2-(Methylthio)-1,3-dithiolium tetrafluoroborate (3)115
1,3-Dithiole-2-thione 2 (5.29 g, 39.39 mmol) was suspended in Me2SO4 (39.4
mL, 416.40 mmol), heated at 95 ºC during 30 minutes and then left to cool to 0 ºC. At this temperature, glacial acetic acid (8 mL) was added and kept stirring during 10 minutes. HBF4-Et2O (5.4 mL, 39.39 mmol) was added and
the solution was stirred during 20 minutes extra, followed by the addition of diethyl ether (125 mL) to yield a precipitate that was filtered and washed with diethyl ether (95 %).
1
H-NMR (DMSO-d6, 300 MHz), δ: 8.73 (s, 2H), 3.17 (s, 3H).
2-(Methylthio)-1,3-dithiole (4)115
NaBH4 (0.28 g, 7.41 mmol) was slowly added to a 0 ºC cooled solution of 2-
(methylthio)-1,3-dithiolium tetrafluoroborate 3 (1.72 g, 7.29 mmol) in absolute ethanol under Ar atmosphere, and the mixture was kept stirring during 2 hours. The solvent was removed under reduced pressure, washed with water and extracted with DCM. The organic layer was dried over MgSO4,
filtered and taken to dryness to yield the desired product as a dark oil (95 %).
1
H-NMR (CDCl3, 300 MHz), δ: 6.12 (s, 1H), 6.07 (s, 2H), 2.20 (s, 3H).
1,3-Dithiolium tetrafluoroborate (5)115
To a solution of 2-(methylthio)-1,3-dithiole 4 (0.77 g, 5.12 mmol) in acetic anhydride (12.5 mL) at 0 ºC, HBF4·Et2O (0.7mL, 5.22 mmol) was added
dropwise. The solution was stirred during 15 minutes, when diethyl ether (125 mL) was added. The mixture was stirred again during 30 minutes to yield a white solid that was filtered and washed with ether (95 %).
1
91
Dimethyl-(1,3-dithiol-2-yl)-phosphonate (6)115
To a solution of 1,3-dithiolium tetrafluoroborate 5 (0.63 g, 3.31 mmol) in acetonitrile, P(OMe)3 (0.4 mL, 3.31 mmol) and NaI (0.48 g, 3.31 mmol) was
added successively, stirring the resultant mixture at r.t. during 2 hours. The crude reaction solvent was then removed under reduced pressure, washed with water and extracted with DCM. The organic layer is dried over MgSO4,
filtered and the solvent is removed to yield the desired product as a dark oil (90 %).
1H NMR (CDCl
3, 300 MHz), δ: 5.98 (2H, s), 4.73 (d, 1 H, J = 4.5 Hz), 3.75 (d, 6H,
J = 10.5 Hz).
2-(((Tert-butyldiphenylsilyl)oxy)methyl)anthraquinone (8)131
2-Hydroxymethylanthraquinone 7 (1.00 g, 4.20 mmol) was dissolved in 50 mL of anhydrous THF and, under argon atmosphere, imidazole (1.43 g, 21.00 mmol) and tert-butyldiphenylsilane chloride (1.3 mL, 5.03 mmol) were added. The reaction mixture was kept stirring overnight. Then, the solvent was removed under reduced pressure and the residue was dissolved in DCM and washed with water. The organic layer was dried with MgSO4 and filtered,
the solvent was then evaporated to yield a crude that is purified by silica gel column chromatography, using a hexane/DCM (2:1) mixture as eluent. The final product was obtained as a pale yellow solid (90 %).
1
H-NMR (CDCl3, 300 MHz), δ: 8.33-8.25 (m, 4H), 7.83-7.79 (m, 3H), 7.73- 7.70
(m, 4H), 7.47-7.38 (m, 6H), 4.92 (s, 2H), 1.16 (s, 9H).
