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New fluorous gelators for perfluorodecalin
Journal of Fluorine Chemistry 222–223 (2019) 24–30
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New fluorous gelators for perfluorodecalin Hiroki Miyajima, Maria Carmelita Z. Kasuya, Kenichi Hatanaka
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Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
ARTICLE INFO
ABSTRACT
Keywords: Gelator Fluorous gel Anthraquinone Perfluorodecalin Cell culture
Fluorous gels of perfluorodecalin (PFD) were prepared using chemically synthesized fluorous gelators. To enhance the fluorophilicity of gelators, fluoroalkyl chains were introduced to the alkyl chains of known gelators. The synthesized fluoroalkyl-containing anthraquinone formed gels of PFD. The prepared gel of PFD was used for cell culture and the cytotoxicity of the gel was assessed in view of its potential biomedical application.
1. Introduction Fluorous solvents are fluorophilic. They are immiscible with water or organic solvents. Fluorous solvents dissolve oxygen 20–25 times as much as water, and can function as potential oxygen carriers [1]. In biomedical engineering, these solvents have been applied for liquid breathing [2], and as blood substitute in vivo [3]. To utilize the dissolved oxygen in fluorous solvents, cell culture has also been carried out in the presence of the solvent to serve as an oxygen supplier [4]. As a fluorous solvent for biological use, perfluorodecalin (PFD) has been widely studied because of its low cytotoxicity [5]. PFD is a cyclic perfluorocarbon as shown in Fig. 1A. Owing to the solubility of oxygen and biological inertness, PFD has been applied for cell culture [5] or organ preservation [6]. Gels of PFD have also been investigated for application as material [7]. Gels have been studied as cell scaffold in biological field [8]. The sol-gel transition of physical gels that were prepared using low-molecular mass gelator (LMMG) can be controlled with external stimuli [9]. Gelation of LMMGs occurred through intermolecular interactions such as hydrogen bonding, van der Waals forces or π-π stacking. Some compounds containing anthracene moiety (Fig. 1C) or anthraquinone moiety (Fig. 1D) are known as LMMGs for organic solvent such as ethanol and n-heptane [10]. In our previous research, fluorous gel of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-1-heptanol (DFH, Fig. 1B) was prepared by using 2,3-di-n-decyloxyanthracene (DDOA, Fig. 1C) [11] which is known gelator having anthracene moiety and long alkyl chains. The previous study showed that DDOA formed fluorous gels only when fluoroalkylated alcohols and esters were used as fluorous solvent. When PFD was used as a fluorous solvent, the gelator did not dissolve in PFD and gelation did not occur [11]. This might be due to
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the low affinity of the gelator to PFD. To obtain the fluorous gel of PFD, the chemical structure of a gelator requires modification and a fluorous moiety can be introduced to the compound in order to enhance fluorophilicity of the gelator. It has been reported that the three linearly fused rings and alkoxyl parts were important for DDOA and the related anthraquinone to function as a gelator [10]. In order to interact with fluorous solvents, introduction of fluoroalkylated chains to the alkyl moieties of the gelators is considered. In this work, fluoroalkyl-containing anthracene and fluoroalkyl-containing anthraquinone were synthesized. The gelation ability of synthesized fluoroalkyl-containing anthracene and anthraquinone for PFD was investigated. Moreover, the prepared fluorous gel was used for cell culture to assess the cytotoxicity. 2. Results and discussion 2.1. Synthesis of fluoroalkyl-containing anthracene Fluoroalkyl-containing anthracene derivatives (Ant-H10F4 6a and Ant-H10F6 6b) were synthesized. Each number refers to the number of methylene and difluoromethylene units, respectively. The chemical structure is based on the DDOA gelator. The desired anthracene derivatives were obtained by preparing fluoroalkyl-containing alcohols and introducing them to the anthracene moiety (Scheme 1). Initially, the fluoroalkyl-containing alcohols were synthesized in two steps according to literature [12]: addition of perfluoroalkyl iodide 2a-b to allyl alcohol such as 9-decene-1-ol 1 followed by reduction of the iodide (Scheme 1i, ii). For the last step of the reaction pathway, ether-ether exchange reaction was carried out according to literature [13]. 2,3-Dimethoxyanthracene (DMOA) 5 which was previously prepared [11,14] was
Corresponding author. E-mail address: [email protected] (K. Hatanaka).
https://doi.org/10.1016/j.jfluchem.2019.04.008 Received 19 February 2019; Received in revised form 8 April 2019; Accepted 9 April 2019 Available online 10 April 2019 0022-1139/ © 2019 Elsevier B.V. All rights reserved.
Journal of Fluorine Chemistry 222–223 (2019) 24–30
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Fig. 1. Chemical structure of (A) perfluorodecalin (PFD), (B) dodecafluoro-1-heptanol (DFH), (C) 2,3-di-n-decyloxyanthracene (DDOA), and (D) 2,3-di-n-decyloxyanthraquinone.
0.060 wt% (1.5-1.0 mM), respectively. As the gelation of PFD occurred at concentrations below 0.1 wt%, both Anq-H10F4 and Anq-H10F6 qualify in the class of super-gelators [16]. Scanning electron microscopy was carried out to observe the morphologies of the gels. For this measurement, two types of gel of PFD, Anq-H10F4 and Anq-H10F6, were prepared and the gels were dried under vacuum as xerogels. From the obtained SEM images (Fig. 3), fibers and their bundles whose widths were ca. 5–10 μm and ca. 20–100 μm were observed, respectively.
used as a reaction substrate. During the reaction, the methoxy groups of DMOA were substituted by a fluoroalkyl-containing alcohol 4a-b to afford the fluoroalkyl-containing anthracene 6a-b (Scheme 1-iii). 2.2. Trial of the gelation of perfluorodecalin using fluoroalkyl-containing anthracene The gelation ability of PFD was investigated by using the fluoroalkyl-containing anthracenes (Ant-H10F4 6a and Ant-H10F6 6b). Stock solution of each compound in chloroform was prepared. Aliquot of the stock solution was transferred to a screw cap tube and the solvent was dried. Afterwards, the fluorous solvent PFD was added to the tube and the mixture was heated at around 70 °C to dissolve the compound. Previous research showed that DDOA gelator which is a non-fluorinated compound, did not dissolve in PFD [11]. On the other hand, the synthesized fluoroalkyl-containing compounds were able to dissolve in the fluorous solvent by heating at 70 °C. Hence, the introduction of fluoroalkyl chains to DDOA has made the obtained compounds fluorophilic enough to dissolve in PFD. However, gelation of PFD did not occur using Ant-H10F4 6a or Ant-H10F6 6b.
2.5. Evaluation of cytotoxicity of the fluorous gel In order to determine the cytotoxicity of the fluorous gel of PFD, NIH 3T3 cells were cultured using the fluorous gel of PFD that was prepared from 5 mM of Anq-H10F4 or Anq-H10F6. The cells were pre-incubated in culture medium on 96-well plate with 5% CO2 at 37 °C. After 24 h, culture medium was removed and the prepared fluorous gel was added to the well exposing the cells to the fluorous gel. After 24-h incubation in the gel, cytotoxicity was assessed based on the number of viable cells obtained. Results showed that the fluorous gel of PFD was non-toxic to the cells after 24-h incubation (Fig. 4B). Moreover, cell spreading was also maintained in the presence of the fluorous gel (Fig. 4A). The number of viable cells after 24-h incubation in the presence of the fluorous gel did not significantly decrease compared with culture medium only. Based on these results, the fluorous gels have potential application as cell culture substrate.
