Syntheses of octasubstituted zinc azaphthalocyanines with thiophene or thiophene combined with sulfanyl, amino or imido substituents: Influence of the substituents on photochemical and photophysical properties

Available online at www.sciencedirect.com

Polyhedron 27 (2008) 1368–1374 www.elsevier.com/locate/poly

Syntheses of octasubstituted zinc azaphthalocyanines with thiophene or thiophene combined with sulfanyl, amino or imido substituents: Influence of the substituents on photochemical and photophysical properties Petr Zimcik a,*, Eva H. Mørkved b, Trygve Andreassen b, Juraj Lenco c, Veronika Novakova a a

Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy, Charles University, Heyrovskeho 1203, Hradec Kralove 50005, Czech Republic b Norwegian University of Science and Technology, Department of Chemistry, N-7491 Trondheim, Norway c Institute of Molecular Pathology, Faculty of Military Health Sciences, University of Defence, Hradec Kralove 50005, Czech Republic Received 22 October 2007; accepted 3 January 2008 Available online 7 March 2008

Abstract Several octasubstituted zinc azaphthalocyanines (ZnAzaPcs) of the tetrapyrazinoporphyrazine type have been synthesized as potential sensitizers for photodynamic therapy (PDT). Octasubstituted complexes, with thiophen-2-yl, thiophen-3-yl or benzo[b]thiophen-3-yl peripheral groups, were synthesized and characterized. Octa(thiophen-2-yl) ZnAzaPc is a better singlet oxygen producer and has a red shifted UV absorption Q-band compared to both thiophen-3-yl and benzo[b]thiophen-3-yl substituted ZnAzaPcs. Thus, the thiophen-2-yl substituent is better suited for our purpose. Unsymmetrically substituted ZnAzaPcs were synthesized by cyclotetramerisations of pyrazine-2,3-dicarbonitriles attached to one thiophen-2-yl group and one alkylsulfanyl, thiomorpholinyl or imide group. Constitutional isomers were detected by NMR spectroscopy for some of these complexes. Compared to unsubstituted ZnAzaPc, red shifted Q-bands were observed for all these complexes, due to the presence of thiophen-2-yl groups. The least promising complexes are ZnAzaPcs with thiomorpholine or imide peripheral substituents, i.e. where the peripheral substituents are attached to the macrocycle through nitrogen atoms. Low singlet oxygen quantum yields (UD) and also low fluorescence quantum yields (UF) were observed for these ZnAzaPcs. In the case of combined thiophen-2-yl and alkylsulfanyl substituents, the values of UD were the highest and reached values of approximately 0.69. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: Azaphthalocyanine; Tetrapyrazinoporphyrazine; Singlet oxygen quantum yield; Fluorescence; Diphenylisobenzofuran

1. Introduction Phthalocyanines (Pc) are well-known macrocyclic compounds with strong absorptions in the far red-region. Azaphthalocyanines (AzaPc) are analogues where some carbon atoms in the macrocyclic core are replaced by nitrogen atoms. AzaPcs may be used as colorants [1], fluorescent *

Corresponding author. Tel.: +420 495067257; fax: +420 495067167. E-mail addresses: [email protected] (P. Zimcik), eva.morkved@ chem.ntnu.no (E.H. Mørkved). 0277-5387/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.poly.2008.01.015

films [2] or as sensitizers in photodynamic therapy (PDT) [3]. The present work is a continuation of our previous studies of potential sensitizers for PDT [4] where zinc and magnesium complexes of octasubstituted AzaPcs were prepared. The peripheral substituents were aromatic or heteroaromatic groups attached through carbon atoms. Efficient production of singlet oxygen is an important characteristic of sensitizers for PDT. The substituent which induced the highest singlet oxygen quantum yield (UD) was the thiophen-2-yl group (UD = 0.64) followed by pyridin-2-yl (UD = 0.53) and phenyl (UD = 0.49) substituents.

