Investigation of synthetic pathways of carboxylic acid phthalocyanines from glycolic and lactic acids

Accepted Manuscript Research paper Investigation of synthetic pathways of carboxylic acid phthalocyanines from glycolic and lactic acids Francisco B. do Nascimento, Anderson O. Ribeiro PII: DOI: Reference:

S0020-1693(17)30767-3 http://dx.doi.org/10.1016/j.ica.2017.07.053 ICA 17776

To appear in:

Inorganica Chimica Acta

Received Date: Revised Date: Accepted Date:

15 May 2017 12 July 2017 26 July 2017

Please cite this article as: F.B. do Nascimento, A.O. Ribeiro, Investigation of synthetic pathways of carboxylic acid phthalocyanines from glycolic and lactic acids, Inorganica Chimica Acta (2017), doi: http://dx.doi.org/10.1016/ j.ica.2017.07.053

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Investigation of synthetic pathways of carboxylic acid phthalocyanines from glycolic and lactic acids Francisco B. do Nascimento, Anderson O. Ribeiro* Universidade Federal do ABC – UFABC Avenida dos Estados, 5001, Bloco B, Santo André, SP, Brasil. *[email protected]

Abstract We present the study of synthetic pathways to prepare carboxylic acid substituted phthalocyanines from glycolic and lactic acids. Hydroquinone was used as an alternative catalyst for cyclotetramerization reaction of metal free and zinc phthalocyanines, which were characterized by 1H MR spectroscopy, infrared absorption and mass analysis. The photophysical and photochemical properties in dimethyl sulfoxide (DMSO) were analyzed. We verified that the presence of the methyl radical group, that distinguish both structures, diminish the macrocycle aggregation in solution and promote higher quantum yields of fluorescence and for singlet oxygen generation.

Keywords: phthalocyanine, glycolic acid, lactic acid, photosensitizer, photodynamic therapy

1. Introduction Phthalocyanines (Pc’s) are aromatic macrocycles with highly conjugated π-electron structure [1, 2]. Although they have been mainly used as blue and green dyes in the textile and paper industries [1], their chemical, photochemical, and thermal stabilities

endorses applications as photoconduction agents in photocopying machines [3], photoelectrochemical sensors [4-6], electrochromic display devices [7], photosensitizers for dye sensitized solar cells [8, 9] and oxidation or reduction catalysts and photocatalysts [10-13]. Also, these compounds are promise photosensitizers for photodynamic therapy (PDT) [14], due to their high absorption extinction coefficient in 600 to 800 nm region and their high quantum yield of singlet oxygen generation [1518]. However, one problem related to biological applications of these macrocycles is their spontaneous self-aggregation in solution, which is unfavorable to PDT because dimers and oligomers are considered inactive or extremely inefficient to generate singlet oxygen compared to monomers [19],[20]. To overcome this problem, synthetic strategies have been described to introduce bulky substituents or appropriate functional groups at the α peripheral and/or β positions [21]. Among other substituents, carboxylic acid is very interesting due to their possible interconversion in others functional groups and to form a covalent linkage to biological molecules that can be used as specific target to the cells [22-25]. The mostly used method for the synthesis of tetra-carboxy phthalocyanines (TcPc’s) and octa-carboxyphthalocyanines (OcPc’s) apply trimellitic anhydride (or pyromellitic dianhydride), urea, a metal salt and ammonium heptamolybdate (as catalyst) grounded together and irradiated under microwave irradiation, followed by total hydrolysis of amide groups in KOH 50%/NaCl saturated solution [26-28]. Whereas OcPc’s are soluble in alkaline aqueous solutions [22, 29], owing to high number of carboxyl groups incorporated into the macrocycle, TcPc’s are poor soluble in weak alkaline conditions. [30].

Mono-functionalized carboxyphthalocyanines were also described. Nyokong has reported, for example, the synthesis and characterization of germanium, titanium and tin phthalocyanine complexes with only one reactive carboxy group as an electrophile [31] These syntheses generally apply a statistic condensation of two different phthalonitriles, being one of them modified with a carboxylic group. Unsymmetrical phthalocyanines modified with carboxyl and naphtol [32, 33], diethylaminoethanol [25], cysteine [34], hexylthiol [35] 5-trifluoromethyl-2-mercaptopyridine [36] and others were reported [37] including its attach to carbon nanotubes [38] ZnO and TiO2 films [39], GnRH receptor [19] and gold nanoparticles [40, 41]. In our study, synthetic pathways and convenient methods to prepare carboxylic acidsubstituted phthalocyanines from glycolic and lactic acids were investigated. These two substituents were chosen because they have very similar structure, diverging from a methyl radical group. The photophysical and photochemical properties of all compounds were investigated in order to evaluate their potential to be applied as photosensitizer in PDT.

2. Experimental Section 2.1. General considerations All reagents and starting materials were purchased from commercial sources and used as received. When necessary, solvents were purified following standard literature procedures. Some reactions were carried out under a nitrogen atmosphere, as specified in experimental procedures. Britton–Robinson buffer was prepared from acetic acid, orthophosphoric acid, boric acid, and sodium hydroxide. Melting point analysis was performed in the Büchi Melting Point B-540 equipment. Elemental analysis was carried

out using a Analisador Elementar Flash EA 1112 CNHS instrument. UV/Vis absorption spectra were recorded with Perkin Elmer Lambda 35 equipment in 10.00 mm quartz cells. Fluorescence excitation and emission spectra were measured with an Agilent Technologies Cary Eclipse Spectrofluorimeter in 10.00 mm quartz cells. Infrared spectra were recorded with a Varian FTIR 660 spectrometer. Mass spectra were recorded by HMRS-MALDI-TOF spectrometer (Bruker-Daltonics). 2.2. Synthesis of ethyl (3,4-dicyanophenoxy)acetate (1) 13 (4.0 g, 38.4 mmol) and 4-nitrophthalonitrile (6.65 g, 38.4 mmol) were stirred in a three-necked flask for three days in DMF (6 mL) at room temperature in the presence of an excess of anhydrous K2CO3 (5 g). The reaction mixture was poured into ice water to give light yellow precipitate which was collected by filtration and washed with water. The product was dissolved in CH2Cl2 (100 mL) and washed with distilled water (3 x 50 mL). The organic phase was dried over with Mg2SO4, filtered and concentrated under reduced pressure. The crude product was further purified by chromatography on a silica gel column using hexane-ethyl acetate 2:1 v/v resulting in a yellow solid which was finally purified by recrystallization in methanol, yielding 1 as a white solid, (5.63 g, 63.7%). m.p. 115.35 °C m/z 230.01. 300 MHz 1H NMR (CDCl3): δ (ppm) 7.75 (d, J=8 Hz, 1H, H-6); 7.27 (d, J=4 Hz, 1H, H-3); 7.21 (dd, J1=8 Hz, J2=4 Hz, 1H, H-1); 4.74 (s, 2H, H-10); 4.30 (q, J=8 Hz, 2H, H-14); 1.32 (t, J=8 Hz, 3H, H15). 100 MHz