2.3. Synthesis of fluoroalkyl-containing anthraquinone To prepare the desired anthraquinone, 2,3-dihydroxy-9,10-anthraquinone 8 previously synthesized [11,14] was used as a reaction substrate. Fluoroalkyl bromide 7a-b obtained from fluoroalkyl alcohol 4ab following literature [15] (Scheme 2-i) was introduced to the anthraquinone 8 in order to yield two types of fluoroalkyl-containing anthraquinones, Anq-H10F4 9a and Anq-H10F6 9b (Scheme 2-ii).
3. Conclusion The preparation of fluorous gels of PFD was achieved using fluoroalkyl-containing anthraquinone. The non-cytotoxicity of the fluorous gel of PFD was confirmed during cultivation of NIH 3T3 cells in the presence of the gel. Since fluorous solvents have been reported as oxygen reservoir and gels have been used as cell scaffold, the fluorous gels have potential application as cell culture substrate that can supply oxygen to cells.
2.4. Gelation test of perfluorodecalin using fluoroalkyl-containing anthraquinone The obtained Anq-H10F4 9a or Anq-H10F6 9b was dissolved in PFD by heating at 85 °C in a water bath. After cooling to room temperature, the solutions turned into gel (Fig. 2). Therefore, the anthraquinone (9a, 9b) could function as a gelator of PFD. Pozzo and coworkers have previously reported that 2,3-dialkoxyl-substituted anthraquinone is an organogelator for ethanol or n-heptane [10]. In our study, anthraquinone, Anq-H10F4 or Anq-H10F6 functioned as gelators for fluorous solvent such as PFD owing to the fluoroalkyl parts that enhanced fluorophilicity. Moreover, Anq-H10F4 and Anq-H10F6 formed a fluorous gel of PFD at a critical concentration of 0.050-0.025 wt% (1.0-0.5 mM) and 0.090-
4. Materials and methods Most of the reagents were purchased from Wako Pure Chemical Industries Ltd. (Osaka, Japan) or TCI (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan). Fluoroalkyl-containing alcohols were synthesized by using allyl alcohol (9-decene-1-ol). Perfluoroalkyl iodide 25
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Scheme 1. Synthesis of fluoroalkyl-containing anthracene (Ant-H10F4, Ant-H10F6). (i) NaHCO3 (1.0 equiv.), Na2S2O4 (1.0 equiv.), CH3CN:H2O = 1:1, r.t., 4 h; (ii) LiAlH4 (2.0 equiv.), dry THF, 0 °C→r.t., 12 h; (iii) H2SO4 (1.0 equiv.), toluene, reflux, 24 h.
(perfluorobutyl iodide or perfluorohexyl iodide) from TCI was used as starting material. 2,3-Dimethoxyanthracene (DMOA) and 2,3-dihydroxy-9,10-anthraquinone were prepared following previous reports [11,14]. 1 H, 13C, 19F NMR spectra were measured with a spectrometer (JEOL ECP-600). Fourier transform infrared spectroscopy (FTIR) was carried out on a JASCO FT/IR 4100 spectrometer. Elemental analyses were conducted on an Organic Elemental Analyzer (Thermo Flash 2000). SEM images were obtained by a FE-SEM S-4500 (Hitachi) and Aucoated xerogels were observed.
and sodium hydrogen carbonate (NaHCO3) (5.2 mmol) were added to the reaction mixture and the solution was stirred at room temperature for 4 h. The reaction mixture was extracted with ethyl acetate and washed three times with water. The organic layer was dried over sodium sulfate (Na2SO4), filtered, and evaporated to yield 3a (2.433 g, 96.9%) or 3b (2.786 g, 92.6%) as yellow liquid. 4.1.1. 3a. 11,11,12,12,13,13,14,14,14-nonafluoro-9-iodo-1-tetradecanol [17] 1 H NMR (600 MHz, CDCl3): δ (in ppm) = 1.32 (s, 10H, ((CH2)5CH2CHI), 1.56 (m, 2H, OCH2CH2), 1.78 (m, 2H, CH2CH2CHI), 2.84 (m, 2H, CHICH2CF2), 3.64 (t, J = 6.6 Hz, 2H, OCH2), 4.33 (m, 1H, CHI). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.9 (CHI), 25.7 (O (CH2)2CH2), 28.5–29.6 ((CH2)4CH2CHI), 32.8 (OCH2CH2), 40.4 (CH2CH2CHI), 41.6 (t, J = 22.5 Hz, CHICH2CF2), 63.1 (OCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -125.8 (2 F, CF2CF3), -124.5 (2 F, CF2CF2CF3), -113.4 (2 F, CH2CF2), -80.9 (3 F, CF3).
4.1. General procedure for synthesis of fluoroalkyl-containing alcohols 3a-b (Scheme 1-i) In a three-necked round flask, 9-decene-1-ol (5.0 mmol) and perfluoroalkyl iodide (6.0 mmol) were dissolved in a mixture of CH3CN and H2O (1:1, 10 mL total). Sodium dithionate (Na2S2O4) (5.8 mmol) 26
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Scheme 2. Synthesis of fluoroalkyl-containing anthraquinone (Anq-H10F4, Anq-H10F6). (i) DDQ (1.2 equiv.), PPh3 (1.2 equiv.), TBAB (1.2 equiv.), CH2Cl2, r.t., 2 h. (ii) K2CO3 (5.0 equiv.), DMF:THF = 1:1, reflux, 18 h.
4.1.2. 3b. 11,11,12,12,13,13,14,14,15,15,16,16,16-tridecafluoro-9-iodo1-hexadecanol [18] 1 H NMR (600 MHz, CDCl3): δ (in ppm) = 1.33 (s, 10H, ((CH2)5CH2CHI), 1.57 (m, 2H, OCH2CH2), 1.80 (m, 2H, CH2CH2CHI), 2.84 (m, 2H, CHICH2CF2), 3.65 (t, J = 6.6 Hz, 2H, OCH2), 4.33 (m, 1H,CHI). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 21.0 (CHI), 25.8 (O (CH2)2CH2), 28.6–29.7 ((CH2)4CH2CHI), 32.9 (OCH2CH2), 40.4 (CH2CH2CHI), 41.8 (t, J = 37.5 Hz, CHICH2CF2), 63.2 (OCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.8 (2 F, CF2CF2CF3), -121.7 (2 F, CF2CF2CF2CF3), -113.1 (2 F, CH2CF2), -80.6 (3 F, CF3). 4.2. General procedure for synthesis of fluoroalkyl-containing alcohols 4a-b (Scheme 1-ii)
Fig. 2. Photograph of fluorous gels of PFD by using 5 mM of (A) Anq-H10F4, and (B) Anq-H10F6.
In a three-necked round flask, 3a or 3b (2.4 mmol) was dissolved in 27
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Fig. 3. SEM images of xerogels prepared from fluorous gels of PFD using 5 mM of (A, B) Anq-H10F4 and (C, D) Anq-H10F6.
dried THF (25 mL). Lithium aluminium hydride (LiAlH4) (5 mmol) was added to the reaction mixture at 0 °C and the solution was stirred at room temperature for 12 h. The reaction mixture was extracted with ethyl acetate and washed three times with water. The organic layer was dried over sodium sulfate (Na2SO4), filtered, and evaporated. The crude product was purified by silica gel column chromatography (eluent, ethyl acetate:hexane = 1:2) to yield fluoroalkyl-containing alcohols 4a (0.4356 g, 51.6%) as colorless liquid or 4b (0.619 g, 54.4%) as white solid.