92
2-(((Tert-butyldiphenylsilyl)oxy)methyl)-9,10-bis(1,3-dithiol-2-ylidene)-9,10- dihydroanthracene (9)114
A volume of 2.0 mL of nBuLi (1.6 M in hexane, 3.20 mmol) was added to a solution of dimethyl (1,3-dithiol-2-yl)phosphonate 6 (0.58 g, 2.75 mmol) in anhydrous THF (100 mL) at -78 ºC under argon atmosphere and the mixture was kept stirring during 45 minutes at the same temperature. Then, 2-(((tert- butyldiphenylsilyl)oxy)methyl)anthraquinone 8 (0.22 g, 0.47 mmol) was dissolved in anhydrous THF (100 mL) and added dropwise. The mixture was kept at -78 ºC during 1 hour and then was left to reach r.t. overnight. The solvent was removed under reduced pressure and the crude was washed with water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers are washed with water (2 x 100 mL) and a saturated NaCl aqueous solution (2 x 100 mL), dried over MgSO4 and filtered. The solvent
was removed and the residue was purified by silica gel column chromatography using an hexane/DCM (2:1) mixture as eluent. The final product was obtained as a yellow solid (96 %).
1
H-NMR (CDCl3, 300 MHz), δ: 8.25-8.14 (m, 7H), 8.03-7.72 (m, 10H), 6.79 (s,
4H), 4.83 (m, 2H), 1.16 (s, 9H).
2-(hydroxymethyl)-9,10-bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracene (10)114
To a solution of 2-(((tert-butyldiphenylsilyl)oxy)methyl)--exTTF 9 (0.29 g, 0.50 mmol) in anhydrous THF, a volume of 0.16 mL of TBAF (0.54 mmol, 1.0 M in THF) was added under argon atmosphere. The mixture was kept stirring during 2 hours at r.t. After this time, the reaction mixture was washed with water and extracted with DCM. The organic layer was dried over MgSO4,
filtered and the solvent was removed. The residue was purified by silica gel column chromatography, using DCM as eluent, to yield a yellow solid (98 %).
93 1 H-NMR (DMSO-d6, 300 MHz), δ: 7.66-7.57 (m, 4H), 7.36-7.23 (m, 3H), 6.74- 6.73 (m, 4H), 5.29 (t, 1H, J = 5.6 Hz), 4.54 (d, 2H, J = 5.6 Hz). [9,10-Bis(1,3-dithiol-2-ylidene)-9,10-dihydroanthracen-2-yl]methyl methanesulfonate (11)116
A solution of 2-hydroxymethyl--exTTF 10 (0.17 g, 0.42 mmol), triethylamine (0.06 mL, 0.4 mmol) and methanosulfonyl chloride (0.04 mL, 0.55 mmol) in anhydrous DCM (50 mL) was stirred during 2 hours. The reaction mixture was then washed with water (2 x 100 mL) and extracted with (2 x 75 mL) DCM. The organic layer was washed again with water (2 x 100 mL), dried over MgSO4 and filtered. After removing the solvent, the crude was quickly
percolated over silica gel using DCM as eluent, to yield a yellow solid (95 %).
1
H-NMR (CDCl3, 200 MHz), : 7.71-7.67 (4H, m), 7.45-7.29 (3H, m), 6.32 (4H,
s) 4.65 (2H, s), 3.07 (3H,s).
9,10-Bis(1,3-dithiol-2-yliden)-2-azidomethyl-9,10-dihidroanthracene (12)116
A 2--exTTF-methyl mesylate 11 (0.21 g, 0.24 mmol) suspension in acetonitrile (100 mL) was heated at 60 ºC under argon atmosphere. Previously activated sodium azide (0.82 g, 12.60 mmol) was added in small portions and the mixture was stirred overnight. The reaction was left to get r.t. and water was added (100 mL). The crude was extracted with DCM (2 x 100 mL) and the organic layer was dried over MgSO4, filtered and taken to
dryness. The residue was purified by silica gel column chromatography using a hexane/DCM (1:1) mixture as eluent to yield a yellow solid (95 %).