13

C NMR (CDCl3): δ (ppm) 167.11 C-11; 160.91 C-12; 135.35 C-6;

(119.90; 119.56; 117.55; 115.49; 115.12; C-Ar); 65.43 C-10; 62.14 C-14; 14.16 C-15. FTIR (KBr) (νmax): 3118 cm-1, 3081 cm-1 (Ar-H), 2996 cm-1 (C-H), 2225 cm-1 (C≡N), 1741 cm-1 (C=O), 1594, 1488 cm-1 (C=C) , 1382 cm-1 (C-O), 1236 cm-1 (C-O-C).

2.3. Synthesis of ethyl 2-(3,4-dicyanophenoxy)propanoate (2) According to the procedure for 1, compound 14 (4.71 g, 39.8 mmol) was treated with 4-nitrophthalonitrile (6.90 g, 39.8 mmol) and an excess of anhydrous K2CO3 (5 g) in DMF (6 mL) for three days at room temperature. The compound was isolated as a white solid (6.99 g, 72%). m.p. 117.75 °C m/z 244,08. 400 MHz 1 H NMR (CDCl3): δ (ppm) 7.72 (d, J=8 Hz, 1H, H-6); 7.23 (d, J=4 Hz, 1H, H-3); 7.15 (dd, J1=8 Hz, J2=4 Hz, 1H, H-1); 4.83 (q, J=8 Hz, 1H, H-10); 4.25 (q, J=8 Hz, 2H, H-15); 1.69 (d. J=8 Hz, 3H, H-12); 1.28 (t, J=8 Hz, 3H, H-16). 100 MHz

13

C NMR (CDCl3): δ (ppm)

170.20 C-11; 160.76 C-2; 135.32 C-6; (120.21; 119.68; 117.48; 115.53; 115.15; C-Ar.); 108.05 C-7, C-8; 73.21 C-10; 62.10 C-15; 18.24 C-12; 14.15 C-16. FTIR (KBr) (ν max): 3114 cm-1, 3085 cm-1, 3046 cm-1(Ar-H), 2996 cm-1, 2977 cm-1, 2942 cm-1 (C-H), 2235 cm-1 (C≡N), 1743 cm-1 (C=O), 1592 cm-1 , 1496 cm-1 (C=C), 1382 cm-1 (C-O), 1236 cm-1 (C-O-C), 1024 cm-1 (C-O).

2.4. Synthesis of zinc carboxyphthalocyanines derivatives. 2.4.1. 2,9(10),16(17),23(24)-Tetra[(pentyloxycarbonyl)methyloxy]phthalocyaninato zinc (II) (3). Phthalonitrile 1 (300 mg, 1.30 mmol) was stirred in n-pentanol (5 ml) at 70 oC for 10 min, and then hydroquinone (143.61 mg, 1.30 mmol) and anhydrous zinc acetate (120 mg, 0.63 mmol) were added. The resulting mixture was stirred at 150 oC under nitrogen atmosphere for 12 h. After removing the volatiles in vacuo, the residue was purified by a silica gel column chromatography using 200 mL of DCM and then hexane–ethyl acetate (2:1, v/v) affording 3 (126 mg, 34%). m.p. > 300 °C; HRMS-

MALDI-TOF m/z calculated for C60H64N8O12Zn [M+1]+ 1152.394, found [M+1]+ 1153.384. Elemental Analysis. Calculated: C, 62.42%; H, 5.59%; N, 9.71%. Found: C, 62.47%; H, 5.41%; N, 9.80%. FTIR (KBr) (νmax): 2956 cm-1, 2927 cm-1, 2856 cm-1 (CH), 1760 cm-1 (C=O), 1608 cm-1, 1488 cm-1, 1398 cm-1 (C=C), 1338 cm-1 (C-O), 1201 cm-1 (C-O-C), 1091 cm-1 (C-O-C).1H NMR (CDCl3): δ (ppm) 7.81 – 7.40 (m, 4H, H-6); 7,35 – 7.26 (m, 8H, H-1 e H-3); 5.04 (s, 8H, H-8); 4.15 – 4.09 (m, 8H, H-12); 1.60 – 1.53 (m, 8H, H-15); 1.29 – 1.19 (m, 8H, H-14 e H-13); 0.85 – 0.81 (m, 8H, H-16).

2.4.2. 2,9(10),16(17),23(24)-Tetra[1-(pentyloxycarbonyl)ethyloxy]phthalocyaninato zinc (II) (4). According to the above procedure for 3, a suspension of 2 (300 mg, 1.23 mmol) in n-pentanol was treated with hydroquinone (135 mg, 1.23 mmol) and anhydrous zinc acetate (112.80 mg, 0.60 mmol) to give compound 4 (126 mg, 41%). m.p. > 300 °C; HRMS-MALDI-TOF m/z calculated for C64H72N8O12Zn [M+1]+ 1208.456, found [M+1]+ 1208.454. Elemental Analysis. Calculated: C, 63.49%; H, 5.99%; N, 9.26%. Found: C, 63.57%; H, 6.65%; N, 9.18%. FTIR (KBr) (ν max): 2958 cm-1, 2927 cm-1, 2861 cm-1 (C-H), 1766 cm-1 (C=O), 1614 cm-1, 1482 cm-1, 1452 cm-1 (C=C), 1373 cm-1 (C-O), 1226 cm-1 (C-O-C), 1099 cm-1 (C-O-C).1H NMR (CDCl3): δ (ppm) 8.85 – 8.47 (m, 4H, H-6); 8.41 – 7.94 (m, 4H, H-3); 7.75 – 7.35 (m, 4H, H-1); 5.62 – 5.19 (m, 8H, H-8); 4.50 – 4.13 (m, 8H, H-12); 2.16 – 2.04 (m, 8H, H-13); 1.89 – 1.68 (m, 8H, H-14); 1.59 – 0.91 (m, 19H, H-15 e H-22); 0.87 – 0.55 (m, 12H, H-16).

