Stable Radical Cations-Containing Covalent Organic Frameworks

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Stable Radical Cations-Containing Covalent Organic Frameworks Exhibiting Remarkable Structure-Enhanced Photothermal Conversion Zhen Mi, Peng Yang, Rong Wang, Junjuda Unruangsri, Wuli Yang, Changchun Wang, and Jia Guo J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07695 • Publication Date (Web): 19 Aug 2019 Downloaded from pubs.acs.org on August 20, 2019

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Journal of the American Chemical Society

Stable Radical Cations-Containing Covalent Organic Frameworks Exhibiting Remarkable Structure-Enhanced Photothermal Conversion Zhen Mi†, Peng Yang†, Rong Wang†, Junjuda Unruangsri‡, Wuli Yang*†, Changchun Wang†, and Jia Guo*† †State

Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, China. ‡Research group on Materials for Clean Energy Production STAR, Department of Chemistry, Chulalongkorn University, Bangkok 10330, Thailand. KEYWORDS: Covalent organic frameworks; Radical cations; Near infrared; Photothermal effect; Redox ABSTRACT: The production of radical cation-containing covalent organic framework (COF) has been accomplished by sequential in-situ reactions, quaternization and one-electron reduction, of the 2,2’-bipyridine-based COFs. The acid-catalyzed COF formation enables the cis-configuration of 2,2’-bipyridyl moieties in the structure, of which the stability arises from the eclipsed stacking of two-dimensional layered structure. The post-functionalization generates cyclic alkylated diquats as sole products from the controlled quaternization. The reduction of diquat cations on the COF skeletons results in a large number of radical cations, which delocalize and uniaxially stack on top of one another by virtue of interlayered π-electronic couplings. The absorption of the near-infrared (NIR) region exhibited by the cationic radical COF is remarkably high owing to the inter-charge transfer across the π-coupling interlayers. Also, the long-range array of extended and planar frameworks in such the COF renders the extra stability of the radical cations against external stresses. The structure-enhanced performance of the COF material is witnessed with the photothermal conversion efficiencies as high as 63.8% and 55.2%, when exposed to 808 nm and 1064 nm lasers, respectively. The further PEG modification on such the COF allows photoacoustic imaging and photothermal therapy in vivo under the NIR light illumination to be manifested.

INTRODUCTION Conjugated radical cations are stable in redox chemistry and associated to the diverse redox-driven changes. They have laid the important foundation for a plethora of advanced applications such as redox-catalysis, energy storage, and electrochromic display.1 The stability of the radical cation species can be elevated through supramolecular assembly into foldamers,2 dimers,3 and supramolecular organic frameworks.4,5 Nevertheless, highly ordering arrangement of conjugated radical cations in long-range domains has remained challenging due to the presence of electrostatic repulsion. Two-dimensional covalent organic frameworks (2D COFs) are emerging as a family of novel crystalline materials, which can be molecularly pre-designed to a highly periodic atomic framework, and in synthesis, can give the uniaxial stacking of 2D macromolecular frameworks at atomic level.6-9 The incorporation of organic radicals into COF frameworks has imparted distinct redox activity to such materials with prominent optical, electronic and magnetic functionalities. There are two different designing strategies developed so far.

Jiang et al., adopted the post-functionalization to attach radical containing compounds, i.e. TEMPO, on the side of framework skeletons providing neutral radicals in the pore cavities.10 The in-situ redox reaction of COFs is another often-used strategy to generate charged radicals. Such the methodology requires the pre-construction of redox COFs with neutral and conjugated planar molecules such as acenes11,12 and tetrathiafulvalene,13,14 which were converted into charged radical frameworks with preserved crystallinity. The uniqueness of the charged radicals locally produced on COFs is that the eclipsed stacking of 2D organic frameworks could induce the linear alignment of radicals for the interlayered charge transfer and long-range migration toward interfaces. However, if the redox modules are positively charged such as viologens, the overlapping arrangement of COF layers is severely impaired and thus the ordering alignment of charged radicals is altered, resulting in weakened radical properties. Even though the viologen-based COFs with positively charged skeletons have been constructed previously, either their weak crystallinity15 or staggered layerby-layer arrangement16,17 is far from being satisfactory to allow further exploration of distinct redox properties induced by the eclipsed stacking of cationic radical frameworks.

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Figure 1. (a) The two reversible redox states of diquat. (b) Transformation of Py-BPy-COF into cationic Py-BPy2+-COF and cationic radical Py-BPy+•-COF by two-step post-modification. During the process, the trans-form of 2,2’-BPy-DCA is converted to the mono-cationic cis conformer in an acidic condition, and hence enables the formation of cyclic ethylated diquats, which could be reduced further with Na2S2O4.