1
H-NMR (CDCl3, 200 MHz), : 7.70-7.67 (4H, m), 7.43-7.21 (3H, m), 6.31 (4H,
94
Methyl 3,5-bis(propargyloxy)benzoate (14)117
Methyl 3,5-dihydroxybenzoate 13 (6.00 g, 35.70 mmol) was dissolved in a K2CO3 (12.33 g, 89.20 mmol) suspension in acetone. The mixture was heated
at 50 ºC and propargyl bromide was then added, keeping stirring overnight. The mixture was filtered and the solvent was removed to yield the desired product as pale brown crystals (98 %)
1
H-NMR (CDCl3, 300 MHz), : 7.31 (d, 2H, J = 2.3 Hz), 6.83 (t, 1H, J = 2.3 Hz),
4.73 (d, 4H, J = 2.4 Hz), 3.92 (s, 3H), 2.55 (t, 2H, J = 2.4 Hz).
3,5-Bis(propargyloxy)benzyl alcohol (15)117
To a stirred solution of methyl 3,5-bis(propargyloxy)benzoate 14 (2.05 g, 8.40 mmol) in anhydrous THF (75 ml), lithium aluminum hydride (0.49 g, 12.6 mmol) in small portions was added. A few minutes later, a white solid appears suspended into the reaction mixture. The remaining lithium aluminum hydride was then quenched with AcOEt and EtOH consecutively, and the mixture was filtered under vacuum, rinsing the solid with DCM. The filtrate was dried with MgSO4 filtered and taken to dryness, yielding the
desired product as white crystals (90 %).
1
H-NMR (CDCl3, 300 MHz), : 6.56 (d, 2H, J = 2.2 Hz), 6.46 (t, 1H, J = 2.2 Hz),
4.61 (d, 4H, J = 2.4 Hz), 4.45 (s, 2H), 2.46 (t, 2H, J = 2.4 Hz), 1.67 (bs, 1H).
3,5-Bis(propargyloxy)benzyl chloride (16)117
3,5-Bis(propargyloxy)benzyl alcohol 15 (0.500 g, 2.31 mmol) was dissolved in anhydrous DCM (25 mL) and pyridine (0.37mL, 4.62 mmol). Thionyl chloride (0.25 mL, 3.47 mmol) was then added dropwise and the mixture was kept stirring under Ar atmosphere overnight. The reaction was quenched with water and the organic layer separated and washed again with water (3 x 50 mL). The organic layer was dried over MgSO4, filtered and the solvent was
95 removed. The crude was purified by silica gel column chromatography using a DCM/Hexane (2:1) mixture as eluent to yield the desired product as a white solid (95 %). 1 H-NMR (CDCl3, 300 MHz), : 6.80 (d, 1H, J = 2.2 Hz), 6.59 (t, 2H, J = 2.2 Hz), 4.73 (d, 4H, J = 2.4 Hz), 4.55 (s, 2H), 2.57 (t, 2H, J = 2.4 Hz). 5-(Chloromethyl)-1,3-bis(((9,10-di(1,3-dithiol-2-ylidene)-9,10- dihydroanthracen-2-yl)methyl)-1H-4-(1,2,3-triazolyl)methyloxy) benzene (17)
A DMSO suspension of azidomethyl--exTTF 12 (0.150 g, 0.345 mmol), 3,5- bis(propargyloxy)benzyl chloride 16 (0.041 g, 0.173 mmol), CuBr·SMe2 (0.014
g, 0.07 mmol), sodium ascorbate (0.009 g, 0.07 mmol) and copper wires were sealed under Ar atmosphere and irradiated under microwave conditions (110 ºC, 850 W) during 2 hours. The resulting dark solution was percolated through a small column containing Quadrasyl-MT to remove the remaining copper. Ethanol was then added to precipitate the desired product that after several cycles of centrifugation/EtOH washing was isolated as a dark yellow solid (65 %).
1
H-NMR (CDCl3, 300 MHz), : 7.71-7.63 (Ar-H, m, 6H), 7.58 (N-CH, s, 2H), 7.51
(Ar-H, d, 2H, J = 1.3 Hz), 7.31-7.25 (Ar-H, m, 4H), 7.16 (Ar-H, d, 2H, J = 8.1 Hz), 6.59 (Ar-H, s, 2H), 6.55 (Ar-H, s, 1H), 6.27 (S-CH, s, 4H), 6.23 (S-CH, d, 2H, J = 6.7 Hz), 6.18 (S-CH, d, 2H, J = 6.7 Hz), 5.53 (CH2N, s, 4H), 5.13 (CH2O, s, 4H),
4.45 (CH2Cl, s, 2H).