2.4.3. 2,9(10),16(17),23(24)-Tetra(carboxymethyloxy)phthalocyaninato zinc (II) (5). In a closed reaction tube, phthalonitrile 1 (300 mg, 1.30 mmol) and zinc acetate dihydrate (142.68 mg, 0.65 mmol) in DMAE (5 mL) were heated at 150 oC, under nitrogen atmosphere and constant stirring for 10 h. After cooling, the reaction mixture was poured into a water/ethanol 10 % solution) to give dark blue precipitate, which was collected by filtration and washed with water. The residue was solubilized in NaOH (1 mol.L-1) solution and then acidified to pH 2 with HCl (1 mol.L-1) solution, until coagulation. The solid was centrifuged and purified by successive precipitation, using solutions of HCl (1 mol.L-1) and NaOH (1 mol.L-1). The crude product was purified by silica gel column chromatography using methanol-ethyl acetate 2:1 v/v to give compound 5 (180 mg, 64%). m.p. > 300 °C; HRMS-MALDI-TOF m/z calculated for C40H24N8O12Zn [M+1]+ 872.081, found [M+1]+ 872.067. Elemental Analysis. Calculated: C, 54.97%; H, 2.77%; N, 12.82%. Found: C, 54.96%; H, 2.84%; N, 12.91%. FTIR (KBr) (νmax): 3500 – 2500 cm-1 (O-H), 2921 cm-1, 2827 cm-1 (C-H), 1724 cm-1 (C=O), 1604 cm-1, 1479 cm-1, 1400 cm-1 (C=C), 1334 cm-1 (C-O), 1220 cm-1 (C-OC), 1070 cm-1 (C-O-C).1H NMR (CDCl3): δ (ppm) 9.25 – 8.83 (m, 4H, H-6); 8.83 – 8.30 (m, 4H, H-3); 7.84 – 7.66 (m, 4H, H-1); 5.28 (s, 8H, H-8). 2.4.4. 2,9(10),16(17),23(24)-Tetra(1-carboxyethyloxy)phthalocyaninato zinc (II) (6). Compound 6 was synthesizedtized and purified with the same conditions adopted for 5, reacting phthalonitrile 2 (300 mg, 1.23 mmol) and zinc acetate dihydrate (154.3 mg; 0.61 mmol) in DMAE (5 mL) to give compound 6 (208.30 mg, 73%). m.p. > 300 °C; HRMS-MALDI-TOF m/z calculated for C44H32N8O12Zn [M+1]+ 928.143, found [M+1]+ 928.148. Elemental Analysis. Calculated: C, 56.82; H, 3.47; N, 12.05. Found: C, 56.80; H, 3.51; N, 12.15. FTIR (KBr) (νmax): 3500 – 2500 cm-1 (O-H), 2987 cm-1, 2937 cm-1 (C-H), 1728 cm-1 (C=O), 1606 cm-1, 1479 cm-1, 1400 cm-1 (C=C), 1336

cm-1 (C-O), 1226 cm-1 (C-O-C), 1093 cm-1 (C-O-C).1H NMR (CDCl3): δ (ppm) 9.24 – 8.80 (m, 4H, H-6); 8.78 – 8.40 (m, 4H, H-3); 7.79 – 7.63 (m, 4H, H-1); 5.58 – 5.42 (m, 8H, H-8); 1.98 – 1.79 (m, 12H, H-22).

2.5. Synthesis of metal free carboxyphthalocyanines Derivatives. 2.5.1. 2,9(10),16(17),23(24)-Tetra[(pentyloxycarbonyl)methyloxy]phthalocyanine (7). Phthalonitrile 1 (300 mg; 1.30 mmol) was stirred in n-pentanol at 70 oC for 10 min, and then hydroquinone (47.7 mg, 0.434 mmol) were added. The resulting mixture was stirred at 150 oC under nitrogen atmosphere for 12 h. After the solvent removing, the residue was poured into ice water to give green precipitate, which was collected by filtration, washed with the aqueous solutions of HCl (2 mol.L-1) and NaOH (1 mol.L-1), respectively, followed by water until pH 7, and then dried in vacuo. The crude product was purified by a silica gel column chromatography using using 200 mL of DCM and then hexane–ethyl acetate (1:1, v/v) to give compound 7 (126 mg, 41%). m.p. > 300 °C. FTIR (KBr) (νmax): 2956 cm-1, 2927 cm-1, 2856 cm-1 (C-H), 1760 cm-1 (C=O), 1608 cm1

, 1488 cm-1, 1398 cm-1 (C=C), 1338 cm-1 (C-O), 1201 cm-1 (C-O-C), 1091 cm-1 (C-O-

C).1H NMR (CDCl3): δ (ppm) 7.81 – 7.40 (m, 4H, H-6); 7.35 – 7.26 (m, 8H, H-1 e H3); 5.42 – 5.30 (m, 8H, H-8); 4.40 – 4.34 (m, 8H, H-12); 1.80 – 1.69 (m, 8H, H-15); 1.47 – 1.35 (m, 16H, H-14 e H-13); 0.88 – 0.81 (m, 8H, H-16); -0.12 (s, 1H, NH);

2.5.2. 2,9(10),16(17),23(24)-Tetra[1-(pentyloxycarbonyl)ethyloxy]phthalocyanine (8). According to the above procedure for 7, a suspension of 2 (300 mg; 1,23 mmol) in n-pentanol was treated with hydroquinone (47.7 mg, 0.434 mmol) to give compound 4 45% (126 mg). m.p. > 300 °C; FTIR (KBr) (νmax): 2956 cm-1, 2927 cm-1, 2856 cm-1 (C-H), 1760 cm-1 (C=O), 1608 cm-1, 1488 cm-1, 1398 cm-1 (C=C), 1338 cm-1 (C-O), 1201 cm-1 (C-O-C), 1091 cm-1 (C-O-C).1H NMR (DMSO-d6): δ (ppm) 8.14 – 7.04 (m, 12H, H-6, H-3, H1); 5.49 – 5.10 (m, 4H, H-8); 4.81 – 3.63 (m, 8H, H-12); 2.05 – 0.58 (m, 48H, H-22, H-13, H-14, H-15, H-16); -0.12 (s, 1H, NH).

