Subscriber access provided by UNIV OF TEXAS DALLAS
Article
Porphyrinic Metal-Organic Frameworks Installed with Brønsted Acid Sites for Efficient Tandem Semisynthesis of Artemisinin Liang Feng, Ying Wang, Shuai Yuan, Kun-Yu Wang, Jialuo Li, Gregory S. Day, Di Qiu, Lin Cheng, Wen-Miao Chen, Sherzod Madrahimov, and Hong-Cai Zhou ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04960 • Publication Date (Web): 07 Mar 2019 Downloaded from http://pubs.acs.org on March 7, 2019
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Catalysis
Porphyrinic Metal-Organic Frameworks Installed with Brønsted Acid Sites for Efficient Tandem Semisynthesis ofArtemisinin Liang Feng‡§, Ying Wang†‡⊥§*, Shuai Yuan‡, Kun-Yu Wang‡, Jia-Luo Li‡, Gregory S. Day‡, Di Qiu†, Lin Cheng†,Wen-Miao Chen‡, Sherzod T. Madrahimov∥and Hong-Cai Zhou‡#* †
College of Chemistry, Tianjin Normal University, Tianjin, 300387, China
‡
Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, United States
∥Department #
of Chemistry, Texas A&M University at Qatar, P.O. Box 23874, Doha, Qatar
Department of Materials Science and Engineering, Texas A&M University, College Station, Texas 77842, United States
⊥Key
Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), Nankai University, Tianjin 300071, China
ABSTRACT:Artemisinin, an essential antimalarial drug, requires a synthetic pathway that has a high environmental and financial cost. Conventionalhomogeneousphoto- and acid catalysts usually suffer from recycling problems that lead to dramatic decrease in catalytic activity, whilecurrent heterogeneous catalysts with low surface areas are limited by issues such as active-site accessibility and precise reaction tailorability. Herein, we report the successful installation of Brønstedacid sites into a series of porphyrinic metal-organic frameworks (MOFs) that feature large channels, high surface areas and tailored pore environments for catalysis via a post-synthetic installationstrategy. Accordingly, the resulting dualfunction solid acid/photocatalystcan be utilized for the tandem semisynthesis ofartemisinin from dihydroartemisinic acid, and demonstrates excellent catalytic performance.It is worth noting that, this dual functionalized nanoreactor acts as the most efficient catalyst for artemisinin production amongst all known homogeneous and heterogeneous photocatalysts. The facile heterogeneous catalytic system can be efficiently recycled, showing enhanced stability compared to the traditional homogeneous catalysts. The result highlights the advantage of the hierarchically porous MOF catalyst with tailored functionalities and cooperative motifs as a highly accessible and recyclable heterogeneous catalyst, providing a more efficient and recyclableapproach to drug production.
INTRODUCTION Malaria, caused by the protozoan parasite Plasmodium falciparum, has long been a major global health problem.1 In 2016, there were an estimated 216 million cases of malaria, and at least 445,000 deaths. Substantial funding of over US$ 19 billion since 2010 has been invested in the elimination and prevention of malaria, according to World Malaria Report 2017.2 The World Health Organization recommends artemisinin-based combination therapies (ACTs) as first-line drugs due to the fact that the sesquiterpene endoperoxide artemisinin is currently the most effective treatment against malaria. Artemisinin can be extracted from the plant Artemisia annua, whichconsists of about 1% artemisinin.However, the plant supply is unstable, resulting in supply deficiencies and price oscillations of the plant-derived artemisinin.3 Synthetic chemists have developed multiple routes to achieve the total synthesis of artemisinin. Yet those approaches are typically too complicated and expensive to produce significant amounts of artemisinin. An effective alternative to minimize the cost is through the semi-synthesis from a biosynthetic precursors,
artemisinic acid, which can be efficiently transformed into artemisinin through photochemical processes.4-5 This conversion involves a peroxide intermediate formed via a 1 O2 ene reaction, followed by an acid-induced Hock cleavage and a cyclization cascade.6 This cascade acidand photo-catalysed route has been successfully demonstrated with multi-functional immobilized catalysts. However, these previously reported catalysts are restricted to nonporous immobilized catalysts, which limits the levels of active site incorporation, as well as prevents the positive influence of sorptive capacities.610 This feature of the nonporous catalysts impeded reactant difussion thereby limiting active-site accessibility and catalytic activity. Furthermore, the precise tunability of the reaction environment of the surface catalysts are limited, which hampers further rational optimization of the catalysts. Porous catalysts with tailored pore environments are highly desired in heterogeneous catalysis due to the high tunability of their pore sizes and functionalization.11 Among porous catalysts, metal-organic frameworks (MOFs) have become well-known for their designable topology, adjustable porosity, tunable functionality, and
ACS Paragon Plus Environment
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
variable surface moieties, all as a result of their high crystallinity.12-14 Synergistic effects originating from the precisely controlled apportionment of specific functional groups in the proper proximity are especially expected to improve the efficiency of cascade catalysis.15-16 In order to design recyclable MOF catalysts with molecularly-defined catalytic motifs for the acid- and photo-catalysed preparation of artemisinin, three prerequisites should be considered: 1) the MOF should contain Brønsted-acid sites, either on the linkers or the clusters of the framework;17-19 2) the MOF should be stable in acidic environments;20-21 3) the MOF should contain effective photosensitizers for 1O2 generation, such as porphyrinic units.22-25Herein, we rationally designed a series of MOF catalysts, PCN-22X-SO4 (X =2, 3 and 4) on the basis of the aforementioned considerations. Taking advantage of the defective nature of Zr-based MOFs, Brønstedacid sites are post-synthetically anchored on the coordinatively unsaturated sitesof a porphyrinic MOF for the first time, which further allows the efficient tandem semisynthesis of artemisinin within the acidic channels. By treating acid-stable zirconium-porphyrinicPCN-22X with aqueous sulfuric acid, their sulfate installed analogues, PCN-22X-SO4, were obtained and studied for their activity and recycability in the photochemical synthesis of artemisinin.
