao Xia, and Huaping Xu* Key Lab of Organic Optoelectronics & Molecular Engineering, Department of Chemistry, Tsinghua University, Beijing 100084, China

ABSTRACT: The application of selenium in the responsive polymer system and the enzyme mimic system have been well studied. Our group initiated this line of research in 2009 by first extending selenium chemistry to dynamic chemistry. In this article, the discovery, progress, and application of selenium-related dynamic covalent bonds will be introduced. The dynamic property of Se−N bond and Se−Se bond were revealed and have been applied in the polymer system as enzyme mimic and selfhealing materials, respectively. Further studies that need to be done and potential application of selenium-related dynamic chemistry will also be discussed. elenium, which was first discovered by Jöns Jacob Berzelius in 1817, is a semimetallic chemical element lying in the group XVI of the periodic table.1 In 1957, selenium was determined to be one of the necessary elements in the human body, after that, selenoproteins were also discovered, which prevent cell damage from free radicals. As free radicals are related to several chronic diseases, such as cancer and heart disease, various small antioxidant molecules containing selenium were synthesized and studied.2−5 The previous applications of selenium in polymer chemistry, however, were mostly related to polyselenophenes by using their photovoltaic properties.6−9 Selenium-containing macrocycles were also studied.10,11 In our group, we have developed a series of selenium-containing polymers and used them in biosystems as responsive materials.12 In these studies, we took advantage of low bond energies of C−Se and Se−Se (C−Se, 244 kJ mol−1; Se−Se, 172 kJ mol−1, while C−S, 272 kJ mol−1; S−S, 240 kJ mol−1),13 which makes the monoselenide and diselenide easy to be oxidized or reduced. Among them, the diselenide bonds have been applied as GPx (glutathione peroxidase) mimics or as sensitive redox responsive groups.14−18 Recently, considering the bond energy of several Se−X bonds (Se−Se, Se−N) is lower than S−S, which is widely used as dynamic covalent bond; the dynamic properties of selenium-related covalent bonds were also studied, along with their application in polymer systems.19−23

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© 2015 American Chemical Society

Dynamic covalent bonds (DCBs) are covalent bonds that can form or cleave under certain conditions. As a result of their dynamic property, they are extensively used in dynamic combinatorial chemistry (DCC) and supramolecular chemistry.24−27 The traditional DCBs include disulfide bonds, imine bonds, acylhydrazone bonds, hexatomic ring formed via Diels− Alder cycloaddition reaction, and so on. They have wide applications, such as self-healing materials and responsive systems, so it is of significance to search for a new kind of DCB and new conditions for the dynamic chemistry. As mentioned, the bond energies of Se−X bonds are low enough to be used as dynamic covalent bonds, however, there have rarely been any reports about selenium-related dynamic properties. To expand the DCBs and also the selenium chemistry, our group has studied the dynamic chemistry of selenium in recent years. Here we will introduce the studied Se−N and Se−Se dynamic covalent bonds and their applications. Till now, these two DCBs were both used in polymers to achieve functionality. Potential development of selenium-related dynamic chemistry will also be discussed. The first attempt to study selenium-related dynamic chemistry was Se−N noncovalent interaction.19 Two small molecules were designed: azacalix[6]pyridine (APy6) and a Received: November 23, 2015 Accepted: December 16, 2015 Published: December 22, 2015 78

DOI: 10.1021/acsmacrolett.5b00849 ACS Macro Lett. 2016, 5, 78−82

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ACS Macro Letters

The Se−N dynamic covalent bond was realized by reaction between electron donating pyridine derivative and electron accepting phenylselenyl halogen species PhSeBr (Figure 2A).20

three-armed Se containing amphiphile (SeG; Figure 1A). The original intention was to realize a molecular inclusion complex

Figure 2. (A) Se−N dynamic covalent bond formed between PhSeX and pyridine derivatives. (B) Structure of molecules used in this work. (C) UV−vis spectra of PhSeBr with 4-chloropyridine, pyridine, and DMAP, respectively. The absorption of PhSeBr at 470 nm declines with the increasing of electron-donating ability of the N atoms in the model molecules, indicating that the formation of Se−N covalent bond can be controlled by adjusting the electron donating ability of the N atoms in the building block. Reproduced with permission from ref 20. Copyright 2013 Wiley-VCH.