P. Zimcik et al. / Polyhedron 27 (2008) 1368–1374

Another characteristic of an efficient photosensitizer is a Q-band absorption close to 700 nm. The Q-band of octa(thiophen-2-yl) ZnAzaPc was found at 673 nm, whereas unsubstituted AzaPc has a Q-band at 635 nm [5] and both octaphenylZnAzaPc and octa(pyridin-2-yl)ZnAzaPc absorb at 657 nm [4]. In other words, thiophen-2-yl peripheral substituents induce substantially red shifted Q-bands for these macrocycles. We have reported several investigations on the synthesis [6–8] and photodynamic properties [9–12] of alkylheteroatom (N, O, S) substituted AzaPcs. AzaPcs substituted peripherally with pyridin-2-yl were also investigated by another group from the UV–Vis spectral and electrochemical point of view [13–16]. However, as far as we know, there has been no systematic study of how mixed types of substituents (heteroaromatic and alkylheteroatom) on the AzaPcs influence the Q-band positions, singlet oxygen and fluorescence quantum yields. Our aim for the present investigation is to extend our knowledge about how various types of substituents on ZnAzaPc influence the three characteristics: Q-band positions, singlet oxygen and fluorescence quantum yields of the complexes. The most interesting substituent among the carbon attached heterocycles, the thiophen-2-yl group, will be compared to thiophen-3-yl and benzo[b]thiophen-3-yl groups. However, good solubility and low tendency to aggregate are important for efficient PDT sensitizers as well. Both characteristics are expected to improve for octasubstituted AzaPcs with two different types of peripheral substituents instead of one. Therefore, ZnAzaPcs with a combination of thiophen-2-yl and either sulfur or nitrogen attached substituents, will be synthesized and studied. We have not considered substituents attached through oxygen, since the carbon–oxygen bond is labile during normal reaction conditions for cyclotetramerisations [8,11]. However, an interesting and successful approach to the synthesis of AzaPcs with ether linked substituents has been reported recently [2]. The choice of sulfur attached substituents was made among alkylsulfanyl groups, since arylsulfanyl groups are somewhat labile and may be replaced by nucleophiles. The two nitrogen attached substituents were chosen so that one is electron donating (thiomorpholine), and the other is electron withdrawing (a substituted maleimide). Both the sulfur and nitrogen attached substituents are relatively bulky in order to prevent aggregation. 2. Experimental 2.1. Materials and methods Electron impact (EI) mass spectra of compounds 2–5 were obtained on a Finnigan MAT 95XL spectrometer at 70 eV electron energy and 1.0 mA electron current. MALDI-TOF mass spectra of compounds 6 and 7 were recorded in the negative reflectron mode on a mass spec-

1369

trometer Voyager-DE STR (Applied Biosystems, Framingham, MA, USA). For each sample, 0.5 ll of the mixture was spotted onto the target plate, air-dried and covered with 0.5 ll of matrix solution consisting of 10 mg of a-cyano-4-hydroxycinnamic acid in 100 ll of 50% ACN in 0.1% TFA. The instrument was calibrated externally with a five-point calibration using Peptide Calibration Mix1 (LaserBio Labs, Sophia-Antipolis, France). IR spectra were obtained on a Nicolet 20-SXC FT IR spectrometer. 1H and 13C NMR spectra were recorded on a Bruker Avance DPX 400 NMR spectrometer or on a Bruker Avance Digital 600 NMR spectrometer at 100.4, 399.65 or 600.18 MHz, respectively. Chemical shifts are given relative to internal tetramethyl silane (TMS). UV–Vis spectra were recorded on a Cary 50 UV–Vis spectrophotometer or a UV-2401PC spectrophotometer from Shimadzu. Fluorescence data were obtained on an AMINCO-Bowman Series 2 luminescence spectrometer. Melting points were obtained on a Bu¨chi 530 melting point apparatus and are uncorrected. The elemental analyses were carried out on an Automatic Microanalyser EA1110CE (Fisons Instruments S.p.A., Milano, Italy). Merck Kieselgel 60F 254 was used for thin layer chromatography (TLC) and Merck silica 63–200 lm was used for column chromatography. Zinc phthalocyanine (ZnPc) was purchased from Eastman Organic Chemicals (New York, USA). 1,3-Diphenylisobenzofuran (DPBF) was obtained from Aldrich. 2.2. Synthesis The following compounds have been prepared previously in our laboratories and published: 2c and 6c [4], 5a and 7a [17], 7c [18] and 7d [22]. Compound 3 was prepared according to a published procedure [19]. 2.2.1. Compounds 2 2.2.1.1. General procedure for the synthesis of compounds 2. A solution of 3,30 -thenil (1a) [20] or 3,30 -benzo[b]thenil (1b) [21] (10 mmol) and diaminomaleonitrile (15 mmol) in glacial acetic acid (30 ml) was heated under reflux for 2a 24 h, and for 2b 3 h. The solvent was removed under reduced pressure and the residue was extracted with dichloromethane (DCM) and chromatographed on silica with DCM. 2.2.1.2. 5,6-Di(thiophen-3-yl)pyrazine-2,3-dicarbonitrile (2a). Yield: 2.38 g (81%) of a pale yellow powder, m.p. 218–220 °C. EIMS: m/z (% rel. int.) 295 (22.9), 294 (M, 100), 293 (50.0), 261 (44.3), 250 (15.6). Found 294.00338, calcd. for C14H6N4S2 294.00339. UV–Vis (DCM): kmax, nm (e, M1 cm1) 280 (16 000), 350 (17 000). 1H NMR (CDCl3): d, ppm 7.25 (2H, dd, J4,5 = 5 Hz, J4,2 = 1.3 Hz), 7.38 (2H, dd, J5,2 = 3 Hz, J5,4 = 5 Hz), 7.83 (2H, dd, J2,5 = 3 Hz, J2,4 = 1.3 Hz). 13C NMR (CDCl3): d, ppm 113.17 (CN), 126.94, 127.73, 129.18, 130.61, 136.63, 149.81. IR (KBr): m, cm1 3105, 2239 (CN), 1651, 1503, 1387, 1218, 1162, 806, 701.