EXPERIMENTAL SECTION Synthesis of PCN-222. PCN-222(No Metal) was synthesized on the basis of previous reports with slight modifications.12ZrCl4 (70 mg), TCPP (tetrakis(4carboxyphenyl)porphyrin, 50 mg) and benzoic acid (2700 mg) in N,N-diethylformamide (8 mL) were ultrasonically dissolved in a 20 mL Pyrex vial. The mixture was heated at 120 °C in an oven for 48 h. After cooling down to room temperature, needle-shaped crystals were harvested by filtration. Synthesis of PCN-222(M, M = Ni, Co and Zn). PCN222(M) was synthesized on the basis of previous reports with slight modifications.12 ZrCl4 (70 mg), TCPP-M (50 mg) and benzoic acid (2700 mg) in N,N-diethylformamide (8 mL) were ultrasonically dissolved in a 20 mL Pyrex vial. The mixture was heated at 120 °C in an oven for 48 h. After cooling down to room temperature, needle-shaped crystals were harvested by filtration. Synthesis of PCN-222-SO4.As-synthesized PCN222(No Metal) was immersed in anhydrous DMF for two days followed by water for two days. About 50 mg of water exchanged PCN-222 was immersed in 5 mL of various concentrations (0.005, 0.01, 0.02, 0.05, 0.10, 0.20, 1.00 and 2.00 M) of sulfuric acid for 24 h. The solution was then decanted and the remaining solid material was then exchanged with 50 mL water for two days, and then quickly exchanged with anhydrous acetone and chloroform several times. The chloroform-exchanged samples were then activated under dynamic vacuum for 24 h at 150 oC.
Synthesis of PCN-222(Ni)-SO4. As-synthesized PCN222(Ni) was immersed in anhydrous DMF for two days followed by water for two days. About 50 mg of water exchanged PCN-222(Ni) was immersed in 5 mL of 0.005 M sulfuric acid for 24 h. The solution was then decanted and the remaining solid material was then exchanged with 50 mL water for two days, and then exchanged with anhydrous acetone and chloroform several times. The chloroform-exchanged samples were then activated under dynamic vacuum for 24 h at 150 oC. Gas adsorption measurements. Gas adsorption measurements were conducted using a Micrometritics ASAP 2020 system. Before gas sorption experiments, MOF samples were washed with DMF and exchanged with acetone for 3 days, during which the solvent was decanted and replenished with fresh solvent daily. The solid was dried under vacuum at 100oC for 10 h, yielding a porous material. Thermogravimetric analysis. For thermogravimetric analysis, about 10 mg of the sample was heated on a TGA/DSC1 (Mettler-Toledo) thermogravimetric analyzer from room temperature to 700 °C at a rate of 5 °C·min -1 under N2 flow of 50 mL·min-1. Powder X-ray diffraction (PXRD). PXRD was carried out with a Bruker D8-Focus Bragg-Brentano X-ray Powder Diffractometer equipped with a Cu sealed tube (λ = 1.54178 Å) at 40 kV and 40 mA. 1
H NMR spectroscopy. Nuclear magnetic resonance (NMR) data were collected onan Inova 500 MHz spectrometer. For 1H NMR spectroscopy, the activated samples (around 10 mg) were dissolved in 600 µL DMSO-d6 solution containing 20 µL HF. Scanning electron microscopy(SEM). SEM was performed on FEI Quanta600 FE.SEM-EDX images and analyses were taken with a FEI Quanta 600 FE-SEM. The Quanta 600 FEG is a field emission scanning electron microscope capable of generating and collecting highresolution and low-vacuum images. Source: Field emission gun assembly with Schottky emitter source. Voltage: 200 V to 30 kV. Beam Current: >100 nA. Transmission electron microscopy (TEM). TEM imaging was performed with FEI Tecnai G2 F20 ST FE-TEM Materials (200 kV) with Gatan CCD. The same instrument was used to collect energy dispersive X-ray spectra (EDX) and STEM images on a Fischione ultrahigh-resolution STEM HAADF detector. Raman scattering spectrum.Raman scattering spectrum was carried out to study the compositions of PCN222-SO4 by using Witec Alpha300 R confocal Raman Microscope. UV-Vis spectroscopy andFourier transform infrared (IR). The UV-vis absorption spectra were recorded on a Shimadzu UV-2450 spectrophotometer.IR measurements were performed on a SHIMADZU IR Affinity-1 spectrometer.