Herein, we propose a novel strategy to convert a 2,2’bipyridine-based COF from neutral to positively charged and ultimately to cationic radical framework, which enables the superimposition of redox centers with each other in framework. The inter-charge transfer, occurring through the π-coupling multilayers, contributes to the outstanding photophysical properties, namely near-infrared (NIR) absorption and photothermal conversion by nonradiative relaxation process. Furthermore, the structure-to-activity relationship on photothermal effect has been established to acquire the exceptionally high efficiency of heat generation from NIR photoexcitation. Building upon this intriguing phenomenon, the cationic radical framework has also been explored for photoacoustic imaging and photothermal therapy in vivo.

RESULTS AND DISCUSSION We first commenced our studies from the reversible redox compounds, viologens, in order to bestow radical formation in COFs. Viologens, (C5H4NR)2n+, with tunable pyridyl groups are well known as redox active compounds with desirable electronaccepting ability. Their di-cationic derivatives are air-stable salts, which can undergo two-step reversible reductions forming a radical cation and a neutral species, respectively (Figure 1a). Viologen radical cations are considered among the most stable organic radicals.18 In light of this, the 2,2’-bipyridinecontaining COF was solvothermally synthesized through the Schiff-base condensation of 4,4',4'',4'''-(pyrene-1,3,6,8-tetrayl) tetraaniline (Py-TA) and [2,2'-bipyridine]-5,5'-dicarbaldehyde (2,2’-BPy-DCA) (Figure 1b). The reaction proceeded in a mixed solvent of mesitylene and dioxane (v/v of 1:1) at 120 oC


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for 7 days, catalyzed by 6M HOAc aqueous solution. The yellow product was obtained in 76.8% yield. The use of HOAc solution not only catalyzes the aldimine condensation, but also facilitates the inter-conversion of the trans-form 2,2’-BPy-DCA to the more stable mono-cationic cis-conformer. The pKa value of 2,2’-BPy-DCA was estimated by potentiometric titration at 3.83 (Figure S1a), which is larger than the pH (2.60) of the reaction mixture [mesitylene/dioxane/6M HOAc], indicating that 2,2’-BPyDCA should be singly protonated during the reaction. As early reported, 2,2’-bipyridine exists in a trans-conformation in the solid state as well as in organic solvents and in basic solutions.19 However, when 2,2’-bipyridine is protonated in acidic solution, the trans-conformer of mono-cationic species could be interconverted into the much more stable cis-form. This transformation arises from the formation of intramolecular [NH+•••N] hydrogen-bonding interaction, along with a small contribution from the increasing extend of π-conjugation.19 To prove this, the UV-Vis absorption spectra were recorded to elucidate the favored configuration of 2,2’-BPy-DCA in the reaction solution. When 6M HOAc was added to the aqueous solution of 2,2’-BPy-DCA, the two distinct bands appear at 253 nm and 312 nm (Figure S1b), which are both red-shifted when compared to the solution without HOAc. These two bands were attributed to the characteristic absorption of the mono-cation of 2,2’-bipyridine. Moreover the spectrum is in line with that obtained from metal chelated bipyridine compounds such as [Ni(bipy)3]Cl2,19 implying the cis-configuration of the monocationic 2,2’-BPy-DCA in an acidic medium. The trans dication species were not observed in the 6M HOAc solution because they only exist in extremely strong acids. As a result, we can be certain that the large population of cis-form 2,2’bipyridyl mono-cations was incorporated into the COF framework during the reaction. Lastly the cis configuration of the 2,2’-bipyridine derivatives in Py-BPy-COF is rigidly locked in place by the extended π-interaction in the stacked layers. This is an essential prerequisite for the formation of cyclic alkylated diquats in the post-quaternization of Py-BPy-COF. To optimize the conditions for a quaternization reaction, the model reaction between 2,2’-bipyridine and 1,2-dibromoethane was systematically studied. The optimal yield of cyclic diquats was found in nitrobenzene at elevated temperature and prolonged reaction time with 1.4 equiv. 1,2-dibromoethane (Table S1 and Figure S2). Py-BPy-COF was hence quaternized according to the optimized conditions. During the reaction, a distinctive change from yellow to brown solution was observed. The more precise quantitative measurement of quaternization conversion was performed by potentiometric titration analysis of the counter anions of the diquats, Br-. The quaternization conversion can also be reflected from the relative molar ratio of cyclic diquats in Py-BPy2+-COF to the total of bipyridine moiety. The conversions depend largely on the reaction conditions, of which the maximum conversion of 72.7% was obtained (Table S2 and Figure S3). Although higher quaternization conversion was achieved when prolonging reaction time, lower yield was obtained indicating the possibility of COF destruction. It is noteworthy that only certain degrees of quaternization can attain layered structure of cationic frameworks through the multicenter π-π interaction of pyrene moieties, otherwise the exfoliation of the multilayers is likely.