2.5.3. 2,9(10),16(17),23(24)-Tetra(carboxymethyloxy)phthalocyanine (9). In a closed reaction tube, phthalonitrile 1 (300 mg, 1.30 mmol) was stirred in DMAE (5 Ml) at 70 oC for 10 min, and then an excess of metallic lithium (5 mg) was added. The resulting mixture was stirred at 150 oC under nitrogen atmosphere and constant stirring for 4 h. After cooling, the reaction mixture was poured into a water/ethanol 10 % solution to give dark blue precipitate, which was collected by filtration and washed with water. The residue was solubilized in NaOH (1 mol.L-1) solution and then acidified to pH 2 with HCl (1 mol.L-1) solution, until coagulation. The solid was centrifuged and purified by successive precipitation, using solutions of HCl (1 mol.L-1) and NaOH (1 mol.L-1) The crude product was purified by silica gel column chromatography using methanol-ethyl acetate 2:1 v/v to give the compound 9 75.00% (216 mg). m.p. > 300 °C. FTIR (KBr) (νmax): 3448 cm-1 (O-H, N-H), 1716 cm-1 (C=O), 1616 cm-1, 1481 cm-1 (C=C), 1342 cm-1 (C-O), 1236 cm-1 (C-O-C), 1101 cm-1 (C-O-C).

2.5.4. 2,9(10),16(17),23(24)-Tetra(carboxymethyloxy)phthalocyanine (10). Compound 10 was synthesizedtized under the same conditions adopted for 9, reacting phthalonitrile 2 (300 mg, 1.23 mmol) and then an excess of metallic lithium (5 mg) in 5 mL of DMAE to give a dark green solid (216 mg, 82.0%). m.p. > 300° C;. FTIR (KBr) (νmax): 3448 cm-1 (O-H, N-H), 1716 cm-1 (C=O), 1616 cm-1, 1481 cm-1 (

C=C), 1342 cm-1 (C-O), 1236 cm-1 (C-O-C), 1101 cm-1 (C-O-C).1H NMR (DMSO-d6):

δ (ppm) 8.25 – 7.29 (m, 12H, H-1, H-3 e H-6); 5.66 – 4.89 (m, 4H, H-13); 2.27 – 1.61 (m, 12H, H-17). 2.6. Metallation reaction of metal free carboxyphthalocyanines derivatives 2.6.1. Metallation reaction of compound 7 A solution of 7 (0.1 g, 0.09 mmol) and anhydrous Zn(CH3COO)2 (49.5 mg, 0.27 mmol) was refluxed in 2 ml of n-pentanol with stirring for 6 h under nitrogen atmosphere. The resulting suspension was cooled and the volatiles removed in vacuo, the residue was purified by a silica gel column chromatography using 200 mL of DCM and then hexane–ethyl acetate (2:1, v/v) affording the ZnPc. The structural analysis and photofisical and photochemical properties matched with the compound 3 (section 2.4.1). 2.6.2. Metallation reaction of compound 8 According to the above procedure for 7, a solution of 8 (0.1 g, 0.087 mmol) and anhydrous Zn(CH3COO)2 (48 mg, 0.26 mmol) was refluxed in 2 ml of n-pentanol with stirring for 6 h under nitrogen atmosphere to give the respective zinc phthalocyanine. The structural analysis and photophysical and photochemical properties matched with the compound 4 (section 2.4.2).

2.6.3. Metallation reaction of compound 9 In a closed reaction tube, a solution of 9 (0.1 g, 0.09 mmol) and anhydrous Zn(CH3COO)2 (49.5 mg, 0.27 mmol) was stirred in DMF (2 mL) at 90 oC for 6h. The reaction mixture was cooled and poured into a water/ethanol 10 % solution to give dark blue precipitate, which was collected by filtration and washed with water. The residue was solubilized in NaOH (1 mol.L-1) solution and then acidified to pH 2 with HCl (1 mol.L-1) solution, until coagulation. The solid was centrifuged and purified by successive precipitation, using solutions of HCl (1 mol.L-1) and NaOH (1 mol.L-1), and then washed with distilled water until the filtrate became neutral. The crude product was purified by silica gel column chromatography using methanol-ethyl acetate 2:1 v/v. The structural analysis and photofisical and photochemical properties matched with the compound 5 (section 2.4.3). 2.6.4. Metallation reaction of compound 10 According to the above procedure for 9, a solution of 10 (0.1 g, 0.11 mmol) and anhydrous Zn(CH3COO)2 (63.5 mg, 0.33 mmol) was stirred in DMF (2 mL) at 90 oC for 6h to give the respective zinc phthalocyanine. The structural analysis and photophysical and photochemical properties matched with the compound 6 (section 2.4.4).

2.7. Photophysichal and photochemical studies All emission, excitation and electronic absorption spectra of the phthalocyanines were recorded in 10 mm path length fluorescence cuvettes in DMSO. 2.7.1. Fluorescence quantum yields Fluorescence quantum yields (Φ ) of all compounds were determined by comparative method using the following equation (Eq.1):

 =  ( )

 .  .   .  .  

(1)

were  and   are the areas under the fluorescence emission curves of the phthalocyanineslocyanines (3-12) and the standard, respectively.  and   are the relative absorbance of the sample and standard at the excitation wavelength, respectively.  and   are the refractive indices of the solvents for the sample and standard, respectively. The unsubstituted ZnPc (ΦF=0.20) [42] was employed as the standard.

2.7.2.

Phthalocyanine photooxidation Photogeneration quantum yields of singlet oxygen (Φ∆ ) were obtained by

indirect method, using diphenylisobenzofuran (DBPF) as chemical quencher [43, 44]. Typically, a mixture of the phthalocyanine (absorption ~0.2 in 680 nm) and the DPBF (absorption ~ 1.2 in 418 nm) was irradiated with a red LED lamp (23 mW) in 20 cycles of 6 seconds each one. The Φ∆ values were determined using zinc phthalocyanine (ZnPc) (Eq.2): ∆ = ∆ 

 .      . 

(2)

where   is the singlet oxygen quantum yield for the ZnPc (Φ∆= 0.67 in DMSO [42];  and   is the DPBF photobleaching rates in the presence of the phthalocyanine and ZnPc, respectively (this value was obtained by the first exponential curves using the Origin® program);  and    are the light absorption rates by the phthalocyanines and ZnPc, respectively.

2.7.3. Phthalocyanine photodegradation The photodegradation quantum yield of a given substance is the ratio of the number of oxidized molecules of this substance to the number of absorbed photons. It can be determined by using Eq. (3) [16]:  = −

(  ).   . 

(3)

where C0 and Ct in mol L−1 are the concentrations before and after irradiation, respectively; V is the reaction volume; S the irradiated cell area; t is the irradiation time; and NA is the Avogadro’s number. The absorbed intensity Iabs is the fraction of absorbed light times the radiation intensity Ip in photons per area per time unit:  = (! − !" ) "

(4)

was utilized for the calculation of phthalocyanine photobleaching, with no need of a standard. 2.8. Determination of partition coefficients (PO/W) Five milliliters of 10 µM solution from each phthalocyanine derivative was prepared in n-octanol. The UV-vis spectrum of solution was sampled. Then water (5 mL) was added to solution and the container was stirred for 30 minutes. The centrifugation (5 minutes at 5000 rpm) enabled a phase separation and the organic phase was sampled again. The partition coefficient was obtained from the difference in the phthalocyanine absorption intensity in both stages. At least three independent measures were performed and the corresponding PO/W value was taken as the overall average.

