MIF) is a master regulator of proinflammatory cytokines and plays pathological roles when not properly regulated in rheumatoid arthritis, lupus, atherosclerosis, asthma and cancer. Unlike canonical cytokines, MIF has vestigial keto‐enol tautomerase activity. Most of the current MIF inhibitors were screened for the inhibition of this enzymatic activity. However, only some of the enzymatic inhibitors inhibit receptor‐mediated biological functions of MIF, such as cell recruitment, through an unknown molecular mechanism. The goal of this study was to understand the molecular basis underlying the pharmacological inhibition of biological functions of MIF. Here, we demonstrate how the structural changes caused upon inhibitor binding translate into the alteration of MIF‐induced downstream signalling. Macrophage migration inhibitory factor activates phosphoinositide 3‐kinases (PI3Ks) that play a pivotal role in immune cell recruitment in health and disease. There are several different PI3K isoforms, but little is known about how they respond to MIF. We demonstrate that MIF up‐regulates the expression of Class IB PI3Ks in leucocytes. We also demonstrate that MIF tautomerase active site inhibitors down‐regulate the expression of Class IB PI3Ks as well as leucocyte recruitment in vitro and in vivo. Finally, based on our MIF:inhibitor complex crystal structures, we hypothesize that the reduction in Class IB PI3K expression occurs because of the displacement of Pro1 towards the second loop of MIF upon inhibitor binding, which results in increased flexibility of the loop 2 and sub‐optimal MIF binding to its receptors. These results will provide molecular insights for fine‐tuning the biological functions of MIF.Macrophage migration inhibitory factor ( The expression levels of Class IB PI3Ks are down‐regulated when MIF is occupied with active site inhibitors that induce the displacement of Pro1 towards the second loop (L2) of MIF. Together, correlating the inhibitor‐induced structural alteration of the MIF active site with the changed MIF activation of downstream signalling molecules contributes to identifying biologically relevant structural determinants of MIF.1 and 12 were purchased from Sigma‐Aldrich . 2 was purchased from Maybridge . THP‐1 cells (monocytic cell line) were purchased from American Type Culture Collection. HL60 (human promyelocytic leukaemia cell line) cells were a kind gift from Dr. David Ford . Recombinant human MIF was expressed in BL21(DE3) Escherichia coli cells and enriched in flow‐through by interconnected anion‐ (Diethylaminoethyl Sepharose Fast Flow) and cation‐ (SP Sepharose Fast Flow) exchange columns . Macrophage migration inhibitory factor in the flow‐through was further purified by Superdex 200 size exclusion column (>95% purity based on Coomassie staining). For cell‐based assays, the column‐purified protein was run through a Sep‐Pak reverse‐phase column from Waters  in a denaturing condition (e.g. acetonitrile gradient) to remove endotoxin. Resulting endotoxin‐free MIF was refolded in a phosphate buffer at pH 7.4. Endotoxin level was <0.1 EU/ml when measured using a Kinetic Turbidimetric LAL reagent from Charles River .4‐Hydroxyphenylpyruvic acid (HPP), THP‐1 and HL60 cells were starved overnight in RPMI 1640 medium with 0.5% heat‐inactivated fetal bovine serum (FBS). The cells were then treated with MIF for 3 hrs. To evaluate the MIF inhibitors, 50 ng/ml of MIF was incubated with 0.5 μM of inhibitors for 2 hrs at room temperature prior to the treatment of THP‐1 and HL60 cells. After the incubation, the cells were lysed in 2× SDS loading buffer by sonication and subjected to Western blot analysis. The blots were probed with anti‐phospho‐PI3Kp85 (Tyr458)/p55 (Tyr199) , anti‐PI3Kp85 (19H8) , anti‐PI3Kp110α (C73F8) , anti‐PI3Kp110β (C33D4) , anti‐PI3Kp110γ (D55D5)  and anti‐PI3Kp101 (5569S)  antibodies from Cell Signaling Technology . To confirm equal loading, membranes were stripped and re‐probed with α‐tubulin (Sigma‐Aldrich). The blots were developed using a chemiluminescence detection system (Thermo Fisher Scientific). Bands were quantified by performing densitometric analysis using ImageJ software. All assays reported here were repeated at least three times independently with three replicates per assay unless otherwise stated.Covalent inhibitor binding to MIF was examined as described earlier 6 cells/mL. Macrophage migration inhibitory factor (50 ng/ml) was incubated with each inhibitor (0.5 μM) at room temperature for 1 hr. After the incubation, 30 μl of each MIF/inhibitor mixture was transferred to the bottom of the chemotaxis chamber and 50 μl of cells was transferred to the top of the chemotaxis chamber. As quantitation standards for migrated cells, a separate set of cells diluted in a series were transferred to the lower chambers within one section of the assay plate without addition of MIF inhibitor mixture. Then, the assay plate was incubated for 150 min. at 37°C. Cells remained on the top of the filter were removed using a cell harvester and were flushed with phosphate‐buffered saline. The plate was centrifuged at 500 × g for 10 min. to settle all migrated cells down to the bottom chamber. The migrated cells (5 μl) were mixed with the same volume of the CellTiter 96® AQueous One Solution Reagent (Promega) and incubated for 3 hrs at 37°C. Then, formazan formation was measured using an Enspire multimode plate reader  at 492 nm. Results were presented as a migration index. Each assay was carried out in triplicate. We conducted Student's t‐test with the migration indexes to compare cells treated and untreated with inhibitors.Inhibition of THP‐1 and HL60 cell migration was studied using the ChemoTx 96‐well disposable chamber with a framed filter with 5 μm pores  and quantitated using the AQueous cell proliferation assay kit . Cells were harvested and re‐suspended in the assay medium  at the density of 106) were washed with PBS and re‐suspended in a FACS staining buffer . Nonspecific binding of antibodies to Fc receptors was blocked with Fc blocker . Cells were incubated with fluorochrome‐conjugated antibodies  and their receptive isotype controls for 1 hr at 4°C. All antibodies were from eBioscience . The cells were then washed with FACS staining buffer and tested immediately using a FACS LSRII flow cytometer (BD Biosciences) at the Flow Cytometry Research Core at Saint Louis University. Analysis was performed with Flow Jo software .Surface staining of CXCR2, CXCR4, CXCR7 and CD74 was performed on THP‐1 and HL60 cells. Cells were collected from plates using a cell scraper. Then, cells (0.1 × 104)2SO4, and 3% isopropanol. Crystals were grown at 18°C within 2 weeks. X‐ray diffraction data were collected from a single crystal for each inhibitor at X29 beamline of National Synchrotron Light Source at the Brookhaven National Laboratory. The diffraction data were indexed using MOSFLM Column‐purified MIF was concentrated to 10 mg/ml and crystallized in complex with 2.5 mM of each inhibitor in 0.1 M TrisHCl, pH 7.5, 1.9 M  was used as the reference for structural comparison with inhibitor‐bound ones. B‐factor values, indicating the degree of flexibility, for backbone alpha carbon (CA) atoms were obtained from PDB files for the apo‐ and the inhibitor‐bound MIF structures and graphed using Prism6. For structural comparison, all the inhibitor‐bound structures were loaded into PyMOL software and aligned to the apo‐structure. The built‐in Putty function in PyMOL was used for the graphical presentation of B‐factor.via the intranasal route in 50 ml of saline solution. After 5 hrs, the mice were killed and the BAL fluids were collected (3 × 0.8 ml PBS) and transferred to labelled microscope slides for analysis. After an overnight incubation at room temperature, the dried slides were stained using HEMA 3 . The percentage of recruited neutrophils was calculated based on the count of minimum 200 cells. Statistical analysis was carried out using the two‐tailed t‐test. Each experiment was repeated in triplicate. The animal protocol was approved by the Yale University Institutional Animal Care and Use Committee .Neutrophil recruitment assay was performed in the lungs of male C57BL/6J mice (8–12 weeks old) as described versus PI. The frequency of cells in each quadrant, Q1 , Q2 , Q3  and Q4  was determined using Flow Jo software .The frequency of apoptosis in THP‐1 and HL60 cells following treatment with MIF inhibitors  was assayed. Cells were treated with MIF (50 ng/ml) and its inhibitors (0.5 μM) for 180 min. After termination of the culture, cells were washed twice with PBS and re‐suspended in 100 μl of Annexin‐V binding buffer . To the cell suspension, 5 μl of FITC‐conjugated Annexin‐V and 10 μl of PI (50 μg/ml) solution were added and further incubated for 15 min. at room temperature. After staining, 400 μl of Annexin binding buffer was added, and the samples were stored on ice until data acquisition. About 10,000 events were acquired in FACS Canto flow cytometer (BD Biosciences). The results were represented as dot plots of FITC As different PI3K isoforms account for distinct functions, identifying which isoforms are activated by MIF will clarify the mechanisms underpinning PI3K‐related signalling networks and lay the groundwork for understanding their regulation. Currently, reliable antibodies are available only for the p85, p101, p110α, β and γ isoforms. Among those, anti‐phospho antibody is only available for p85. Therefore, we examined the changes in protein expression of each isoform and phosphorylation level of p85 in THP‐1 monocytes and HL60 neutrophil‐like cells after the treatment with 50 ng/ml of MIF. As MIF activation of extracellular signal‐regulated kinase 1/2 is biphasic (15 and 150 min.) 1, 2 and 12) for use as molecular probes to identify the structural determinants on MIF associated with the activation of PI3Ks. 1 and 12 are new inhibitors and 2 was recently reported elsewhere, but numbered differently 2 and 1 to inhibit 50% of MIF was 50 and 70 min. respectively. In contrast, 12 showed the complete covalent bond formation with MIF within 30 min. Furthermore, the extrapolated MIF activity in the presence of 12 at time 0 was 33%. This suggests that 12 may have both covalent and non‐covalent tautomerase inhibitory activity as described for a known covalent inhibitor, NAPQI 1 and 2 in THP‐1 monocytes , whereas 12 did not  in most areas except the second loop   in 2‐bound structure, and to the fully open position (light pink) in 12‐bound structure. However, the position of the side chain of Tyr36 seems not significant for receptor binding because the MIF‐induced THP‐1 monocyte chemotaxis showed subtle or no effect with 12 , so each MIF trimer structure was analysed. As three monomers in each MIF trimer demonstrate very similar B‐factor profiles, one representative monomer for each MIF:inhibitor complex is shown in Figure 12 complexes exhibit B‐factors under 5 Å2 for L2 loop, indicating low flexibility and possibly stable interactions with receptors. In contrast, MIF:ISO‐1, MIF:1 and MIF:2 show relatively increased B‐factors  for the L2 loop. MIF:1, MIF:2 and MIF:4‐iodo‐6‐phenylpyrimidine (4‐IPP) (PDB ID:3B9S) show high B‐factors for L3 loop, whereas MIF:ISO‐1 does not. This suggests that L3 loop is disturbed depending on inhibitors and may not be critical for receptor binding leading to PI3K expression. MIF:12 shows high B‐factors only for L1 and this also suggests that L1 may not be critical for receptor binding. As MIF:1, MIF:2 and MIF:ISO‐1 inhibited MIF‐induced leucocyte migration  followed by 4‐IPP (1.1 Å), 2 (0.8 Å), 12 (0.5 Å) and ISO‐1 (0.4 Å). This suggests that 1 might disturb the protein the most. Also, to examine steric hindrance between the inhibitor‐attached Pro1 and L2 loop, we measured displacement of the closest carbon of each Pro1 towards the side chain oxygen of Thr30. The displacements are 1.1 Å for 1, 0.6 Å for 4‐IPP, 0.6 Å for 2 and 0.5 Å for ISO‐1 and 0.2 Å for 12. This suggests that the displacement of Pro1 upon inhibitor binding within the tight active site pushes and destabilizes the L2 loop, resulting in suboptimal MIF binding to receptor.To further understand the structural basis of the increased flexibility of L2, we scrutinized the positions of the inhibitor‐attached Pro1 relative to Thr30 belonging to L2 loop Fig. . We incl1 inhibited 79% of the total number of neutrophils otherwise recruited by MIF. In contrast, 12 did not significantly inhibit neutrophil recruitment. 