Figure 2. (a) Solid-state 13C CP/MAS NMR spectrum of the PyBPy2+-COF. (b) XPS spectra of N 1s and Br 3d (inset) for the PyBPy2+-COF.

The quaternized Py-BPy2+-COF was further validated employing FT-IR spectroscopy. The FT-IR analysis showed the stretches of methylene (-CH2-) appeared at 2923 cm-1 and 2850 cm-1, indicative of the ethylene groups attached on the PyBPy2+-COF framework. The signals were absent in the corresponding spectrum of Py-BPy-COF (Figure S4). Solidstate CP/MAS 13C NMR spectrum again verified the presence of alkyl C(1) at 50 ppm, assigned to the ethylene group, as well as the other multiple signals corresponding to the pyridine C(26), phenyl C(8-11), pyrene C(12-16) and imine C(7), respectively (Figure 2a). X-ray photoelectron spectroscopy (XPS) spectrum provided an insight into the different nitrogen forms in the quaternized Py-BPy2+-COF. As the broad peak of N 1s signal was deconvoluted into the three individual forms (Figure 2b), the imine and diquat forms of nitrogen appearing at 399.5 eV and 402.0 eV were predominant, while the signal corresponding to the pyridine nitrogen at 398.3 eV was mostly negligible. This is in stark contrast to the parent Py-BPy-COF, where the diquat form of N atom is absent (Figure S5). Also, the cis-form 2,2’-bipyridyl mono-cations are not found in the Py-BPy-COF, implying its complete deprotonation after the wash with plenty amount of deionized water during the workup step. As shown in Figure 2b-inset, without deconvolution,



the Br 3d signal of Py-BPy2+-COF was well fitted into a single peak appearing at 67.6 eV, assigning to the bromide anion. This strong evidence points toward the formation of cyclic alkylated diquats as sole species present in Py-BPy2+-COF. The formation of the linear alkylated diquats species is negligible as no XPS signal corresponding to bromoalkane was witnessed. Additionally, the thermal stability of the main skeleton in PyBPy-COF was corroborated by the thermogravimetric analysis, showing that the decomposition was not observed until 400 oC (Figure S6). The initial weight loss during 250-400 oC of PyBPy2+-COF could be attributed to the loss of diquat moieties.

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Both poly(Py-BPy2+)-A and -B gave no diffraction peaks in the PXRD patterns (Figure S7), confirming the amorphous nature. This is largely due to the immense electron repulsion impeding the formation of layer-stacked structure during the bottom-up growth and to the milder reaction condition in the postpolymerization synthesis. H 2N

(A) OHC

N Br

N Br

H 2N

NH 2

+

CHO

Mesitylene/Dioxane (1/1) 6M HOAc, 120 oC, 7days,

Na 2S2O 4

Poly(Py-BPy +•)-A

NH 2

OHC

(B) N N

CHO

Dioxane 6M HOAc, r.t. 24h,

1. BrCH 2CH 2Br 2. Na 2S2O 4

Poly(Py-BPy +•)-B

Figure 4. The syntheses of cationic radical containing polymeric materials, via the bottom-up (A) and the post-modification (B) methods, respectively. The quaternization in (B) and reduction reaction in (A) and (B) followed the typical routes for the postmodification of Py-BPy-COF. Figure 3. PXRD patterns of Py-BPy-COF, Py-BPy2+-COF and PyBPy+•-COF.

Next, the redox reaction on Py-BPy2+-COF was carried out using aqueous sodium dithionite (Na2S2O4) at 50 oC for 24 h. The color change from brown to dark green solution implied the successful reduction from cyclic diquats [BPy]2+ to cationic radicals [BPy]+• moieties, hence giving the cationic radical containing COF. As evidenced from the powder X-ray diffraction (PXRD) measurement (Figure 3), the reduced PyBPy+•-COF is as crystalline as the quaternized Py-BPy2+-COF. By referencing to the PXRD pattern of the parent Py-BPy-COF, the dominant peak at 3.16o corresponds to the (100) reflection plane, and the others at 4.62o, 6.38o, 9.74o, 12.98o and 23.86o are assigned to the (020), (220), (330), (440) and (001) lattice facets.20 Aside from the crystalline structure unchanged, the assynthesized Py-BPy+•-COF showed the same FT-IR spectrum and thermal decomposition tendency with the Py-BPy2+-COF (Figures S4 and S6), indicating that the framework composition remained intact through the post-modification. To evaluate the physical properties arising from the uniqueness of the COF materials, comparative experiments were performed to synthesize the cationic radical containing amorphous polymers via two possible methods. The reaction between aldehyde-substituted diquats dibromide and Py-TA was conducted by the bottom-up approach, giving poly(PyBPy2+)-A. While the post-modification approach, which was reminiscent of that employed in the synthesis of the COF counterpart, provided poly(Py-BPy2+)-B. Both cationic polymers were in-situ reduced under the identical condition, affording poly(Py-BPy+•)-A and -B, respectively (Figure 4).