ACS Paragon Plus Environment
Page 2 of 9
Page 3 of 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Catalysis
Figure 1. Structural comparison between PCN-224, 222 and 223. (a-c) Illustration of three porphyrinicZr-MOFs. (d-f) Corresponding Zr6 clusters (6-, 8- and 12-connected, respectively) found in PCN-224, 222 and 223.
Hammett Indicator Tests. All Hammett indicator tests were performed in an inert atmosphere glovebox. A set of Hammett indicator solutions (0.5 wt%) were prepared by dissolving Hammett indicators in anhydrous benzene. During testing, 5 mL Hammett indicator solution was added to 10 mg of activated PCN-222, PCN-222SO4, PCN-222(Ni)-SO4sample in a 20-mL glass vial. The suspension was swirled every 30 mins, and after 8 h the color of the solid was then recorded. Photocatalytic oxidation of dihydroartemisinic acid to artemisinin. The synthesis of artemisinin was conducted using PCN-222(M, M = H2, Ni, Co and Zn)-SO4 samples as recyclable photocatalysts under visible light in the presence of O2. In a typical reaction, dihydroartemisinic acid (25 mg, 0.106 mmol) and the MOF catalysts (0.002 mmol based on the porphyrin) were dispersed in dichloromethane (5 mL) and slowly bubbled with O2 under the irradiation of LED lamps (150 W) at 5-10°C for 6 hours. After the removalof dichloromethane, conversion and selectivity to artemisinin was measured by 1H-NMR in CDCl3 using biphenyl (16.3 mg, 0.106 mmol) as an internal standard.
RESULTS AND DISCUSSION Stability screening of sulfate installed porphyrinicMOFs. PCN-22X represents three zirconiumporphyrinic frameworks that show outstanding chemical stability under aqeous conditions at various pH values. They are all constructed from Zr6 clusters and tetratopic TCPP linkers, but with different cluster connectivities and linker configurations (Figure 1).12, 26-27 For example, in the crystal structure of PCN-222, each Zr6 cluster [Zr6(μ3O)4(μ3-OH)4(OH)4(H2O)4(COO)8] is linked to eight TCPP units to form a hierarchically porous framework with csq topology, while in the structure of PCN-223 and 224, each
cluster is linked to six and twelve linkers, respectively. To assess the acid stability of the aforementioned MOFs, they were immersed indifferent concentrations (0.005-2.0 M) of aqueous sulfuric acid for 24 h. As indicated by the PXRD patterns, PCN-224 shows the lowest acid stability, most likely due to the highly defective Zr6 clusters in the framework being prone to attack by water molecules (Figure S3). In contrast, the less defective or nondefective Zr6 based PCN-222 and 223 exhibit better acid stability, maintaining crystallinity when immersed in a 0.20 M sulfuric acid solution (Figure 2f, S4-5). However, when considering the acid uptakes of the MOF supports, more defective structures are desired since the coordinatively unsaturated sites are supposed to hold more SO42- species in the framework. Therefore, PCN-222 presents an excellent candidate for the photochemical synthesis of artemisinin, not to mention that the 3.2 nm channels in PCN-222 will benefit the diffusion of reactants and products during the catalytic reaction. Characterization of acidicporphyrinicPCN-222SO4.After sulfate installation, no notable changes in crystal shape were observed. According to optical microscopy (Figure 2b),transmission electron microscopy (TEM,Figures 3a) and scanning electron microscopy (SEM, Figures S7-12), the needle PCN-222-SO4 microcrystals remained in good condition, with the supernatants of the acid solutions after sulfate incorporation remaining colorless, indicating the high stability of PCN-222 insulfuric acid solutions. TEM and SEM coupled with energy-dispersive X-ray (EDX) analysis indicated that the amount of SO42- found in PCN-222-SO4 increased as the concentration of the mother solution increased (Figures 3a, S7-12, Table S1).This is consistent with thermogravimetric analysis (TGA) results, which confirmed the in-
ACS Paragon Plus Environment
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
creased amount of adsorbed sulfate as estimated by the weight loss around 300oC (Figure 2g). The successful coordination of sulfate groups on the Zr clusters can be confirmed by the DRIFTS spectra. As indicated by Figure 3b, before sulfate acid treatment, the PCN-222 with only OH groups on the defective Zr6 clusters have IR absorption bands from the terminal OH around 3667 cm-1, while these Zr-OH peaks disappear after acid treatment, indicating that the sulfates
