Effective monofunctional azaphthalocyanine photosensitizers for photodynamic therapy

Article abstract of DOI:10.1071/CH08392

In this work we present a rational design of the active part of third generation photosensitizers for photodynamic therapy based on phthalocyanine and an azaphthalocyanine core. The preferred zinc complexes of the AAAB type that contain bulky tert-butylsu

Full text of DOI:10.1071/CH08392

10.1071/CH08392
©CSIRO 2009
Accessory Publication: Australian Journal of Chemistry, 2009, 62(5),
425-433
Effective monofunctional azaphthalocyanine photosensitizers for
photodynamic therapy
Accessory Publication
Australian Journal of Chemistry
Petr Zimcik, Miroslav Miletin, Veronika Novakova, Kamil Kopecky, Marcela Nejedla, Vendula
Stara and Katerina Sedlackova
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Content
Content.......................................................................................................................................... S2
Synthesis ....................................................................................................................................... S3
NMR spectra................................................................................................................................. S5
UV-vis absorption, fluorescence emission and fluorescence excitation spectra .......................... S6
MS (MALDI-TOF) spectra........................................................................................................... S8
References:.................................................................................................................................. S10
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Synthesis
4,5-bis(tert-butylsulfanyl)phthalonitrile (12): NaH (60% mineral oil dispersion, 2.46 g, 61
mmol) has been washed from the mineral oil by dry hexane and dried using the argon stream.
Anhydrous DMF (100 mL) was added and the dispersion was cooled down to 0°C with
water/ice. 2-methylpropan-2-thiol (54 mmol, 6.1 mL) has been added dropwise under argon
atmosphere. After the stop of the gas evolution, Cu2O (52 mmol, 7.38 g) and 4,5-
dichlorophthalonitrile (25 mmol, 4.84 g) were added and the mixture was heated for 30 min at
90°C. The mixture was stirred and left to cool down at r.t. for next 30 min and poured into ice
cold water (500 mL). The suspension was filtered and the solid was extracted several times by
chloroform. The filtrate was also washed 3 times with chloroform and organic layer was dried.
The chloroform solutions of crude 12 were combined, evaporated and purified by column
chromatography on silica (chloroform/toluene 2:1) to receive white-yellow solid (4.85 g, 65%).
Mp 157.5-158°C (methanol) (lit.[1] 150-152°C). (Found: C 62.81, H 6.50, N 8.83%. C16H20N2S2
requires: C 63.12, H 6.62, N 9.20%.) δH (CDCl3) 1.44 (s, 18H, CH3), 7.86 ppm (s, 2H, aromH).
δC (CDCl3) 30.9, 49.6, 112.5, 115.2, 136.9, 146.9 ppm.
5,6-bis(tert-butylsulfanyl)pyrazine-2,3-dicarbonitrile (15): Aqueous NaOH solution (34.5 mL,
34.5 mmol) was slowly stirred at room temperature and 2,2-dimethyl-propane-1-thiol (4.0mL,
35.5 mmol) was added by syringe. Care was taken to put the thiol directly to the solution of
hydroxide. Mixture was stirred at r.t. for 30 min and a solution of 5,6-dichloropyrazine-5,6-
dicarbonitrile[2] (3.0 g, 15 mmol) in THF (80 mL) was added. Reaction was stirred for 15 min,
ethyl-acetate was added and two layers were separated. The water layer was washed two more
times with ethyl-acetate and discarded. Organic layers were combined, dried and evaporated.
The crude product was purified by flash chromatography on silica (toluene) to give yellow solid
(4.3 g, 93%). Mp 161.8-162.3°C (methanol)(lit.[1] 161-162°C). (Found: C 54.81, H 5.80, N
18.53%. C14H18N4S2 requires: C 54.87, H 5.92, N 18.28%.) δH (CDCl3) 1.64 ppm (s, 9H, CH3).
δC (CDCl3) 29.6, 52.3, 113.8, 125.0, 161.0 ppm.
[2,11(12),20(21),29(30)-Tetracarboxytetra[2,3]quinoxalinoporphyrazinato] magnesium (II)
(5): Anhydrous butanol (10 mL) was refluxed with magnesium (7 mmol, 168 mg) and a small
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crystal of iodine for 3 h. Compound 17 (1 mmol, 224 mg) was added and the reflux continued for
next 24 h. Solvent was evaporated and the green solid was stirred with 50% acetic acid (50 mL)
for 30 min. Crude product was filtered off and washed thoroughly and sonicated with 50% acetic
acid, water, acetone, pyridine, diethylether and dried. Black-blue solid (125 mg, 55%).
Compound is soluble in 1M aqueous NaOH (see Figure S1).
1.5
6 in pyridine
5 in aqueos NaOH
1.0
0.5
0.0
300
400
500
600
700
800
 / nm
Figure S1: UV-vis spectra of compound 5 in aqueous NaOH (1M) (blue) and compound 6 in pyridine
(red). Broad Q-band of 5 together with much stronger B-band than Q-band indicate strong aggregation.
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NMR spectra
The signals of aromatic hydrogens of
quinoxaline ring in dyes 1-4 are shifted to lower
fields comparing to precursors. The closer to
centre of the macrocycle, the stronger shift of
aromatic hydrogens was observed. Thus signal
of hydrogen Ha was detected close to 10 ppm
and hydrogens Hb and Hc fused together to form
one broad signal around 9 ppm. Even stronger
effect can be observed for hydrogens Hd of
benzene rings in 1 and 3 which are located
closer to the centre of macrocycle than
hydrogens Ha, Hb and Hc. The signal of these
aromatic hydrogens in phthalonitrile 12 appears
at 7.86 ppm (in CDCl3). After tetramerization,
these hydrogens are detected over 10 ppm
(C5D5N).
Figure S2. NMR spectra of a) 1, b) 2, c) 3, d) 4
in [D5]-pyridine and e) 16 in [D6]-acetone.
Asterisk indicates residuals of non-deuterated
solvent.
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UV-vis absorption, fluorescence emission and fluorescence
excitation spectra
For all following figures: solvent pyridine, UV-vis absorption spectra (red), fluorescence excitation
spectra (blue), fluorescence emission spectra (green). Emission spectra were taken after excitation at 375
nm. Wavelengths of emission that was observed during collecting the excitation spectra differ and are
mentioned for each compound.
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
500
600
700
800
900
500
600
700
800
900
 / nm
 / nm
Figure S3: Compound 1, emission wavelength
Figure S4: Compound 2, emission wavelength
770 nm.
750 nm.
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
500
600
700
800
900
500
600
700
800
900
 / nm
 / nm
Figure S5: Compound 3, emission wavelength
Figure S6: Compound 4, emission wavelength
770 nm.
750 nm.
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1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
500
600
700
800
900
500
600
700
800
900
 / nm
 / nm
Figure S7: Compound 6, Emission wavelength
Figure S8: Compound 7, Emission wavelength
800 nm.
800 nm.
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MS (MALDI-TOF) spectra
Enlarged parts of the MALDI-TOF spectrum of compound 7 (measured without addition of TFA) and
corresponding calculated isotope distributions. For comparison also the spectra calculated for [M+2X-H]+
(where X is Na or K) are shown. The loss of one proton would explain only one charge but the calculated
spectra do not correspond to measured values.
1207
1207
1200
1205
1210
1215
1220
1200
1205
1210
1215
1220
m/z
m/z
Figure S9: [M+Na]+ measured.
Figure S10: Calculated isotope distribution
for [M+Na]+.
1245