1370

P. Zimcik et al. / Polyhedron 27 (2008) 1368–1374

2.2.1.3. 5,6-Di(benzo[b]thiophen-3-yl)pyrazine-2,3-dicarbonitrile (2b). Yield: 1.65 g (42%) of a yellow powder, m.p. 254–258 °C (decomp). EIMS: m/z (% rel. int.) 395 (21.3), 394 (M, 15.2), 393 (21.2), 362 (26.9), 159 (67.2). Found 394.03447, calc. for C22H10N4S2 394.03462. UV– Vis (DCM): kmax, nm (e, M1 cm1) 265 (22 000), 362 (15 300), 395 (15 800). 1H NMR (CDCl3): d, ppm 7.36, H5 (2H, dd, J5,4 = 8 Hz, J5,6 = 7 Hz), 7.42, H6 (2H, dd, J6,7 = 8 Hz, J6,5 = 7 Hz), 7.67, H2 (2H, s), 7.87, H7 (2H, ddd, J7,6 = 8 Hz, J7,5 = 2 Hz, J7,4 = 0.7 Hz), 7.93, H4 (2H, ddd, J4,5 = 8 Hz, J4,6 = 2 Hz, J4,7 = 0.7 Hz). 13C NMR (CDCl3): d, ppm 113 (CN), 122.91, 123.61, 125.60, 125.61, 129.48, 130.96, 132.98, 135.72, 140.08, 151.21 (after 24 h, an orange precipitate separates from the CDCl3 solution). IR (KBr): m, cm1 3109(w), 2238 (w, CN), 1500, 1429, 1382, 1246, 1182, 1063, 856, 803, 758, 735. 2.2.2. Compounds 5 2.2.2.1. 5-(tert-Butylsulfanyl)-6-(thiophen-2-yl)pyrazine2,3-dicarbonitrile (5b). A solution of tert-butanethiol (3 mmol, 0.78 g) in 0.1 M NaOH (3.3 mmol, 3.3 ml) was stirred at ambient temperature for 0.5 h. A solution of 3 (3 mmol, 0.74 g) in THF (6 ml) was added with stirring. The reaction mixture was stirred for 15 min, water (25 ml) was added, and the precipitate was collected by filtration and was washed thoroughly with water. Yield: 0.87 g (97%) of a yellow powder, m.p. 184–186 °C (decomp). EIMS: m/z (% rel. int.) 300 (M, 4.5), 246 (9.6), 245 (33.5), 244 (84.0), 243 (100). Found 300.04949, calc for C14H12N4S2 300.05034. UV–Vis (DCM): kmax, nm (e, M1 cm1) 390 (14 100), 345 (16 300), 285 (14 600). 1H NMR (CDCl3): d, ppm 1.69 (9H, s), 7.23, H4 (1H, dd, J4,3 = 4 Hz, J4,5 = 5 Hz), 7.71, H5 (1H, dd, J5,4 = 5 Hz, J5,3 = 1 Hz), 8.22, H3 (1H, dd, J3,4 = 4 Hz, J3,5 = 1 Hz). The pulse techniques HSQC and HMBC were used for identification of the 13C signals. 13C NMR (CDCl3): d, ppm 29.63 (CH3), 52.39 (CMe3), 113.33 (CN), 113.42 (CN), 125.66 (C2-pyrazine), 126.74 (C3-pyrazine), 128.71 (C4-thiophene), 133.03 (C3-thiophene), 133.95 (C5-thiophene), 138.44 (C2-thiophenyl), 148.06 (C6-pyrazine), 159.73 (C5-pyrazine). IR (KBr): m, cm1 2998, 2959, 2232 (w, CN), 1488, 1423, 1326, 1264, 1138, 1092, 1049, 909, 850, 728. 2.2.3. Compounds 6 2.2.3.1. General procedure for the synthesis of compounds 6. Compound 2 (1 mmol) and dry zinc(II) acetate (1 mmol) were ground together in a mortar, transferred to a round bottomed flask, quinoline (0.5 ml) was added, and nitrogen was passed over the reaction mixture for 20 min at ambient temperature. The mixture was heated to 155–160 °C for 50 min (2a) and 15 min (2b). The dark solid that formed was thoroughly washed, using sonification, with water, acetone and a mixture of DCM and acetone. 2.2.3.2. [Octa(thiophen-3-yl)-(octazaphthalocyaninato)]zinc(II) (6a). Yield: 0.2 g (64%) of a black powder. UV–