substitute on the Zr6clusters. In addition, peaks corresponding to the asymmetric stretching (νas) and bending (νab) of SO42- groups were observedat 1108 cm-1 and 621 cm1 in PCN-222-SO4, while these peaks were not observed in spectra of baseline PCN-222. The successful incorporation of Brønstedacids and protonation on TCPP linkers in PCN-222-SO4 can also be examined by Raman scattering spectrum (Figure 3c, Table S3).As indicated by Figure 3c, at an excitation light
Figure 2. Structural illustration of PCN-222 and PCN-222-SO4. (a) Optical images of PCN-222 andPCN-222-SO4; (b) The high chemical stability of PCN-222 as indicated by treatment under various concentrations of aqueous H2SO4; (c) Sulfate 2installation process on PCN-222 with SO4 cooridnated on the Zr6 clusters and trapped within the pores; (d) N2 sorption isotherms, (e) pore size distributions and (f) PXRD patterns of PCN-222 and PCN-222-SO4 soaked in 0.005, 0.01 and 0.1 mol/L H2SO4 solution, respectively; (g) TGA plots of PCN-222 and PCN-222-SO4.
ACS Paragon Plus Environment
Page 4 of 9
Page 5 of 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Catalysis of 532 nm, bands at ~1030 cm-1 can be observed in PCN222-SO4, which can be attributed to SO3 symmetric stretch of HSO4-. With increase of concentrations of sulfuric acid, the intensities of HSO4- stretch peaks are boosted, which is consistent with elemental analysis results (Table S2). Raman bands at ~1187 cm-1 and ~1364 cm1 belong to pyrrole ring deformation. C-C stretching at ~1480 cm-1 and 1620 cm-1 show a slight shift with increasing acid concentration, corresponding to theprotonation on porphyrin ligands. The precise illustration on the placement of Brønstedacid sites inside defective Zr-MOFs have been reported very recently by Yaghi and coworkers, showing the important role of the arrangement of adsorbed water and sulfate
moieties on Zr6 clusters.28 Interestingly, as shown in the example of superacidicMOF-808-SO4, sulfate incorporation within the MOFs results in almost identical porosities.29 However, after sulfate incorporation into PCN-222, the N2 uptakes and overall porosity of PCN-222 decreased as a function of increased H2SO4 concertration. This can be attributed to the protonation of porphyrinic linkers, leading to more trapped SO42- species inside the channels. The charge interaction between protoned TCPP and SO42- anions makes these trapped species difficult to remove, leading to a decrease in the N2 uptakes, along with a smaller mesopore volume, while sulfate incorporation in MOF808 causes nearly no changes on the porosity. This TCPP protonation can be easily distinguished by the color change from purple to green after acid treatment (Figure 2a). The formula of the acidified PCN-222 is calculated based on the elemental analysis of digested samples. The total amount of coordinated and trapped sulfate in PCN222-SO4 was determined and listed in Table S2. To further study the acidity of PCN-222-SO4, the Hammett indicator method was utilized. We found PCN-222-SO4 displayed moderate acidity (−0.2 ≥ H0 ≥ −5.9) while no acidity was observed for PCN-222, demonstrating the successful installation of Brønstedacid sites in porous photocatalysts (Table S4). Sequential photochemical synthesis ofartemisinin by dual functionalPCN-222. Encouraged by these results, we choose PCN-222 soaked in 0.005 M sulfuric acid, denoted as PCN-222-0.005M, to investigate the catalytic performance of the material in the photocatalytic synthesis of artemisinin. The synthesis of artemisinin was conducted using PCN-222-0.005M as a recyclable photo- and acid catalyst under visible light in the presence of O2. Remarkably, compared to the reported most effective homogeneous catalyst, [Ru(bpy)3]Cl2/TFA (trifluoroacetic acid), PCN-222-0.005M shows almost full conversion and comparable yield of targeted product 1 (Table 1, entry 1 and 4). It should be noted that the selectivity of this photo- and acid catalysis is always limited to 50 to 60% after optimization due to the inevitableformation of byproducts during the 1O2 ene step (Figure 4a).