CF2CF3), -124.4 (2 F, CF2CF2CF3), -114.6 (2 F, CH2CF2), -80.9 (3 F, CF3). 4.2.2. 4b. 11,11,12,12,13,13,14,14,15,15,16,16,16-tridecafluoro-1hexadecanol [18] 1 H NMR (600 MHz, CDCl3): δ (in ppm) = 1.30 (m, 12H, (CH2)6CH2CH2CF2), 1.58 (m, 4H, OCH2CH2, CH2CH2CF2), 2.04 (m, 2H, CH2CF2), 3.64 (m, 2H, OCH2). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 25.9 (OCH2CH2CH2), 29.1–29.6 (CH2), 31.0 (t, J = 22.5 Hz, CH2CF2), 32.9 (OCH2CH2), 63.2 (OCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.8 (2 F, CF2CF2CF3), -121.9 (2 F, CF2CF2CF2CF3), -114.3 (2 F, CH2CF2), -80.7 (3 F, CF3).
4.2.1. 4a. 11,11,12,12,13,13,14,14,14-nonafluoro-1-tetradecanol [17,19] 1 H NMR (600 MHz, CDCl3): δ (in ppm) = 1.25–1.36 (m, 12H, (CH2)6CH2CH2CF2), 1.53–1.63 (m, 4H, OCH2CH2, CH2CH2CF2), 2.03 (m, 2H, CH2C4F9), 3.63 (m, 2H, OCH2). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.1 (CH2CH2CF2), 25.8 (O(CH2)2CH2), 29.2–29.6 ((CH2)5CH2CH2CF2), 30.9 (t, J = 22.5 Hz, CH2CF2), 32.8 (OCH2CH2), 63.2 (OCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F,
4.3. General procedure for synthesis of fluoroalkyl-containing anthracene 6a-b (Scheme 1-iii) In a three-necked round flask, 2,3-dimethoxy-anthracene (DMOA)
Fig. 4. (A) Brightfield images of NIH 3T3 cells in the presence of the fluorous gel of PFD from Anq-H10F4 after 24-h incubation. Scale bar, 100 μm. (B) Number of viable cells after 24-h incubation in the fluorous gel of PFD (Anq-H10F4 or Anq-H10F6) and in culture medium (control). 28
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(1 equivalent) and fluoroalkyl-containing alcohol (4 equivalent) were mixed with toluene. Then, H2SO4 was added dropwise to the mixture. After 24-h reflux, the reaction mixture was extracted with ethyl acetate and washed three times with water. The organic layer was dried over sodium sulfate (Na2SO4), filtered, and evaporated. The crude product was purified by silica gel column chromatography (eluent, chloroform:hexane = 1:2) to yield fluoroalkyl-containing anthracene 6a (38.8%) or 6b (58.8%) as white solid.
-126.0 (2 F, CF2CF3), -124.4 (2 F, CF2CF2CF3), -114.6 (2 F, CH2CF2), -81.0 (3 F, CF3). 4.4.2. 7b. 11,11,12,12,13,13,14,14,15,15,16,16,16-heptadecafluorohexadecyl bromide [20] 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.28–1.33 (m, 8H, (CH2)4CH2CH2CH2CF2), 1.37 (m, 2H, CH2CH2CH2CF2), 1.43 (m, 2H, BrCH2CH2CH2), 1.59 (m, 2H, CH2CH2CF2), 1.85 (m, 2H, BrCH2CH2), 2.04 (m, 2H, CH2CF2), 3.41 (t, J = 7.2 Hz, 2H, BrCH2). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 28.3 (BrCH2CH2CH2), 28.9 (BrCH2CH2CH2CH2), 29.2 (CH2CH2CH2CF2), 29.3–29.5 ((CH2)3CH2CH2CH2CF2), 31.0 (t, J = 22.5 Hz, CH2CF2), 33.0 (BrCH2CH2), 34.1 (BrCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.1 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.9 (2 F, CF2CF2CF3), -121.9 (2 F, CF2CF2CF2CF3), -114.4 (2 F, CH2CF2), -80.8 (3 F, CF3).
4.3.1. 6a. 2,3-bis[(11,11,12,12,13,13,14,14,14-nonafluorotetradecyl) oxy]-anthracene (Ant-H10F4) 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.26–1.41 (m, 20H, (CH2)5CH2CH2CF2), 1.55 (m, 4H, OCH2CH2CH2), 1.60 (m, 4H, CH2CH2CF2), 1.94 (m, 4H, OCH2CH2), 2.05 (m, 4H, CH2C4F9), 4.16 (t, J = 6.6 Hz, 4H, OCH2), 7.18 (s, 2H, H1, H4), 7.39 (m, 2H, H6, H7), 7.91 (m, 2H, H5, H8), 8.19 (s, 2H, H9, H10). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2C4F9), 26.2 (O(CH2)2CH2), 29.2–29.8 (OCH2CH2, (CH2)5CH2CH2CF2), 30.9 (t, J = 22.5 Hz, CH2CF2), 68.9 (OCH2), 106.0 (C1, C4), 123.8 (C9, C10), 124.5 (C6, C7), 127.7 (C5, C8), 128.8 (C4a, C9a), 130.8 (C8a, C10a), 150.1 (C2, C3). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F, CF2CF3), -124.4 (2 F, CF2CF2CF3), -114.6 (2 F, CH2CF2), -81.0 (3 F, CF3). IR (KBr): 2928, 2856, 1729, 1630, 1491, 1467, 1383, 1359, 1289, 1223, 1131, 1072 cm−1. Anal. Calcd for C42H48F18O2: C, 54.43; H, 5.22; Found: C, 54.13; H, 5.45.
4.5. General procedure for synthesis of fluoroalkyl-containing anthraquinone 9a-b (Scheme 2-ii) In a three-necked round flask, 2,3-dihydroxy-9,10-anthraquinone (1 equivalent) and potassium carbonate (5 equivalent) were dissolved in absolute DMF. Fluoroalkyl-containing bromide (4.5 equivalent) in dried THF was added from a dropping funnel over 5 min and the solution was refluxed for 18 h. After cooling to room temperature, the solution was hydrolyzed with water and extracted with chloroform. The organic layer was dried over sodium sulfate (Na2SO4), filtered, and evaporated of chloroform. The crude product was purified by silica gel column chromatography (eluent, chloroform:hexane = 1:1) to yield fluoroalkyl-containing anthraquinone 9a (42.8%) and 9b (45.6%) as yellow solid.
