Appendix A.2. Syntheses of Fluorocompounds (4)–(12)
Appendix A.2.1. Synthesis of Bis-(4-trifluoromethoxybenzoyl) Peroxide (4)
Demineralized water (25 mL) was measured into a round-bottomed flask and cooled to 0–5 °C. Sodium peroxide (3.0 g, 0.04 mol) was added. A solution of 4-trifluoromethoxybenzoyl chloride (11.2 g, 0.05 mol) in toluene (25 mL) was then added immediately. The reaction flask was stoppered and the mixture stirred vigorously for 2 h. The peroxide product was filtered off, washed with cold demineralised water and dried. It was obtained as a white powder (5.95 g, 58% yield). After recrystallization from dry toluene (100 mL), it had:
Mpt: 73–75 °C.
IR Spectrum: νmax 3113 (Ar C–H), 1766 (C=O), 1606 (C=C), 1505 (C–C), 1279 (C–O), 1208 cm−1
(C–F).
1H-NMR Spectrum (in CD2Cl2): δ 7.45 (d, 4H), 8.2 ppm (d, 4H).
19F-NMR Spectrum (in CD2Cl2): δ -53 ppm.
Appendix A.2.2. Synthesis of CTA (5)
(a) 2-(4-Trifluoromethyl)phenylpropene: A sodium hydride dispersion in mineral oil (60% by weight sodium hydride, 1.6 g, 0.04 mol) was added to a solution of methyltriphenylphosphonim bromide (12.9 g, 0.036 mol) in anhydrous diethyl ether (50 mL) in a round-bottomed flask. The mixture was stirred under reflux (~45 °C), under dry nitrogen, for 3 h. 4-Trifluoromethylacetophenone (4.7 g, 0.025 mol) in anhydrous diethyl ether (15 mL) was added dropwise and the reaction mixture was stirred under reflux (~45 °C) overnight (16 h). The reaction mixture was added to demineralized water (100 mL) and the product was extracted with dichloromethane (3×, 50 mL). The combined dichloromethane extracts were dried and concentrated and the product mixture was dried. The desired product was distilled under reduced pressure from the crude reaction product in a Kugelröhr apparatus (Büchi UK, Newmarket, UK). The product was an oil (3.07 g, 66% yield). It had:
Bpt: 174–174.5oC
MS (CI) m/z: 186 (M, 100%), 117 (37%), 59 (42%).
IR Spectrum: νmax 3088 (Ar C–H), 3050 (Ar C–H), 2975 (C–H), 2946 (C–H), 1631 (C=C), 1600
(C=C), 1495 (C–C), 1442 (C–C), 1233 cm−1 (C–F).
1H-NMR Spectrum: δ 2.2 (s, 3H), 5.15 (d, 1H), 5.42 (d, 1H), 7.25–7.6 ppm (m, 4H).
19F-NMR Spectrum: δ -59 ppm (s).
(b) 4-Fluorodithiobenzoic acid: Magnesium turnings (2.0 g, 0.082 mol), a catalytic amount of iodine, 1-bromo-4-fluorobenzene (1.0 g) and dry tetrahydrofuran (10 mL) were placed in a dry round-bottomed flask in an ice-water bath. The flask was flushed with dry nitrogen for 20 min. When the Grignard reaction commenced, a solution of 1-bromo-4-fluorobenzene (14 g, 0.08 mol) in dry tetrahydrofuran (30 mL) was added dropwise over 30 min. The Grignard reaction finished in 1.5 h. Carbon disulphide (6.1 g, 0.08 mol) was then added dropwise over 20 min, maintaining the reaction temperature below 20 °C. The reaction mixture was stirred at 20 °C under dry nitrogen for a further 1 h. The product was hydrolyzed by the slow addition of cold distilled water (100 mL). The salts formed, along with any excess magnesium turnings, were removed by filtration. The tetrahydrofuran solvent was removed under reduced pressure. The remaining reaction mixture was acidified to pH 1 by dropwise addition of fuming hydrochloric acid (37%). The colour of the reaction solution changed from brown-red to a permanent deep purple. The product was extracted with diethyl ether (3×, 200 mL). The organic phase was dried and concentrated under reduced pressure. The product was a purple oil (10.37 g, 84% yield). This was used immediately to prepare CTA (5).