Figure 3. Characterization of the presence of sulfate in PCN-222. (a)TEM image, corresponding TEM-EDXelemental mapping and high-angle annular dark-field scanning transmission electron microscopy (HAADF STEM) images of PCN-222-0.005M. (b)The full DRIFTS spectra of PCN-222 ACS Paragon with and without sulfate acid treatment. (c) Raman spectra Plus Environment of PCN-222 and PCN-222-0.005M (all spectra were normalized for clarity).
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 6 of 9
selectivity (Table 1, entry 4, 5 and 6). The PXRD patterns confirm that catalyst crystallinity is well-maintained after catalysis (Figure S27). To study whether there is a leaching of catalytic species, we collected the UV-vis spectra of the reaction supernatants, with no TCPP observed in the solution after catalysis(Figure S19). SEMEDX mapping of PCN-222-SO4 after catalysis show similar Zr to S ratio, indicating there is no notable SO42- leaching from the system during the catalysis. A hot filtration test was further conducted to verify the heterogeneous nature of the catalytic process during the reaction (Figure S26). In contrast to the highly active PCN-222-0.005M, PCN223-0.005M showed a much lower yield of the targeted artemisinin, mainly because of limited pore sizes and restricted substrate diffusion (Table S5, entry 9). In addition, in absence of coordinatively unsaturated sites, PCN223 is unable to immobilize H2SO4 effectively, as such decreased yields of artemisinin were observed during subsequent cycles (Table S5, entry 10 and 11).
Figure 4. Semi-synthetic photochemical preparation of artemisinin (1) by recyclable and efficient PCN-222-SO4. (a)Reaction mechanism of photocatalytic oxidation of dihydroartemisinic acid to artemisinin; (b)Illustrationof the sequential catalytic process within mesoporous channels of photosensitive and acidic PCN-222-SO4.
Recyclability and stability of the combined photo-/acid catalyst are the vital performance metrics of drug production. As one of the most stable MOF materials, this heterogeneous bifunctional catalyst can be utilized for the photooxidation of dihydroartemisinic acid for at least 3 cycles without any noticeable decrease in activity or
It should be noted that the homogenous molecular catalyst, H4TCPP/TFA, has a much lower yield as compared with the PCN-222-0.005M (Table 1, entry 2, 4), possibly because PCN-222-SO4 exhibits a better ability to concentrate the reactants inside the channels, as well as provide a more acidic environments for the conversion. Similar phenomena have also been observed in other photocatalytic systems.30 In comparison, PCN-222 without acid can initiate the 1O2 ene step of 2, however, it cannot proceed further to 1 without the addition of acid, indicating the important cooperative role of acid during the catalysis. Further increasing the H2SO4 concentration in PCN-222 is unnecessary, as the second step, the acidinduced Hock cleavage, does not consume H+; therefore, PCN-222-0.005M, 0.01M and 0.1M show comparable conversion and yield (Table 1, entry 4, 7 and 8). MOF catalysts present as a highly tunable platform for sequential catalytic conversion. To further improvearte-
Table 1. Synthesis of artemisinin (1) from dihydroartemisinic acid (2) using different photocatalysts.a Conversion Entry Catalyst Solvent (%)b
Yield (%)b
1
[Ru(bpy)3]Cl2/TFA
THF:H2O
98
55
2
H4TCPP/TFA
CH2Cl2
98
35
3
PCN-222
CH2Cl2
54
0
4
PCN-222-0.005M
5
CH2Cl2
98
53
c
CH2Cl2
98
51
c
PCN-222-0.005M-C1
6
PCN-222-0.005M-C2
CH2Cl2
98
50
7
PCN-222-0.01M
CH2Cl2
98
52
8
PCN-222-0.1M
9 10 11
CH2Cl2
98
52
d
CH2Cl2
98
71
d
CH2Cl2
98
65
d
CH2Cl2
97
61
PCN-222(Ni)-0.005M
PCN-222(Zn)-0.005M
PCN-222(Co)-0.005M
a
Generally, dihydroartemisinic acid (25 mg, 0.106 mmol), MOF catalyst (4 mg, 0.002 mmol based on porphyrin) were dispersed in dichloromethane (5 mL)
and slowly bubbled with O2 under the irradiation of LED lamps (150 W) at 5-10°C for 6 h. bReaction conversions and yields were monitored by 1H-NMR using biphenyl as an internal standard.cCatalyst cycling performance. dReaction completed within 5 h instead of 6 h.