4.3.2. 6b. 2,3-bis[(11,11,12,12,13,13,14,14,15,15,16,16,16-tridecafluorohexadecyl)oxy]-anthracene (Ant-H10F6) 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.25–1.45 (m, 20H, (CH2)5CH2CH2CF2), 1.55 (m, 4H, OCH2CH2CH2), 1.60 (m, 4H, CH2CH2CF2), 1.93 (m, 4H, OCH2CH2), 2.04 (m, 4H, CH2CF2), 4.15 (t, J = 6.6 Hz, 4H, OCH2), 7.18 (s, 2H, H1, H4), 7.39 (m, 2H, H6, H7), 7.90 (m, 2H, H5, H8), 8.18 (s, 2H, H9, H10). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 26.3 (OCH2CH2CH2), 29.2–29.7 (OCH2CH2, (CH2)5CH2CH2CF2), 31.0 (t, J = 22.5 Hz, CH2CF2), 68.8 (OCH2), 106.1 (C1, C4), 123.9 (C9, C10), 124.6 (C6, C7), 127.7 (C5, C8), 128.9 (C4a, C9a), 130.9 (C8a, C10a), 150.1 (C2, C3). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.1 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.8 (2 F, CF2CF2CF3), -121.9 (2 F, CF2CF2CF2CF3), -114.3 (2 F, CH2CF2), -80.7 (3 F, CF3). IR (KBr): 2938, 2855, 1729, 1631, 1492, 1465, 1385, 1368, 1290, 1224, 1123, 1080 cm−1. Anal. Calcd for C46H48F26O2: C, 49.03; H, 4.29; Found: C, 49.07; H, 4.20.
4.5.1. 9a. 2,3-bis[(11,11,12,12,13,13,14,14,14-nonafluorotetradecyl) oxy]-9,10-anthraquinone (Anq-H10F4) 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.31–1.41 (m, 20H, (CH2)5CH2CH2CF2), 1.50 (m, 4H, OCH2CH2CH2), 1.59 (m, 4H, CH2CH2CF2), 1.89 (m, 4H, OCH2CH2), 2.04 (m, 4H, CH2CF2), 4.18 (t, J = 6.6 Hz, 4H, OCH2), 7.66 (s, 2H, H1, H4), 7.73 (m, 2H, H6, H7), 8.24 (m, 2H, H5, H8). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 26.1 (O(CH2)2CH2), 29.0–29.6 (OCH2CH2, (CH2)5CH2CH2CF2), 30.9 (t, J = 22.5 Hz, CH2CF2), 69.5 (OCH2), 109.5 (C1, C4), 127.1 (C5, C8), 128.3 (C4a, C9a), 133.8 (C6, C7 and C8a, C10a), 153.9 (C2, C3), 182.8 (C9, C10). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F, CF2CF3), -124.4 (2 F, CF2CF2CF3), -114.6 (2 F, CH2CF2), -81.0 (3 F, CF3). IR (KBr): 2919, 2850, 1731, 1672, 1578, 1515, 1470, 1377, 1335, 1318, 1221, 1134, 1110, 1087, 1044, 1012 cm−1. Anal. Calcd for C42H46F18O4: C, 52.72; H, 4.85; Found: C, 52.95; H, 5.02.
4.4. General procedure for synthesis of fluoroalkyl-containing bromides 7ab (Scheme 2-i) In a three-necked round flask, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (1.2 equivalent), triphenylphosphine (PPh3) (1.2 equivalent), and tetrabutylammonium bromide (TBAB) (1.2 equivalent) were dissolved in dried CH2Cl2. Fluoroalkyl-containing alcohol 4a or 4b (1 equivalent) was added to the reaction mixture and the solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane) to yield fluoroalkyl-containing bromides 7a (81.5%) or 7b (83.9%) as colorless liquid.
4.5.2. 9b. 2,3-bis[(11,11,12,12,13,13,14,14,15,15,16,16,16-tridecafluorohexadecyl)oxy]-9,10-anthraquinone (Anq-H10F6) 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.31–1.41 (m, 20H, (CH2)5CH2CH2CF2), 1.51 (m, 4H, OCH2CH2CH2), 1.60 (m, 4H, CH2CH2CF2), 1.90 (m, 4H, OCH2CH2), 2.04 (m, 4H, CH2CF2), 4.19 (t, J = 6.6 Hz, 4H, OCH2), 7.68 (s, 2H, H1, H4), 7.75 (m, 2H, H6, H7), 8.26 (m, 2H, H5, H8). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.3 (CH2CH2CF2), 26.1 (O(CH2)2CH2), 29.0–29.6 (OCH2CH2, (CH2)5CH2CH2CF2), 31.0 (t, J = 22.5 Hz, CH2CF2), 69.5 (OCH2), 109.5 (C1, C4), 127.1 (C50, C8), 128.3 (C4a, C9a), 133.8 (C6, C7 and C8a, C10a), 153.9 (C2, C3), 182.8 (C9, C10). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.1 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.8 (2 F, CF2CF2CF3), -121.9 (2 F, CF2CF2CF2CF3), -114.4 (2 F, CH2CF2), -80.7 (3 F, CF3). IR (KBr): 2919, 2850, 1729, 1672, 1578, 1515, 1469, 1376, 1335, 1318, 1240, 1145, 1111, 1086, 1050, 1012 cm−1. Anal. Calcd for C46H46F26O4: C, 47.76; H, 4.01; Found: C, 47.62; H, 3.92.
4.4.1. 7a. 11,11,12,12,13,13,14,14,14-nonafluorotetradecyl bromide [20] 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.28–1.33 (m, 8H, (CH2)4CH2CH2CH2CF2), 1.37 (m, 2H, CH2CH2CH2CF2), 1.42 (m, 2H, BrCH2CH2CH2), 1.59 (m, 2H, CH2CH2CF2), 1.85 (m, 2H, BrCH2CH2), 2.04 (m, 2H, CH2CF2), 3.41 (t, J = 7.2 Hz, 2H, BrCH2). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 28.3 (BrCH2CH2CH2), 28.9 (BrCH2CH2CH2CH2), 29.2 (CH2CH2CH2CF2), 29.3–29.5 ((CH2)3CH2CH2CH2CF2), 30.9 (t, J = 22.5 Hz, CH2CF2), 33.0 (BrCH2CH2), 34.1 (BrCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = 29
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4.6. Gelation Stock solutions of the fluoroalkyl-containing anthracene and the fluoroalkyl-containing anthraquinone in chloroform were prepared. Aliquots of the solutions were transferred to screw tubes and chloroform was evaporated. Then, perfluorodecalin (PFD) was added and the solution was heated in a water bath to dissolve the fluoroalkyl-containing compounds. After cooling the solution to room temperature, gelation was confirmed when the solution remained at the bottom of the tube even after inversion.
[5] [6] [7]
4.7. Cell culture NIH 3T3 cells were incubated in culture medium (DMEM/F-12) supplemented with 10% FBS and 1% antibiotic-antimycotic. Cells (1.0 × 104 cells per well) were seeded in 96-well plate (Nunclon Delta Surface, Thermo Fisher Scientific) and incubated (5% CO2, 37 °C) for cell attachment to the plate. After 24 h, culture medium was replaced with a prepared fluorous gel of PFD from 5 mM of Anq-H10F4 or AnqH10F6. After 24-h incubation with the fluorous gel, brightfield images of cells were obtained and the number of living cells were counted from the images.
[8]
[9] [10]
Acknowledgments
[11]
We are grateful to Prof. Masaru Ogura and Dr. Takahiko Moteki of Institute of Industrial Science (IIS), The University of Tokyo, for the SEM measurement. We also thank Prof. Kazuaki Kudo and Dr. Kengo Akagawa of IIS, The University of Tokyo, for the IR measurement.
[12]
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jfluchem.2019.04.008.