The detailed investigation using XPS revealed the poly(PyBPy2+)-A gives one single and symmetric peak around 67.6 eV for the Br 3d signal, which is characteristic of Br- anion (Figure S8). The result is expected for poly(Py-BPy2+)-A as the dialdehyde-containing cyclic alkylated diquat was used as a starting material. Nevertheless, the Br 3d signal in the XPS spectrum from the poly(Py-BPy2+)-B could be deconvoluted into the two peaks, one at 67.6 eV corresponding to Br- anion and the other at 70.5 eV corresponding to bromoalkane. This reflects that some trans 2,2’-bipyridyl moiety is present in the poly(Py-BPy2+)-B, resulting in the formation of linear alkylated quats with remaining terminal bromoalkane moieties. A further spectroscopic test was carried out to examine whether the linear alkylated diquats could be reduced to generate radicals by Na2S2O4 in the same manner as did the cyclized diquats. As displayed in Figure S9, there is no any change in the whole spectrum from UV to NIR windows before and after reduction reaction of linear alkylated diquats, [2,2’-BPy(CH2CH2Br)2]2+. Furthermore, the colors of the reaction solution remained unchanged. This observation is in a stark contrast to the feasible reduction of the cyclic ethylated diquat, [2,2’-BPy(CH2)2]2+, as a comparative model. Therefore, the poly(Py-BPy2+)-B comprises some ethylated trans-2,2’-bipyridyl bromides which cannot be further reduced, and some of diquats which after reduction give rise to the cationic radicals. It should be noted that the quaternization conversion of the poly(Py-BPy2+)-B was calculated to be 34.7% (Table S2). N2 sorption measurement was carried out at 77 K to analyze the pore characters. As shown in Figure 5a, Py-BPy-COF features a type IV adsorption isotherm, indicative of a typical mesopore character. Brunauer–Emmett–Teller (BET) surface


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areas and pore volumes were calculated to be as high as 1903 m2/g and 1.8322 cm3/g. In comparison, the other two derivative COFs give type-I-like adsorption profiles, and smaller BET surface areas and pore volumes of 461 m2/g and 0.2745 cm3/g for Py-BPy2+-COF, and 398 m2/g and 0.1984 cm3/g for PyBPy+•-COF, respectively. Also, the pore-size distributions of the derivatized COFs are much broader than that of the parent Py-BPy-COF and shift to the micropore range of 1-2 nm (Figure 5b). The change in porosity reflects the effect of the quaternization on the pore channels. The amorphous poly(PyBPy2+)-A and -B both had small BET surface areas as well as flawed pore-size distributions (Figure S10).

singly reduced monomer [2,2’-BPy-DCA]+• was much weaker than those of polymer radicals (Figure S11). This underlines that the unpaired electrons with the assembled dimers are readily recombined or quenched in air.

Figure 6. EPR spectra of amorphous poly(Py-BPy+•)-B and PyBPy+•-COF.

Figure 5. (a) N2 sorption isotherms of Py-BPy-COF, Py-BPy2+COF, and Py-BPy+•-COF. (b) Pore-size distributions of Py-BPyCOF, Py-BPy2+-COF and Py-BPy+•-COF.

To investigate the photophysical properties in aqueous solution, the quaternized Py-BPy2+-COF solids were dispersed by ultrasound and modified with NH2-ended polyethylene glycol (PEG) through the Schiff-base reaction between amines and residual aldehydes on the Py-BPy2+-COFs. FT-IR spectrum proved that the disappearance of C=O stretching frequency peak at 1697 cm-1 in Py-BPy2+-COF/PEG signified the successful chemical functionalization between the aldehyde group residue of Py-BPy2+-COFs and PEG-amine (Figure S12). The grafting content of PEG was determined to be 9.9 wt.% from the TGA curve (Figure S6). Such the external modification improves hydrophilicity and dispersibility of COFs in physiological media, while there is only marginal change in their crystallinity and porosity (Figure S13). The PEG-modified Py-BPy+•-COF was prepared by the direct reduction of Py-BPy2+-COF/PEG, by which the amount of modifying PEG chains has retained (Figure S6). This could be illustrated as both Py-BPy2+-COF/PEG and Py-BPy+•COF/PEG exhibited the similar grain sizes of ca. 90 nm in SEM images (Figure S14) as well as the similar hydrodynamic diameters of ca. 164 nm with the equal polydispersity index of 0.12 in aqueous solution (Figure S15). The presence of PEG altered a positively charged surface to an electrically neutral one (Figure S16), facilitating the cell membrane crossing as well as lengthening the circulating time in body.