ACS Paragon Plus Environment
Page 7 of 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Catalysis misininsemisynthesis yields, the first step involving single oxygen from 2 to 3 should be optimized to eliminatethe possible formation of side products. Considering the feasibility of tuning metal substitutes in porphyrin linkers of PCN-222(M)-0.005M, we further studied the influence of metal substitutes on overallsemisynthesis ofartemisinin (Figure 5a, Table 1, entry 9, 10 and 11).It has been reported that TCPP-Ni based MOFs manifest higher photoreaction kinetics compared to TCPP-H2 based MOFs.30-31Thefaster generation of 1O2by TCPP-Ni based PCN-222(Ni) was also supported by the photocatalytic
[4+2] cycloaddition of anthracene (Figure S18). As such, we prepared a PCN-222(Ni)-0.005M catalyst which contains TCPP-Ni units with the aim of improving artemisinin yield. Remarkably, PCN-222(Ni)-0.005M exhibits faster kinetics for the conversion of 2, achieving 63% conversion within 1 h, while PCN-222-0.005M can only achieve 15% conversion after 1 h (Figures 5b-c, Table S6). More importantly, the accelerated1O2 ene step could possibly limit the formation of byproducts (Figure 4a), leading to an overall artemisinin yield of 71% within 5 h (Figure 5,Table 1, entry 4 and 9). The high activity and selectivity was well-maintained within at least six catalytic runs (Figure S25). These results make PCN222(Ni)-0.005M stand out as the most efficient catalyst among all homogenous and heterogeneous catalysts. Moreover, it highlights the advantage of hierarchically porous MOF catalysts with tailored functionalities and cooperative motifs as highly accessible and recyclable heterogeneous catalysts (Figure 4b). In conclusion, we report the first highly porous dualfunctional catalyst for the tandem semisynthesis of artemisinin. Through a post-synthetic installation strategy, catalytic Brønstedacidic sites are anchored inside the mesoporous channels of porphyrinic MOFs. The tailored pore environment and enhanced cooperativity within one channel during catalytic conversion make the material the most efficient catalyst for tandem semisynthesis of artemisinin, showing enhanced selectivity, recyclability and stability even compared with conventional homogeneous catalysts. The strategy therefore paves a way for developing MOF catalyst as a new paradigm for drug production.
ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: xxxxxxx. Materials and methods, synthesis and characterization, andcatalytic experiment details (PDF).
AUTHOR INFORMATION §
These authors contributed equally to this work.
Corresponding Author *
[email protected] *
[email protected] Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT The catalytic part of this research is supported by NPRP award NPRP9-377-1-080 from the Qatar National Research Fund.The gas adsorption-desorption studies of this research were supported by the Center for Gas Separations, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Award Number DESC0001015. Structural analyses were supported by the Robert A. Welch Foundation through a Welch Endowed
Figure 5. Optimization ofartemisininsemisynthesisyields.(a) Tunability of metal substitutes inporphyrin linkers of PCN-222(M)-0.005M. Conversion/Yield vs. time graphs ACS Paragon for the photochemical synthesis of artemisinin fromPlus Environment dihydroartemisinic acid catalyzed by PCN-222-0.005M (b) and PCN-222(Ni)-0.005M (c).
ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Chair to HJZ (A-0030). The authors also acknowledge the financial supports of U.S. Department of Energy Office of Fossil Energy, National Energy Technology Laboratory (DE-FE0026472) and National Science Foundation Small Business Innovation Research (NSF-SBIR) under Grant No. (1632486), National Natural Science Foundation of China (21471113), Training Program of Outstanding Youth Innovation Team of Tianjin Normal University, National Top-Level Talent Training Program of Tianjin Normal University, Training Program of Young and middle-aged Innovative Talent and Backbone, Tianjin "131" Innovative Talent, 111 project (B12015), Opening Fund of Key Laboratory of Advanced Energy Materials Chemistry (Ministry of Education), Nankai University and the Innovation Team Training Plan of the Tianjin Education Committee (TD135073).Parts of chemicals in this work are provided by CSN pharm. We acknowledge the experimental assistance and discussion from Mr. Sheng-Xiang Wu and Dr. Matthew Sheldon.