2 was not tested in this study as it revealed 57% of inhibition elsewhere To verify the physiological consequences of the aforementioned structure‐function relationships, we treated mice with MIF alone or MIF:inhibitor complex and investigated how many neutrophils were inhibited to migrate by each inhibitor Fig. . 1 inhibWe evaluated the expression levels of Class I PI3K catalytic subunits, p110α, β and γ, after MIF treatment of THP‐1 monocytes and HL60 neutrophil‐like cells. The expression level of p110γ increased, but the expression level of p110α and β did not change. Likewise, the expression of the regulatory subunit of p110γ increased in both the cell lines. The time required to reach to the later phase expression of p110γ was 90 min. earlier for HL60 cells when compared with THP1 cells. Neutrophils are the first responders to infection, so highly motile and rapidly congregate at the infection site and provide signals for the activation of macrophages None of the inhibitors tested here inhibited the phosphorylation of p85 in THP‐1 monocyte cells Fig. B but did12 increased the flexibility of L1, whereas other inhibitors did not. L1 contains Arg11 that is a part of the pseudo‐(E)LR C‐X‐C chemokine receptor binding motif 12 disrupts L1 interaction with either CXCR2 or CXCR4 and is also responsible for the partial inhibition of p110γ expression. ISO‐1 exhibited B‐factors (>10) between 1 (>30) and 12 (<5). However, it exhibited an equal level of inhibitory effect with 1 and 2 against the MIF‐induced THP‐1 cell migration. Thus, it suggests that ISO‐1 partially interferes receptor binding with the solvent‐exposed ring structure as 2 does with minimal disturbance of L2. In fact, the solvent‐exposed ring structure of ISO‐1 and 2 are well overlaid.In summary, our study suggests that the L2 loop of MIF plays a pivotal role in activating the expression of Class IB PI3Ks, p101 regulatory subunit and p110γ catalytic subunit. We also demonstrate that structurally diverse MIF active site inhibitors can be used as molecular probes to elucidate the molecular basis of potential receptor binding sites on MIF and the activation of downstream signalling pathways.1, 2 and 12 were deposited to the Protein Data Bank (PDB) and their PDB codes are 4Z15, 4Z1T, 4Z1U, respectively.The structural coordinates of MIF in complex with Authors have no conflict of interest to declare.Table S1 Crystallographic data collection and refinement statistics.Figure S1 PI/Annexin cell viability assays.Click here for additional data file.


Apart from their two phototherapeutic modalities, fluorescence, photoacoustic signals, and thermal imaging in vivo can be simultaneously achieved because of their enhanced permeability and retention effects. This work demonstrates that the prepared TBTPNPs are “all‐five‐in‐one” phototheranostic agents that can exhibit properties to satisfy the “one‐fits‐all” requirement for future phototheranostic applications. Thus, the prepared TBTPNPs can provide fundamental insights into the development of PNP‐based nanoagents for cancer therapy.Attaining consistently high performance of diagnostic and therapeutic functions in one single nanoplatform is of great significance for nanomedicine. This study demonstrates the use of donor–acceptor (D–A) structured polymer (TBT) to develop a smart “all‐five‐in‐one” theranostic that conveniently integrates fluorescence/photoacoustic/thermal imaging and photodynamic/photothermal therapy into single nanoparticle. The prepared nanoparticles (TBTPNPs) exhibit near‐infrared emission, high water solubility, excellent light resistance, good pH stability, and negligible toxicity. Additionally, the TBTPNPs exhibit an excellent singlet oxygen ( Apart from the two phototherapeutic modalities, FL, PA signal, and thermal imaging using TBTPNPs can be simultaneously achieved. Our in vitro and in vivo studies indicated that the as‐prepared TBTPNPs are versatile phototheranostic agents for tri‐modal imaging‐guided simultaneous PDT and PTT. As far as we know, our study is the first to investigate “all‐five‐in‐one” phototheranostics based on a single type of PNP.Previously, our group synthesized versatile PNPs based on polythiophene (PT2) as two‐photon‐excited photosensitizers to localize lysosomes for simultaneous cellular and deep‐tissue imaging and PDT.22.1FigureThe thiophene‐BT‐based D–A polymer (TBT) was successfully prepared , and the detailed synthesis is summarized in the Supporting Information. Nanoprecipitation induced by DSPE‐mPEG2000 produced water‐soluble TBTPNPs as clear violet solutions. As shown in −2 or 635 nm laser, 1 W cm−2) and HeLa cells  were continuously irradiated under different conditions, and the results showed that the TBTPNPs had high photostability .The UV−vis absorption spectrum of the TBTPNP aqueous solution exhibited a broad absorption band in the range from 400 to 750 nm Figure f. Meanwh2.2tertbutoxycarbonyl‐5‐methyl‐1‐pyrroline‐N‐oxide (BMPO) were used as 1O2 and O2−· (or OH·) trappers, respectively, under 635 nm laser irradiation. As shown in Figure1O2‐induced signal was observed, and the signals of 1O2 increased with the prolonged irradiation time. In contrast, no other ROS signal (O2−· or OH·) was detected  was used as the standard photosensitizer (1O2 quantum yield ΦMB = 52% in water).1O2 quantum yield of the TBTPNPs was ≈40%. Sodium azide (NaN3), a 1O2 quencher, was then added into the TBTPNP solutions to demonstrate that the decomposing of ADPA was induced by the generated 1O2. As shown in Figure S8 (Supporting Information), the decrease in the ADPA absorbance in the present of NaN3 was negligible during light irradiation, demonstrating the 1O2 production of the TBTPNPs. To further exclude the possible direct reaction between ADPA and the TBTPNPs, we subjected the TBTPNPs to a continuous O2 and N2 purge for 45 min, respectively . The absorbance of ADPA dramatically decreased in the O2‐saturated solution, while it remained nearly unchanged in the N2‐saturated solution, indicating that the 1O2 generation of the TBTPNPs was responsible for the ADPA degradation. The NIR 1O2 emission around ≈1270 nm was also measured to determine the 1O2 generation of the TBTPNPs in EtOH.1O2 quantum yield of the TBTPNPs was approximately 43% when MB (ΦMB = 49% in ethanol) was used as ref. 1O2 sensor green (SOSG), which can selectively react with 1O2 and form a green fluorescent endoperoxide product, was used to stain fixed cancer cells in order to investigate the 1O2 generation of the TBTPNPs in vitro. As shown in Figure 1O2 generation by the TBTPNPs under irradiation.Electron spin resonance (ESR) was initially performed to investigate the ROS production of the TBTPNPs. For this method, 2,2,6,6‐tetramethylpiperidine (TEMP) and 5‐−1) were exposed to a 635 nm laser at a power density of 1 W cm−2 to investigate the photothermal properties of the TBTPNPs. Pure water was used as negative control. The temperatures of all TBTPNP solutions increased with prolonged irradiation times  to 23.5 °C (200 µg mL−1). In contrast, the temperature of pure water increased by only 4.5 °C  sunder 635 nm laser at power density of 1 W cm−2. As shown in Figure S10 (Supporting Information), 1O2 can be formed efficiently, indicating that PDT and PTT effect can be simultaneously achieved under this condition. To calculate the photothermal conversion efficiency of the TBTPNPs, η, the temperature change of the solution  was recorded as a function of time under continuous irradiation using a 635 nm laser (1 W cm−2) until the solution reached a steady‐state temperature  at excitation wavelength of 640 nm. As shown in 1O2 when subjected to laser irradiation. Calcein AM (green) and PI (red) co‐staining assays, which can distinguish live from dead cells, were further performed to evaluate the photoinduced cell death effect of the TBTPNPs. The controls included samples that underwent laser irradiation (1 W cm−2) without TPTPNPs and those with TBTPNPs (200 µg mL−1) incubation alone. As shown in Figure −2, 10 min), some parts of the cells were destroyed due to the ease with which 1O2 was produced and the inability to generate heat under such low laser power doses. When the laser power density was increased to 1 W cm−2, all the cells were completely killed, as indicated by the intense homogeneous red fluorescence. This result was ascribed to the fact that both 1O2 and heat were produced by TBTPNPs at this condition, suggesting that PDT and PTT effects can be achieved and thus can be used to kill cells completely just by using a single laser. The cytotoxicity and light‐triggered synergistic PDT/PTT efficacy of the TBTPNPs on the viabilities of the HeLa cells were further investigated using standard 3‐‐ 2,5‐diphenyl‐2H‐tetrazolium hydrobromide (MTT) assays. As shown in Figure −1 TBTPNP concentration were observed, demonstrating the good biocompatibility of the TBTPNPs. However, in the PDT group (0.1 W cm−2), the cell viability gradually decreased with the increasing TBTPNP concentration, and ≈60% cell mortality rate was achieved at 500 µg mL−1. In the PDT + PTT group (1 W cm−2), more than 95% cell mortality rate was observed at TBTPNP concentrations of 200 and 500 µg mL−1, thereby verifying that the synergistic PDT and PTT effects could efficiently kill cancer cells  was injected into nude mice with HeLa tumors via the tail vein. Initially, the Maestro 2 multispectral small‐animal imaging system was used to record the FL images of the mice. FigureTo evaluate the capability of the TBTPNPs as imaging agents for in vivo NIR FL and PA imaging, a PBS solution containing TBTPNPs  or were injected with the same volume of PBS and then subjected to irradiation with a 635 nm laser at laser power density of 1 W cm−2 (laser only). For comparison, the mice injected with TBTPNPs and exposed to a 635 nm laser at power densities of 0.1 and 1 W cm−2 were selected as the PDT group and PDT + PTT group, respectively. The time evolution of the local tumor temperature during irradiation for 10 min is represented in Figure−2) and the PDT groups slightly increased by ≈6 ≈C. We then measured the tumor sizes of the mice from all groups every 2 d after treatment. As shown in Figure To investigate the in vivo therapeutic effect of