Electronic paramagnetic resonance (EPR) spectroscopy was employed to provide the radical-forming evidence. With the same treatment and measurement conditions, Py-BPy+•-COF and poly(Py-BPy+•)-B both gave the typical localized EPR signals, while much stronger peak was observed for the PyBPy+•-COF, indicating an increment of radical concentration (Figure 6). This proves again that the formation of cis-2,2’bipyridyl moiety is dominant in the bottom-up growth of COF, thus being more favorable than the amorphous counterpart on radical production. The g-factor of Py-BPy+•-COF (2.0037) was almost equal to that of a free electron (2.0023), indicative of an organic radical character. As expected, the radical signal on the

UV-Vis-NIR spectra provided the evidence for the absorption in the long-wavelength window of each COFs (Figure 7). The dispersion of Py-BPy+•-COF/PEG exhibited a broad featureless band in the range of 600-1300 nm, which the absorbance was remarkably higher than those of Py-BPyCOF/PEG and Py-BPy2+-COF/PEG at the same concentration. The light scattering effect was eliminated by the diffuse reflectance attachment in measurement. The calculated extinction coefficients exhibit the similar increasing trends at the wavelengths of 808 nm and 1064 nm, respectively. The maximum extinction coefficient of the Py-BPy+•-COF/PEG is as high as 16.6 (L/g cm) at 808 nm and 15.9 (L/g cm) at 1064



nm (Table S3). Therefore, such the remarkable longwavelength absorption can be attributed to the columnar alignment of diquat radical cations in a long-range order, which may be constituted by the eclipsed stacks of radical cations [BPy+•] or mixed-valences of [BPy2+] and [BPy+•] entities alternating along the stacking axis. Furthermore, the radical cations-containing COF not only possesses the single occupied molecular orbital (SOMO), which is higher in energy than the highest occupied molecular orbital (HOMO), but also generates the fine electronic bands within the narrow bandgap of SOMO/HOMO.[21] This results in a broad absorption in the NIR region and no hyperfine lines being observed in Figure 7. Additionally, a slight decrease of 5% in absorbance was observed for the Py-BPy+•-COF after 6 days in an oxygen deficient condition (Figure S17a), marking the advantage of stable radical cations embedded in the COF skeletons. While, the absorptions of amorphous poly(Py-BPy+•)-A and -B at 808 nm and at 1064 nm were distinctively lower than those of the COF analogues and decreased to the levels of the corresponding cationic polymers over 6 days. The absorption of cationic radical monomer, cyclic ethylated [2,2’-BPy(CH2)2]+•, at an 808 nm-wavelength completely disappeared within an hour, emphasizing the more active and less stable nature of cationic radical in the monomer compared to the polymer and COF, respectively (Figure S17b). In addition, the fluorescence emission was largely reduced for the Py-BPy2+-COF/PEG and nearly quenched for the Py-BPy+•-COF/PEG when compared with the Py-BPy-COF/PEG. This demonstrates that the predominant relaxation of excitons is non-radiative favoring the heat generation in Py-BPy+•-COF/PEG (Figure S18).

Figure 7. UV-Vis-NIR spectra of the dispersions of Py-BPyCOF/PEG, Py-BPy2+-COF/PEG and Py-BPy+-COF/PEG in phosphate buffer saline, respectively, at a concentration of 50 μg/mL. The inset is the photographs of the aqueous dispersions of the different PEG-modified COFs.

Photothermal effect generally arises as a result of nonradiative relaxation upon photoexcitation. Both strong absorption and low fluorescence quantum yield are significant factors to maximize the conversion of absorbed photons into heat. For the first time, we have demonstrated the photothermal effect promoted by the enhanced π-π interaction between layers in the keto-enamine-linked COFs,22 albeit with moderate efficiency compared to other known photothermal agents.23,24

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Herein, the functionalized COF is featured in structure with the singly reduced radicals that could be delocalized across πcoupling interlayers. Such the structure-enhanced inter-charge transfer offers the remarkable photoenergy conversion as we expected. Therefore, the photothermal performance of cationic radical COFs has been successively explored in detail. Besides an 808-nm NIR laser, a 1064-nm NIR laser which is in the range of second NIR window (1000-1350 nm, NIR-II), has also been applied. This longer wavelength NIR laser can provide the maximum penetration through tissues as well as lower background autofluorescence emission.25

Figure 8. Elevated temperature change vs. time for the dispersions of different PEG-modified COFs (100 μg/mL) and PBS as a control set upon exposure to 808-nm laser (a) and 1064-nm laser (b) for 5 min at a power of 1 W/cm2.