REFERENCES 1. Ro, D. K.; Paradise, E. M.; Ouellet, M.; Fisher, K. J.; Newman, K. L.; Ndungu, J. M.; Ho, K. A.; Eachus, R. A.; Ham, T. S.; Kirby, J.; Chang, M. C. Y.; Withers, S. T.; Shiba, Y.; Sarpong, R.; Keasling, J. D., Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 2006,440 (7086), 940-943. 2.World malaria report 2017, World Health Organization,Geneva,2017. 3. Schmid, G.; Hofheinz, W., Total Synthesis of Qinghaosu. J Am Chem Soc 1983,105 (3), 624-625. 4. Burgard, A.; Gieshoff, T.; Peschl, A.; Horstermann, D.; Keleschovsky, C.; Villa, R.; Michelis, S.; Feth, M. P., Optimisation of the photochemical oxidation step in the industrial synthesis of artemisinin. Chem. Eng. J. 2016,294, 83-96. 5. Turconi, J.; Griolet, F.; Guevel, R.; Oddon, G.; Villa, R.; Geatti, A.; Hvala, M.; Rossen, K.; Goller, R.; Burgard, A., Semisynthetic Artemisinin, the Chemical Path to Industrial Production. Org. Process Res. Dev. 2014,18 (3), 417-422. 6. Amara, Z.; Bellamy, J. F. B.; Horvath, R.; Miller, S. J.; Beeby, A.; Burgard, A.; Rossen, K.; Poliakoff, M.; George, M. W., Applying green chemistry to the photochemical route to artemisinin. Nat. Chem. 2015,7 (6), 489-495. 7. Levesque, F.; Seeberger, P. H., Continuous-Flow Synthesis of the Anti-Malaria Drug Artemisinin. Angew. Chem. Int. Ed.2012,51 (7), 1706-1709. 8. Paddon, C. J.; Westfall, P. J.; Pitera, D. J.; Benjamin, K.; Fisher, K.; McPhee, D.; Leavell, M. D.; Tai, A.; Main, A.; Eng, D.; Polichuk, D. R.; Teoh, K. H.; Reed, D. W.; Treynor, T.; Lenihan, J.; Fleck, M.; Bajad, S.; Dang, G.; Dengrove, D.; Diola, D.; Dorin, G.; Ellens, K. W.; Fickes, S.; Galazzo, J.; Gaucher, S. P.; Geistlinger, T.; Henry, R.; Hepp, M.; Horning, T.; Iqbal, T.; Jiang, H.; Kizer, L.; Lieu, B.; Melis, D.; Moss, N.; Regentin, R.; Secrest, S.; Tsuruta, H.; Vazquez, R.; Westblade, L. F.; Xu, L.; Yu, M.; Zhang, Y.; Zhao, L.; Lievense, J.; Covello, P. S.; Keasling, J. D.; Reiling, K. K.; Renninger, N. S.; Newman, J. D., High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 2013,496 (7446), 528-532. 9. Tambosco, B.; Segura, K.; Seyrig, C.; Cabrera, D.; Port, M.; Ferroud, C.; Amara, Z., Outer-Sphere Effects in Visible-Light Photochemical Oxidations with Immobilized and Recyclable Ruthenium Bipyridyl Salts. ACS Catal. 2018,8 (5), 4383-4389. 10. Triemer, S.; Gilmore, K.; Vu, G. T.; Seeberger, P. H.; SeidelMorgenstern, A., Literally Green Chemical Synthesis of
Artemisinin from Plant Extracts. Angew. Chem. Int. Ed.2018,57 (19), 5525-5528. 11. Lee, J.; Farha, O. K.; Roberts, J.; Scheidt, K. A.; Nguyen, S. T.; Hupp, J. T., Metal-organic framework materials as catalysts. Chem. Soc. Rev.2009,38 (5), 1450-1459. 12. Feng, D. W.; Gu, Z. Y.; Li, J. R.; Jiang, H. L.; Wei, Z. W.; Zhou, H. C., Zirconium-Metalloporphyrin PCN-222: Mesoporous Metal-Organic Frameworks with Ultrahigh Stability as Biomimetic Catalysts. Angew. Chem. Int. Ed.2012,51 (41), 10307-10310. 13. Kirchon, A.; Feng, L.; Drake, H. F.; Joseph, E. A.; Zhou, H. C., From fundamentals to applications: a toolbox for robust and multifunctional MOF materials. Chem. Soc. Rev.2018,47, 86118638. 14. Furukawa, H.; Muller, U.; Yaghi, O. M., "Heterogeneity within Order" in Metal-Organic Frameworks. Angew. Chem. Int. Ed.2015,54 (11), 3417-3430. 15. Yuan, S.; Qin, J. S.; Li, J. L.; Huang, L.; Feng, L.; Fang, Y.; Lollar, C.; Pang, J. D.; Zhang, L. L.; Sun, D.; Alsalme, A.; Cagin, T.; Zhou, H. C., Retrosynthesis of multi-component metal-organic frameworks. Nat. Commun. 