(c) CTA (5): 4-Fluorodithiobenzoic acid (10.34 g, 0.07 mol) was dissolved in carbon tetrachloride (80 mL), in a round-bottomed flask. 2-(4-Trifluoromethylphenyl)propene (13.96 g, 0.075 mol) was added dropwise over 15 min. The reaction mixture was stirred under reflux (~70 °C), under dry nitrogen, for 18 h. The carbon tetrachloride solvent was then removed under reduced pressure, yielding the crude reaction product (19.12 g). The crude product was subjected to flash column chromatography on aluminium oxide (Aldrich, activated, neutral, Brockmann 1, grade 2, ca. 150 mesh), using hexane as the eluent. This gave the desired pure product as a viscous purple oil (7.34 g, 34% yield). It had:
MS (CI) m/z: 186 (100%), 117 (78%), 49 (71%).
EA: Expected%: C 55.48, H 4.07, S 18.51, F 21.97; Found%: C 55.23, H 3.82, S 18.56, F 22.39.
IR Spectrum: νmax 3067 (Ar C–H), 2970 (C–H), 2928 (C–H), 2869 (C–H), 1617 (C–C), 1594 (C–C),
1498 (C–C), 1409 (C–C), 1328 (Ar C–F), 1235 cm−1 (C–F).
1H-NMR Spectrum: δ 2.0 (s, 6H), 7.0–8.0 ppm (m, 8H).
19F-NMR Spectrum: δ -59 (s, CF3), −104 ppm (m, ArF).
Appendix A.2.3. Synthesis of E-4,4′-Bis(Trifluoromethyl)stilbene (6)
(a) 4-Trifluoromethylbenzyltriphenylphosphonium chloride: 4-Trifluoromethylbenzyl chloride (15.2 g, 0.08 mol) and triphenylphosphine (23.0 g, 0.088 mol) were weighed into a round-bottomed flask. Chloroform was added to dissolve the reactants. The reaction solution was stirred under reflux (~65 °C), under dry nitrogen for 48 h. The reaction solution was then concentrated under reduced pressure. A large excess of cold diethyl ether was added to dissolve any reactants and precipitate the salt product. The precipitate was filtered off and dried. The product was a white solid (36.2 g, 100% yield). It had:
Mpt: 348–350 °C.
EA: Expected%: C 68.35, H 4.63, Cl 7.76, P 6.78, F 12.48; Found%: C 68.10, H 4.23, Cl 8.99, P 6.08,
F 12.60.
IR Spectrum: νmax 3041 (Ar C–H), 2856 (C–H), 2785 (C–H), 1586 (C=C), 1435 (C–C), 1110 cm−1
(C–F).
1H-NMR Spectrum: δ 5.9–6.1 (d, 2H), 7.2–7.9 ppm (m, 19H).
19F-NMR Spectrum: δ -59 ppm (s).
(b) E-4,4′-Bis-(trifluoromethyl)stilbene (6): 4-Trifluoromethylbenzyltriphenyl phosphonium chloride (23.76 g, 0.052 mol) and 4-trifluoromethylbenzaldehyde (5.97 g, 0.034 mol) were weighed into a round-bottomed flask. Tetra-n-butylammonium bromide (phase transfer catalyst, 0.83 g, 0.003 mol), 10% aqueous sodium hydroxide (80 mL) and dichloromethane (80 mL) were added. The reaction mixture was stirred vigorously under dry nitrogen for 96 h. The product was extracted with dichloromethane (3×, 50 mL). The combined extracts were washed with demineralized water (5×, 100 mL), dried and concentrated under reduced pressure. TLC analysis, using hexane as the eluent, revealed a mixture of species present. Therefore, the product was passed through a column of aluminium oxide (Aldrich, activated, neutral, Brockmann 1, grade 1, ca. 150 mesh), using hexane as the eluent. Product containing fractions were combined and concentrated under reduced pressure and the products were dried. The Z-isomer was an oil and the E-isomer (4) a white solid (total mass 8.06 g, 75%; ratio of Z:E isomers 2.3:1.0). The E-isomer had:
Mpt: 130–131 °C, cf. literature value of 124–127 °C [
22].
IR Spectrum: νmax 3084 (Ar C–H), 3051 (Ar C–H), 1614 (C=C), 1418 (C–C), 1328 cm−1 (C–F).
1H-NMR Spectrum: δ 7.2–7.8 ppm (m, 10H).
19F-NMR Spectrum: δ -59 ppm (s).