[13] [14] [15]
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Journal of Fluorine Chemistry journal homepage: www.elsevier.com/locate/fluor
New fluorous gelators for perfluorodecalin Hiroki Miyajima, Maria Carmelita Z. Kasuya, Kenichi Hatanaka
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T
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
ARTICLE INFO
ABSTRACT
Keywords: Gelator Fluorous gel Anthraquinone Perfluorodecalin Cell culture
Fluorous gels of perfluorodecalin (PFD) were prepared using chemically synthesized fluorous gelators. To enhance the fluorophilicity of gelators, fluoroalkyl chains were introduced to the alkyl chains of known gelators. The synthesized fluoroalkyl-containing anthraquinone formed gels of PFD. The prepared gel of PFD was used for cell culture and the cytotoxicity of the gel was assessed in view of its potential biomedical application.
1. Introduction Fluorous solvents are fluorophilic. They are immiscible with water or organic solvents. Fluorous solvents dissolve oxygen 20–25 times as much as water, and can function as potential oxygen carriers [1]. In biomedical engineering, these solvents have been applied for liquid breathing [2], and as blood substitute in vivo [3]. To utilize the dissolved oxygen in fluorous solvents, cell culture has also been carried out in the presence of the solvent to serve as an oxygen supplier [4]. As a fluorous solvent for biological use, perfluorodecalin (PFD) has been widely studied because of its low cytotoxicity [5]. PFD is a cyclic perfluorocarbon as shown in Fig. 1A. Owing to the solubility of oxygen and biological inertness, PFD has been applied for cell culture [5] or organ preservation [6]. Gels of PFD have also been investigated for application as material [7]. Gels have been studied as cell scaffold in biological field [8]. The sol-gel transition of physical gels that were prepared using low-molecular mass gelator (LMMG) can be controlled with external stimuli [9]. Gelation of LMMGs occurred through intermolecular interactions such as hydrogen bonding, van der Waals forces or π-π stacking. Some compounds containing anthracene moiety (Fig. 1C) or anthraquinone moiety (Fig. 1D) are known as LMMGs for organic solvent such as ethanol and n-heptane [10]. In our previous research, fluorous gel of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-1-heptanol (DFH, Fig. 1B) was prepared by using 2,3-di-n-decyloxyanthracene (DDOA, Fig. 1C) [11] which is known gelator having anthracene moiety and long alkyl chains. The previous study showed that DDOA formed fluorous gels only when fluoroalkylated alcohols and esters were used as fluorous solvent. When PFD was used as a fluorous solvent, the gelator did not dissolve in PFD and gelation did not occur [11]. This might be due to
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the low affinity of the gelator to PFD. To obtain the fluorous gel of PFD, the chemical structure of a gelator requires modification and a fluorous moiety can be introduced to the compound in order to enhance fluorophilicity of the gelator. It has been reported that the three linearly fused rings and alkoxyl parts were important for DDOA and the related anthraquinone to function as a gelator [10]. In order to interact with fluorous solvents, introduction of fluoroalkylated chains to the alkyl moieties of the gelators is considered. In this work, fluoroalkyl-containing anthracene and fluoroalkyl-containing anthraquinone were synthesized. The gelation ability of synthesized fluoroalkyl-containing anthracene and anthraquinone for PFD was investigated. Moreover, the prepared fluorous gel was used for cell culture to assess the cytotoxicity. 2. Results and discussion 2.1. Synthesis of fluoroalkyl-containing anthracene Fluoroalkyl-containing anthracene derivatives (Ant-H10F4 6a and Ant-H10F6 6b) were synthesized. Each number refers to the number of methylene and difluoromethylene units, respectively. The chemical structure is based on the DDOA gelator. The desired anthracene derivatives were obtained by preparing fluoroalkyl-containing alcohols and introducing them to the anthracene moiety (Scheme 1). Initially, the fluoroalkyl-containing alcohols were synthesized in two steps according to literature [12]: addition of perfluoroalkyl iodide 2a-b to allyl alcohol such as 9-decene-1-ol 1 followed by reduction of the iodide (Scheme 1i, ii). For the last step of the reaction pathway, ether-ether exchange reaction was carried out according to literature [13]. 2,3-Dimethoxyanthracene (DMOA) 5 which was previously prepared [11,14] was
Corresponding author. E-mail address: [email protected] (K. Hatanaka).
https://doi.org/10.1016/j.jfluchem.2019.04.008 Received 19 February 2019; Received in revised form 8 April 2019; Accepted 9 April 2019 Available online 10 April 2019 0022-1139/ © 2019 Elsevier B.V. All rights reserved.
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Fig. 1. Chemical structure of (A) perfluorodecalin (PFD), (B) dodecafluoro-1-heptanol (DFH), (C) 2,3-di-n-decyloxyanthracene (DDOA), and (D) 2,3-di-n-decyloxyanthraquinone.
0.060 wt% (1.5-1.0 mM), respectively. As the gelation of PFD occurred at concentrations below 0.1 wt%, both Anq-H10F4 and Anq-H10F6 qualify in the class of super-gelators [16]. Scanning electron microscopy was carried out to observe the morphologies of the gels. For this measurement, two types of gel of PFD, Anq-H10F4 and Anq-H10F6, were prepared and the gels were dried under vacuum as xerogels. From the obtained SEM images (Fig. 3), fibers and their bundles whose widths were ca. 5–10 μm and ca. 20–100 μm were observed, respectively.
used as a reaction substrate. During the reaction, the methoxy groups of DMOA were substituted by a fluoroalkyl-containing alcohol 4a-b to afford the fluoroalkyl-containing anthracene 6a-b (Scheme 1-iii). 2.2. Trial of the gelation of perfluorodecalin using fluoroalkyl-containing anthracene The gelation ability of PFD was investigated by using the fluoroalkyl-containing anthracenes (Ant-H10F4 6a and Ant-H10F6 6b). Stock solution of each compound in chloroform was prepared. Aliquot of the stock solution was transferred to a screw cap tube and the solvent was dried. Afterwards, the fluorous solvent PFD was added to the tube and the mixture was heated at around 70 °C to dissolve the compound. Previous research showed that DDOA gelator which is a non-fluorinated compound, did not dissolve in PFD [11]. On the other hand, the synthesized fluoroalkyl-containing compounds were able to dissolve in the fluorous solvent by heating at 70 °C. Hence, the introduction of fluoroalkyl chains to DDOA has made the obtained compounds fluorophilic enough to dissolve in PFD. However, gelation of PFD did not occur using Ant-H10F4 6a or Ant-H10F6 6b.
2.5. Evaluation of cytotoxicity of the fluorous gel In order to determine the cytotoxicity of the fluorous gel of PFD, NIH 3T3 cells were cultured using the fluorous gel of PFD that was prepared from 5 mM of Anq-H10F4 or Anq-H10F6. The cells were pre-incubated in culture medium on 96-well plate with 5% CO2 at 37 °C. After 24 h, culture medium was removed and the prepared fluorous gel was added to the well exposing the cells to the fluorous gel. After 24-h incubation in the gel, cytotoxicity was assessed based on the number of viable cells obtained. Results showed that the fluorous gel of PFD was non-toxic to the cells after 24-h incubation (Fig. 4B). Moreover, cell spreading was also maintained in the presence of the fluorous gel (Fig. 4A). The number of viable cells after 24-h incubation in the presence of the fluorous gel did not significantly decrease compared with culture medium only. Based on these results, the fluorous gels have potential application as cell culture substrate.