the TBTPNPs, as a proof of principle experiment, four groups (5 mice per group) of HeLa tumor‐bearing nude mice with tumor sizes of ≈25 mm31O2 quantum yield and ≈37.1% photothermal conversion efficiency. Furthermore, aside from the two phototherapeutic modalities, FL, PA signal, and thermal imaging using the TBTPNPs were achieved simultaneously. The results of the in vitro and in vivo studies indicated that the as‐prepared TBTPNPs can be used as single versatile phototheranostic agents for trimodal and imaging‐guided simultaneous PDT/PTT. Achieving a better understanding of the in vivo behaviors of the prepared TBTPNPs and their quantitative pharmacokinetics and long‐term toxicity is of extreme importance and requires further exploration. The developed “all‐five‐in‐one” phototheranostic agents in this work may fulfill the “one‐fits‐all” requirement for future phototheranostic applications and thus may provide fundamental insights into the development of PNP‐based nanoagents for cancer therapy.In summary, we prepared a novel single nanoplatform for the first time as “all‐five‐in‐one” phototheranostic agent using a facile, one‐step nanoprecipitation method. The developed TBTPNPs exhibited broad absorption that ranged from 400 to 750 nm and an NIR emission peak at ≈690 nm. In addition to possessing the previously reported merits of PNPs, such as high water solubility, excellent light resistance, good pH stability, and negligible toxicity, the prepared TBTPNPs simultaneously possessed PDT and PTT effects under single‐laser irradiation (635 nm), with ≈40% 4Materials: 1,2‐Distearoyl‐sn‐glycero‐3‐phosphoethanolamine‐N‐[methoxy(polyethylene glycol)‐4 2000] was purchased from Shanghai Yanyi Co. SOSG and ADPA were purchased from Sigma‐Aldrich. All other chemicals were obtained from J&K and Beijing Chemical Co. unless otherwise stated Experimental Details.Characterization: Transmission electron microscope (TEM) images were taken on a JEOL JEM‐2100F TEMat an acceleration voltage of 150 kV. UV–Vis and fluorescence spectra were obtained using Hitachi U‐3010 and F‐4500 spectrophotometers, respectively. Zeta potentials were recorded on Zetasize 3000 HS . ROS was detected using electron spin resonance technique . The fluorescence spectrum of singlet oxygen was detected in HITACHI FL 900 fluorescence spectrophotometer with a NIR detector (λex = 635 nm). The fluorescence images of the HeLa cells were acquired with a Nikon A1R confocal and multiphoton system using 640 nm laser and an oil immersion 60× objective lens.Preparation of TBTPNPs: A solution of polymer TBT in tetrahydrofuran (THF)  and a solution of DSPE‐mPEG2000 in water  were rapidly injected into distilled‐deionized water (9 mL) under continuous sonication for 3 min. THF was subsequently removed and the TBTPNPs were further purified through dialysis and filtered through a 0.22 µm filter membrane.Photostability of TBTPNPs In Vitro: HeLa cells  were cultured in culture media  at 37 °C in a humidified incubator containing 5% CO2. The cells were then stained with TBTPNPs in culture media for 6 or 1 h at 37 °C. The cells were washed with PBS and then fixed with ice methanol for 1 min, carefully washed with PBS again for three times, and then irradiated and imaged using NIS element analysis with a cooled CCD camera.1O2Quantum Yield Measurements via Chemical Method: ADPA was used as the 1O2‐trapping agent, and MB was used as the standard photosensitizer. In the experiments, 60 µL of ADPA solution (1 mg mL−1) was added to 1.5 mL of TBTPNPs solution, and 635 nm laser was employed as the irradiation source. To eliminate the inner‐filter effect, the absorption maxima of MB and the TBTPNPs were adjusted to ≈0.2 OD. The absorption of ADPA at 378 nm was recorded at various irradiation times to obtain the decay rate of the photosensitizing process. The 1O2 quantum yield of the TBTPNPs in water was calculated using the following formulatMB is the time for the decrease in absorption of ADPA in the presence of MB free in water adjusted to a first‐order exponetial decay, tTBTPNPs is the time for the decrease in absorption of ADPA in the presence of TBTPNPs in water adjusted to a first‐order exponetial decay, and ΦMB is the singlet oxygen quantum yield of MB free in water given as 0.52.1O2Quantum Yield Measurements by Detecting1O2Emission: The 1O2 emission signals of the TBTPNPs were detected in a HITACHI FL 900 fluorescence spectrophotometer with a 635‐nm excitation laser and a NIR detector. Considering the short PL lifetime of 1O2 in water, the MB and TBTPNPs solution were prepared in EtOH solution. The absorptions of MB and TBTPNPs at 635 nm were adjusted to ≈0.2 OD. The 1O2 quantum yield of the PNPs could be obtained using the followingITBTPNPs and IMB represent the PL peak areas of 1O2 produced by the TBTPNPs and MB, respectively, and φMB = 0.49.Measurement of Photothermal Performance and Calculation of the Photothermal Conversion Efficiency: Various solutions of TBTPNPs (1.0 mL) with different concentrations (0 –200 µg mL−1) were introduced in a quartz cuvette and irradiated with a 635 nm laser at a power density of 1 W cm−2 for 10 min at room temperature to measure the photothermal conversion performance. The temperature changes of TBTPNPs (200 µg mL−1) were also measured under irradiation with the 635 nm laser at different powder density. The temperature was recorded every 1 s with a digital thermometer using a thermocouple probe with an accuracy of 0.1 °C. In order to calculate photothermal conversion efficiency η, which defined as the fraction of the absorbed power that is transformed into heat, the temperature during a cycle of laser‐induced heating and subsequent cooling of an aqueous dispersion of TBTPNPs was measured and then using the equationh is the heat transfer coefficient and A is the surface area of the container where the solution is placed, while ΔTmax is the temperature change of the TBTPNPs solution at the maximum steady‐state temperature. QDIS corresponds to the heat dissipated from the light absorbed by the solvent and container, I is the laser power, and λA is the optical density of the TBTPNPs solution at 635 nm. And the thermal imaging was performed using a Ti400 infrared camera when the tumors were exposed to lasers.PA Imaging In Vitro: The TBTPNPs with different concentrations  were added into the agarose tube (37 °C) with the same concentration of micelles as the control. Then, they were scanned with a PA imaging instrument , and the PA signal was recorded through a mean pixel intensity of the same area in the images.Cell Imaging and PDT/PTT In Vitro: HeLa cancer cells were seeded in 35 mm cell culture dishes and were incubated with TBTPNPs . After 4 h, cells were washed with PBS twice to remove nonspecifically bound TBTPNPs. Images were acquired with a Nikon C1si laser scanning confocal microscope. For PDT/PTT in vitro, HeLa cancer cells were incubated with and without TBTPNPs (1mg mL−1 50 µL) for 6 h and then irradiated by 635 nm laser at different power densities  for 10 min. After that, the cells were costained with calcein AM and propidium iodide (PI) for 10 min, washed with PBS, and then imaged by a Nikon C1si laser scanning confocal microscope. To determine cell viabilities, MTT assay was carried out under various conditions to further confirm the cytotoxicity and phototherapy efficacy of TBTPNPs. Cells were seeded into 96‐well plates and incubated with different concentrations  of TBTPNPs at 37 °C for 24 h in 5% CO2 atmosphere, each concentration of TBTPNPs was carried out with six parallel groups. For in vitro PDT and PDT/PTT, HeLa cancer cells were incubated with TBTPNPs  at 37 °C for 6 h under the same conditions and then irradiated by 635 nm laser  for 10 min. After illumination, the cells were incubated for another 24 h. The cell medium solutions were exchanged for 100 µL of fresh medium, followed by the addition of 20 µL of MTT solution to each well. The culture plates were then incubated at 37 °C in 5% CO2 for 4 h. The culture medium was discarded, and 100 µL of dimethyl sulfoxide (DMSO) was added. The absorbance of the untreated cell population under the same experimental conditions was used as the reference point to establish 100% cell viability.FL/PA/Thermal Imaging In Vivo: Animal experiments were approved by the China Committee for Research and Animal Ethics in compliance with the law on experimental animals. A subcutaneous HeLa tumor was established by injecting a suspension of 2 × 107 HeLa cells in PBS (100 µL) into the buttock of each female nude mouse  and was allowed to grow for 8–10 d when the tumor size reached 20–25 mm3. The TBTPNPs solution  was intravenously injected into tumor‐bearing mice. The fluorescence images of mice were then recorded on a Maestro 2 Multispectral Small‐animal Imaging System. Excitation wavelength was set at 570 nm. Fluorescent scans were performed at various time points  postinjection. The tumor‐bearing mice were sacrificed by exsanguinations at 24 h postinjection, and the tumor and major organs were harvested. The in vivo PA imaging was performed on a commercial MSOT InVision128 PA tomography system . The system houses 128 unfocused ultrasound transducers (with 5 MHz center frequency and 3 mm diameter) arranged in a hemispherical bowl filled with water and a temperature monitor of the water bath (37 °C). Prior to intravenous administration of the TBTPNPs , we first obtained precontrast data with excitation wavelength from 680 to 980 nm. Then, postcontrast data were acquired at various time points  after intravenous administration of TBTPNPs under the same scan wavelength ranges. The PA images were reconstructed offline using data acquired from all 128 transducers at each view through a modified back‐projection algorithm. Thermal imaging was recorded by a Ti400 infrared camera when the tumors were exposed to 635 nm laser with a power density of 0.1 or 1 W cm−2 for 10 min.Phototherapy In Vivo: When the tumor size reached 20–25 mm3, the HeLa tumor mice were randomly divided into four groups (5 mice per group). For the treatment groups, mice were intravenously injected with TBTPNPs solution  and were covered by home‐made baffle with hole of 5 × 5 mm2, which could cover the normal tissue and expose the tumor tissue under irradiation. Then, mice were irradiated by 635 nm laser  for 10 min. The control groups included mice with TBTPNPs injection only and mice with laser irradiation only (1 W cm−2 of laser only). Tumor sizes, body weight, and survival rate were measured every other day after treatment. Tumor volume (V) was determined by Equation a and b are the length and width of the tumor, respectively. The relative tumor volume was normalized to its initial size before administration and laser irradiation of BTTPNPs.Histopathological Examination: The tissues  were harvested and fixed in 10% formalin solution. The histopathological tests were performed according to standard laboratory procedures. Tissue samples were numbered and given blind to a pathologist for conventional processing and analysis. The tissue samples were embedded in paraffin blocks, sectioned into 5 µm slices, and mounted onto the glass slides. After H&E staining, the sections were observed, and photos were taken using an optical microscope .The authors declare no conflict of interest.SupplementaryClick here for additional data file.