Appendix A.2.4. Synthesis of 1,1-Bis-(4-Trifluoromethylphenyl)ethene (7)
(a) 1,1-bis-(4-trifluoromethylphenyl)ethanol: Magnesium turnings (3.16 g, 0.13 mol), a catalytic quantity of iodine and dry tetrahydrofuran (10 mL) were placed in a dry round-bottomed flask and flushed with dry nitrogen for 20 min. 4-Trifluoromethylbromobenzene (28.6 g, 0.127 mol) in dry tetrahydrofuran (60 mL) was added dropwise. Mild heating was used to commence the reaction. The remaining 4-trifluoromethylbromobenzene solution was added at a rate to maintain a steady reflux. The mixture was stirred at room temperature, under dry nitrogen, for 2 h. The reaction solution was cooled in ice to 0–5 °C. Ethyl acetate (2.25 g, 0.255 mol) dissolved in dry tetrahydrofuran (30 mL) was added dropwise over 15 min and the solution was heated under reflux (~75 °C) for 3 h. The reaction solution was cooled to 0–5 °C. Saturated aqueous sodium carbonate solution (50 mL) and 5% sodium thiosulphate solution (50 mL) were added. The product was extracted with diethyl ether (3×, 100 mL). The combined organic extracts were washed with demineralised water (100 mL), dried and concentrated under reduced pressure. The dried crude product, 1,1-bis-(para-trifluoromethylphenyl)ethanol, was a brown crystalline solid (17 g, 98% yield) and was used in further reactions without purification. It had:
Bpt: 334–336 °C, c.f. literature value of 330 °C [
23].
1H-NMR Spectrum: δ 2.1 (s, 3H), 7.15–7.4 ppm (dd, 8H).
(b) 1,1-Bis-(4-trifluoromethylphenyl)ethene (7): 1,1-Bis-(p-trifluoromethylphenyl)ethanol, potassium hydrogen sulphate (4.1 g, 0.03 mol) and chloroform (20 mL) were placed in a round-bottomed flask and stirred under reflux (~65 °C) for 3 h. The mixture was cooled and filtered. The filtrate was added to demineralized water (50 mL). The product was extracted with dichloromethane (3×, 50 mL). The combined organic extracts were dried and concentrated under reduced pressure. The dried product was an oil (4.65 g, 58% yield) which slowly crystallized. It had:
Mpt: 31–33 °C, cf. literature value of 33–34 °C [
24].
IR spectrum: νmax 3096 (Ar C–H), 3052 (Ar C–H), 1690 (C=C), 1616 (C=C), 1409 (C–C), 1328 cm−1
(C–F).
1H-NMR Spectrum: δ 5.65 (s, 2H), 7.4–7.8 ppm (m, 8H).
19F-NMR Spectrum: δ - 59 ppm (s).
Appendix A.2.5. 1,1-Bis-(4-(4,4,4-Trifluorobutoxy)phenyl)ethane (8)
(a) 4,4′-di(4,4,4-trifluorobutoxy)benzophenone: Potassium iodide (0.17 g, 0.001 mol), potassium carbonate (3.45 g, 0.05 mol) and anhydrous N,N-dimethylformamide (25 mL) were measured into a dry round-bottomed flask, which was cooled in an ice-water bath and flushed with dry nitrogen for 15 min. Then, 4,4′-Dihydroxybenzophenone (1.93 g, 0.009 mol), in anhydrous N,N-dimethylformamide (25 mL), was added dropwise over 15 min. The reaction solution was stirred under reflux (~130 °C), under dry nitrogen, for 3 h. The reaction mixture was then cooled in an ice-water bath and 1-bromo-4,4,4-trifluorobutane (4.0 g, 0.021 mol) in anhydrous N,N-dimethylformamide (25 mL) was added dropwise over 15 min. The reaction mixture was stirred under reflux (~90 °C), under dry nitrogen, for 17 h. Once cooled, the reaction solution was poured into 10% hydrochloric acid (100 mL). The desired reaction products were extracted using dichloromethane (3×, 100 mL) and the combined extracts were washed with demineralized water (10×, 100 mL), dried and concentrated under reduced pressure. The product was recrystallized from hot absolute ethanol. It was obtained as a white-pale yellow crystalline solid (3.86 g, 99% yield). It had:
Mpt: 163–165 °C.
EA: Expected%: C 58.07, H 4.64, F 26.24; Found%: C 57.59, H 4.70, F 26.19.
IR Spectrum: νmax 2955 (Ar C–H), 2886 (C–H), 1642 (C=O), 1600 (C=C), 1480 (C–C), 1253 (C–F),
1151 cm−1 (C–O).