Vis (pyridine): kmax, nm (e, M1 cm1) 661 (224 000), 599 (26 000), 385 (113 000). MALDI-TOF MS m/z 1240.08 [M+H+]. Anal. Calc. for C56H24N16S8Zn + 5H2O: C, 50.46; H, 2.57; N, 16.81. Found: C, 50.49; H, 2.33; N, 16.74%. 2.2.3.3. [Octa(benzo[b]thiophen-3-yl)-(octazaphthalocyaninato)]zinc(II) (6b). Yield: 0.18 g (44%) of a black powder. UV–Vis (pyridine): kmax, nm (e, M1 cm1) 664 (187 000), 600 (37 000), 390 (91 000). The DQF-COSY pulse technique was used for identifications of 1H NMR signals. 1 H NMR (pyridine-d5): d, ppm 7.24 H5 (4H, partly superimposed on the pyridine signal), 7.37, H6 (4H, m), 8.01, H7 (4H, d, J = 7.8 Hz), 8.17, H2 (4H, s), 8.53 H4 (4H, d, J = 7.8). The use of the HSQC pulse technique allowed identification of the following 13C NMR signals: 13C NMR (pyridine-d5): d, ppm C7 123.3, C4 124.5, C5 125.3, C6 125.3, C2 131.2. MALDI-TOF MS m/z 1641.03 [M+H+]. Anal. Calc. for C88H40N16S8Zn + 5H2O: C, 60.98; H, 2.91; N, 12.93. Found: C, 57.86; H, 2.61; N, 12.33%. 2.2.4. Compounds 7 2.2.4.1. [Tetra(tert-butylsulfanyl)-tetra(thiophen-2-yl)(octazaphthalocyaninato)]zinc(II) (7b). Compound 7b was prepared from 5b and Zn(OAc)2 in quinoline as described for compounds 6. The crude product was purified as for compounds 6. The crude product was then chromatographed on silica with pyridine. Yield 40% of a black, shiny solid. UV–Vis (pyridine): kmax, nm (e, M1 cm1) 671 (234 000), 605 (47 000), 395 (160 000). NMR: Four different signals were found for each of the three thiophene protons, apparent due to isomers. The corresponding 13C signals were found by HSQC and HMBC pulse techniques. Each isomer is listed separately with the corresponding 1H/13C NMR signals (pyridine-d5): d, ppm: Isomer 1: H5/C5, 8.08 (d, J = 5 Hz)/131.8, H4/C4, 7.49 (m)/129.0, H3/C3, 8,77 (m)/131.5, C2, 143.7, C6-pyrazine, 147.6. Isomer 2: H5/C5, 8.06 (d, J = 5 Hz)/131.8, H4/C4, 7.48 (m)/129.0, H3/C3, 8,74 (m)/131.6, C2, 143.7, C6-pyrazine, covered by the pyridine signal. Isomer 3: H5/C5, 7.87 (d, J = 5 Hz)/131.2, H4/C4, 7.41 (m)/128.6, H3/C3, 8,66 (m)/131.5, C2, 142.8, C6-pyrazine, 147.6. Isomer 4: H5/ C5, 7.85 (d, J = 5 Hz)/131.2, H4/C4, 7.39 (m)/128.6, H3/ C3, 8,62 (m)/131.6, C2, 143.0, C6-pyrazine, 147.7. tert-butyl groups: 1H NMR (pyridine-d5): d, ppm 2.23–2.32 (broad singlets, several signals). MALDI-TOF MS m/z 1265.08 [M+H+]. Anal. Calc. for C56H48N16S8Zn + 2H2O: C, 51.62; H, 4.02; N, 17.20. Found: C, 51.70; H, 3.89; N, 17.05%. 2.2.5. (Tetra{1-[3-chloro-4-(4-thiomorpholinyl) maleimidyl]}tetra(thiophen-2-yl)-(octazaphthalocyaninato))zinc(II) (7d) The previously reported product [22] was further purified by absorbing a DCM solution of the compound on a silica column. Impurities were eluted with DCM, and compound 7d was eluted with pyridine, which was removed