Using a combination of density functional theory and lattice models, we study the effect of CO2 adsorption in an amine functionalized metal–organic framework. 2 adsorption in an amine functionalized metal–organic framework. These materials exhibit a step in the adsorption isotherm indicative of a phase change. The pressure at which this step occurs is not only temperature dependent but is also metal center dependent. Likewise, the heats of adsorption vary depending on the metal center. Herein we demonstrate via quantum chemical calculations that the amines should not be considered firmly anchored to the framework and we explore the mechanism for CO2 adsorption. An ammonium carbamate species is formed via the insertion of CO2 into the M–Namine bonds. Furthermore, we translate the quantum chemical results into isotherms using a coarse grained Monte Carlo simulation technique and show that this adsorption mechanism can explain the characteristic step observed in the experimental isotherm while a previously proposed mechanism cannot. Furthermore, metal analogues have been explored and the CO2 binding energies show a strong metal dependence corresponding to the M–Namine bond strength. We show that this difference can be exploited to tune the pressure at which the step in the isotherm occurs. Additionally, the mmen–Ni2(dobpdc) framework shows Langmuir like behavior, and our simulations show how this can be explained by competitive adsorption between the new model and a previously proposed model.Using a combination of density functional theory and lattice models, we study the effect of CO In fact, the natural gas industry has been utilizing the well-known ability of monoethanolamine (MEA) to capture CO2 since 1930.3 The capability now exists to use this technology to capture CO2 from flue gas and it is the only technology currently advanced enough for use in power plants. However, while amines are highly effective at separating CO2 from other flue gases, the regeneration of amine solutions requires boiling, which is an energy intensive step. Solid sorbents, like metal–organic frameworks, are highly promising as these materials require less energy to be regenerated. While much work has focused on designing new porous materials for CO2 capture, another approach is to functionalize a nanoporous material with amines with the aim of combining the selectivity of the amine while maintaining the low regeneration energy requirement of the porous framework.As carbon capture and sequestration is the only viable technology to reduce CO2 capture to design advanced solid adsorbents represents one of the most exciting uses of this class of compounds. The mmen–M2(dobpdc) framework  is of particular interest due to its stability in water and unique CO2 adsorption mechanism  pressure induces a large change in the amount of gas adsorbed. However, to take advantage of such a step one needs to be able to select a material that has the step at exactly the right conditions for a given separation. A prerequisite for the rational design of such a material is a better understanding of the molecular mechanism for CO2 adsorption in mmen–M2(dobpdc). In this context an important question is to have a quantitative understanding why the Mg, Mn, Fe, Co, and Zn versions of the mmen–M2(dobpdc) have a step in the isotherm, while Ni does not. Recently, Lee et al. have synthesized dmen–Mg2(dobpdc)  and also observe this characteristic step in the isotherm.12 In this work, we report a combined quantum chemical and classical simulation study aimed at elucidating the manner in which CO2 binds to the mmen–M2(dobpdc) framework, but the underlying concepts are extendable to the other amine appended MOFs in the amine appended M2(dobpdc) family. Some initial results of this work have been published as part of an extensive experimental study and we will note explicitly in the following which results were previously published and which are included herein for the first time.11To this end, the use of amine-grafted MOFs for COnism see . For som2(dobpdc) is to determine the manner in which CO2 binds to the amines in the framework. Given the open metal site in the MOF, it is reasonable to assume that one of the amine is bound to the metal site and the other amine will adsorb CO2. With this assumption, the first experiments performed by McDonald et al. for the Mg framework showed that CO2 adsorption occurs with 1 : 1 (CO2 : amine) stoichiometry, in contrast to the 1 : 2 ratio observed for aqueous amine solutions, and has a heat of adsorption of –71 kJ mol–1.10 Given that one of the amine groups is assumed to be strongly bound to the open metal site and that it is not involved in the interaction with CO2, this 1 : 1 ratio is surprising. To explain this observation, Planas et al.13 performed a density functional theory (DFT) study and proposed a possible adsorption mechanism. In Planas et al.'s work, the amine was assumed to be grafted to the open metal center with only its terminal end free to capture CO2, and a binding configuration involving a carbamic acid pair was reported. We refer to this structure as the pair model (see 2 capture could occur in the ab-plane (across the organic linker) or by forming the same pair between neighboring amines along the c-axis .The first step in understanding the unique behavior of mmen–Model see . CO2 capaxis see .13 Pair 2. First, the experiment was repeated for the transition metal analogues (mmen–M2(dobpdc) where M = Mg, Mn, Fe, Co, Ni, and Zn) and the heat of adsorption was shown to be metal dependent. This was inconsistent with CO2 binding only to the terminal end of the amine. Additionally, the CO2 adsorption isotherm has a characteristic step for all of the metals with the exception of nickel, and this step is indicative of a phase change mechanism in which the amines switch from an initially disordered state to some ordered structure. The pressure at which this change occurred was metal dependent and could not be fully explained by the proposed pair mechanism. Likewise, 15N NMR data suggest that CO2 adsorption affects how the amine coordinates to the MOF. At temperatures relevant for CO2 storage, only one peak is observed in the 15N NMR spectra despite the fact that one nitrogen atom is coordinating to the metal center and the other is not. The presence of only a single peak indicates that the amine can alter its coordination at a time scale faster than the NMR can resolve.11Subsequent experimental data however have cast doubt on whether only one amine group is participating in the binding of CO2. First, to quantify the different binding modes and the effect of changing the metal, we have carried out a thorough quantum chemical study to identify the binding mechanism of CO2 in this framework. Ultimately, we aim to go beyond a static picture of the binding mode by performing molecular simulations. Can we demonstrate that the product identified by our calculations and the work of McDonald et al.11 yield the transition observed in the isotherm? Can we predict a change in the adsorption mechanism by tuning the energetics?These new experimental data suggest that the amine group bound to the metal site must participate in the binding of CO2 : amine ratio is a model in which CO2 binds at the metal site with two amine groups. In this model, CO2 coordinates to the metal bound nitrogen but has favorable interactions with the neighboring amine down the c-axis forming a highly ordered chain and is therefore referred to as the chain model. However, there is more than one way to form an ordered “chain” structure, and one can show that there are ten such binding modes of CO2 that maintain the 1 : 1 CO2 : amine ratio . The rationale for choosing the ten structures is as follows. Four categories of CO2 binding modes in mmen–Mg2(dobpdc) have been identified. CO2 can (1) bind to the nitrogen atom coordinated to metal center , (2) bind to the terminal nitrogen group , or (3) and (4) insert into the metal–nitrogen bond. For the latter, CO2 insertion can result in either (3) a monodentate product (Monodentate Insertion) or (4) a bidentate product (Bidentate Insertion). One would expect the binding of CO2 at the Metal–N and Terminal–N sites to be similar to the well-known reactions that occur in solution between CO2 and amines like MEA. MEA solutions have been used commercially for CO2 separations for many decades and the mechanism for their reaction with CO2 includes the formation of a zwitterion, an ammonium carbamate intermediate;14 therefore, both charged and neutral groups are considered as possible products in the Metal–N and Terminal–N groups. Furthermore, for the Monodentate Insertion group, four structures can be formed, two carbamates and two carbamic acids  and this step has a barrier of +37.59 kJ mol–1. The resulting product is lower in energy by –29.76 kJ mol–1 with respect to the separated reactants (or 47.77 kJ mol–1 lower in energy than the transition state barrier). The second CO2 forms favorable interactions with the –COOH hydrogen and the nitrogen of the other amine. The barrier to form the second –COOH group is similar to the first, +40.38 kJ mol–1. The final step proposed in c-axis; however, the final product (denoted the pair model herein) includes the “pairing” of two carbamaic acid groups across the ab-plane. In the previous work, this was determined to yield a binding energy of –138.25 kcal mol–1 with respect to reactants, or –69.13 kcal mol–1 per CO2. The reader should note that the values are electronic energies based on the cluster model from previous work. After this work was published, two new experimental results were the first to call this mechanism (and resulting product) into question. First, the heat of adsorption varied with the metal, and second 15N NMR data suggested that the two N atoms on the amine were equivalent. Both of these would be unlikely if CO2 reacted with the terminal end of the amine.11 Neither of these results would not be expected if CO2 reacts with the terminal end of the amine.Additionally, the chain model has been compared to the pair model proposed by Planas et al.  and 4.13et al. employed a cluster model, in the present study we fully optimized products and reactants with periodic boundary conditions. The formation of the dicarbamic acid product (the pair model) is exothermic by only –42.9 (or –45.8) kJ mol–1 per CO2 with the PBE (or M06L) functionals, respectively. First of all, an important difference between these calculations is that the framework atoms were kept rigid in the cluster model and secondly the cluster model most likely omits steric interactions between adjacent carbonated amines along the c-axis. Both of these effects could contribute to the differences between these calculations. As such, the calculated energies obtained for the pair model with the PBE or MO6L functionals and periodic boundary conditions are not in agreement with the experimental enthalpy of –71 kJ mol–1.10 It should also be noted that the lowest energy structure obtained with these functionals is a zwitterionic ammonium carbamate species  both before and after CO2 adsorption at a variety of temperatures. The predominant features supporting the formation of a carbamate group include two diagnostic bands at 1334 cm–1 and 658 cm–1 that can be assigned to ν(C–N) and [β(OCO) + β(NCO)] modes.11 While the region between 1000 and 1600 cm–1 cannot be used to distinguish between the pair and chain models as both contain carbamate groups, the calculated carbamate C PBM data was replaced with SVG by xgml2pxml:<glyph-data id="z.dbd" format="PBM" resolution="300" x-size="34" y-size="34" xml:space="preserve"> 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000	</glyph-data><svg xmlns="http://www.w3.org/2000/svg" version="1.0" width="16.000000pt" height="16.000000pt" viewBox="0 0 16.000000 16.000000" preserveAspectRatio="xMidYMid meet"><metadata>Created by potrace 1.16, written by Peter Selinger 2001-2019</metadata><g transform="translate scale" fill="currentColor" stroke="none"><path d="M0 1440 l0 -80 1360 0 1360 0 0 80 0 80 -1360 0 -1360 0 0 -80z M0 960 l0 -80 1360 0 1360 0 0 80 0 80 -1360 0 -1360 0 0 -80z"/></g></svg>O stretching mode, the amine methylene C–H stretches, and the carbamate C–Namine stretching modes occur at 1565.0 ± 100, 1440.6 ± 100, and 1265.9 ± 100 cm–1, respectively, in the chain model confirming the assignment of the 1690 and 1334 cm–1 peaks as the CO and C–Namine vibrations of the carbamate.11 Additionally, the most intense experimental peak due to product formation occurs at about 2250 cm–1.11 The pair model has an intense carbamic acid O–H stretch at 2582.7 ± 100 cm–1, while the analogous peak in the chain model occurs at 2158.2 ± 100 cm–1. As was the case for the binding energies, the chain model is in better agreement with experiment.Furthermore, infrared spectra have been measured for mmen–Mg2(dobpdc) family is particularly convenient since this MOF topology can be readily synthesized with many first row transition metal atoms. In M2(dobpdc), trends in the lattice constant as a function of changing the metal follow the same trend observed in