2.3. Synthesis of fluoroalkyl-containing anthraquinone To prepare the desired anthraquinone, 2,3-dihydroxy-9,10-anthraquinone 8 previously synthesized [11,14] was used as a reaction substrate. Fluoroalkyl bromide 7a-b obtained from fluoroalkyl alcohol 4ab following literature [15] (Scheme 2-i) was introduced to the anthraquinone 8 in order to yield two types of fluoroalkyl-containing anthraquinones, Anq-H10F4 9a and Anq-H10F6 9b (Scheme 2-ii).
3. Conclusion The preparation of fluorous gels of PFD was achieved using fluoroalkyl-containing anthraquinone. The non-cytotoxicity of the fluorous gel of PFD was confirmed during cultivation of NIH 3T3 cells in the presence of the gel. Since fluorous solvents have been reported as oxygen reservoir and gels have been used as cell scaffold, the fluorous gels have potential application as cell culture substrate that can supply oxygen to cells.
2.4. Gelation test of perfluorodecalin using fluoroalkyl-containing anthraquinone The obtained Anq-H10F4 9a or Anq-H10F6 9b was dissolved in PFD by heating at 85 °C in a water bath. After cooling to room temperature, the solutions turned into gel (Fig. 2). Therefore, the anthraquinone (9a, 9b) could function as a gelator of PFD. Pozzo and coworkers have previously reported that 2,3-dialkoxyl-substituted anthraquinone is an organogelator for ethanol or n-heptane [10]. In our study, anthraquinone, Anq-H10F4 or Anq-H10F6 functioned as gelators for fluorous solvent such as PFD owing to the fluoroalkyl parts that enhanced fluorophilicity. Moreover, Anq-H10F4 and Anq-H10F6 formed a fluorous gel of PFD at a critical concentration of 0.050-0.025 wt% (1.0-0.5 mM) and 0.090-
4. Materials and methods Most of the reagents were purchased from Wako Pure Chemical Industries Ltd. (Osaka, Japan) or TCI (Tokyo Chemical Industry Co., Ltd., Tokyo, Japan). Fluoroalkyl-containing alcohols were synthesized by using allyl alcohol (9-decene-1-ol). Perfluoroalkyl iodide 25
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Scheme 1. Synthesis of fluoroalkyl-containing anthracene (Ant-H10F4, Ant-H10F6). (i) NaHCO3 (1.0 equiv.), Na2S2O4 (1.0 equiv.), CH3CN:H2O = 1:1, r.t., 4 h; (ii) LiAlH4 (2.0 equiv.), dry THF, 0 °C→r.t., 12 h; (iii) H2SO4 (1.0 equiv.), toluene, reflux, 24 h.
(perfluorobutyl iodide or perfluorohexyl iodide) from TCI was used as starting material. 2,3-Dimethoxyanthracene (DMOA) and 2,3-dihydroxy-9,10-anthraquinone were prepared following previous reports [11,14]. 1 H, 13C, 19F NMR spectra were measured with a spectrometer (JEOL ECP-600). Fourier transform infrared spectroscopy (FTIR) was carried out on a JASCO FT/IR 4100 spectrometer. Elemental analyses were conducted on an Organic Elemental Analyzer (Thermo Flash 2000). SEM images were obtained by a FE-SEM S-4500 (Hitachi) and Aucoated xerogels were observed.
and sodium hydrogen carbonate (NaHCO3) (5.2 mmol) were added to the reaction mixture and the solution was stirred at room temperature for 4 h. The reaction mixture was extracted with ethyl acetate and washed three times with water. The organic layer was dried over sodium sulfate (Na2SO4), filtered, and evaporated to yield 3a (2.433 g, 96.9%) or 3b (2.786 g, 92.6%) as yellow liquid. 4.1.1. 3a. 11,11,12,12,13,13,14,14,14-nonafluoro-9-iodo-1-tetradecanol [17] 1 H NMR (600 MHz, CDCl3): δ (in ppm) = 1.32 (s, 10H, ((CH2)5CH2CHI), 1.56 (m, 2H, OCH2CH2), 1.78 (m, 2H, CH2CH2CHI), 2.84 (m, 2H, CHICH2CF2), 3.64 (t, J = 6.6 Hz, 2H, OCH2), 4.33 (m, 1H, CHI). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.9 (CHI), 25.7 (O (CH2)2CH2), 28.5–29.6 ((CH2)4CH2CHI), 32.8 (OCH2CH2), 40.4 (CH2CH2CHI), 41.6 (t, J = 22.5 Hz, CHICH2CF2), 63.1 (OCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -125.8 (2 F, CF2CF3), -124.5 (2 F, CF2CF2CF3), -113.4 (2 F, CH2CF2), -80.9 (3 F, CF3).
4.1. General procedure for synthesis of fluoroalkyl-containing alcohols 3a-b (Scheme 1-i) In a three-necked round flask, 9-decene-1-ol (5.0 mmol) and perfluoroalkyl iodide (6.0 mmol) were dissolved in a mixture of CH3CN and H2O (1:1, 10 mL total). Sodium dithionate (Na2S2O4) (5.8 mmol) 26
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Scheme 2. Synthesis of fluoroalkyl-containing anthraquinone (Anq-H10F4, Anq-H10F6). (i) DDQ (1.2 equiv.), PPh3 (1.2 equiv.), TBAB (1.2 equiv.), CH2Cl2, r.t., 2 h. (ii) K2CO3 (5.0 equiv.), DMF:THF = 1:1, reflux, 18 h.
4.1.2. 3b. 11,11,12,12,13,13,14,14,15,15,16,16,16-tridecafluoro-9-iodo1-hexadecanol [18] 1 H NMR (600 MHz, CDCl3): δ (in ppm) = 1.33 (s, 10H, ((CH2)5CH2CHI), 1.57 (m, 2H, OCH2CH2), 1.80 (m, 2H, CH2CH2CHI), 2.84 (m, 2H, CHICH2CF2), 3.65 (t, J = 6.6 Hz, 2H, OCH2), 4.33 (m, 1H,CHI). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 21.0 (CHI), 25.8 (O (CH2)2CH2), 28.6–29.7 ((CH2)4CH2CHI), 32.9 (OCH2CH2), 40.4 (CH2CH2CHI), 41.8 (t, J = 37.5 Hz, CHICH2CF2), 63.2 (OCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.8 (2 F, CF2CF2CF3), -121.7 (2 F, CF2CF2CF2CF3), -113.1 (2 F, CH2CF2), -80.6 (3 F, CF3). 4.2. General procedure for synthesis of fluoroalkyl-containing alcohols 4a-b (Scheme 1-ii)
Fig. 2. Photograph of fluorous gels of PFD by using 5 mM of (A) Anq-H10F4, and (B) Anq-H10F6.
In a three-necked round flask, 3a or 3b (2.4 mmol) was dissolved in 27
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Fig. 3. SEM images of xerogels prepared from fluorous gels of PFD using 5 mM of (A, B) Anq-H10F4 and (C, D) Anq-H10F6.
dried THF (25 mL). Lithium aluminium hydride (LiAlH4) (5 mmol) was added to the reaction mixture at 0 °C and the solution was stirred at room temperature for 12 h. The reaction mixture was extracted with ethyl acetate and washed three times with water. The organic layer was dried over sodium sulfate (Na2SO4), filtered, and evaporated. The crude product was purified by silica gel column chromatography (eluent, ethyl acetate:hexane = 1:2) to yield fluoroalkyl-containing alcohols 4a (0.4356 g, 51.6%) as colorless liquid or 4b (0.619 g, 54.4%) as white solid.