Upon exposure to the two NIR lasers for 5 min, the phosphate buffer saline (PBS) solution as a blank control experiment generated insignificant amount heat, signifying negligible amount of heat being produced by the NIR lasers. Meanwhile, among all COFs, Py-BPy+•-COF/PEG (100 µg/mL) generated highest amount of heat resulting in rapid increases in temperatures up to 75 oC and 65 oC when irradiated with 808nm and 1064-nm lasers at 1 W/cm2 power, respectively (Figures 8a and 8b). The heating process could be steadily recycled for all COFs with the lasers being switched on/off for the five


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consecutive runs (Figure S19). Similar temperatures were reached in each run. The photothermal conversion efficiency (PCE) was calculated by the time constant method26 to be 19.3%, 47.2% and 63.8% at 808 nm, and 10.4%, 40.1% and 55.2% at 1064 nm, for Py-BPy-COF/PEG, Py-BPy2+-COF/PEG and Py-BPy+•-COF/PEG, respectively (Figures S20 and S21). On the other hand, the discrete radical diquats, [2,2’BPy(CH2)2]+•, just gave only 3.7% of PCE at 808 nm under the identical conditions (Figure S22). The finding strongly supports the structure-enhanced photothermal effect in the COF materials. Amid the well-known photothermal agents, the cationic radical COFs presented here is ranked among the top materials generating heat when irradiated with NIR lasers (Figure S23).

treated with Py-BPy+•-COF/PEG (100 µg/mL) were most noticeably damaged (Figure 9b and 9c). The cumulative viability was as low as 10% and 12% after illuminated with an 808-nm and a 1064-nm laser, respectively. The confocal laser scanning microscope (CLSM) again verified the effectiveness of photothermal ablation of the COF-incubated cells under a 1064-nm NIR laser. It was found that the cell death only occurred when the laser was on (Figure 9d). The similar effect was also found using an 808-nm laser (Figure S37).

As the post modification strategy gives functional groups and sites in a control manner, the structural effect on the photothermal efficiency has been investigated in detail. By varying the quaternization conversion of the COF from 3.3% to 72.7%, it was found that the PCE values of Py-BPy2+-COF/PEG were largely promoted from 23.1% to 47.2% at 808 nm, and 16.9% to 40.1% at 1064 nm, respectively (Table S4 and Figures S27-S32). Also, the subsequent redox reaction for the radical Py-BPy+•-COF/PEG could be optimized to make the PCE escalated from 54.4% to 63.8% at 808 nm and 46.1% to 55.2% at 1064 nm (Table S5 and Figures S33 and S34). As shown in Table 1, the 2-3 times higher PCE values were obtained from the optimal PEG-modified COFs, in comparison to those obtained from the PEG-modified amorphous materials. Irrespective of the preparation methods used, both of the amorphous poly(Py-BPy+•) afforded the moderate PCE values of 19-30% (Figures S35 and S36). The underlying mechanism elucidates that the high heat generation is dependent on the uniaxial stacking of the cationic radical diquats with COFs, which facilitates the inter-charge transfer in the long-range domains. Additionally, as the poly(Py-BPy2+)-B partly comprises ethylated trans-2,2’-bipyridyl bromide, its post reduction cannot attain much improvement on photothermal efficiency. Table 1. Comparison of photothermal conversion efficiencies for the different PEG-modified polymers and COFs synthesized by the bottom-up (A) and post-modification (B) routes.

Materials

Quaternizati on conversion (%)

PCE (%) at 808 nm

PCE (%) at 1064 nm

Poly(Py-BPy2+)-A/PEG

100

24.6

19.5

Poly(Py-BPy+•)-A/PEG

N.A.

29.6

23.3

Poly(Py-BPy2+)-B/PEG

34.7

21.2

15.4

Poly(Py-BPy+•)-B/PEG

N.A.

23.7

19.1

Py-BPy2+-COF/PEG

72.7

47.2

40.1

Py-BPy+•-COF/PEG

N.A.