2018,9, 808. 16. Zhang, L. L.; Yuan, S.; Feng, L.; Guo, B. B.; Qin, J. S.; Xu, B.; Lollar, C.; Sun, D. F.; Zhou, H. C., Pore-Environment Engineering with Multiple Metal Sites in Rare-Earth Porphyrinic Metal-Organic Frameworks. Angew. Chem. Int. Ed.2018,57 (18), 5095-5099. 17. Jiang, J.; Yaghi, O. M., Brønsted acidity in metal–organic frameworks. Chem.Rev.2015,115 (14), 6966-6997. 18. Miao, Z. C.; Zhou, Z. H.; Tang, H. L.; Yu, M. D.; Ramella, D.; Du, X.; Luan, Y., Homodimerization of 2H-chromenes catalyzed by BrOnsted-acid derived UiO-66 MOFs. Catal. Sci. Technol. 2018,8 (13), 3406-3413. 19. Xu, C. Y.; Sun, K. J.; Zhou, Y. X.; Ma, X.; Jiang, H. L., Light-enhanced acid catalysis over a metal-organic framework. Chem. Commun. 2018,54 (20), 2498-2501. 20. Bai, Y.; Dou, Y. B.; Xie, L. H.; Rutledge, W.; Li, J. R.; Zhou, H. C., Zr-based metal-organic frameworks: design, synthesis, structure, and applications. Chem Soc Rev 2016,45 (8), 23272367. 21. Yuan, S.; Feng, L.; Wang, K.; Pang, J.; Bosch, M.; Lollar, C.; Sun, Y.; Qin, J.; Yang, X.; Zhang, P.; Wang, Q.; Zou, L.; Zhang, Y.; Zhang, L.; Fang, Y.; Li, J.; Zhou, H. C., Stable Metal-Organic Frameworks: Design, Synthesis, and Applications. Adv. Mater. 2018, 30, 1704303. 22. Ghogare, A. A.; Greer, A., Using Singlet Oxygen to Synthesize Natural Products and Drugs. Chem. Rev.2016,116 (17), 9994-10034. 23. Park, J.; Feng, D. W.; Yuan, S.; Zhou, H. C., Photochromic Metal-Organic Frameworks: Reversible Control of Singlet Oxygen Generation. Angew. Chem. Int. Ed.2015,54 (2), 430-435. 24. Chen, Y. Z.; Jiang, H. L., Porphyrinic Metal-Organic Framework Catalyzed Heck-Reaction: Fluorescence "Turn-On" Sensing of Cu(II) Ion. Chem. Mater. 2016,28 (18), 6698-6704. 25. Farha, O. K.; Shultz, A. M.; Sarjeant, A. A.; Nguyen, S. T.; Hupp, J. T., Active-Site-Accessible, Porphyrinic Metal-Organic Framework Materials. J. Am. Chem. Soc.2011,133 (15), 56525655. 26. Feng, D. W.; Gu, Z. Y.; Chen, Y. P.; Park, J.; Wei, Z. W.; Sun, Y. J.; Bosch, M.; Yuan, S.; Zhou, H. C., A Highly Stable Porphyrinic Zirconium Metal-Organic Framework with shp-a Topology. J. Am. Chem. Soc.2014,136 (51), 17714-17717. 27. Feng, D. W.; Chung, W. C.; Wei, Z. W.; Gu, Z. Y.; Jiang, H. L.; Chen, Y. P.; Darensbourg, D. J.; Zhou, H. C., Construction of Ultrastable Porphyrin Zr Metal-Organic Frameworks through Linker Elimination. J. Am. Chem. Soc.2013,135 (45), 1710517110.
ACS Paragon Plus Environment
Page 8 of 9
Page 9 of 9 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ACS Catalysis 28. Trickett, C. A.; Popp, T. M. O.; Su, J.; Yan, C.; Weisberg, J.; Huq, A.; Urban, P.; Jiang, J.; Kalmutzki, M. J.; Liu, Q., Identification of the strong Brønsted acid site in a metal–organic framework solid acid catalyst. Nat.Chem.2019, 11, 170-176. 29. Jiang, J. C.; Gandara, F.; Zhang, Y. B.; Na, K.; Yaghi, O. M.; Klemperer, W. G., Superacidity in Sulfated Metal-Organic Framework-808. J. Am. Chem. Soc.2014,136 (37), 12844-12847. 30. Liu, Q.; Cong, H. J.; Deng, H. X., Deciphering the Spatial Arrangement of Metals and Correlation to Reactivity in
Multivariate Metal-Organic Frameworks. J. Am. Chem. Soc.2016,138 (42), 13822-13825. 31. Chen, Y. Z.; Wang, Z. U.; Wang, H. W.; Lu, J. L.; Yu, S. H.; Jiang, H. L., Singlet Oxygen-Engaged Selective Photo-Oxidation over Pt Nanocrystals/Porphyrinic MOF: The Roles of Photothermal Effect and Pt Electronic State. J. Am. Chem. Soc.2017,139 (5), 2035-2044.
Table of Contents
ACS Paragon Plus Environment