CF2CF3), -124.4 (2 F, CF2CF2CF3), -114.6 (2 F, CH2CF2), -80.9 (3 F, CF3). 4.2.2. 4b. 11,11,12,12,13,13,14,14,15,15,16,16,16-tridecafluoro-1hexadecanol [18] 1 H NMR (600 MHz, CDCl3): δ (in ppm) = 1.30 (m, 12H, (CH2)6CH2CH2CF2), 1.58 (m, 4H, OCH2CH2, CH2CH2CF2), 2.04 (m, 2H, CH2CF2), 3.64 (m, 2H, OCH2). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 25.9 (OCH2CH2CH2), 29.1–29.6 (CH2), 31.0 (t, J = 22.5 Hz, CH2CF2), 32.9 (OCH2CH2), 63.2 (OCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.8 (2 F, CF2CF2CF3), -121.9 (2 F, CF2CF2CF2CF3), -114.3 (2 F, CH2CF2), -80.7 (3 F, CF3).
4.2.1. 4a. 11,11,12,12,13,13,14,14,14-nonafluoro-1-tetradecanol [17,19] 1 H NMR (600 MHz, CDCl3): δ (in ppm) = 1.25–1.36 (m, 12H, (CH2)6CH2CH2CF2), 1.53–1.63 (m, 4H, OCH2CH2, CH2CH2CF2), 2.03 (m, 2H, CH2C4F9), 3.63 (m, 2H, OCH2). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.1 (CH2CH2CF2), 25.8 (O(CH2)2CH2), 29.2–29.6 ((CH2)5CH2CH2CF2), 30.9 (t, J = 22.5 Hz, CH2CF2), 32.8 (OCH2CH2), 63.2 (OCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F,
4.3. General procedure for synthesis of fluoroalkyl-containing anthracene 6a-b (Scheme 1-iii) In a three-necked round flask, 2,3-dimethoxy-anthracene (DMOA)
Fig. 4. (A) Brightfield images of NIH 3T3 cells in the presence of the fluorous gel of PFD from Anq-H10F4 after 24-h incubation. Scale bar, 100 μm. (B) Number of viable cells after 24-h incubation in the fluorous gel of PFD (Anq-H10F4 or Anq-H10F6) and in culture medium (control). 28
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(1 equivalent) and fluoroalkyl-containing alcohol (4 equivalent) were mixed with toluene. Then, H2SO4 was added dropwise to the mixture. After 24-h reflux, the reaction mixture was extracted with ethyl acetate and washed three times with water. The organic layer was dried over sodium sulfate (Na2SO4), filtered, and evaporated. The crude product was purified by silica gel column chromatography (eluent, chloroform:hexane = 1:2) to yield fluoroalkyl-containing anthracene 6a (38.8%) or 6b (58.8%) as white solid.
-126.0 (2 F, CF2CF3), -124.4 (2 F, CF2CF2CF3), -114.6 (2 F, CH2CF2), -81.0 (3 F, CF3). 4.4.2. 7b. 11,11,12,12,13,13,14,14,15,15,16,16,16-heptadecafluorohexadecyl bromide [20] 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.28–1.33 (m, 8H, (CH2)4CH2CH2CH2CF2), 1.37 (m, 2H, CH2CH2CH2CF2), 1.43 (m, 2H, BrCH2CH2CH2), 1.59 (m, 2H, CH2CH2CF2), 1.85 (m, 2H, BrCH2CH2), 2.04 (m, 2H, CH2CF2), 3.41 (t, J = 7.2 Hz, 2H, BrCH2). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 28.3 (BrCH2CH2CH2), 28.9 (BrCH2CH2CH2CH2), 29.2 (CH2CH2CH2CF2), 29.3–29.5 ((CH2)3CH2CH2CH2CF2), 31.0 (t, J = 22.5 Hz, CH2CF2), 33.0 (BrCH2CH2), 34.1 (BrCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.1 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.9 (2 F, CF2CF2CF3), -121.9 (2 F, CF2CF2CF2CF3), -114.4 (2 F, CH2CF2), -80.8 (3 F, CF3).
4.3.1. 6a. 2,3-bis[(11,11,12,12,13,13,14,14,14-nonafluorotetradecyl) oxy]-anthracene (Ant-H10F4) 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.26–1.41 (m, 20H, (CH2)5CH2CH2CF2), 1.55 (m, 4H, OCH2CH2CH2), 1.60 (m, 4H, CH2CH2CF2), 1.94 (m, 4H, OCH2CH2), 2.05 (m, 4H, CH2C4F9), 4.16 (t, J = 6.6 Hz, 4H, OCH2), 7.18 (s, 2H, H1, H4), 7.39 (m, 2H, H6, H7), 7.91 (m, 2H, H5, H8), 8.19 (s, 2H, H9, H10). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2C4F9), 26.2 (O(CH2)2CH2), 29.2–29.8 (OCH2CH2, (CH2)5CH2CH2CF2), 30.9 (t, J = 22.5 Hz, CH2CF2), 68.9 (OCH2), 106.0 (C1, C4), 123.8 (C9, C10), 124.5 (C6, C7), 127.7 (C5, C8), 128.8 (C4a, C9a), 130.8 (C8a, C10a), 150.1 (C2, C3). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F, CF2CF3), -124.4 (2 F, CF2CF2CF3), -114.6 (2 F, CH2CF2), -81.0 (3 F, CF3). IR (KBr): 2928, 2856, 1729, 1630, 1491, 1467, 1383, 1359, 1289, 1223, 1131, 1072 cm−1. Anal. Calcd for C42H48F18O2: C, 54.43; H, 5.22; Found: C, 54.13; H, 5.45.
4.5. General procedure for synthesis of fluoroalkyl-containing anthraquinone 9a-b (Scheme 2-ii) In a three-necked round flask, 2,3-dihydroxy-9,10-anthraquinone (1 equivalent) and potassium carbonate (5 equivalent) were dissolved in absolute DMF. Fluoroalkyl-containing bromide (4.5 equivalent) in dried THF was added from a dropping funnel over 5 min and the solution was refluxed for 18 h. After cooling to room temperature, the solution was hydrolyzed with water and extracted with chloroform. The organic layer was dried over sodium sulfate (Na2SO4), filtered, and evaporated of chloroform. The crude product was purified by silica gel column chromatography (eluent, chloroform:hexane = 1:1) to yield fluoroalkyl-containing anthraquinone 9a (42.8%) and 9b (45.6%) as yellow solid.
4.3.2. 6b. 2,3-bis[(11,11,12,12,13,13,14,14,15,15,16,16,16-tridecafluorohexadecyl)oxy]-anthracene (Ant-H10F6) 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.25–1.45 (m, 20H, (CH2)5CH2CH2CF2), 1.55 (m, 4H, OCH2CH2CH2), 1.60 (m, 4H, CH2CH2CF2), 1.93 (m, 4H, OCH2CH2), 2.04 (m, 4H, CH2CF2), 4.15 (t, J = 6.6 Hz, 4H, OCH2), 7.18 (s, 2H, H1, H4), 7.39 (m, 2H, H6, H7), 7.90 (m, 2H, H5, H8), 8.18 (s, 2H, H9, H10). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 26.3 (OCH2CH2CH2), 29.2–29.7 (OCH2CH2, (CH2)5CH2CH2CF2), 31.0 (t, J = 22.5 Hz, CH2CF2), 68.8 (OCH2), 106.1 (C1, C4), 123.9 (C9, C10), 124.6 (C6, C7), 127.7 (C5, C8), 128.9 (C4a, C9a), 130.9 (C8a, C10a), 150.1 (C2, C3). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.1 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.8 (2 F, CF2CF2CF3), -121.9 (2 F, CF2CF2CF2CF3), -114.3 (2 F, CH2CF2), -80.7 (3 F, CF3). IR (KBr): 2938, 2855, 1729, 1631, 1492, 1465, 1385, 1368, 1290, 1224, 1123, 1080 cm−1. Anal. Calcd for C46H48F26O2: C, 49.03; H, 4.29; Found: C, 49.07; H, 4.20.