13
C-NMR (CDCl3, 75 MHz), : 159.6 (ArC-O), 144.4 (C-N), 139.7 (ArC-CH2Cl),
137.0 (ArC), 136.8 (ArC), 136.3 (ArC), 135.8 (ArC), 135.2 (ArC), 135.1 (ArC), 131.9 (ArC), 126.2 (ArCH), 126. 1(ArCH), 125.6 (ArCH), 125.5 (ArCH), 125.0 (ArCH), 124.9 (ArCH), 124.5 (ArCH), 122.9 (N-CH), 121.4 (ArC-S), 121.1 (ArC- S), 117.4 (SCH), 117.1 (SCH), 108.1 (ArCH), 101.8 (ArCH), 62.3 (CH2N), 54.2
(CH2OAr), 46.1 (CH2Cl).
FTIR (CHCl3) cm-1: 3068, 3009, 2926, 2859, 1666, 1599, 1548, 1510, 1457,
96
HRMS (MALDI): m/z calculated for C55H37ClN6O2S8Na: 1127.0330,
experimental: 1127.0365. UV-Vis (CHCl3), λmax: 367, 414, 425 nm. m.p. (ºC):275-277. 5-(Azidomethyl)-1,3-bis(((9,10-di(1,3-dithiol-2-ylidene)-9,10- dihydroanthracen-2-yl)methyl)-1H-4-(1,2,3-triazolyl)methyloxy) benzene (18)
A solution of chloride 17 (0.050 g, 0.05 mmol) and NaN3 (0.059 g, 0.90 mmol)
in THF/water was heated under Ar atmosphere at 70 ºC overnight. The reaction was followed by 1H-NMR observing the decrease in the methylene signal at 4.45 ppm and the increase in the signal at 4.22 ppm corresponding to the azidomethyl group. When the CH2Cl signal disappeared totally, the
reaction was allowed to reach r.t. The crude is extracted with CHCl3, dry over
MgSO4, filtered and taken to dryness, yielding the desired product as a dark
yellow product (98 %).
1
H-NMR (CDCl3, 300 MHz), : 7.71-7.63 (Ar-H, m, 6H), 7.59 (N-CH, s, 2H), 7.53
(Ar-H, d, 2H, J = 1.3 Hz), 7.30-7.25 (Ar-H, m, 4H), 7.18 (Ar-H, d, 2H, J = 8.1 Hz), 6.57 (Ar-H, s, 1H), 6.52 (Ar-H, m, 2H), 6.29 (S-CH, s, 4H), 6.25 (S-CH, d, 2H, J = 6.7 Hz), 6.20 (S-CH, d, 2H, J = 6.7 Hz), 5.54 (CH2N, s, 4H), 5.15 (CH2O, s, 4H),
4,22 (CH2N3, s, 2H). 13
C-NMR (CDCl3, 75 MHz), : 159.9 (ArC-O), 144.4 (C-N), 140.8 (ArC-CH2Cl),
137.1 (ArC), 136.9 (ArC), 136.5 (ArC), 136.0 (ArC), 135.3 (ArC), 135.2 (ArC), 131.9 (ArC), 126.3 (ArCH), 126.2(ArCH), 126.1 (ArCH), 125.7 (ArCH), 125.1 (ArCH), 125.0 (ArCH), 124.7 (ArCH), 123.0 (N-CH), 121.8 (ArC-S), 121.6 (ArC- S), 117.5 (SCH), 117.2 (SCH), 107.8 (ArCH), 101.9 (ArCH), 62.3 (CH2N), 54.2
(CH2OAr), 29.9 (CH2 N3).
FTIR (CHCl3) cm-1: 2924, 2856, 2099, 1735, 1597, 1548, 1511, 1459, 1349,
1259, 1217, 1161, 1049, 801, 755.
HRMS (MALDI): m/z calculated for C55H37N9O2S8Na: 1134.0734.
97 UV-Vis (CHCl3), λmax (log ε): 369 , 416 , 423 nm.
m.p. (ºC):260-263.