the analogous family of MOFs, M2(dobdc) where dobdc is the 2,5-benzenedicarboxlyate linker.11 The M2(dobdc) and M2(dobpdc) frameworks differ only by the length of the linker. In both cases, lattice constants are longer for metals with a larger ionic radius (Mn > Fe > Co > Zn > Mg > Ni). For example, the difference in the length of the unit cell is 0.29 Å between Mn and Ni in M2(dobpdc) compared to 0.33 Å in M2(dobdc). On the other hand, when the six amine groups are added to the unit cell, the lattice constants are on average 0.36 Å shorter in the ab-plane than in M2(dobpdc) but 0.16 longer in the c-direction for the same metal.Working with the M2 adsorption in mmen–M2(dobpdc) has been performed for M = Mg, Mn, Fe, Co, Ni, and Zn and the adsorption behavior shows a strong metal center dependence. However after CO2 adsorption, powder X-ray diffraction data is only available for the Mn analog.11 Most notably, the XRD results show an elongation of the M–Namine bonds from ∼2.44 Å in the bare MOF to ∼4.43 Å after CO2 adsorption and the structure is consistent with our chain model. The binding geometries and energies for the chain model calculated within DFT using the PBE and M06-L functionals were discussed in our previous combined experimental and theoretical study.11 Our DFT calculations for the pair model were not presented in previous work but were used to justify the choice of interaction energies for the molecular simulations.Currently, CO2 binding energies and metal–nitrogen bond distances correlate with one another and periodic trends are consistent with well-established behavior for first row transition metals atoms  frameworks with shorter M–Namine bonds to have less favorable energetics for the CO2 insertion step. In Moreover, the COtoms see . Accordio Ni see . When thamine bond lengths in the pair model remain virtually unchanged (contraction by only 0.00–0.08 Å) from the reactant to the pair model product. Furthermore, the adsorption energies and Mg–Namine bond distance are independent of the metal for the pair model in mmen–M2(dobpdc) contrary to experiment  for M = Mg, Mn, Fe, Zn, and Co.Our DFT calculations show that the chain model can account for some of the structural and energetic experimental observations. The next step is to show that this model also results in the characteristic step in the adsorption isotherm observed for mmen–M2–amine complexes influence the shape of the isotherms, we have extended the approach of Sillar et al.16 to include the energetics of the complexes proposed in the previous section  or along the c-axis (2 orientations). In the pair model, we assume that two CO2 molecules can only adsorb if the two amines on neighboring adsorption sites point towards each other. In the chain model, we assume that CO2 is optimally adsorbed in a chain-like configuration (the chain model) giving the full energy contribution of 100%; a CO2 at the end of a chain is less favorable (80% of the full-chain energy), as is an isolated adsorbed CO2 molecule (24% of the full-chain energy). The energy for a fully formed chain is taken to be equal to the binding energies for the different metals shown in 17 The chemical potentials of our lattice model were scaled to reproduce the chemical potential of CO2 in the gas phase.To investigate how the two proposed COtion see  and 4 intion see  we assum2 in mmen–Mg2(dobpdc) at 298 K with the simulated adsorption isotherm of CO2 for all of the metals, as well as for the pair model. If only the pair model is included in the simulations, conventional Langmuir behavior is observed, while simulations employing the chain model result in the distinctive step observed experimentally. It should be noted that our previous study included the comparison of the pair and chain models for the mmen–Mg2(dobpdc) framework.11In 2(dobpdc), chain formation is more favorable than pair formation resulting in behavior qualitatively different from a Langmuir isotherm due to the formation of chains  shown in 11 but the results for Ni and Zn were not.Moreover, changing the metal influences the location of the step of the isotherm: the smaller the binding energy the higher the pressure of this step. The experimental results and our calculated results in –1 while the pair model is –45.8 kJ mol–1. While the chain model showed a strong metal dependence in the binding energy, the pair model did not and the binding energy of nickel in the chain model is –46.4 kJ mol–1 per CO2, while the pair model has a binding energy of –47.2 kJ mol–1. If we use the nickel energetics as a basis for our lattice model, a Langmuir isotherm is observed , the carbamate group is on the terminal nitrogen.9Additionally, the experimental isotherm for nickel is of particular interest since it does not contain the characteristic step. In the lattice model, the ratio between chain and pair formation was determined at the M06-L level of theory. In the Mg system, the chain model has a binding energy of –69.4 kJ mol2. For this we developed a combined DFT lattice model approach, in which we used DFT calculation to estimate the different binding modes of CO2. These binding energies then serve as input for our lattice model.In this work we are interested in understanding the importance of the collective behavior of the amines on the adsorption isotherms for CO2(dobpdc) framework. All calculations were performed on the hexagonal unit cell containing six metal atoms and therefore six amine groups. The starting structure for the M2(dobpdc) frameworks was taken from experimental powder XRD data for the Mg system. Planas et al. had previously performed test calculations on cluster models of mmen–Mg2(dobpdc) with DFT using the PBE functional to determine the most favorable arrangement for mmen in Mg2(dobpdc).13 The amines were arranged in the periodic unit cell by hand in this most favorable arrangement as an initial guess prior to optimization.2–(dobpdc) MOF contains six unsaturated metal sites per unit cell. To calculate the binding energies of CO2 in its amine appended analogue mmen–M2(dobpdc), one mmen ligand per CO2 was added per unit cell. The smaller sized ethylenediamine (en) was used to saturate the remaining amines not involved in CO2 binding.The M The PBE and M06-L functionals were employed to examine the energetics of CO2 adsorption. On-site Hubbard U corrections were employed for metal d electrons. The U values are determined to reproduce oxidation energies in the respective metal oxides.22 This has been shown to lead to excellent binding energies for small molecules to open metal sites in M2-(dobdc) in prior work.23 The electron–ion interactions in these calculations were described with the projector augmented wave (PAW) method developed by Blöchl24 with an energy cutoff of 550 eV. The suitability of DFT  for studying gas adsorption in MOFs has been recently described.25 This combination of the PBE functional, PAW scheme, and energy cutoff was used for full geometry optimization of the various species investigated until the forces on all atoms were smaller than 0.05 eV Å–1. The sensitivity of binding energies to the sampling of the Brillouin-zone during geometry optimizations tested using the PBE functional at the Γ-point and while employing 1 × 1 × 3 and 2 × 2 × 2 Monkhorst–Pack K-point meshes. As the larger K-point meshes did not significantly change the reaction energies, only results obtained from Γ-point calculations are reported in the manuscript. Additional calculations were performed on the mmen–Mg2(dobpdc) framework with the PBE functional. First, a variety of configurations were explored to determine the CO2 binding. Likewise, infrared (IR) spectra were computed with density functional perturbation theory.26 Vibrational modes were computed for the amine, Mg and its first coordination sphere, as well as for bound CO2 when present. The remainder of the framework was kept rigid to reduce computational cost.All DFT calculations were performed with periodic boundary conditions carried out using the VASP 5.3.3 package.2 adsorption in mmen–M2(dobpdc) was studied by employing a lattice model. Each lattice point represents an amine fixed to a metal, and the energy of each site (its status) is determined by whether CO2 is bound at that point or not, the orientation of the amine with respect to the neighboring lattice sites, and whether CO2 is adsorbed or not on these neighboring sites. The energy contribution from each state was estimated based on the energy determined in the DFT calculations. The contribution in each state is given relative to the full-chain. We consider several different configurations: chain formation , end-points (the start or end of a chain), pair-formation (two sites with CO2 interacting in either the c-direction or in the ab-plane), and, in addition, we have a small energy contribution for amines with CO2 bound but are not a part of a chain or a pair. It should be noted that the primary difference between the two pairing mechanisms is the distance between the two metals that anchor the amines. We expect this difference to result in changes on the order of a few kJ mol–1 and therefore is not significant enough to be represented in our coarse-grained model.COvia grand-canonical Monte Carlo (GCMC) simulations, using the conventional acceptance rules.17 To make as direct a comparison of our lattice model with the experimental data as possible, we applied a shift of the pressure. This shift was obtained by fitting to the experimental isotherms for the highest and lowest temperatures. For the intermediate results we used a simple interpolation. The lattice model can in this way be related to models of the different metals and also test the limit of the phase-change behavior seen in experiments.Adsorption isotherms are computed 2 adsorption on the amine-functionalized mmen–M2(dobpdc) framework have demonstrated that the previously proposed mechanism is not able to explain the metal dependence or the distinctive shape of the isotherm.11 As a result, our multi-scale study determined that a zwitterionic ammonium carbamate species formed by CO2 insertion in the M–Namine bond is consistent not only with experimentally observed binding enthalpies but can also demonstrate that the resulting chain formation is responsible for the characteristic step in the isotherm. The chain model is further supported by the heat of adsorption, observed metal dependence, IR data, and the elongation of the M–Namine bond distance upon CO2 adsorption, NEXAFS spectra, and 15N NMR data.11 Herein, we confirm that the long-range order imposed by the chain model is sufficient to cause the unusual step-shaped isotherm for mmen–M2(dobpdc). In contrast, the pair model produces a Langmuir-like isotherm. Furthermore, forming a long chain must be favorable over forming pairs. For all of the metals with the exception of Ni, the chain is favored and a stepped isotherm is observed. In mmen–Ni2(dobpdc), the binding energy in the chain is approximately the same as the energy to form a pair, resulting in favorable formation of pairs and a Langmuir like adsorption behavior.New studies of CO


Herein, the key attributes of hydroxides and oxygen vacancies are experimentally identified in non‐stoichiometric indium oxide nanoparticles, In2O3‐x(OH)y, that function in concert to reduce CO2 to CO under simulated solar irradiation. Enabling this technology will allow the greenhouse gas, CO2, emitted from energy production and manufacturing exhaust streams to be converted into valuable products , thereby creating huge economic and environmental benefits by simultaneously addressing energy security and climate change issues.2O splitting, the photocatalytic reduction of CO2 remains a significant challenge and thus form the focus of our work.2 reduction.2 and pipes out large volumes of carbon‐based fuels. Clearly, the key component of this artificial leaf system is a functional material that utilizes the energy from absorbed solar photons to drive the complex multi‐electron and proton transfer reactions involved in reducing CO2 to fuels. As a result, there is growing interest in synthesizing semiconductor nanomaterials, which have the surface, optical, and electronic properties that can enable photocatalytic reduction of gas‐phase CO2 to generate solar fuels.The emerging field of solar fuels centers on storing radiant solar energy in the form of chemicals that can be used as an alternative to fossil fuels. A major goal in this field is to realize an “artificial leaf” – a material that converts light energy in the form of solar photons into chemical energy – using CO2 are oxygen deficient metal oxides. Oxygen vacancies can function as active catalytic sites and enhance both the absorption of visible light and the photocatalytic activity of the material.2‐xHx, which exhibits a substantial increase in light absorption and photoactivity for water splitting after hydrogen treatment.2 capture capacity of the nanoparticle surface. Several groups have demonstrated that surface hydroxides can enhance the affinity of CO2 for a photocatalytic surface, which can have a significant effect on the photocatalytic activity and CO2 