3. Results and discussion 3.1. Preparation and structural characterization Scheme 1 describe the synthetic pathways to prepare tetra-carboxylic acid and tetra-carboxylic ester metal and metal free phthalocyanines (MTcPc’s and TcPc’s).

Zn

(O

Ac

)2

,1

50

°C

D 15

0°

M C

AE

,L

i°

Scheme 1. Synthetic routes to prepare new carboxyphthalocyanine derivatives.

For the synthesis of tetra-carboxylate ZnPc’s 5 and 6 we investigated different routes: one through to the direct metal template preparation of ZnTcPc’s and other was the introduction of central metal into metal free phthalocyanine ring. In both cases, subsequent hydrolysis of the ester groups was carried out to obtain the carboxylic acid groups.

The starting compounds 13 and 14 were synthesizedtized by a selective esterification reaction of α-hydroxycarboxylic acids using boric acid as catalyst to convert glycolic and lactic acids to their ethyl esters [45]. Phthalonitriles precursors 1 and 2 were prepared by a nucleophilic ipso-nitro substitution reaction of 4nitrophthalonitrile with compounds 13 and 14 in the presence of potassium carbonate as base. The reactions provide the ester phthalonitriles in high yields of 64 and 72%, respectively (Scheme 2). Purity of 1 and 2 was identified by GC-MS analysis that sowed one single pick at retention times of 18.25 and 18.10 min and their correspondent mass, respectively.

Scheme 2. Synthesis of ethyl dicyanophenoxy)propanoate (2).

(3,4-dicyanophenoxy)acetate (1) and

ethyl 2-(3,4-

Esterification reaction was a very important step. The conditions to obtain pthalonitriles precursors from glycolic and lactic acids use heat and strong basic media, resulting in low yields for unprotected carboxylic lactic and glycolic groups. Afterward, the attempt in synthesize the ZnTcPc’s from these precursors fail. ZnTcPc’s 5 and 6 were synthesized using the classical method refluxing phthalonitriles 1 and 2 in DMAE in the presence of zinc acetate as a metal template.

The products were very soluble in water, indicating that, under these conditions, the ester groups were totally hydrolyzed during the cyclotetramerization reaction. The same procedure using metallic lithium as a metal template and subsequent acidification at the end of reaction was employed to synthesize TcPc’s 9 and 10. Again, the ester groups were totally hydrolyzed during the process. Purification of these compounds can be accomplished by washing the precipitate with a solution of water/ethanol 10% and dissolving the solid in aqueous hydroxide solution and re-precipitating the free acid (TcPc or ZnTcPc) into aqueous hydrochloric acid solution. A silica chromatographic column was applied as a final purification process to eliminate impurities. The reaction of metal free Pc’s 9 and 10 in the presence of zinc acetate was an alternative route employed with success to synthesize ZnPc’s complexes 5 and 6 in high yields. The first attempting to synthesize ester phthalocyanines 3 and 4 was the ciclotetramerization reaction with phthalonitrile precursors 1 and 2 in the presence of zinc acetate and organic base (1,8- diazabicyclo[5.4.0]undec-7-ene (DBU)) in npentanol. These react conditions [46] led to a mixture of ZnPc’s and Pc’s esters with both ethoxycarbonyl and pentoxycarbonyl groups, due to partial transesterification, complicating their purification and leading to lower yields for the desired product. In order to minimize such complications, hydroquinone was tested in the place of DBU. Hydroquinone is a suitable organic reducing agent and used in the cyclotetramerisation of phthalonitrile to give metal free phthalocyanines that requires two electrons and two protons. In some cases the use of hydroquinone can greatly increase yields of metal free and metallophthalocyanines in conventional preparations starting from 1,2-dicyanobenzene and a metal salt [47].

One equivalent of hydroquinone and the substituted phtalonitrile were refluxed in n-pentanol and inert atmosphere, to give the transesterificated ZnPc’s 3 and 4 and free Pc’s 7 and 8 (when the reaction is carried out in the absence of salt metal) increasing the formation of pentoxycarbonyl groups in more quantity. Purification of the crude products were done by column chromatography using a binary mixture solvents of ethyl acetate/hexane as well described in the experimental section. Another synthetic route to obtain compounds 3 and 4 was the metalation reaction refluxing 7 and 8 in n-pentanol and an excess of anhydrous zinc acetate. The newly synthesized phthalonitrile compounds and their phthalocyanine derivatives were characterized by general spectroscopic methods such as 1 H NMR, FTIR, MALDI-TOF, UV-vis and fluorescence spectra. In the FTIR spectra of phthalonitriles, the vibrational peaks for the nitrile groups were observed at 2225 cm-1 for 1 and 2235 cm-1 for 2, absorptions at 2981–2994, 2952– 2931, 2900, 2875, 1745–1747, 1274, 1241–1250, and 1090–1093 cm-1 are attributed to the asymmetric and symmetric C-H stretching vibrations, C=O stretching vibrations, and the asymmetric and symmetric C-O-C stretching vibrations. The 1 H NMR spectra of 1 and 2 in CDCl3 showed characteristic signals for esters (CH3CH2OOC–) protons at 4.30-1.32 ppm for 1 and 4.25–1.20 ppm for 2. The singlet at 4.74 ppm for 1 and the quartet and duplet at 4.83 and 1.69 ppm for 2 indicated, respectively, the presence of the -CH2-, -CH- and -CH3 protons from glycolic and lactic acids substituents. Cyclotetramerization of phthalonitriles derivatives 1 and 2 to the Pcs 3–10 were first confirmed by the disappearance of the sharp nitrile vibration peaks about 2225 cm1

. In this study, synthesized tetra-substituted phthalocyanine compounds were obtained

as isomer mixtures as expected. The separation of regioisomers by the preparative

chromatography was not successful. No further attempt was made to separate the isomers of complexes. The FTIR spectra for Pcs 3–10 were recorded and all expected vibration frequencies of the functional groups such as CH2, CH3, benzene, ether, esters, NH and well Pc core was assigned and presented in Table 1.