P. Zimcik et al. / Polyhedron 27 (2008) 1368–1374

under reduced pressure. The dark solid residue was triturated with diethyl ether and filtered to give a dark blue to black shiny solid. UV–Vis (pyridine): kmax, nm (e, M1 cm1) 675 (208 000), 615 (49 000), 390 (172 000), 315 (191 000). NMR: Two different signals were found for each of the three thiophene protons, apparently due to isomers. The corresponding 13C signals were found by DQF-COSY, HSQC and HMBC pulse techniques. Each isomer is listed separately with the corresponding 1H/13C NMR signals (pyridine-d5): d, ppm: Isomer 1: H5/C5, 7.84/132.3, H4/ C4, 7.27/129.4, H3/C3, 8.61/132.2, C2, 139.3. Isomer 2: H5/C5, 7.79/132.4, H4/C4, 7.21/129.3, H3/C3, 8.48/ 132.2, C2, 139.3. Two isomers were found for thiomorpholine, and they are listed as above. Isomer 1: H2/C2, 2.92/28.4, H3/C3, 4.33/51.8, C3-maleimide, 143.2. Isomer 2: H2/C2, 2.89/28.4, H3/C3, 4.30/51.8, C3-maleimide, 143.3. MALDI-TOF MS m/z 1832.94 [M+H+]. Anal. Calc. for C72H44Cl4N24O8S8Zn + 5H2O: C, 44.78; H, 2.82; N, 17.44. Found: C, 47.25; H, 3.06; N, 17.74%. 2.3. Singlet oxygen measurements Singlet oxygen production was monitored as DPBF (1,3diphenylisobenzofuran) decomposition reactions, as reported by us previously [10], but with a slight modification. Pyridine solutions of the metal complexes 6a–c and 7a–d were heated at approximately 115 °C for a few minutes to ensure complete dissolution and monomerisation of possible dimers. The pyridine solutions were cooled to ambient temperature, diluted until the Q-band kmax absorption became 0.1 and then kept strictly in the dark. A 2.4 ml sample of these solutions was transferred into a 10  10 mm quartz optical cell, 24 ll of a 5 mM stock solution of DPBF in pyridine was added, and the resulting solution was purged with oxygen for 1 min. A Tip 200 W halogen lamp was used for irradiation of the oxygen purged solution, and exact time intervals were used. The decomposition of DPBF was monitored at 417 nm, and irradiation was stopped before the decomposition of DPBF had reached 15%. Other conditions (filters, etc.) as well as the calculations of UD have been described previously [10]. ZnPc in pyridine was used as the standard (UD = 0.61 [23]). 2.4. Fluorescence measurements Fluorescence quantum yields of the dyes were determined in pyridine and calculated according to following equation (Eq. (1)): R

USF ¼ UR F

AUCS 1  10A S AUCR 1  10A

ð1Þ

where UF is the fluorescence quantum yield, AUC is the integrated area under the emission spectrum and A is absorbance at the excitation wavelength. Superscripts R and S correspond to reference and sample, respectively. ZnPc in pyridine was used as a reference (UF = 0.20 in

1371

pyridine [23]). The dye solutions prepared as mentioned above were used for measurements after the appropriate dilution. In all cases the absorbance at kmax of the Q-band was below 0.04 in order to minimize reabsorption of the emitted light. Fluorescence emission spectra were recorded after excitation at 606 nm. Fluorescence excitation spectra were recorded observing the fluorescence signal at 720 nm. 3. Results and discussion 3.1. Syntheses and characterisation The syntheses of pyrazine-2,3-dicarbonitriles 2a–c, 3 and 5a,b are shown in Scheme 1. The macrocycles ZnAzaPcs 6a–c and 7a–b were obtained from monomers 2, 3 and 5 and their structures are shown in Fig. 1. Compounds 2a, b were obtained from a condensation between diaminomaleonitrile and 3,30 -thenil (1a) or 3,30 -benzo[b]thenil (1b) dissolved in acetic acid. The extended conjugation of the benzo[b]thiophene group is reflected in the UV–Vis absorption at 395 nm for compound 2b compared to 350 nm for 2a. Compound 3 was used for syntheses of the sulfanyl substituted monomers 5a,b. The zinc complexes 6a–c and 7a–d were obtained from cyclotetramerization with zinc(II) acetate and quinoline. Attempts to tetramerize compound 3 by the same procedure gave an AzaPc macrocycle (kmax(e) = 670 (81 000)) of low solubility. Neither MALDI-TOF nor elemental analyses confirmed the expected structure. The chlorine atom of 3 is most likely labile and was exchanged either during cyclisation or work up procedures. The thiophen-3-yl substituted compound 6a has very low solubility in most organic solvents, including pyridine, and therefore NMR spectra could not be properly measured for 6a. Compounds 6b–c and 7a–d are somewhat more soluble and pyridine-d5 solutions were used for NMR studies of these substances. 1H NMR spectra of 6b–c and 7a–d were recorded, and the pulse techniques DQF-COSY, HSQC and HMBC were used to correlate proton and carbon signals. NMR spectra of compound 6b, dissolved in pyridine-d5, show all the aromatic protons, including the thiophen-2-yl protons, at a higher field than for the corresponding protons of monomer 2b. Complexation with zinc is expected to have, and indeed it has, the same effect on all these macrocycles. It was noted that the pyridine-d5 solution of 6b deposited a dark precipitate after about 24 hours, apparently due to slow aggregation. Complexes 7a–d are expected to be mixtures of four constitutional isomers due to the unsymmetrically substituted monomers. Compound 7b, with equal numbers of thiophen-2-yl and tert-butylsulfanyl groups, gave four different proton signals for each of the three thiophen-2-yl hydrogens. We interpret these as signals from four isomers. The tendency of aggregation plays an important role in the interpretation of NMR spectra. The tert-butylsulfanyl groups may cause more steric strain than the 4-chlorobenzylsulfanyl group of 7a and consequently 7b is less