This DCB could be cleaved and reformed under certain conditions. The molecules used in this work were drawn in Figure 2B. For the fabrication of Se−N DCB, polystyrene-bpoly(4-vinylpyridine) (PS-b-P4VP), and PhSeX were mixed in CH2Cl2 or CHCl3 in the ratio of 1 to 1 for the pyridine groups to PhSeBr. The formation of Se−N covalent bond could be finished within 1 min under sonication, and it could be determined via various characterization methods. Peak shifts in 1 H NMR, 77Se NMR, XPS, and new peaks in FT-IR spectroscopy all confirmed the formation of Se−N bonds. And from the UV−vis spectrum, the formation and cleavage of this bond were easily monitored as the absorption peak of PhSeBr at 470 nm disappeared after Se−N formation. Different pyridine derivative with increasing electron-donating ability, 4chloropyridine, pyridine, and 4-dimethylaminopryidine (DMAP), were utilized to test the controllability of the DCB. As monitored by UV−vis spectroscopy, with better electrondonating, the Se−N bond formed better (Figure 2C); this result agreed with the electron-donating and -accepting roles of Se and N and also showed that the formation of Se−N DCB could be regulated. The cleavage and reversibility of the Se−N bond were also studied. First, this bond could be cleaved when heated to 120 °C, and it could also be cleaved by adding DMAP to PS-b-P4VP/PhSeBr system, as DMAP possessed better electron donating ability and thus took the PhSe− group away from the polymer. Then, besides the cleavage, the reversibility under certain conditions was also determined. By adding acid to the system, the N atom would be protonated and dissociate from Se atom, the Se−N bond was cleaved. And by adding base to the acidified system, N atom would be free again and form the Se−N bond again. This reversible procedure could be repeated for several cycles and monitored by the absorbance

Figure 1. (A) Fabrication of well-defined azacalix[6]pyridine nanosheets assisted by Se−N noncovalent interactions. TEM (B) and AFM (C) images of the nanosheets (1−2 mm long, 300−500 nm wide). TEM images of (D) micelles of SeG in water (140 nm in diameter) and (E) irregular aggregates of the insoluble APy6 in aqueous solution. Reproduced with permission from ref 19. Copyright 2012 The Royal Society of Chemistry.

with a certain ratio (APy6)x(SeG)y. However, an unexpected result appeared; instead of molecular complex, large scale nanosheets were fabricated. As shown in Figure 1D,E, SeG would form micelles in aqueous solution, while APy6 formed irregular aggregates by itself. By mixing them in a ratio of SeG/ APy6 4/1, well-defined nanosheets could be generated (Figure 1B,C). The morphology change indicated interaction between these two molecules; further tests confirmed the interaction was related to the Se atom. Shift of the Se 3d3 binding energy from 51.80 to 50.82 eV in X-ray photoelectron spectroscopy (XPS), along with a shift of the C−Se bond vibration from 561 to 568 cm−1 in Fourier transform infrared (FT-IR) spectroscopy, confirmed the change of Se atom, thus, the formation of Se−N noncovalent interaction. The interaction was also dynamic, though was not DCB. By adding acid or oxidant to the mixture, cleavage occurred, as either change from N to NH+ or Se to SeO would disrupt the Se−N interaction. This work was the first study of our group concerning selenium-related dynamic chemistry and led to the following work that realized Se−N dynamic covalent bond. 79

DOI: 10.1021/acsmacrolett.5b00849 ACS Macro Lett. 2016, 5, 78−82

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ACS Macro Letters change at 470 nm. This work indicated the Se−N bond was easily formed, and could be cleaved under given conditions or reversibly cleave and reform. These properties are in agreement with the DCB, and this work introduced selenium into DCB study. Besides the discovery of the dynamic property of Se−N bond, the application of this bond has also been studied. There was a significant amphiphilicity change before and after the formation of Se−N bond, as the formed bond would be in cation form. Taking advantage of this character, the amphiphilicity of polymer could be tuned and thus achieved one-step double emulsion preparation.21 By adding PhSeBr to PS-b-P4VP, which was a hydrophobic polymer, hydrophilicity could be imparted to the P4VP block (Figure 3A) and reverse