Table 1: Characteristics frequencies of phthalocyanines 3-10 KBr pellets in FTIR. Frequency [cm-1] [48, Vibration mode* H2Pc 3 4 5 6 7 8 9 10 49] 759 1008 1093

744

746

742

744

1090 1221 1484 1608 1740 2860 2929

1097 1228 1482 1610 1731 2958 2927

1090 1222 1479 1604 1724

1093 1226 1479 1600 1729

2921

2930

2871

2871

2861

3000 3068 3289

3066

3066

1467 1600

744 1010 1099 1222 1477 1610 1766 2960 2933

746 1010 1095 1220 1477 1612 1753 2956 2935

2855

22855

3289 3380

3400

3289

740 1008 1101 1232 1479 1612 1730

740 1012 1095 1232 1479 1614 1722

C – H out-of-plane δ (N – H)o.o.p δ (isoindole)breath + δ (C – H) ν (Car – O – C)as ν(CH2, CH3,aliph,) ν(C-N)s ν (C=C benzene)s ν (C=O)

2932

2929

ν (C – H,aliph)as ν (C – H,aliph)s

* 3448

3289 3417

ν (C – Haro C – Npyrrole)s ν (C – Haro)s ν (N – H)s ν (COO – H)s broad signal

* Symbols ν, δ denote the stretching and bending respectively. Notations s, as,o.o.p, breath have been used for symmetric, asymmetric, out of plane and breathingmodes, respectively.

As showed in Table 1, C – O – C and C=O vibrations were assigned at 1220 – 1232 cm-1 and 1722 – 1766 cm-1, respectively, for all compounds. COO – H vibrations appeared at expected frequencies as a broad signal (3380 – 3448 cm-1). Aliphatic vibrations groups for esters Pcs 3 – 4 and 7 – 8 assigned at 2855 – 2961 cm-1 showed to be more intense than their hydrolyzed pairs 5 – 6 and 9 – 10 due their extended carbon

chain. The important N – H vibration modes to metal free Pcs 7 – 8 and 9 – 10 were assigned at 3289 and 1008 – 1012 cm-1. The 1H NMR spectra of Pcs 3 – 10 can be analyzed in two groups: the esters Pcs and acids Pcs. The characteristic chemical shifts to each group can be observed in the 1

H NMR spectra of Pcs 6 and 8 (Figure 1).

Figure 1. 1H NMR (300 MHz) spectrum of 4 in CDCl3 (A) and 6 in DMSO-d6 (B) compounds.

The 1H NMR analysis of all Pcs compounds 3 – 10 were recorded in deuterated chloroform and dimethyl sulfoxide depending on their solubility. To acid Pcs a drop of deuterated trifluoroacetic acid was add into the solution to reduce the aggregation of the compounds. For compound 4 and 6 the aromatic protons were observed as three broad multiple signals with a total of twelve protons at 8.85 – 8.47 ppm, 8.41 – 7.94 ppm and 7.75 – 7.35 ppm for 4 and 9.24 – 8.80 ppm, 8.78 – 8.40 ppm and 7.79 – 7.63 ppm for 6 (Figure 1). The same patterns to all Pcs were find in the aromatic protons region with broad multiple signals due the aggregation and the mixed isomer character of these compounds that have two kinds of α ring protons Hα1 and Hα2. CH2 protons can be

observed 5.62 – 5.19 ppm for compound 4 and the CH at 5.58 – 5.42 ppm for 6, while the two CH3 protons for compound 6 appeared as a multiple at 1.88 ppm and as a multiple 1.59 – 0.91 ppm, in this case the assignment was more difficult due to overlapping signals. The same problem was find to assign the signals protons -(CH2)4groups of the esters phthalocyanines 3 – 4 and 7 – 8. The hydrogens next to the carbonyl group were observed as a broad multiple about 4.35 ppm, while the others appeared as a multiple overlap of signals in higher field (Figure 1). The terminal proton of the carboxyl group is often difficult to observe, as in this case which accounts for its absence in the 1H NMR spectrum [50]. The characteristic protons from the ring cavity of free phthalocyanines were hardly observed in CDCl3 and not appeared in the spectra because of strong aggregation, especially in the spectra of compounds 9 – 10 [51, 52]. The mass spectra of novel compounds were taken and also confirmed the proposed structures. The expanded MALDI spectrum for compound 4 and 6 revealed molecular ion peaks at 1206.454 and 928.148 Da, respectively (Figure 2), indicating the success synthesis of the ester Pcs and their hydrolyzed analogues. Another important thing to observe is the characteristic signals of the presence of isotopes pattern peaks in the spectra of zinc complexed into phthalocyanine ring, indicating complex formation.

A

B

Figure 2. The MALDI-TOF spectra of the 4 (a) and 6 (b) compounds.

3.2.Ground state electronic absorption spectra Solvent studies reveal that ester phthalocyanine derivatives 3 – 4 and 7 – 8 show good solubility in most organic solvents as ethyl acetate, acetone, CHCl3, DCM, DMF, DMSO and THF. Complexes 5 and 6, also have good solubility in acetone, DMF and DMSO, while 9 and 10 are hardly soluble due the absence of the central metal. Furthermore, the ZnTcPc’s and TcPc’s are readily soluble in alkaline medium. Spectroscopic properties of phthalocyanines 3 – 10 were measured in DMSO, a solvent that offers convenient solubility for all of the studied phthalocyanines, and the data are summarized in Table 2. Table 2: photophysical and photochemical data for phthalocyanines in DMSO. -7

Entry

 "#$ ( #)

%& '

"(# #$ ( #)

∆) * ( #)

+

+,

+- (x10 )

%&

3

690

5,01

698

8

0,97

0,12

0,36

0,001

4

687

5,12

699

12

0,83

0,14

5,80

0,002

5

680

4,36

690

10

0,93

0,08

4,42

1,69

6

680

4,53

691

11

0,84

0,14

7,44

1,32

7

707, 676

3,64, 3,75

717

10

0,01

0,10

2,69

-

8

711, 679

3,77, 3,83

718

7

0,02

0,14

6,33

-

9

703, 670

4,83, 4,80

713

10

0,08

0,09

3,44

1,60

10

703, 671

4,85, 4,90

713

10

0,05

0,12

4,21

1,57

The electronic absorption spectra of the novel tetra-carboxylic acid and tetracarboxylic ester metal and metal free phthalocyanines (3 – 10) were recorded in the ultraviolet and visible (UV-Vis) regions of the electronic spectra. These compounds showed strong absorptions around 240–345 nm (B band) and the other in the visible part of the spectrum at around 670–700 nm (Q band) because of π−π∗ transitions (Figure 3).