1246
1240
1245
1250
1255
m/z
Figure S12: Calculated for
[M+Na+K-H]+.
1240
1245
1250
1255
m/z
1246
Figure S11: [M+Na+K]+ measured.

1240
1245
1250
1255
m/z
Figure S13: Calculated for [M+Na+K]+.
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1262

1262
1255
1260
1265
1270
1275
m/z
Figure S15: Calculated for [M+2K]+.
1255
1260
1265
1270
1275
m/z
1261
Figure S14: [M+2K]+ measured.

1255
1260
1265
1270
1275
m/z
Figure S16: Calculated for [M+2K-H]+.
2395
2395
2391
2391
2385
2390
2395
2400
2405
2385
2390
2395
2400
2405
m/z
m/z
Figure S17: [2M+Na]+ measured.
Figure S18: [2M+Na]+ calculated.
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2391 [2M+Na]+
2407 [2M+K]+
2430 [2M+Na+K]+
2453 [2M+2Na+K]+
2437 [2M+3Na]+
2414 [2M+2Na]+
2476 [2M+3Na+K]+
2469 [2M+2K+Na]+
2446 [2M+2K]+
2460 [2M+4Na]+
2400
2425
2450
2475
m/z
Figure S19: Dimer area of MALDI-TOF spectrum of 7 with analysis of the adducts.
References:
[1]
M. Kostka, P. Zimcik, M. Miletin, P. Klemera, K. Kopecky, Z. Musil, J. Photochem.
Photobiol. A: Chem. 2006, 178, 16.
[2]
E. H. Mørkved, L. T. Holmaas, H. Kjøsen, G. Hvistendahl, Acta Chem. Scand. 1996, 50,
1153.
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