2-((methylsulfonyloxy)methyl)anthraquinone (19)
A solution of 2-hydroxymethylanthraquinone (0.25 g, 1.05 mmol), methanosulfonyl chloride (0.2 mL, 2.10 mmol) and triethylamine (0.3 mL, 2.10 mmol) in anhydrous DCM (50 mL) was stirred during 2 hours. The reaction mixture was then washed with water (2 x 50 mL) and extracted with DCM (2 x 75 mL). The organic layer was washed again with water (2 x 50 mL), dried over MgSO4 and filtered. After removing the solvent, the crude was
quickly percolated over silica gel using DCM as eluent, to yield a yellow solid (95 %). Because its low stability, only 1H-NMR could be performed.
1
H-NMR (CDCl3, 200 MHz), : 8.39 (d, 1H, J = 8.0 Hz), 8.38-8.31 (m, 3H), 7.86
(dd, 1H, J = 8.0 Hz, J = 2.0 Hz), 7.85 (d, 1H, J = 6.0 Hz), 7.84 (d, 1H, J = 6.0 Hz), 5.40 (s, 2H), 3.1 (s, 3H).
2-(Azidomethyl)anthraquinone (20)132
A modified procedure was utilized for the preparation of 20. A 2-(methyl methanesulfonate)anthraquinone 19 (1.33 g, 0.24 mmol) suspension in acetonitrile (50 mL) was heated at 60 ºC under argon atmosphere. Previously activated sodium azide (8.20 g, 126.00 mmol) was added in little portions and the mixture was stirred overnight. The reaction was left to get r.t. and water was added (100 mL). The crude was extracted with DCM(2 x 100 mL) and the organic layer was dried over MgSO4, filtered and taken to dryness.
The residue was purified by silica gel column chromatography using a hexane/DCM (1:1) mixture as eluent to yield a yellow solid (95 %).
1
H-NMR (CDCl3, 200 MHz), : 8.36 (d, 1H, J = 8.1 Hz), 8.35 (d, 1H, J = 5.7 Hz),
8.34 (d, 1H, J = 5.7 Hz), 8.27 (d, 1H, J = 1.7 Hz), 7.84 (d, 1H, J = 5.7 Hz), 7.84 (d, 1H, J = 5.7 Hz), 7.78 (dd, 1H, J = 8.0 Hz, J = 1.7 Hz), 4.58 (s, 2H).
98
2-Azidomethyl-9,10-bis-(dicyamomethylen)anthracene (21)
A solution of 2-(methyl azide)anthraquinone 20 (0.16 g, 0.61 mmol) and malonitrile (0.10 g, 1.52 mmol) in CHCl3 (50 mL) was heated under Ar
atmosphere at 65 ºC. Then, TiCl4 and pyridine are added dropwise, keeping
the solution stirring at this temperature 24 hours. The same amounts of malonitrile, TiCl4 and pyridine are added again, stirring 24 hours more. The
reaction mixture was left to reach r.t. and filtered over celite, washed with water, dry over Na2SO4, and filtered. The crude was taken to dryness and
then purified by silica gel column chromatography using a hexane/DCM (2:1) mixture as eluent to yield a yellow solid (90 %).
1
H-NMR (CDCl3, 300 MHz), : 8.22-8.16 (m, 3H), 8.14 (d, 1H, J = 1.4 Hz), 7.72-
7.65 (m, 2H), 7.62 (dd, 1H, J = 8.1 Hz, J = 1.7 Hz), 4.52 (s, 2H).
13
C-NMR (CDCl3, 75 MHz), : 160.2 (ArC), 160.0 (ArC), 141.5 (C-CH2N3), 133.0
(ArCH), 131.9 (ArCH), 131.2 (ArC), 130.5 (ArC), 130.4 (ArC), 128.5 (ArCH), 128.1 (ArCH), 127.1 (ArCH), 113.3 (C≡N), 84.0 (C-C≡N), 83.7 (C-C≡N), 54.1 (CH2N3).
FTIR (CHCl3) cm-1: 3005, 2970, 2228, 2105, 1589, 1560, 1337, 1282, 1221,
836, 767, 694.
HRMS (MALDI): m/z calculated for C21H9N7Na: 382.0817. Experimental:
382.08205.
UV-vis (CHCl3), λmax: 354 nm.