1372

P. Zimcik et al. / Polyhedron 27 (2008) 1368–1374

Scheme 1. Scheme of the synthesis of the precursors. Reaction conditions: (i) acetic acid, reflux; (ii) pyridine, acetone (for 4a) or NaOH, water, THF (for 4b).

Fig. 1. Structures of the substituted ZnAzaPc systems examined in the study.

aggregated. Only one set of 1H NMR signals were observed for the thiophen-2-yl groups of 7a [17], indicating one isomer only. However, the presence of other isomers could have been masked by aggregation. Compound 7d, with a large substituted maleimide group, shows two sets of proton signals for each of the three thiophen-2-yl hydrogen atoms and also for each of the two different kinds of thiomorpholine hydrogen atoms. This indicates that there are at least two different isomers of 7d. Similarly to the previous compound, the presence of two other isomers may be masked by aggregation.

The mass spectra of the dyes were measured by MALDI-TOF spectrometry. The mass M+H+, as well as the adducts with Na+ and K+, were detected for all the new macrocycles, i.e. for compounds 6a–b, 7b and 7d. Due to ionisation, a stepwise removal of isobutenes from the tert-butylsulfanyl substituents of 7b was observed in accordance with previous observations [10]. These observations confirm the expected structure of 7b. No other than the expected molecular ions were detected in the mass spectra of compounds 6a–b, 7b and 7d. Elemental analyses of the dyes were satisfactory for compounds 6a and 7b. However the elemental analyses of 6b and 7d are not quite satisfactory, and we conclude that these compounds are slightly contaminated. Due to the low solubilities of compounds 6b and 7d, further purifications were not successful. Table 1 summarizes the spectral, photophysical and photochemical data for compounds 6a–c and 7a–d. Complex 6a with thiophen-3-yl substituents has a Q-band at 661 nm, whereas 6c, with thiophen-2-yl substituents, has a Q-band at 673 nm. The 12 nm red shift for 6c is most likely caused by better conjugation, i.e. more resonance forms, between the macrocycle and thiophen-2-yl groups. Compound 6b shows a 3 nm red shifted Q-band compared to 6a and this probably reflects the higher aromaticity of benzo[b]thiophene compared to thiophene. Compounds 7a–d are substituted with four thiophen-2-yl groups and either four sulfanyl, amino or imido groups. The following Q-band positions were measured for these compounds: 669 (7a), 671 (7b), 669 (7c) and 675 nm (7d). Compound 6c is substituted with eight peripheral thiophen-2-yl groups, and its Q-band position is 673 nm. Therefore it appears that four peripheral thiophen-2-yl substituents will induce almost the same red shift of a Q-band as eight thiophen2-yl groups. Except for the substituted maleimide group of compound 7d, the other sulfanyl or amino groups of 7a–7c have negligible effects on the Q-band positions of these compounds. Incidentally, maleimide substituents were originally used in order to facilitate cyclotetramerisations since imido-nitrogens would be electron withdrawing [22]. Electron donating substituents make the cyclization procedure complicated [7] while electron withdrawing groups facilitate macrocycle formation [2,12].