reduction rates.2 to occur; understanding this relationship is critical for the advancement towards a practical global scale solar fuels technology.A class of materials capable of photocatalytically reducing CO2 reduction photocatalyst. For example, its conduction band (CB) and valence band (VB) positions on an energy band diagram straddle the H2O oxidation and CO2 reduction half reaction energies required to drive artificial photosynthetic production of hydrocarbons and carbon monoxide.2O3 has a direct “forbidden” band gap where the lowest‐energy optical transition from the top of its VB to the bottom of its CB and vice‐versa is forbidden by symmetry.2O3 have garnered interest in the field of thermally driven heterogeneous catalysis. Sun et al. have demonstrated the high activity of In2O3 towards the reverse water gas shift (RWGS) reaction at high temperatures, specifically citing CO2 capture as a key factor in enhancing the activity.Indium oxide is a material with surface, optical, and electronic properties that make it a compelling choice as a CO2O3‐x(OH)y), populated with surface hydroxides and oxygen vacancies, are investigated as a gas‐phase CO2 reduction photocatalyst. We use a temperature‐programmed thermal dehydration reaction to make In2O3‐x(OH)y nanoparticles from In(OH)3. This simple and “green” fabrication method has numerous advantages including high atom economy, ease of scale‐up, and negligible residual carbon contamination, which can block active sites and lower the overall gas‐phase adsorption capacity and catalytic activity.2O3 films for photoelectrochemical water splitting2O3‐x(OH)y nanoparticles prepared via thermal dehydration reactions at 250 °C, 350 °C, and 450 °C, in addition to crystalline In(OH)3 nanoparticles prepared from the same precursor.In this paper, hydroxylated indium oxide nanoparticles (In13C‐labelled CO2 (13CO2) as a reactant while testing the photocatalytic performance of these nanoparticles for CO2 photocatalytic activity. Light‐driven CO2 conversion rates reported in the literature are often low and the ubiquitous carbon contamination from carbon‐containing precursors, organic solvents, and organic additives that are used to control the size and morphology of the nanostructure can create false positive results, calling into question the validity of previously reported photoactivity.Although minimal amounts of organics are present in our synthesis, we still took precaution by using 2 and H2O is highly endergonic, with the majority of the energy consumed in splitting water; but vast improvements in H2O splitting systems have opened the possibilities for a sustainable and economically competitive supply of H2 as a reactant. Reactions with H2 and CO2 are thermodynamically favourable relative to those between H2O and CO2. Thus, H2 generated separately via solar‐driven water splitting can be used in the subsequent photocatalytic reduction of CO2 – such as the one described herein – to maximize the potential of the harvested sunlight. Therefore, CO2 reduction photocatalyts that operate in a H2 environment at reasonably elevated temperatures provide valuable insights into CO2 reduction mechanisms and increase the opportunity for researchers to discover components for a scalable artificial leaf.The overall reaction between CO2 reduction photocatalysts reported in the literature operate at room temperature or 80 °C for gas‐ and aqueous‐phase reactions, respectively.2 reduction photocatalyst. These moderate temperatures can easily be reached by using simple solar trough concentrators,The majority of CO13CO2 in the presence of H2 to generate 13CO at a rate as high as 0.25 μmol gcat−1 h−1 in a batch reactor at 150 °C under simulated solar illumination intensities of 2200 W m−2 on hydroxylated indium oxide nanoparticle films. We then perform the isotope tracing experiments with coupled gas chromatography‐mass spectroscopy (GC‐MS) analysis to confirm – with complete certainty – that the observed gaseous products originate from 13CO2 feedstock rather than adventitious carbon sources.13CO2 at a rate of 70 nmol gcat−1 h−1 at the same light intensity. Finally, by using a tubular flow reactor under similar conditions but with flowing CO2 and H2, the observed CO production rate can be further increased to 15 μmol gcat−1 h−1. Our results show that by combining the favourable optical and electronic properties inherent to indium oxide with a judiciously tailored surface, In2O3‐x(OH)y nanoparticles can function as an active photocatalyst for gas‐phase CO2 reduction. This study provides valuable insight about key parameters for the composition selection, materials design and performance optimization of photocatalysts suited for large‐scale solar fuels production.In this work we report gas‐phase photocatalytic conversion of 22.13 y does not occur until approximately 210 °C, only samples heated above this temperature undergo dehydration to form indium oxide.3 sample calcined at 185 °C 3 decomposes. As the calcination temperature increases further to 350 °C 3 crystalline phases. For clarity, the series of In2O3 samples prepared at the different calcination temperatures of 250 °C, 350 °C, and 450 °C will be referred to as I‐250, I‐350, and I‐450 respectively.Hydroxylated indium oxide nanoparticles were produced via a thermal dehydration of In(OH)3 Figure1. As t2O3‐x(OH)y is significantly red‐shifted in comparison to In(OH)3. These diffuse reflectance spectra were fitted with a modified Kubelka‐Munk functionF) data obtained from X‐ray photoelectron spectroscopy (XPS), we can calculate the band alignment relative to the vacuum level  just below the conduction band indicates that the as‐prepared In2O3‐x(OH)y samples are n‐type semiconductors2 reduction reactions.The optical properties of each sample were determined from the diffuse reflectance spectra shown in Figure 2.22O3‐x(OH)y samples, carbon‐13 labelled carbon dioxide (13CO2) is used as a tracer molecule to identify products from the photocatalytic reaction in the presence or absence of irradiation. This is an important step that determines whether the carbon source of the products originates from CO2 or from adventitious carbon contamination on the sample.−2 using a 1000 W metal halide bulb) and dark conditions, I‐250 produced CH4, CO, H2O and trace amounts of higher chain hydrocarbons. It was found that CH4 is produced at an average rate of 11 nmol gcat−1 hour−1 under irradiation, and was produced even in the absence of irradiation. It was also observed that the CH4 production rate decreased with subsequent batch reactions. The product ion‐fragmentation pattern obtained using GC‐MS  shows that the intensity of the 16 AMU parent peak of 12CH4 is significant, while the intensity of the 17 AMU parent peak of 13CH4 is barely above noise level. This suggests CH4 is produced by the decomposition or reaction of adventitious carbon on the surface and not from the CO2 feedstock. In contrast, it was found that CO is unequivocally a product of CO2 photocatalytic activity and is produced only under light irradiation at an average rate of 0.25 μmol gcat−1 hour−1 in batch reactors. Figure12CO and the 29 AMU parent peak of 13CO under both dark and light conditions. The absence of the 29 AMU peak in the dark and the significant increase in its intensity under irradiation demonstrates that the conversion of 13CO2 to 13CO is light driven. This finding is further confirmed by a comparison of time dependent product formation. Figure 4 production remains at near baseline levels under both dark and light conditions.In order to confirm the photocatalytic activity of the In2.32O3‐x(OH)y sample films, each loaded with 20 mg of sample and calcined at different temperatures  as well as a 20 mg In(OH)3 control sample film. The CO production rates for these samples under 80 mW cm−1 of irradiation using a 1000 W metal halide lamp at a range of reaction temperatures are shown for each sample in Figure 2 reduction rate at 150 °C for I‐250 is roughly twice that of I‐350 and approximately an order of magnitude greater than that of I‐450. The In(OH)3 control produced almost no CO at any temperature. Both I‐250 and I‐350 demonstrate an increase in photocatalytic CO production with increasing reaction temperature, reaching a maximum at 150 °C and decreasing in activity at 170 °C. Sample I‐450, on the other hand, shows an increase in reaction activity at 170 °C relative to 150 °C, in contrast to I‐250 and I‐350. Due to limitations on the maximum operating temperature of the photoreactors, the reaction was not investigated at temperatures higher than 170 °C. Alternative reactor designs are currently being investigated to understand these trends at higher temperatures. The effect of irradiation on CO production rates for each sample at different reaction temperatures is also shown in Figure S3, Supporting Information. As expected, all samples produced very little CO under dark conditions, with a maximum of 2.8 nmol gcat−1 h−1 measured at 170 °C for I‐250, demonstrating that the observed gas phase CO2 reduction is a light‐driven process.Previous studies have indicated that sample calcination temperature can have a strong effect on the aqueous‐phase photoelectrochemical performance of indium oxide nanostructures.2.42 to CO conversion is a light‐driven reaction. A single sample was used for the duration of these measurements, demonstrating the robustness of this photocatalyst.In order to determine the effect of light intensity on the CO production rate, a 20 mg I‐250 film was irradiated with a Newport 300 W Xe Lamp fitted with an AM1.5 filter to simulate the solar spectrum. The photocatalytic activity of the sample was tested at 150 °C under varying light intensities from 0.8 to 2.2 suns. Figure −2, using a focusing lens to adjust the intensity and a calibrated reference cell to measure the output. When the I‐250 sample was initially irradiated with the AM1.5 filtered light, a CO production rate of 0.20 μmol gcat−1 hour−1 was observed. The second run – with the additional 420 nm high pass filter that cut off all wavelengths with energy greater than 420 nm – produced CO at a rate of 70 nmol gcat−1 hour−1. No CO was detected when a 615 nm high‐pass filter was used. Finally, a repeat of the initial measurement using only the AM1.5 filter was conducted, reproducing the rate of 0.20 μmol gcat−1 hour−1. These results demonstrate that not only is the I‐250 capable of converting gaseous CO2 to CO using only visible light, which correlates well with the diffuse reflectance measurements, but also that In2O3‐x(OH)y is stable under these reaction conditions and can produce rates consistent with the initially measured values even after being irradiated continuously for 4 days.The spectral dependence of CO production was also investigated . A single 20 mg I‐250 film was irradiated with a Newport 300W Xe Lamp, fitted with either an AM1.5 filter or an AM1.5 filter combined with either a 420 nm or a 615 nm high‐pass filter. The light intensity was set to 1700 W m2.52O3‐x(OH)y nanoparticles revealed that under similar conditions to those in the batch photoreactors , under flowing CO2 and H2, CO is photocatalytically produced at a rate of 15 μmol gcat−1 h−1 with 24 mg (3 cm bed length) of the I‐250 nanoparticle powder sample. These rates are higher than previously reported CO production rates for other single component metal oxides; for instance 1.61 μmol gcat−1 h−1 for MgO,cat−1 h−1 for ZrO2.In an attempt to simulate more industrially relevant conditions, preliminary photocatalytic rate measurements were carried out in a tubular fixed bed flow reactor irradiated with a Newport 300W Xe lamp. This investigation of the In2.6Figure5/2 core level peak shifts to a lower binding energy as the calcination temperature is increased, indicating an increase in charge density around the In atoms as a result of the removal of OH groups. The O1s core level spectra in Figure 3 and In2O3‐x(OH)y samples. There is an approximately 2.5 eV shift to lower binding energy of the main O1s peak, from 532.7 eV for In(OH)3 to 530.2 eV for I‐450. Additionally, a shoulder peak appears in the O1s core level peak of the In2O3‐x(OH)y samples, indicating that there is more than one chemical state of oxygen present in the structure. Indeed, the O1s peak for the In2O3‐x(OH)y samples can be de‐convoluted into three distinct peaks: the main oxide peak at 530.3 eV and two additional peaks at 531.7 eV and 532.5 eV y sample was synthesized in situ within a thermogravimetric analyzer. The weight loss observed was attributed to hydroxide condensation to form bridging oxides. Figure S6, Supporting Information, shows the weight loss of each sample after calcination under air flow for 3 hours. It is clear that lower calcination temperatures correspond to less overall weight loss and result in stabilization at a higher relative weight. By comparing these plots to the theoretical maximum weight loss , it is apparent that I‐450 should have almost no hydroxides left. I‐250 and I‐350, on the other hand, have additional weight above the theoretical value, which we attribute to the retained hydroxyl groups. From this