3 7

A

5 9

1,0

Normaliz ed absorbanc e

Normaliz ed absorbanc e

1,0

0,8

0,6

0,4

0,2

B

0,8

0,6

0,4

0,2

0,0 0,0 400

500

600

700

800

400

500

λ (nm) 4 8

C

1,0

Normaliz ed absorbanc e

Normaliz ed absorbanc e

1,0

600

700

800

λ (nm)

0,8

0,6

0,4

0,2

0,0

6 10

D

0,8

0,6

0,4

0,2

0,0 400

500

600

λ (nm)

700

800

400

500

600

700

800

λ (nm)

Figure 3. Normalized ground state electronic absorption spectra of (A) 3 and 7, (B) 5 and 9, (C) 4 and 8, and (D) 6 and 10 compounds in DMSO.

The Q band of the free TcPc’s 7–10 were observed as 2 split bands at λmax 670 and 703 nm, 674 and 704 nm, 677 and 707 nm and 679 and 711 nm, as expected due to D2h symmetry. Figure D and B, show a slightly broadened, less intense and sharp peaks to metal free phthalocyanines 9 and 10 when compared with 7 and 8 due their poor solubility. UV-Vis spectra of phthalocyanines derivatives 3–10 showed intense and sharp Q band absorption in DMSO at λmax = 680-681 nm for complex 3 and 4, and 690-691 nm for complex 5 and 6. The single Q bands in metallophthalocyanine derivatives are characteristic of metalation, which maintains the planarity of the molecule and increases the symmetry to D4h.

The substitution of the glycolic and lactic acids with esterified or non-esterified groups to phthalocyanine ring caused red-shifted Q band absorption around 9 nm for the first case and 19 nm for the second (the Q-band absorption of unsubstituted zinc(II) phthalocyanine is 672 nm DMSO [38]). There is a 10 nm difference between the Qband positions of ester-substituted phthalocyanines and carboxylated-substituted phthalocyanines. This implies that the electron density is higher in the carboxylatedsubstituted phthalocyanine rings due to the COOH group substituents, resulting in the lowering of the HOMO–LOMO gap of these compounds. 3.3. Aggregation studies The aggregation behavior of 3–10 were investigated at different concentrations in DMSO using UV-Vis spectrophotometry. For compounds 3-8, a direct correlation between the concentration and the intensity of absorption of the Q band was find and no new bands were observed for all complexes signifying no aggregation behavior at these concentrations, probably due to the bulky nature of the ring substituents and the presence of central metal. The Beer-Lambert law was obeyed for all of these compounds at concentrations ranging from 1.2 x 10-5 to 2 x 10 -6 M (Figure 4 as an example for compound 6.

1,0

Absorbance

0,8

0,6

Absorbance at 680 nm

1,0 0,9

y = 0,0019x - 0,2022 R² = 0,9996

0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1

0,4

200

300

400

500

600

Concentration (µM)

0,2

0,0 400

500

600

700

800

λ (nm)

Figure 4. UV-Vis spectra of phthalocyanine 6 in different concentrations in DMSO.

Free TcPcs 9 and 10, on the other hand, have lower solubility in DMSO than other compounds. It was confirmed by the broadened and diminished intensity of Qband, meaning that it is some aggregated in the aqueous medium. For these reason the molar absorption coefficients for 9 and 10 were calculated at concentrations ranging from 1.4 x 10−5 to 4 x 10−6 M. Self-aggregation of phthalocyanines compounds in aqueous media is a common phenomenon, which decreases their efficient generation of reactive oxygen species [5]. It can be explained by strong π−π electron interactions between the planar phthalocyanine rings and hydrogen bonding between carboxyl groups of adjacent molecules when the phthalocyanine ring have peripheral functional groups such as COOH, SO3H and NH2. For compounds 5 and 6, we observed a predominance of the monomeric species in solution until a 60% mixture of water in DMSO, which can be verified by following the relative intensities of the Q-band in the absorption spectra

(Figure 5). This is an important result because the water solubility of this kind of compounds is very important for many different applications.

1,0

A

0% 2 0% 4 0% 6 0% 8 0%

0,6

0,8

Abso rban ce

Abso rban ce

0,8

1,0

% H2 O

0,4

0,2

0% 20% 40% 60% 80%

0,6

0,4

0,2

0,0 450

% H2 O

B

0,0 500

550

600

65 0

700

750

800

450

λ (nm)

500

550

600

65 0

700

750

800

λ (nm)

Figure 5: UV-Vis spectra of phthalocyanines 5 (A) and 6 (B) in different proportions of H2 O and DMSO with respectively concentration of 0.18 and 0.22 µM.

3.4. Fluorescence spectra and quantum yields studies Fluorescence spectra of studied phthalocyanine compounds 3-10 were carried out in DMSO at room temperature and the data are summarized in Table 2. The fluorescence excitation and emission spectra of 3, 4, 5 and 6 are typical of metal phthalocyanine complexes in DMSO with maximum intensities in the region between 699 and 690 nm, where the excitation spectra are similar to absorption and both of them were mirror images of the fluorescent spectra, suggesting that the nuclear configurations of the ground and excited states are similar and not affected by excitation [50, 53]. Fluorescence spectra for free TcPc’s 7, 8, 9 and 10 showed a single band of emission with maximum intensities in the region between 718 and 713 nm. The observed Stokes shifts of the phthalocyanines analogues 3-10 were within the region observed for typical phthalocyanine complexes, with similar values than those of the unsubstituted ZnPc (∆)* ( #)= 10 nm) [25] in DMSO. Figure 6 showed fluorescence emission excitation spectra for complex 6 in DMSO as an example.

Normalized Absorbance and Intensity

1,0

0,8

0,6

0,4

0,2

0,0 400

500

600

700

800

900

λ (nm)

Figure 6. Absorption and emission spectra of compound 6 in DMSO. Excitation wavelength = 612 nm.

The fluorescence quantum yields of Pcs 3-10 in DMSO are given in Table 2. The ratio of excited photons to relaxed photons via fluorescence is called fluorescence quantum yield (./) and can be measured observing the process when an electron absorbs a photon of light, is excited to higher quantum state in the phthalocyanine and then deactivation processes (fluorescence, internal conversion, vibrational relaxation and intersystem crossing) occur. The fluorescence quantum yields of the compounds 3-10 were lower as compared to unsubstituted zinc(II) phthalocyanine complex in DMSO (./ = 0,08 [42, 51]), especially in cases of 5 (./ = 0,08) and 9 (./ = 0,09).