1H-NMR Spectrum: δ 2.05–2.2 (m, 4H), 2.3–2.5 (m, 4H), 4.1–4.2 (t, 4H), 6.95–7.05 (d, 2H), 7.75–7.9
ppm (d, 2H).
19F-NMR Spectrum: δ -58 ppm (m).
(b) 1,1-Bis-(4-(4,4,4-trifluorobutoxy)phenyl)ethene (8): A sodium hydride dispersion in mineral oil (60% by weight sodium hydride, 0.8 g, 0.02 mol) was added to a suspension of methyltriphenylphosphonium bromide (6.43 g, 0.018 mol) in anhydrous diethyl ether (25 mL) in a round-bottomed flask. The mixture was stirred and heated under reflux (~50 °C) under dry nitrogen for 4 h. The reaction mixture was cooled and a solution of 4,4′-bis-(4,4,4-trifluoro- butoxy)benzophenone (3.8 g, 0.009 mol), in anhydrous diethyl ether (10 mL), was added dropwise over 30 min. The solution was stirred under reflux (~50 °C), under dry nitrogen, for 17 h. The reaction mixture was then added to demineralized water (100 mL) and the products were extracted with dichlormethane (3×, 100 mL). The combined extracts were dried and concentrated under reduced pressure. TLC analysis, using dichloromethane as the eluent, revealed a mixture of species to be present. Hence, the product mixture was subjected to column chromatography on silica gel using dichloromethane as eluent. Product-containing fractions were combined and concentrated under reduced pressure and dried. Removal of the solvent under vacuum left the product as a pale yellow crystalline solid (3.71 g, 98% yield). It had:
Mpt: 77–79 °C
EA: Expected%: C 61.11, H 5.13, F 26.36; Found%: C 61.14, H 5.91, F 25.74.
IR Spectrum: νmax 2954 (Ar C-H), 2925 (Ar C–H), 2871 (C–H), 1608 (C=C), 1475 (C–C), 1453 (C–
C), 1245 (C–F), 1152 cm−1 (C–O).
1H-NMR Spectrum: δ 2.05–2.2 (m, 4H), 2.3–2.5 (m, 4H), 4.05–4.15 (t, 4H), 5.3–5.4 (s, 2H), 6.85–
6.95 (d, 4H), 7.25–7.35 ppm (d, 4H).
19F-NMR Spectrum: δ -58 ppm (m).
Appendix A.2.6. Methyl E-3-Trifluoromethylcinnamate (9)
Pyridine (6.69 g, 0.084 mol), methanol (3.17 g, 0.098 mol) and dichloromethane (50 mL) were placed in a round-bottomed flask, which was cooled in an ice-water bath. E-3-trifluoromethylcinnamoyl chloride (13.84 g, 0.059 mol), dissolved in dichloromethane (50 mL), was added dropwise over 20 min. The reaction mixture was brought to room temperature and stirred under dry nitrogen for 67 h. The mixture was then washed with demineralized water (4×, 50 mL), 2 M hydrochloric acid (100 mL), saturated sodium hydrogen carbonate solution (100 mL) and saturated sodium chloride solution (100 mL). The dichloromethane solution was dried and concentrated under reduced pressure. The product was dried. The product, methyl E-3-trifluoromethylcinnamate (9), was obtained as a white crystalline solid (7.55 g, 56% yield). It had:
Mpt: 34–36 °C.
EA: Expected%: C 57.40, H 3.90, F 24.80; Found%: C 57.43, H 4.01, F 24.62.
IR Spectrum: νmax 3081 (Ar C–H), 2954 (C–H), 1723 (C=O), 1643 (C=C), 1442 (C–C), 1336 (C–F),
1166 cm−1 (C–O).
EA: Expected%: C 57.40, H 3.90, O 13.90, F 24.80; Found%: C 57.43, H 4.01, F 24.62.
1H-NMR Spectrum: δ 3.85 (s, 3H), 6.5–6.65 (d, 1H), 7.5–7.9 ppm (m, 5H).
19F-NMR Spectrum: δ -59 ppm (s).