99
5-(Chloromethyl)-1,3-bis(((9,10-bis(dicyanomethylidene)-9,10-
dihydroanthracen-2-yl)methyl)-1H-4-(1,2,3-triazolyl)methyloxy) benzene (22)
A DMSO suspension of azidomethyl-TCAQ 21 (0.306 g, 0.85 mmol), 3,5- bis(propargyloxy)benzyl chloride 16 (0.100 g, 0.42 mmol), CuBr·SMe2 (0.035
g, 0.17 mmol), sodium ascorbate (0.022 g, 0.17 mmol) and copper wires were sealed under Ar atmosphere and irradiated under microwave conditions (110 ºC, 850 W ) during 2 hours. The resulting dark solution was percolated through a small column containing Quadrasyl-MT to remove the remaining copper. Ethanol was then added to precipitate the desired product that after several cycles of centrifugation/EtOH washing was isolated as dark yellow solid (85 %).
1
H-NMR (CDCl3, 300 MHz), : 8.28-8.21 (Ar-H, m, 6H), 7.95 (N-CH, s, 2H),
7.77-7.74 (Ar-H, m, 6H), 7.61 (Ar-H, dd, 2H, J = 8.0 Hz, J = 1.5 Hz), 6.62 (Ar-H, d, 2H, J = 2.2 Hz ), 6.58 (Ar-H, t, 1H, J = 2.2 Hz), 5.71 (CH2N, s, 4H), 5.20
(CH2O, s, 4H), 4.48 (CH2Cl, s, 2H).
13
C-NMR (CDCl3, 75 MHz), : 159.4 (ArC), 159.3 (ArC-O), 145.0 (C-N), 139.7
(ArC-CH2Cl), 132.7 (ArCH), 131.3 (ArCH), 131.2 (ArC), 130.4 (ArC), 129.9 (ArC),
128.4 (ArCH), 127.7 (ArCH), 126.4 (ArCH), 123.5 (N-CH), 113.1 (C≡N), 113.0 (C≡N), 112.9 (C≡N), 112.8 (C≡N), 108.3 (ArCH), 102. (ArCH), 83.6 (C-C≡N), 62.0 (CH2N). 53.0 (CH2OAr), 46.1 (CH2Cl).
FTIR (CHCl3) cm-1: 3145, 3072, 2932, 2228, 1596, 1558, 1459, 1329, 1294,
1225, 1158, 1048, 825, 771, 733, 693.
HRMS (MALDI): m/z calculated for C55H29ClN14O2Na: 975.2184, experimental:
975.2197.
UV-Vis (CHCl3), λmax (log ε): 353 (4.79) nm.
100
5-(Chloromethyl)-1,3-bis(((9,10-bis(dicyanomethylidene)-9,10-
dihydroanthracen-2-yl)methyl)-1H-4-(1,2,3-triazolyl)methyloxy) benzene (24)117
A suspension of benzylazide 23 (0.306 g, 0.85 mmol), 3,5- bis(propargyloxy)benzyl alcohol 16 (0.100 g, 0.42 mmol), CuBr·SMe2 (0.035 g,
0.17 mmol), sodium ascorbate (0.022 g, 0.17 mmol) and some copper wires in a tBuOH/H2O (1:1) mixture was sealed under Ar atmosphere and kept
stirring during 48 hours. The resulting dark solution was percolated through a small column containing Quadrasyl-MT to remove the remaining copper. The collected fraction was extracted with chloroform (2 x 25 mL) and the resulting organic layer was washed with water, dried over Na2SO4 and then
filtered. The solvent was finally removed to afford a pale yellow oil (90 %).
1
H-NMR (CDCl3, 300 MHz), : 7.55 (N-CH, s, 2H), 7.39-7.32 (Ar-H, m, 6H),
7.29-7.25 (Ar-H, m, 4H), 6.60 (Ar-H, d, 2H, J = 2.2 Hz ), 6.54 (Ar-H, t, 1H, J = 2.2 Hz), 5.52 (CH2N, s, 4H), 5.12 (CH2O, s, 4H), 4.46 (CH2Cl, s, 2H).
101
1.4.2. SYNTHESIS AND CHARACTERIZATION OF NANOCONJUGATES