data and the Brunauer‐Emmett‐Teller (BET) surface area described below, we estimate that the surface hydroxide coverage is on the order of 6 μmol m−2 for I‐250 and 3 μmol m−2 for I‐350. It is expected that the combination of both hydroxide groups and oxygen vacancies is a key feature of our functioning In2O3‐x(OH)y nanoparticle photocatalysts and that both of these entities are present and work in concert at active sites.The hydroxide content of the samples was investigated further by both Fourier transform infrared (FT‐IR) spectroscopy and thermogravimetric measurements. The intensity of the OH stretches in the FT‐IR spectra  decreases with increasing calcination temperature, illustrating that samples treated at higher temperatures have lower hydroxide contents. In order to establish the extent of hydroxide loss during synthesis, each In2.72O3‐x(OH)y samples, the CO2 capture capacity was determined for each sample at 150 °C, the reaction temperature at which the highest CO production rates for all samples were observed. Furthermore, in order to more accurately compare the CO2 capture capacity and the photoactivity, both are normalized to the surface area of each sample, determined using the BET method. The surface areas for the In(OH)3, I‐250, and I‐350 were remarkably similar at 124.7 m2 g−1, 125.0 m2 g−1, and 129.6 m2 g−1, respectively. Only I‐450 had a significantly lower surface area at 90.0 m2 g−1, which is likely a result of some nanoparticle sintering at the higher calcination temperatures. Figure2 capture capacities for each sample plotted together with their corresponding CO production rates. There is a notable strong correlation between CO2 reduction rates and the normalized CO2 capture capacity.To clarify the observed trend in CO production rates between In2.82 has been identified in this study, as well as in others,2 capture capacity of the In2O3‐x(OH)y nanoparticles corresponds very well with photo‐reactivity, indicating that CO2 adsorption plays an important role in the light‐driven reaction. Intuitively, CO2 molecules must be able to approach and interact with the surface for a sufficient amount of time in order for electron transfer to occur. Surface hydroxides have a known affinity for the Lewis‐acidic CO2.2 capture capacity and hydroxide content. However, while the In(OH)3 control sample has the highest hydroxide content and a similar surface area to that of I‐250, it also has a significantly lower CO2 capture capacity. This indicates that surface hydroxides alone are not sufficient to facilitate CO2 capture and photocatalytic reduction of CO2.The affinity of a photocatalyst's surface for CO2O3‐x(OH)y nanoparticles is also populated with oxygen vacancies. The presence of these oxygen vacancies in the In2O3‐x(OH)y samples is supported by both the de‐convolution of the XPS O1s core level peaks y samples. The increase in oxygen vacancies for I‐250 may result from the natural increase in surface defect sites as the particle size decreases. Surface oxygen vacancies may also arise from the crystal structure of In2O3. The cubic In2O3‐x(OH)y samples have a bixbyite structure, which can be understood as the CaF2‐type lattice with 25% of the tetrahedral anion sites vacant. This additional space in the bixbyite structure may result in more dynamic flexibility, especially at the nanoparticle surface, allowing for more atomic mobility in the lattice; indeed In2O3 is a known solid ionic and protonic conductor.3 with its perovskite structure does not have a significant concentration of surface oxygen vacancies. The implied necessary combination of surface hydroxides and oxygen vacancies could provide an explanation for the stark difference in CO2 capture capacity and photocatalytic activity of In(OH)3 and I‐250.In addition to hydroxides, the surface of the Ins Figure c–e as we2 or CO under elevated reaction temperatures. In2O3 has been investigated experimentally2 or CO) and oxidizing environments . Bielz et al. have demonstrated that oxygen vacancies are generated on the surface of In2O3 in H2 environments at temperatures greater than 125 °C, as shown in Equation Surface oxygen vacancies may also form due to interactions between surface oxygen sites and H2 reduction of the surface under these reaction conditions may suggest the temperature dependence of the CO production rates for the In2O3‐x(OH)y is due to the availability of surface oxygen vacancies y surface as shown in Equation H2O, which can block active sites, may desorb enabling more turnovers at these active sites.2O3‐xOHy samples achieve a maximum efficiency at 150 °C, this may indicate that 150 °C is a “sweet spot,” combining efficient CO2 adsorption and efficient CO and H2O desorption.An alternative explanation for the observed dependence on temperature trend is the adsorption and desorption of molecules at the surface. At higher temperatures, product molecules such as H2 and the surface oxygen vacancies, as outlined in Equation 2 at elevated temperature followed by a batch reaction in CO2 yielded no trace of CO under irradiation. Thus it is believed that the observed reaction is the reverse water gas shift (RWGS) reaction as shown in Equation It is also possible that the reaction takes place between CO32 reduction photocatalyst must have surface, optical, and electronic properties working in concert for photocatalytic reduction of CO2 to occur in the gas phase. In this study the In2O3‐x(OH)y nanoparticles demonstrate activity for the photocatalytic reduction of CO2 in the presence of H2 at temperatures as low as 130 °C using both ultraviolet and visible light. Our work strongly suggests that the observed activity of In2O3‐x(OH)y samples is associated with surface populations of oxygen vacancies and hydroxides, which may act in concert as active sites for CO2 adsorption and charge transfer under simulated solar irradiation.A functional single component CO2O3‐x(OH)y materials via a temperature controlled thermal dehydration of In(OH)3. Using 13CO2 as a tracer molecule, strong light and temperature‐dependent photocatalytic reduction of gaseous 13CO2 to 13CO is confirmed in the presence of H2. The surface hydroxide and oxygen vacancy content strongly correlates with both an increase in 13CO2 capture capacity and an increase in photocatalytic activity for 13CO production. By combining the favourable surface, electronic and optical properties of nanostructured In2O3‐x(OH)y with the bixybite crystal structure and its enhanced CO2 capture capabilities, we have demonstrated a combination of key components to be considered in the discovery, optimization, and scaling of new and efficient gas‐phase CO2 reduction photocatalysts for solar fuels production.We have produced a series of nanostructured In42O3‐x(OH)y NanoparticlesSynthesis of In: An In(OH)3 precursor was synthesized and subsequently dehydrated into In2O3 nanoparticles following a modified version of a previously published procedure.Physical Characterization: Powder X‐ray diffraction (PXRD) was performed on a Bruker D2‐Phaser X‐ray diffractometer, using Cu Kα radiation at 30 kV. Nitrogen Brunauer‐Emmet‐Teller (BET) adsorption isotherms were obtained at 77 K using a Quantachrome Autosorb‐1‐C. Sample morphology was determined using a JEOL‐2010 high resolution transmission electron microscope (HR‐TEM). Fourier transform infrared spectroscopy (FT‐IR) was performed using a Perkin Elmer Spectrum‐One FT‐IR fitted with a universal attenuated total reflectance (ATR) sampling accessory with a diamond coated zinc selenide window. Diffuse reflectance of the samples was measured using a Lambda 1050 UV/VIS/NIR spectrometer from Perkin Elmer and an integrating sphere with a diameter of 150 mm. Sample weight loss during the calcination process was determined by placing approximately 10 mg of un‐calcined indium hydroxide precursor in a TA Instruments Q500 thermogravimetric analyzer, jumping to the set temperature of either 250 °C, 350 °C or 450 °C and holding for 3 hours under a flow of compressed air. The sample weight was determined using the built‐in ATI CAHN C‐34 microbalance. The film morphology and thickness was characterized by scanning electron microscopy using a QUANTA FEG 250 ESEM. The borosilicate glass microfiber filters were used as a substrate to provide increased surface area as well as mechanical stability. Figure S8, Supporting Information, shows SEM micrographs of a typical In2O3 sample on the filter. Figure S8a, Supporting Information, shows a cross‐section of the film, indicating its thickness is approximately 50 μm. The magnified image shown in Figure S8b, Supporting Information, indicates that the as‐prepared sample maintains its high porosity, an important factor for gas‐phase reactions.−9 Torr. The spectrometer uses an Al Kα X‐ray source operating at 15 kV and 27 A. The samples used in XPS analyses were prepared by drop‐casting aqueous dispersions onto p‐doped Si(100) wafers in the case of the In2O3 samples and fluorine‐doped tin oxide substrate in the case of the In(OH)3 sample. All data analyses were carried out using the Multipak fitting program and the binding energies were referenced to the NIST‐XPS database and the Handbook of X‐ray photoelectron spectroscopy.X‐ray photoelectron spectroscopy (XPS) was performed using a Perkin Elmer Phi 5500 ESCA spectrometer in an ultrahigh vacuum chamber with base pressure of 1 × 10Gas‐Phase Photocatalytic Measurements: Gas‐phase photocatalytic rate measurements were conducted in a custom fabricated 1.5 mL stainless steel batch reactor with a fused silica view port sealed with Viton O‐rings. The reactors were evacuated using an Alcatel dry pump prior to being purged with the reactant gases H2 (99.9995%) and CO2 (99.999%) at a flow rate of 6 mL min–1 and a stoichiometry of either 4:1 (stoichiometric for Sabatier reaction) or 1:1 (stoichiometric for reverse water gas shift reaction). During purging, the reactors were sealed once they had been heated to the desired temperature. The reactor temperatures were controlled by an OMEGA CN616 6‐Zone temperature controller, with a thermocouple placed in contact with the sample. The pressure inside the reactor during reaction was monitored during the reaction using an Omega PX309 pressure transducer. Reactors were irradiated with a 1000 W Hortilux Blue metal halide bulb  for a period of 16 hours. Product gases were analyzed by a flame ionization detector (FID) and thermal conductivity detector (TCD) installed in a SRI‐8610 Gas Chromatograph (GC) with a 3' Mole Sieve 13a and 6‘Haysep D column. Isotope tracing experiments were performed using 13CO2 (99.9 atomic% Sigma Aldrich). The reactors were evacuated prior to being injected with 13CO2, followed by H2. Isotope product gases were measured using an Agilent 7890A gas chromatographic mass spectrometer (GC‐MS) with a 60 m GS‐Carbonplot column fed to the mass spectrometer. The spectral dependence of the photoactivity of the In2O3 nanoparticles was investigated using a Newport 300 W Xe Lamp  fitted with a combination of AM1.5, 420 nm high‐pass and 615 nm highpass filters. Since each filter reduced the total irradiation intensity, the beam was focused using collimating lenses to maintain an irradiation intensity of 100 mW cm–2. The spectral output was measured with a StellarNet Inc spectrophotometer. Irradiation intensity was measured by a Newport 91150V calibrated reference cell and meter. Additional photocatalytic rate measurements were carried out in a borosilicate tube (3 mm outer diameter and 2.5 mm inner diameter) reactor packed with 24 mg (3 cm bed length) of In2O3‐x(OH)y nanoparticle powder. Quartz wool was used to support either end. The reactor was held in a custom designed stand. Heating was supplied from a heated copper block fixed below the fixed catalyst bed. The top of the reactor was exposed in order to allow light irradiation from a Newport 300 W Xe Lamp (at a distance of 4 cm and a light intensity of 2.2 suns). The reactor was purged with H2 (99.9995%) and CO2 (99.999%) at a flow rate of 10 mL min–1 and a stoichiometric ratio of 1:1 (stoichiometric for reverse water gas shift reaction). The reactor temperatures were controlled by an OMEGA CN616 6‐Zone temperature controller. A thermocouple was in contact with the top of the reactor so that the reactor maintained a constant temperature of 150 °C.2 Capture CapacityCO: The CO2 capture capacity of each sample was measured by thermogravimetric analysis (TGA) with a TA Instruments Q500 thermogravimetric analyzer. A desorption step was first carried out under N2 flow at a rate of 100 mL min–1 with a temperature ramp of 10 °C min–1 up to 150 °C; the temperature was held at 150 °C for 3 hours. To measure the amount of CO2 adsorption, the gas was then switched to 100% dry CO2 at a flow rate of 100 mL min–1; the temperature was then maintained at 150 °C for 10 hours. The weight gain observed during this adsorption step was used to calculate the CO2 capture capacity of the sample. Desorption of CO2 was performed by switching the gas flow back to N2 flow for 5 hours while keeping the temperature constant at 150 °C.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.