3.5. Singlet oxygen generation studies Singlet oxygen production is an important parameter to be observed in PDT. It results of the energy transfer between the triplet state of photosensitizers and ground state molecular oxygen. The amount of singlet oxygen generates depend on the efficiency of this process. The efficiency of singlet-oxygen production was evaluated using the absorbance of DPBF. This compound is a widely utilized singlet-oxygen trapping agent, which strongly absorbs light around 410–420 nm and emits blue-colored fluorescence. DPBF quantitatively reacts with 1O2 to form o-dibenzoylbenzene, which does not absorb visible light. Therefore, the decrease in DPBF absorbance reflects the amount of generated 1O2 (Figure 7)[54, 55]. The data were collected for studied phthalocyanine compounds 3-10 in DMSO and their observed + values were given in Table 2.

1,0

(A) Absorbance in 417 nm

1,0

Absorbance

0,8

0,6

0,8

0,6

0,4

0,2

0,0

0,4

0

20

40

60

80

100

120

time (s)

0,2

0,0 400

500

600

λ (nm)

700

800

1,0

(B) Absorbance in 417 nm

1,0

Absorbance

0,8

0,6

0,8

0,6

0,4

0,2

0

0,4

20

40

60

80

100

120

λ (nm)

0,2

0,0 400

500

600

700

800

λ (nm)

Figure 7. Typical spectral changes for the determination of singlet oxygen quantum yield of 6 (A) and 10 (B) in DMSO. (Inset: plots of DPBF absorbance versus time). Comparing the exponential absorption decay of compound 6 and 10 (Figure 7) and the + values observed during the singlet oxygen quantum yield determination, it can be said that zinc atom effect into the phthalocyanine ring play an important role in the high efficiency of singlet oxygen formation. There was no change in the Q-band intensities of compounds during the light irradiation for

+ determinations. This

supported that the compounds were not degraded by used light irradiation during singlet oxygen measurements. 3.6.Photodegradation studies Photostabilities of all compounds were determined in DMSO by measuring the absorption spectral changes over time by irradiation with red light and listed in Table 2. The decrease in the intensity of Q-bands for the ZnPcs is shown in Figure 7 (giving 3 as an example). It is obvious that photodegradation occurred along with irradiation. The time decay of the absorbance maxima of Q-bands for all the compounds basically followed the first-order kinetics as shown in Figure 8 (insert). It can be seen that the photostabilities of these compounds follow the trend 3 > 7 > 9 > 10 ≈ 5 > 4 > 8 > 6. The

phthalocyanines 3 present higher photostabilitie in DMSO than the others analogues. The ZnTcPc’s 6 shows the lowest photostability.

0s 300s 600s 900s 1200s 1500s 1800s

1.2

1,0 Absorbance

1.0

Absorbance

0,8

0.8

y = -2E-05x + 0,9981 R² = 0,9188

0.6

0.4

0.2

0,6

0.0 0

400

800

1200

1600

2000

time (s)

0,4

0,2

0,0 300

400

500

600

700

800

λ (nm)

Figure 8. Typical spectral changes for the determination of photodegradation quantum yields of compound 3 in DMSO. (Inset: plot of Q band absorbance versus time).

4. Conclusion In our study, the synthesis of tetra-carboxylic acid-substituted phthalocyanines derivatives from glycolic and lactic acids were described. After investigation of some possible synthetic routes, we concluded that the cyclotetramerization reaction in the presence of hydroquinone increased the yields and the selectivity of the esters metal free and metallophthalocyanines substituted with pentoxycarbonyl groups. Metal free phthalocyanines were synthesized in good yields with lithium and hydroquinone as catalyst. The metalation reactions with zinc salt were carried out with relative facility and no need of complicated purification process. The fluorescence properties of these phthalocyanines were affected significantly by the absence of the central metal. Metal freelated phthalocyanines (7-8) showed a low capacity to generate singlet oxygen while

zinc phthalocyanines (3-6) gave good singlet oxygen quantum yields. The value of singlet oxygen quantum yields ranged from 0.01 (for 7) to 0.97 (for 3) in DMSO, indicating the potential of these compounds as photosensitizers for photodynamic therapy applications. Acknowledgment The authors thank FAPESP (2014/18527-8), UFABC, CNPq, and CAPES for financial support. References [1] Nemykin VN, Dudkin SV, Dumoulin F, Hirel C, Gurek AG, Ahsen V. Synthetic approaches to asymmetric phthalocyanines and their analogues. Arkivoc. 2014;1:142204. [2] Dumoulin F, Durmuş M, Ahsen V, Nyokong T. Synthetic pathways to water-soluble phthalocyanines and close analogs. Coordination Chemistry Reviews. 2010;254(23– 24):2792-2847. [3] Zhang X, Huang J, Xi Q, Wang Y. The Excited Triplet State Properties of Titanyl Phthalocyanine and its Sulfonated Derivatives. Australian Journal of Chemistry. 2010;63(10):1471-6. [4] Regmi BP, Galpothdeniya WIS, Siraj N, Webb MH, Speller NC, Warner IM. Phthalocyanine- and porphyrin-based GUMBOS for rapid and sensitive detection of organic vapors. Sensors and Actuators B: Chemical. 2015;209:172-9. [5] Yotsumoto Neto S, Luz RdCS, Damos FS. Visible LED light photoelectrochemical sensor for detection of L-Dopa based on oxygen reduction on TiO2 sensitized with iron phthalocyanine. Electrochemistry Communications. 2016;62:1-4. [6] Zhou R, Josse F, Göpel W, Öztürk ZZ, Bekaroğlu Ö. Phthalocyanines as Sensitive Materials for Chemical Sensors. Applied Organometallic Chemistry. 1996;10(8):55777. [7] Rodriguez-Mendez ML, Antonio de Saja J. Nanostructured thin films based on phthalocyanines: electrochromic displays and sensors. Journal of Porphyrins and Phthalocyanines. 2009;(13):606-15. [8] Alamin Ali HE, Altındal A, Altun S, Odabaş Z. Highly efficient dye-sensitized solar cells based on metal free and copper(II) phthalocyanine bearing 2-phenylphenoxy moiety. Dyes and Pigments. 2016;124:180-7.

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Investigation of synthetic pathways of carboxylic acid phthalocyanines from glycolic and lactic acids Francisco B. do Nascimento, Anderson O Ribeiro

- Hydroquinone as catalyst increases the yields and the selectivity in synthesis of the esters substituted metallophthalocyanines - Metal-free carboxy substituted phthalocyanines were synthesized in good yields with lithium and hydroquinone as catalyst. - Glycolic and lactic acids substituted phthalocyanines present different aggregation in solution due to the methyl radical group that distinguish both structures

Investigation of synthetic pathways of carboxylic acid phthalocyanines from glycolic and lactic acids Francisco B. do Nascimento, Anderson O Ribeiro

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