Appendix A.2.7. Synthesis of 4,4,4-Trifluorobutyl E-Cinnamates (10)–(12)
(a) Synthesis of 4,4,4-Trifluorobutyl E-Cinnamate (10): Pyridine (0.55 g, 0.007 mol), 4,4,4-trifluorobutan-1-ol (1 g, 0.008 mol) and anhydrous dichloromethane (10 mL) were measured into a round-bottomed flask. The solution was stirred under dry nitrogen in an ice-water bath for 20 min. E-Cinnamoyl chloride (0.43 g, 0.003 mol) in anhydrous dichloromethane (10 mL) was added dropwise over 10 min. The reaction solution was allowed to come to room temperature and was then stirred for 90 h under dry nitrogen. The reaction mixture was washed with demineralized water (4×, 25 mL), 2 M hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL). The dichloromethane extract was dried and concentrated under reduced pressure. TLC analysis, using 20% diethyl ether in 40–65 °C petroleum ether as the eluent, revealed a mixture of species to be present. Hence, the product mixture was subjected to column chromatography on silica gel using 20% diethyl ether in 40–65 °C petroleum ether as the eluent. Product containing fractions were combined and concentrated under reduced pressure and the product was dried. The product was a pale yellow oil (0.27 g, 40% yield). It had:
Bpt: 288–292 °C.
EA: Expected%: C 60.46, H 5.07, F 22.07; Found%: C 60.29, H 5.30, F 21.95.
IR Spectrum: νmax 3063 (Ar C–H), 3030 (Ar C–H), 2961 (C–H), 2901 (C–H), 1723 (C=O), 1639
(C=C), 1451 (C–C), 1177 (C–F), 1051 cm−1 (C–O).
1H-NMR Spectrum: δ 1.8–2 (p, 2H), 2.1–2.3 (m, 2H), 4.15–4.3 (t, 2H), 6.35–6.45 (d, 1H), 7.3–7.4 (m,
3H), 7.4–7.55 (m, 2H), 7.6–7.75 ppm (d, 1H).
19F-NMR Spectrum: δ -58 ppm (m).
(b) Synthesis of 4,4,4-Trifluorobutyl E-4-Methoxycinnamate (11): 4,4,4-Trifluorobutyl E-p-methoxycinnamate (11) was synthesized using a similar method to above but starting with E-3-methoxycinnamoyl chloride (0.79 g, 0.004 mol). The reaction was carried out for 22 h. The product mixture was treated to column chromatography on silica gel using 50:50 diethyl ether: 40–65 °C petroleum ether as the eluent. The product was a pale yellow oil (0.53 g, 46% yield). It had:
Bpt: 268–271 °C.
EA: Expected%: C 58.33, H 5.25, F 19.77; Found%: C 59.30, H 5.65, F 18.93.
IR Spectrum: νmax 3064 (Ar C–H), 2961 (C–H), 2838 (C–H), 1713 (C=O), 1640 (C=C), 1454 (C–C),
1435 (C–C), 1158 (C–F), 1048 cm−1 (C–O).
1H-NMR Spectrum: δ 1.95–2.1 (p, 2H), 2.2–2.4 (m, 2H), 3.85–3.95 (s, 3H), 4.25–4.35 (t, 2H), 6.4–
6.55 (d, 1H), 6.95–7.05 (d, 1H), 7.05–7.15 (s, 1H), 7.15–7.2 (d, 1H), 7.3–7.4 (q, 1H), 7.65–7.8 ppm
(d, 1H).
19F-NMR Spectrum: δ -58 ppm (m).
(c) Synthesis of 4,4,4-Trifluorobutyl E-3-Methoxycinnamate (12): 4,4,4-Trifluorobutyl E-p-methoxycinnamate was synthesized using the same method but starting with E-4-methoxycinnamoyl chloride (0.79 g, 0.004 mol). The product mixture was subjected to column chromatography on silica gel using 40% diethyl ether in 40–65 °C petroleum ether as the eluent. The product was a pale yellow-green oil (0.4 g, 35% yield). It had:
Bpt: 280–283 °C.
EA: Expected%: C 58.33, H 5.25, F 19.77; Found%: C 58.78, H 5.47, F 19.22.
IR Spectrum: νmax 3059 (Ar C–H), 2961 (C–H), 2905 (C–H), 2841 (C–H), 1712 (C=O), 1634 (C=C),
1464 (C–C), 1455 (C–C), 1164 (C–F), 1026 cm−1 (C–O).
1H-NMR Spectrum: δ 1.95–2.1 (p, 2H), 2.2–2.4 (m, 2H), 3.85–3.95 (s, 3H), 4.25–4.35 (t, 2H), 6.3–6.4
(d, 1H), 6.95–7 (d, 2H), 7.45–7.6 (d, 2H), 7.6–7.8 ppm (d, 1H).
19F-NMR Spectrum: δ -58 ppm (m).