Challenges and potential solutions for the design of catalytic cathodes and interlayers in Li–S battery are discussed in detail.Lithium–sulfur (Li–S) battery has emerged as one of the most promising next‐generation energy‐storage systems. However, the shuttle effect greatly reduces the battery cycle life and sulfur utilization, which is great deterrent to its practical use. This paper reviews the tremendous efforts that are made to find a remedy for this problem, mostly through physical or chemical confinement of the lithium polysulfides (LiPSs). Intrinsically, this “confinement” has a relatively limited effect on improving the battery performance because in most cases, the LiPSs are “passively” blocked and cannot be reused. Thus, this strategy becomes less effective with a high sulfur loading and ultralong cycling. A more “positive” method that not only traps but also increases the subsequent conversion of LiPSs back to lithium sulfides is urgently needed to fundamentally solve the shuttle effect. Here, recent advances on catalytic effects in increasing the rate of conversion of soluble long‐chain LiPSs to insoluble short‐chain Li The ca2S2/Li2S to soluble LiPSs and the transformation of soluble long‐chain LiPSs to insoluble Li2S2/Li2S. Moreover, the N‐containing groups in Co‐N‐GC significantly increase its adsorption energy for Li2Sn (n = 4–8), which facilitates the oxidization of Li2S6 to S8. With a high sulfur content of 70%, the formed hybrid delivers a high specific capacity of 1670 mAh g−1 and maintains a stable cycling performance for 500 cycles under 1 C  through the thermal carbonization of a metal–organic framework as shown in Figure The above results show that metal catalysts greatly enhance the electrochemical redox reaction kinetics. More importantly, these metals have a high electronic conductivity, which leads to a significant improvement in the sulfur utilization. However, these catalysts are either costly noble metals or heavy metals, which are not favorable for practical applications. Besides, the utilization of metal catalysts needs to be further improved through increasing their active surface area according to the catalyst design principles in traditional electrochemical processes. Thus, metal catalysts that cooperate with high surface area carbon materials are more appealing candidates for high‐performance electrocatalysts in Li–S batteries.2.22 and Fe3O4, also show a catalytic effect on the conversion of LiPSs. Nazar and co‐workers reported the promoted conversion of LiPSs to insoluble Li2S2/Li2S on an ultrathin MnO2 nanosheet (NS) surface.2 NSs react with LiPSs, forming surface‐bound intermediates, and then these intermediates interact with soluble LiPSs generating polythionates and forming insoluble Li2S2/Li2S. This process is confirmed by XPS  shown in Figure −1 at a current density of C/20, and 1030 mAh g−1 after 200 cycles. However, the low conductivity of MnO2 is not beneficial in improving the sulfur utilization and rate performance, and thus the incorporation of highly conductive materials is normally needed. Cai and co‐workers reported that ultrafine La2O3 NPs decorated on a nitrogen‐doped mesoporous carbon can not only trap LiPSs, but also show catalytic effect on sulfur reduction, revealing the great potential as the sulfur host to realize high capacity and rate performance.Compared with the above metal catalysts, the low‐cost transition metal oxides, such as MnOPS Figure3c in w2O3 NPs promote the transformation of LiPSs into insoluble products and thus restraining the shuttle effect  shows stronger adsorption than a pure graphene foam (PGM), suggesting that the Fe2O3 NPs have a strong interaction with LiPSs. The cyclic voltammetry and charge/discharge profiles in Figure 2O3 NPs promote the fast conversion of soluble LiPSs to insoluble Li2S2/Li2S. With an increase in Fe2O3 content, the E2pc peak shows a higher intensity and becomes narrower, and the E2pa peak shifts to a lower potential indicating better reaction kinetics. The formed cathode material with sulfur delivers a high capacity of 565 mAh g−1 with an ultralow capacity fade of 0.049% per cycle over 1000 cycles at 5 C.Our group reported that Fect Figure4a.11 A2 and Fe3O4, Ti4O7 has a high conductivity (larger than 103 S cm−1 at room temperature) and excellent thermal stability.4O7 showed a strong chemical affinity for LiPSs and promoted the reduction of LiPSs to Li2S.4O7 and LiPSs, and the results showed that the LiPSs chemically adsorbed on the Ti4O7 host were much more easily converted into Li2S than those on the carbon surface. In other words, the Ti4O7 host produced a faster transformation process from LiPSs to Li2S avoiding their dissolution in the electrolyte. As a result, the formed hybrid (sulfur content: 60 wt%) shows good a capacity retention over 250 cycles at 0.5 C with a fade rate as low as 0.08% per cycle.Different from MnO2S2/Li2S, but most of them have poor conductivity, which increases the battery resistance and lowers the rate capability. Although Ti4O7 is more appealing due to its high conductivity, its preparation process is complex and costly. Thus, efforts need to be made to improve the conductivity of low‐cost metal oxides or coupling oxides with conducting networked substrates like carbon materials.The above studies show that some metal oxides promote the transformation of soluble LiPSs to insoluble Li2.32S2/Li2S. Pyrite cobalt disulfide (CoS2) is a typical electrocatalyst in many applications,2 exhibited a high electrocatalytic activity for polysulfide reduction in quantum dot‐sensitized solar cells.2 to a carbon/sulfur cathode in an Li–S battery,2 and LiPSs would accelerate the redox reactions of LiPSs  indicate that the current density increased by an order of magnitude as the CoS2 content increased from 0 to 30 wt%. Electrochemical impedance spectra (EIS) of the symmetrical cells  and fill up the gap of Li2S6 into S8 to complete the sulfur–LiPSs redox routes. This significantly improved the sulfur utilization and the cyclic stability. The ΔE between the charge and the discharge profiles was also greatly reduced, suggesting greatly decreased polarization and improved reaction kinetics.N‐doped carbons have been proposed as nonmetallic catalysts especially for the electrocatalysis process.3N4) has been widely investigated as a photocatalyst due to its chemical stability, tunable electronic structure, and high surface polarization.3N4 and LiPSs, which not only stabilized the cycling stability, but also increased the redox kinetics during the charge/discharge process.3N4 surface by an electrostatic interaction, and this serves as a good immobilizer for LiPSs. p‐C3N4 was integrated with reduced graphene to prepare a sulfur host, which led to a low polarization as well as a low kinetic barrier in the electrochemical redox of LiPSs.Polymeric carbon nitride  and TiN  helps achieve an effective trapping, fast diffusion, and catalytic conversion of LiPSs to insoluble Li2S2/Li2S. With loading such a heterostructure onto the graphene substrate as an interlayer structure, the assembled battery delivered high capacity retentions of 73% and 67%, respectively, for the sulfur loading of 3.1 and 4.3 mg cm−2 after 2000 cycles under 1 C. One step forward, we successfully constructed an in‐plane graphene–TiC heterostructure by the in situ growth of TiC on a graphene plane that not only acts as the 2D growth template but also a carbon source for TiC formation.Most recently, our group proposed a heterostructure design to construct a highly active interface for realizing a smooth trapping–diffusion–conversion of LiPSs toward ultralong life Li–S batteries. 52S2/Li2S is the main cause for the shuttling of LiPSs in the electrolyte, which severely reduces the energy efficiency and cycling performance. Thus, an ideal sulfur host is required to possess not only a strong affinity for LiPSs but also the ability to propel LiPSs‐Li2S2/Li2S conversion, which is expected as the ultimate remedy for suppressing the shuttle effect. This can be realized by the introduction of catalytic materials including catalytic metal‐based materials  and some metal‐free materials with catalytic activities as shown in Table2S2/Li2S.For Li–S batteries, the slow conversion between soluble LiPSs and insoluble Li(1)2S2/Li2S discharge products.The catalyst should have a high electrochemical active surface area, and thus, 2D materials with a more accessible surface and 3D materials with network structures are needed to improve the catalytic activity and efficiency. This not only decreases amount of catalyst needed in the electrode to improve the electrode energy density but also provides a large surface area to realize the uniform adsorption of LiPSs and deposition of the Li(2)2S2/Li2S also calls for highly conductive hosts to ensure good sulfur utilization and decrease the polarization.The catalyst should have high conductivity and the structure should be beneficial to ion transport on its surface because the migration and coupling of ions and electrons are necessary to realize the fast conversion of LiPSs. Besides, the poor conductivity of the sulfur and Li(3)For practical applications, low‐cost catalysts such as metal oxides are highly recommended. But due to their low conductivity, hybridization with carbons is required, and thus, the structure of these hybrid hosts needs to be further optimized to realize a high sulfur loading and high catalytic performance in the sulfide–polysulfide transformation.(4)Designing an out/in‐plane heterostructure, which is built with interfaced highly adsorptive component and catalytic component, is also an effective way to realize a smooth trapping–diffusion–conversion of LiPSs and finally obtain an ultralong life Li–S battery.Several key points for high‐efficiency catalyst design for Li–S batteries must be considered. 2S2/Li2S is key to suppressing the shuttle effect, and combining the “positive” catalytic effects with the “passive” approaches of physical and chemical confinement shows a much more promising way to solve the shuttling of LiPSs, which is expected as a final solution to the development of high performance and practical Li–S batteries.In summary, increasing the speed of transformations between the captured LiPSs and the insoluble LiThe authors declare no conflict of interest.