Figure 3. (A) Tuning the amphiphilicity of PS-b-P4VP via Se−N interactions. (B−D) SEM graphs of the particles obtained with differetn molar ratios between the pyridine group in the PS-b-P4VP and PhSeBr, 1:0.2, 1:0.5, and 1:1, respectively. Reproduced with permission from ref 21. Copyright 2015 Wiley-VCH. Figure 4. (A) Metathesis between different diselenide molecules under visible light. (B) Peak shift in 1H NMR after metathesis. Reaction between 5 mM (PhSe)2 and 5 mM (HOC11Se)2 was monitored. (C) Two new peaks appeared in 77Se NMR after the metathesis reaction between (PhSe) 2 and (HOC11Se) 2 (top) or (BenSe) 2 and (HOC11Se)2 (bottom), belonging to the asymmetric exchange product. (D) Illustration of diselenide containing polystyrene and the exchanged result in GPC. Reproduced with permission from ref 22. Copyright 2014 Wiley-VCH.

micelle would be generated in DCM. This was the basis of the one-step double emulsion process, and by tuning the ratio of the pyridine group to PhSeBr, a particle with different morphology and size could be obtained (Figure 2B-2D). With a higher ratio of PhSeBr, the particle would be more porous. For these particles, the presence of the Se−N bond introduced GPx mimic activity to the system, and the pores greatly enhanced the surface area of a particle, thus, enhanced the catalytic activity. Containing the same amount of Se, the more porous the particle was, the higher activity could be achieved. By using the facile formation of Se−N bond and the activity of Se, one-step fabrication of porous particles with enzyme activity was realized, and this work showed the application of Se−N bond in polymer and enzyme mimic field. Above are the studies about Se−N dynamic chemistry. Since selenium resembles sulfur in terms of its chemical properties, we hypothesized that diselenide bond may also serve as a dynamic covalent bond. And this hypothesis was confirmed; the following parts are an introduction of diselenide dynamic covalent bond, Se−Se. Diselenide bonds could be mixed with disulfide bonds to produce a dynamic combinatorial library in the presence of catalyst/reductant.28 However, in our study, we found that the dynamic property of Se−Se could be simply realized under mild visible light irradiation without any catalyst.22 As shown in Figure 4A, different molecules containing Se−Se would undergo metathesis when mixed together under visible light. The mixture would get to an equilibrium containing 50% exchanged product and 25% of each reactant to achieve the maximum entropy for the system.

The metathesis process could be easily monitored by 1H NMR, as the peak of the Se−Se α-methylene shifted dramatically after exchange reaction (Figure 4B). And by calculating the integration of the peaks, the conversion rate at each time was obtained. With different diselenide molecules and different concentrations, the time for equilibrium was also different. Taking advantage of 77Se NMR, the status of Se atoms could be further determined. As shown in Figure 4C, after metathesis, two new peaks in the 77Se NMR spectra appeared, belonging to the asymmetric exchanged molecules, and the new peaks confirmed the metathesis occurred with a change of diselenide bonds. The mechanism of this dynamic reaction was also determined. As the reaction relied on light, a radical mechanism was proposed. By adding radical scavenger into the system, diselenide metathesis could be hindered; this result supported the radical mechanism. Since radicals could also be generated by heat besides light, simply heating it also triggered the metathesis reaction. Further studies also revealed the reaction had no special requirement for solvents; both nonpolar and polar solvents were suitable. Even in protic solvent like water, the reaction would not be suppressed. This work revealed the 80