63.8

55.2

The photothermal ablation of cancer cells with the PEGmodified COF nanomaterials were examined in vitro in the MTT assay. Prior to the laser exposure, there was almost no cytotoxicity against A549 cells in the presence of COFs with varied concentration, 25-400 µg/mL (Figure 9a). Upon irradiated with the 1 W/cm2 NIR lasers for 5 min, the A549 cells

Figure 9. (a) Cytotoxicity to A549 cells in the presence of PEGmodified COFs at the concentrations of 25 to 400 μg/mL. Viability assay of A549 cancer cells incubated with the different COFs and PBS as a control set, respectively, and followed by illumination of 808-nm (b) and 1064-nm laser (c) at 1 W/cm2 power. (d) CLSM images of A549 cells incubated in the presence of Py-BPy+COF/PEG with or without 1064-nm laser irradiation. The cells were co-stained by calcein-AM and propidium iodide (PI) for imaging of live cells (green) and dead cells (red), respectively.

In light of the prominent photothermal conversion of the COFs both in the NIR-I (750-900 nm) and NIR-II (1000-1350 nm) windows, the photoacoustic (PA) imaging performance was estimated due to the photothermal-induced thermoelastic expansion when the pulse NIR laser irradiated on the photothermal agents (Figure S38a). The PA intensity increased noticeably at the excitation wavelengths around 700-800 nm both for the Py-BPy+•-COF/PEG and Py-BPy2+-COF/PEG. That is presumably owing to the broad and featureless absorption in the long-wavelength window. The maximum of PA signal was obtained for the Py-BPy+•-COF/PEG around 700 nm, which subsides the interference of hemoglobin (760 nm) and oxygenated hemoglobin (850 nm). In stark contrast, the signal intensity of Py-BPy-COF/PEG is almost similar with that of PBS, indicating that the pristine non-modified COF provides no PA images. Meanwhile, it was found that the PA intensity linearly increased with concentrations of Py-BPy+•-COF/PEG and Py-BPy2+-COF/PEG, respectively (Figure S38b and S38c), demonstrating again that they serve as stable contrast agents in PA imaging. To testify the in vivo PA imaging, the colloidal stability of PEG-modified COFs was evaluated in PBS and serum, respectively, by dynamic light scattering analysis, which showed no evident difference in the hydrodynamic diameters (ca. 173 nm in PBS and ca. 184 nm in serum) of the PEG-



modified COFs (Figure S39). Then A549 tumor-bearing nude mice were used as animal models and the Py-BPy+•-COF/PEG dispersion (6 mg/mL, 100 μL) was administered to the mice via a tail vein injection. The PA signals in the tumor region were collected at specific intervals (0, 2, 4, 6, 8, and 24 h). As shown in Figure 10a, the red spots-distributed region is responsible for the tumor site, wherein the PA intensity reaches a maximum at 4 h and gradually declines until it nearly vanishes at 24 h. This implies that the highest accumulation of COF nanomaterials in tumor takes around 4 h through the enhanced permeability and retention effect during the circulation in body (Figure S40).

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6.62 ± 1.53% ID/g to 3.52 ± 1.44% ID/g, it was shown that the significant amount of the COF uptake reduced in liver, spleen and lungs, while increased in kidneys. The finding reflects that the COF nanoparticles could be metabolized after 24 h postinjection, indicating a good biosafety of the PEG-modified COFs in vivo. Furthermore, the polyradicals in the COFs showed a certain degree of stability during the circulation in body (Figure S41). Since Fe3+ ions could act as optical sensors to probe the presence of radicals, the Py-BPy+•-COF/PEG could be found in blood and its concentration was much higher in the early stage (< 6 h) than at 24 h, which is well in line with the profile of pharmacokinetics.

Figure 10. (a) PA imaging in the tumor area after intravenously injected Py-BPy+•-COF/PEG were recorded at different time points. (b) Thermal images of A549 tumor-bearing mice exposed to laser irradiation at 1 W/cm2 power for 5 min after 4 h post-tail intravenous injection of PBS, and Py-BPy+•-COF/PEG.

Further, in vivo thermal imaging with Py-BPy+•-COF/PEG was carried out in A549 tumor-bearing mice. The tumor sites in nude mice were irradiated by 808-nm or 1064-nm lasers, respectively, at 1 W/cm2 power for 5 min after 4 h post-tail intravenous injection of Py-BPy+•-COF/PEG and PBS as a control set. The temperature of the tumor tissue containing PyBPy+•-COF/PEG rapidly increased from 31°C to 67.1°C using an 808-nm laser and 30.9 oC to 63.2°C using a 1064-nm laser (Figure 10b), while only marginal increase in temperature was observed in the control group. This suggests that the Py-BPy+•COF/PEG nanomaterials demonstrate equally effective in vivo NIR-I and -II photothermal conversions. To access the circulation capability in blood and the distribution in organs for Py-BPy+•-COF/PEG, BALB/c mice were intravenously injected with the Py-BPy+•-COF/PEG dispersion (6 mg/mL, 100 μL). Blood was collected at given intervals and the concentration of COFs was measured using high resolution preclinical PA imaging system as reported.27 There was only 4.18 ± 2.27% ID/g of COFs remaining in the blood at 24-h post-injection (Figure 11a). Meanwhile, the in vivo biodistribution of COFs was investigated at 4 h and 24 hpost injection, respectively. Main organs and tumors were dissected to quantify the Py-BPy+•-COF/PEG residues (Figure 11b). Besides the tumor with the decreased accumulation from

Figure 11. The pharmacokinetic profiles (a) and biodistribution (b) of COF modified with PEG in A549 tumor-bearing mice at 4 h and 24 h post-injection. Error bars indicate the SD (n=4).