P. Zimcik et al. / Polyhedron 27 (2008) 1368–1374

1373

Table 1 Spectral, photophysical and photochemical data of the substituted ZnAzaPc systems in pyridine Q-band kmax (nm)

Peripheral substitution ZnPc 6a 6b 6c 7a 7b 7c 7d a b

H thiophen-3-yl benzo[b]thiophen-3-yl thiophen-2-yl thiophen-2-yl thiophen-2-yl thiophen-2-yl thiophen-2-yl

H thiophen-3-yl benzo[b]thiophen-3-yl thiophen-2-yl 4-chlorobenzylsulfanyl tert-butylsulfanyl thiomorpholine substituted maleimide

674 661 664 673 669 671 669 675

Fluorescence kmax (nm) 680 668 672 680 678 680 678 682

UD

UF a

0.61 0.581 0.416 0.635b 0.695 0.672 0.107 0.103

0.20a 0.235 0.102 0.176b 0.177 0.162 0.019 0.036

Used as reference. See [23]. From Ref. [4].

3.2. Fluorescence and singlet oxygen quantum yields The quantum yields were measured in pyridine and with zinc phthalocyanine (ZnPc) as the reference. The data obtained are summarized in Table 1. Singlet oxygen quantum yields were determined using a specific chemical trap for singlet oxygen, 1,3-diphenylisobenzofuran (DPBF)[3]. Several other dyes, previously synthesized by us but not characterized from the point of view of quantum yields, were introduced into this study in order to clarify the influence of peripheral substituents on the photophysical and photochemical properties of AzaPc macrocycles. Fluorescence spectra were of a typical shape for AzaPc, with only a small Stokes shift in the range of 7–9 nm (see Table 1). The calculations of quantum yields were based on the absorption of light in the Q-band area. The presence of low mass impurities, without absorption in the Q-band area, will not influence the results obtained for compounds 6b and 7d. This was confirmed also by a perfect fit between the absorption and fluorescence excitation spectra (for example see Fig. 2). The possible impurities would modify the absorption spectra but not the fluorescence excitation

spectra. The aggregation of the dyes did not influence the results either, because the measurements were performed in very dilute pyridine solutions (below 0.5 lM for UD and below 0.2 lM for UF) where the dyes stay almost exclusively in the monomeric form. Also perfect agreement of absorption and excitation spectra (Fig. 2) confirmed the presence of only the monomeric form during measurements. The sum of the quantum yields (UD + UF) of the macrocycles with octathiophene substitution (6c) and (6a) was the same. The change of position of the thiophene substitution (thiophen-2-yl or thiophen-3-yl) led only to differences in the distribution of released energy between fluorescence and photoprocess type II (higher UD for 6c and reversely higher UF for 6a). An extended conjugation of the benzo[b]thiophene group in compound 6b decreases the overall quantum yields. This is probably due to the larger molecular size, which increases the possibility to release absorbed energy in the form of heat through collision with surrounding molecules. Similarly, larger naphthalocyanines have lower quantum yields compared to Pc [24]. Compounds 7 are unsymmetrically substituted and the influence of the second substituent was also investigated. We have shown previously [11] that alkylsulfanyl substituents have positive effect on UD, while the presence of nitrogen connecting peripheral chains with the macrocycle strongly decreases the overall quantum yields [10]. The obtained results confirmed further such formulated structure-activity relationships. Compounds 7a and 7b with alkylsulfanyl substituents exerted the highest UD value amongst the studied compounds. Their values of UD were very close to each other because both substituents (tert-butylsulfanyl and 4-chlorobenzylsulfanyl) should influence the macrocycle in the same way. Compounds 7c and 7d, with nitrogen atoms connecting the substituents to the macrocycle, showed far lower quantum yields. This is also in good agreement with previously postulated relationships. 4. Conclusion

Fig. 2. Normalized absorption (dashed line), fluorescence excitation (full line) and fluorescence emission (dotted line) spectra of compound 7c.

The present studies have shown that ZnAzaPcs substituted with thiophen-2-yl groups in combination with other

1374

P. Zimcik et al. / Polyhedron 27 (2008) 1368–1374

substituents may be of interest for the development of new photosensitizers. The thiophen-2-yl group will, regardless of the presence of other groups, cause a red shift of the Q-band to 670 nm or higher. A combination of imide substituents, attached to the macrocycle through nitrogen atoms, and thiophen-2-yl substituents, is expected to increase the Q-band red shift further, as seen for compound 7d. However, imide substituents in general are expected to decrease the singlet oxygen quantum yields of ZnAzaPcs, and will be of little interest in our future search for efficient photosensitizers. The thiophen-3-yl substituents are less efficient than thiophen-2-yl groups for inducing red shifted Q-bands, and therefore are less interesting for a future search for photosensitisers. However, the thiophen-3-yl substituents induce a relatively high production of singlet oxygen, which may be of interest for other purposes. The best combination of substituents for the prepared ZnAzaPcs is a mixture of thiophen-2-yl substituents with bulky sulfanyl groups. This combination gives good solubility and little aggregation due to more disorder in these compounds. The bulky tert-butylsulfanyl substituents of 7b inhibit efficiently the aggregation, and together with its high UD and absorbance at 671 nm, this compound is promising for future tests as a potential photosensitizer in PDT. The UD = 0.67 of this AzaPc is more than sufficient for efficient sensitization. For comparison, the sulfonated AlPc approved for various cancer treatments under the name Photosens (developed in NIOPIK, Russia) has UD = 0.42 [25]. Acknowledgement P.Z. would like to thank for financial support to the Research Project MSM 0021620822. References [1] B.H. Lee, J.Y. Jaung, S.C. Jang, S.C. Yi, Dyes Pigment. 65 (2005) 159.