DOI: 10.1021/acsmacrolett.5b00849 ACS Macro Lett. 2016, 5, 78−82

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ACS Macro Letters dynamic nature of diselenide bonds and found a very mild condition for diselenide metathesis, simply visible light. This Se−Se DCB has great potential application in many fields, such as self-healing materials and dynamic combinatorial chemistry. The diselenide exchange reaction was not only studied in small molecule, but also in polymer system.22 Polystyrene of different molecular weight containing diselenide bonds were synthesized and mixed in DMF (Figure 4D). After visible light irradiation, the exchanged product appeared and was determined in gel permeation chromatography (GPC), a new peak between the two original polymer appeared. These results indicated, though the entanglement of polymer chains would affect the exchange rate, the metathesis would still happen. The exchange reaction was further applied in solid materials, rather than in solution. A series of diselenide bond containing polyurethane elastomers were fabricated (Figure 5A). Due to the dynamic Se−Se bond, these materials possessed visible light induced self-healing property.23 The self-healing procedure was achieved simply by attaching two pieces of material together and put under a table lamp. After 24 h healing, the material could sustain 200 kPa stress (Figure 5B), and if pressure was applied to the sample during healing, the crack even disappeared after light irradiation (Figure 5C). As the polymer chain entanglement could not be fully recovered, the mechanical property could not be totally healed, but all samples were healed to a certain extent by irradiation of a table lamp. And considering the Young’s modulus, for all the samples, it was almost fully recovered. For the wavelength of visible light, laser could be easily accessed, which has high light intensity and is spatially controllable. Using laser instead of a table lamp as the light source, the healing time was greatly shortened and the healing result was enhanced. As shown in Figure 5D, the breaking stress could be healed to 80% by 457 nm laser irradiation for 30 min. No heat was generated in this process, so the healing was induced by the light from the laser, though it did not melt. Introduction of laser-use into this system led to remote self-healing, which has potential usage in many systems, especially for those difficult to reach, like satellites. If functional groups, such as graphene or catalyst, are added in the materials, remote healing or control of material function may also be achieved. This work was the first example using diselenide bond in self-healing material and confirmed the possibility of using diselenide metathesis in solid materials. Though the dynamic chemistry of selenium has been realized and studied, there are still more to be developed. The first thing is to expand the application of Se−N and Se−Se DCBs. For Se−N, by introducing it into various systems, controlled enzyme mimic activity can be one of its applications. And via design and synthesis, Se−N cross-linked polymer network should become an acid−based responsive material or selfhealing material. Further study for electron effect can improve the control over Se−N formation. As for Se−Se, further work can be focused on the control of metathesis direction. By defining the electron effect of molecule segment, the stability of each diselenide molecule could be tuned and thus realize a thermodynamic control over the exchange process. Diselenide molecule was reported to be protected by cucurbit[6]uril (CB[6]) host molecule (Figure 6A).29 If the exchange asymmetric product possesses higher binding ability to certain host molecules, a control over the metathesis by a supramolecular method will be achieved. And in a traditional way, Se−Se is capable of fabricating dynamic combinatorial library, especially with biomolecules and in biosystem due to the very

Figure 5. (A) Polyurethane elastomer fabricated with different ration of diselenide containing monomer. With different diselenide content, the transparency, along with mechanical and healing property, varied. (B) Healing of PU1 under a table lamp for 24 h. The upper part was stained with Nile Red for clearance. The hanging was 200 g, and the tensile stress was calculated to be 0.2 MPa. (C) Healing of PU1 with pressure. When light was introduced, the crack would disappear in 24 h, while in darkness no healing occurred even after 48 h. (D) Healing of PU3 with 457 nm blue laser in a distance of 3.5 m. Reproduced with permission from ref 23. Copyright 2015 Wiley-VCH.

mild dynamic condition. Also, the formula of the diselenide bond containing self-healing materials will be studied and optimized to achieve better healing property and additional functions. Besides expanding the application of existing seleniumrelated dynamic covalent bonds, new bonds are to be discovered and studied. According to the Pauling equation,30 estimated bond energies of Se−O and Se−S are 233 and 203 kJ/mol, respectively, and they are both lower than the bond energy of disulfide bond (240 kJ/mol), which means they both have the possibility to act as dynamic covalent bonds. Moreover, the transformation between different Se−X dynamic 81

DOI: 10.1021/acsmacrolett.5b00849 ACS Macro Lett. 2016, 5, 78−82

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ACS Macro Letters

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Figure 6. (A) Protection of diselenide bonds from oxidation or reduction by host−guest interaction. If the exchanged product could be protected, the metathesis will be driven to one direction. Reproduced with permission from ref 29. Copyright 2015 WileyVCH. (B) Reduction process of Ebselen by thiol. The transformation from Se−N to Se−Se has an intermediate with Se−S bond.

covalent bonds is also of interest. The change from Se−N covalent bond to Se−Se covalent bond is actually already realized in the reduction of an Ebselen molecule (Figure 6B), and during the reduction, Se−S is also formed. If the molecule fragment is taken out and studied, transformation among dynamic Se−N, Se−S, and Se−Se bonds may be achieved. It is greatly anticipated that a new series of dynamic covalent bonds will be developed, showing promising applications in polymer and material science.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

DA − B = (DA − A DB − B)1/2 + 96.5(XAXB)2

Notes

The authors declare no competing financial interest.

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in which D is bond energy and X is electronegativity of the element.

ACKNOWLEDGMENTS This work was financially supported by the National Science Foundation for Distinguished Young Scholars (Grant 21425416), the National Basic Research Program of China (Grant 2013CB834502), the Foundation for Innovative Research Groups of the National Natural Science Foundation of China (Grant 21421064), and the National Natural Science Foundation of China (Grant 91427301).

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REFERENCES

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DOI: 10.1021/acsmacrolett.5b00849 ACS Macro Lett. 2016, 5, 78−82