In the investigation of the anticancer efficiency after intravenous injection, A549 tumor-bearing BALB/c nude mice were randomly divided into four groups (n=6) and then the PBS and Py-BPy+•-COF/PEG dispersion were injected through the tail veins, respectively. As shown in Figure 12a, no apparent weight loss could be seen in any groups of mice, indicating that Py-BPy+•-COF/PEG nanomaterials were reasonably safe in vivo. Upon exposure to the lasers for 5 min (808 nm or 1064 nm, 1 W/cm2), the tumor with the accumulated Py-BPy+•COF/PEG were completely eliminated (Figure 12b). The physical measurement of sizes and weights of the tumors was carried out to assure the tumor-eradication in the Py-BPy+•COF/PEG administered groups (Figure 12c). The observation was in contradiction to the control groups administered with PBS. At the 14th day post-injection, all mice were sacrificed because of the extensive tumor burden of the control groups. After that, the major viscera (heart, liver, spleen, lungs, and


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Figure 12. (a) Time-dependent body weight curves of nude mice after different treatments. Error bars indicate the SD (n=6). (b) Timedependent tumor growth curves after different treatments. Error bars indicate the SD (n=6) and the treatments were performed only once. (c) Photographs (left) and weights (right) of typical tumors at the end of the experiment (14th day). (d) H&E staining images of major organs (heart, liver, spleen, lungs, and kidneys). Tissues dissected from each group on the 14th day after different treatments. The scale bar corresponds to 50 μm. *P < 0.05, **P < 0.01, ***P < 0.001.

kidneys) were excised and co-stained by hematoxylin and eosin (H&E). No obvious tissue damages or noticeable pathological changes were found in the Py-BPy+•-COF/PEG administered groups as compared to the control groups (Figure 12d). Therefore, the in vivo antitumor outcomes agree well with the in vitro cytotoxicity results, indicating that the Py-BPy+•COF/PEG could serve as a promising imaging-treatment integrated platform. CONCLUSIONS In conclusion, we report the conversion of 2,2’-bipyridinebased COFs to the cationic radical containing framework with high crystallinity. The long-distance uniaxial stacking of COF layers could suppress the rotation of 2,2’-bipyridyl moieties along the central carbon-carbon bond and contribute to the extra stabilization of the cis-conformer, even in the conditions where trans/cis conversion is possible. Thus, controlled quaternization of cis-form 2,2’-bipyridine moieties in the COF renders the cyclic diquats containing frameworks as well as retains the structural periodicity. The one-electron reduction on the quaternized COF generates cationic π-radicals overlapped by an eclipsed fashion toward a long-range ordering domain. Such radicals embedded within the COF skeletons are extended, stable, and responsible for the broad and intense NIR absorption. More impressively, the cationic radical COF demonstrates the outstanding structure-enhanced photothermal conversion, which is accounted for by the extended inter-charge transfer across the π-coupling interlayers within COF. Hence the photothermal therapy and photoacoustic imaging in vivo is applicable upon exposure to 808-nm or 1064-nm wavelength lasers. As the vast majority of organic mixed valence systems are charged species, our strategy is a feasible and general solution for the versatile design of COF-based mixed valence systems for multidisciplinary applications.

ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Materials and methods, UV-Vis-NIR spectra, potentiometric titration curves, 1H NMR spectra, elemental analysis data, FT-IR spectra, EPR spectra, fluorescence emission spectra, TGA curves, PXRD patterns, N2 sorption isotherms, pore-size distributions, FE SEM images, hydrodynamic diameter distributions, zeta potentials, XPS spectra, recycling-heating profiles, photothermal efficiencies calculation and their comparison among the different materials, CLSM images, in vitro photoacoustic imaging, and time-dependent photoacoustic signal intensity in tumor sites (PDF)

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work is supported by the NSFC (21774023), STCSM (18520744800) and State Key Project of Research and Development (2016YFC1100300).

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Journal of the American Chemical Society A graphic entry for the Table of Contents (TOC)


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Stable Radical Cations-Containing Covalent Organic Frameworks

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