4.5.1. 9a. 2,3-bis[(11,11,12,12,13,13,14,14,14-nonafluorotetradecyl) oxy]-9,10-anthraquinone (Anq-H10F4) 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.31–1.41 (m, 20H, (CH2)5CH2CH2CF2), 1.50 (m, 4H, OCH2CH2CH2), 1.59 (m, 4H, CH2CH2CF2), 1.89 (m, 4H, OCH2CH2), 2.04 (m, 4H, CH2CF2), 4.18 (t, J = 6.6 Hz, 4H, OCH2), 7.66 (s, 2H, H1, H4), 7.73 (m, 2H, H6, H7), 8.24 (m, 2H, H5, H8). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 26.1 (O(CH2)2CH2), 29.0–29.6 (OCH2CH2, (CH2)5CH2CH2CF2), 30.9 (t, J = 22.5 Hz, CH2CF2), 69.5 (OCH2), 109.5 (C1, C4), 127.1 (C5, C8), 128.3 (C4a, C9a), 133.8 (C6, C7 and C8a, C10a), 153.9 (C2, C3), 182.8 (C9, C10). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.0 (2 F, CF2CF3), -124.4 (2 F, CF2CF2CF3), -114.6 (2 F, CH2CF2), -81.0 (3 F, CF3). IR (KBr): 2919, 2850, 1731, 1672, 1578, 1515, 1470, 1377, 1335, 1318, 1221, 1134, 1110, 1087, 1044, 1012 cm−1. Anal. Calcd for C42H46F18O4: C, 52.72; H, 4.85; Found: C, 52.95; H, 5.02.
4.4. General procedure for synthesis of fluoroalkyl-containing bromides 7ab (Scheme 2-i) In a three-necked round flask, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) (1.2 equivalent), triphenylphosphine (PPh3) (1.2 equivalent), and tetrabutylammonium bromide (TBAB) (1.2 equivalent) were dissolved in dried CH2Cl2. Fluoroalkyl-containing alcohol 4a or 4b (1 equivalent) was added to the reaction mixture and the solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane) to yield fluoroalkyl-containing bromides 7a (81.5%) or 7b (83.9%) as colorless liquid.
4.5.2. 9b. 2,3-bis[(11,11,12,12,13,13,14,14,15,15,16,16,16-tridecafluorohexadecyl)oxy]-9,10-anthraquinone (Anq-H10F6) 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.31–1.41 (m, 20H, (CH2)5CH2CH2CF2), 1.51 (m, 4H, OCH2CH2CH2), 1.60 (m, 4H, CH2CH2CF2), 1.90 (m, 4H, OCH2CH2), 2.04 (m, 4H, CH2CF2), 4.19 (t, J = 6.6 Hz, 4H, OCH2), 7.68 (s, 2H, H1, H4), 7.75 (m, 2H, H6, H7), 8.26 (m, 2H, H5, H8). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.3 (CH2CH2CF2), 26.1 (O(CH2)2CH2), 29.0–29.6 (OCH2CH2, (CH2)5CH2CH2CF2), 31.0 (t, J = 22.5 Hz, CH2CF2), 69.5 (OCH2), 109.5 (C1, C4), 127.1 (C50, C8), 128.3 (C4a, C9a), 133.8 (C6, C7 and C8a, C10a), 153.9 (C2, C3), 182.8 (C9, C10). 19F NMR (564 MHz, CDCl3): δ (in ppm) = -126.1 (2 F, CF2CF3), -123.5 (2 F, CH2CF2CF2), -122.8 (2 F, CF2CF2CF3), -121.9 (2 F, CF2CF2CF2CF3), -114.4 (2 F, CH2CF2), -80.7 (3 F, CF3). IR (KBr): 2919, 2850, 1729, 1672, 1578, 1515, 1469, 1376, 1335, 1318, 1240, 1145, 1111, 1086, 1050, 1012 cm−1. Anal. Calcd for C46H46F26O4: C, 47.76; H, 4.01; Found: C, 47.62; H, 3.92.
4.4.1. 7a. 11,11,12,12,13,13,14,14,14-nonafluorotetradecyl bromide [20] 1 H NMR (600 MHz, CDCl3) : δ (in ppm) = 1.28–1.33 (m, 8H, (CH2)4CH2CH2CH2CF2), 1.37 (m, 2H, CH2CH2CH2CF2), 1.42 (m, 2H, BrCH2CH2CH2), 1.59 (m, 2H, CH2CH2CF2), 1.85 (m, 2H, BrCH2CH2), 2.04 (m, 2H, CH2CF2), 3.41 (t, J = 7.2 Hz, 2H, BrCH2). 13C NMR (150 MHz, CDCl3): δ (in ppm) = 20.2 (CH2CH2CF2), 28.3 (BrCH2CH2CH2), 28.9 (BrCH2CH2CH2CH2), 29.2 (CH2CH2CH2CF2), 29.3–29.5 ((CH2)3CH2CH2CH2CF2), 30.9 (t, J = 22.5 Hz, CH2CF2), 33.0 (BrCH2CH2), 34.1 (BrCH2). 19F NMR (564 MHz, CDCl3): δ (in ppm) = 29
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4.6. Gelation Stock solutions of the fluoroalkyl-containing anthracene and the fluoroalkyl-containing anthraquinone in chloroform were prepared. Aliquots of the solutions were transferred to screw tubes and chloroform was evaporated. Then, perfluorodecalin (PFD) was added and the solution was heated in a water bath to dissolve the fluoroalkyl-containing compounds. After cooling the solution to room temperature, gelation was confirmed when the solution remained at the bottom of the tube even after inversion.
[5] [6] [7]
4.7. Cell culture NIH 3T3 cells were incubated in culture medium (DMEM/F-12) supplemented with 10% FBS and 1% antibiotic-antimycotic. Cells (1.0 × 104 cells per well) were seeded in 96-well plate (Nunclon Delta Surface, Thermo Fisher Scientific) and incubated (5% CO2, 37 °C) for cell attachment to the plate. After 24 h, culture medium was replaced with a prepared fluorous gel of PFD from 5 mM of Anq-H10F4 or AnqH10F6. After 24-h incubation with the fluorous gel, brightfield images of cells were obtained and the number of living cells were counted from the images.
[8]
[9] [10]
Acknowledgments
[11]
We are grateful to Prof. Masaru Ogura and Dr. Takahiko Moteki of Institute of Industrial Science (IIS), The University of Tokyo, for the SEM measurement. We also thank Prof. Kazuaki Kudo and Dr. Kengo Akagawa of IIS, The University of Tokyo, for the IR measurement.
[12]
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jfluchem.2019.04.008.
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