[2] S. Makhseed, F. Ibrahim, C.G. Bezzu, N.B. McKeown, Tetrahedron Lett. 48 (2007) 7358. [3] P. Zimcik, M. Miletin, Z. Musil, K. Kopecky, L. Kubza, D. Brault, J. Photochem. Photobiol. A: Chem. 183 (2006) 59. [4] E.H. Mørkved, N.K. Afseth, P. Zimcik, J. Porphyr. Phthalocya. 10 (2007) 130. [5] S.V. Kudrevich, J.E. Van Lier, Coord. Chem. Rev. 156 (1996) 163. [6] E.H. Mørkved, L.T. Holmaas, H. Kjøsen, G. Hvistendahl, Acta Chem. Scand. 50 (1996) 1153. [7] E.H. Mørkved, H. Kjøsen, H. Ossletten, N. Erchak, J. Porphyr. Phthalocya. 3 (1999) 417. [8] E.H. Mørkved, H. Ossletten, H. Kjøsen, Acta Chem. Scand. 53 (1999) 1117. [9] M. Kostka, P. Zimcik, M. Miletin, P. Klemera, K. Kopecky, Z. Musil, J. Photochem. Photobiol. A: Chem. 178 (2006) 16. [10] Z. Musil, P. Zimcik, M. Miletin, K. Kopecky, M. Link, P. Petrik, J. Schwarz, J Porphyr. Phthalocya. 10 (2006) 122. [11] P. Zimcik, M. Miletin, M. Kostka, J. Schwarz, Z. Musil, K. Kopecky, J. Photochem. Photobiol. A: Chem. 163 (2004) 21. [12] Z. Musil, P. Zimcik, M. Miletin, K. Kopecky, P. Petrik, J. Lenco, J. Photochem. Photobiol. A: Chem. 186 (2007) 316. [13] M.P. Donzello, Z. Ou, D. Dini, M. Meneghetti, C. Ercolani, K.M. Kadish, Inorg. Chem. 43 (2004) 8637. [14] M.P. Donzello, Z. Ou, F. Monacelli, G. Ricciardi, C. Rizzoli, C. Ercolani, K.M. Kadish, Inorg. Chem. 43 (2004) 8626. [15] C. Bergami, M.P. Donzello, C. Ercolani, F. Monacelli, K.M. Kadish, C. Rizzoli, Inorg. Chem. 44 (2005) 9852. [16] C. Bergami, M.P. Donzello, F. Monacelli, C. Ercolani, K.M. Kadish, Inorg. Chem. 44 (2005) 9862. [17] E.H. Mørkved, F.M. Pedersen, N.K. Afseth, H. Kjøsen, Dyes Pigment. 77 (2008) 145. [18] E.H. Mørkved, N.K. Afseth, H. Kjøsen, J. Porphyr. Phthalocya. 10 (2006) 1301. [19] A. Nakamura, T. Ataka, H. Segawa, Y. Takeuchi, T. Takematsu, Agric. Biol. Chem. 47 (1983) 1561. [20] J.L. Hyatt, V. Stacy, R.M. Wadkins, K.J.P. Yoon, M. Wierdl, C.C. Edwards, M. Zeller, A.D. Hunter, M.K. Danks, G. Crundwell, P.M. Potter, J. Med. Chem. 48 (2005) 5543. [21] E. Campaign, E.S. Neiss, J. Heterocycl. Chem. 3 (1966) 46. [22] E.H. Mørkved, Chem. Heterocycl. Comp. (2007) 1409. [23] A. Ogunsipe, D. Maree, T. Nyokong, J. Mol. Struct. 650 (2003) 131. [24] D. Wo¨hrle, M. Shopova, S. Muller, A.D. Milev, V.N. Mantareva, K.K. Krastev, J. Photochem. Photobiol. B: Biol. 21 (1993) 155. [25] N.A. Kuznetsova, N.S. Gretsova, V.M. Derkacheva, S.A. Mikhalenko, L.I. Solov’eva, O.A. Yuzhakova, O.L. Kaliya, E.A. Luk’yanets, Russ. J. Gen. Chem. 72 (2002) 300.