Novel thiol-derivatized zinc(II) phthalocyanines

Article abstract of DOI:10.1016/j.tetlet.2009.02.201

Preparation and characterization of tetrasubstituted zinc(II) phthalocyanines in which sulfur is not linked to the macrocycle are reported herein for the first time. Thioacetic acid S-[3-(3,4-dicyano-phenoxy)-propyl]ester (4) was synthesized in 55% yield

Full text of DOI:10.1016/j.tetlet.2009.02.201

Tetrahedron Letters 50 (2009) 2467–2469
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel thiol-derivatized zinc(II) phthalocyanines
María C. García Vior a, Diego Cobice a, Lelia E. Dicelio b, Josefina Awruch a,
*
a Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 1113 Buenos Aires, Argentina
b INQUIMAE, Departamento de Química Inorgánica, Analítica y Química Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria,
Pabellón II, 1428 Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Preparation and characterization of tetrasubstituted zinc(II) phthalocyanines in which sulfur is not linked
to the macrocycle are reported herein for the first time. Thioacetic acid S-[3-(3,4-dicyano-phenoxy)-pro-
pyl]ester (4) was synthesized in 55% yield from 4-nitrophthalonitrile and thioacetic acid S-(3-hydroxy-
propyl)ester (3). Tetrasusbtituted thiol-derivatized zinc(II) phthalocyanine 5 was obtained from 4 and
zinc acetate in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in butanol. Treatment of 5 with
sodium methoxide afforded phthalocyanine 6.
Received 11 February 2009
Revised 25 February 2009
Accepted 26 February 2009
Available online 4 March 2009
Keywords:
Thiol-phthalocyanines
Synthesis
Ó 2009 Elsevier Ltd. All rights reserved.
Spectroscopy
Phthalocyanines play a major role in modern photochemistry.
Complexation of phthalocyanines with metal ions has an influence
on their photophysical properties. These compounds are used as
catalysts as well as photoreceptors in electrographic printing.1 In
medicine, the dyes have been found to qualify as effective photo-
toxic drugs for photodynamic therapy.2 All these applications re-
quire compounds of various solubility and high purity degrees in
order to prevent by-products from impairing their photoconduct-
ing and optical characteristics. Thiol-derivatized metallophthalo-
other hand, their linkage to carriers as well as nanoparticle prepa-
ration.6 To our knowledge, only the synthesis and characterization
of
1,4,8,11,15,18-hexahexyl-22-methyl-25-(11-mercaptounde-
cyl)phthalocyaninatozinc(II) complex have been reported so far,6c
tetrasubstituted phthalocyanines with thiol groups at the end of
the alkyl peripheral substituents of the macrocycle have not been
described in the literature. The great interest in the development
of the above-mentioned compounds has led us to investigate the
synthesis and spectroscopic characterization of the novel thiol-
derivatized zinc (II) phthalocyanine complexes.4,7
cyanine
photochemical properties, such as wavelength absorption over
700 nm.3
systematic comparison of oxygen and sulfur as
complexes
show
excellent
spectroscopic
and
The synthesis of phthalocyanines 5 and 6 is shown in Scheme 1.
The sequence begins with the reaction of methyl 3-mercaptopropi-
onate (1) with acetic anhydride to give 3-acetylsulfanyl-propionic
acid methyl ester (2). The reaction of compound 2 with diborane in
tetrahydrofuran at room temperature afforded thioacetic acid S-(3-
hydroxy-propyl) ester (3). Phthalonitrile 4 was obtained in good
yields, by reaction of 4-nitrophthalonitrile with the corresponding
nucleophile 3.8,9 Phthalocyanine 5 was readily prepared by cyclo-
A
covalent linkers on octasubstituted zinc(II) phthalocyaninates
shows a bathochromic shift of 30 nm in the absorption and
emission maxima, and of 60 nm in the triplet-triplet absorption
spectra when alkylsulfanyl moieties instead of alkyloxyl moieties
were present.4 Recently, the effectiveness in photodynamic
therapy of 2,3,10,16,17,23,24-octakis[(N,N-dimethylamino)ethyl-
sulfanyl] phthalocyaninatozinc(II) was demonstrated by using
MCF-7c3 human breast cancer cells and LM2 adenocarcinoma im-
planted subcutaneously in Balb/c mice.5
Generally, thiol-derivatized metallophthalocyanine complexes
have been less explored than other metallophthalocyanine deriva-
tives, most of the compounds being those phthalocyaninates in
which sulfur is linked to the macrocycle.3,4 The presence of thiol
groups at the end of alkyl peripheral substituents of the macrocy-
cle could improve, on the one hand, dye amphiphilicity and, on the
tetramerization of phthalonitrile
4 employing 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) in butanol and zinc acetate at
130 °C.10a,11 This dye was purified by chromatography, followed
by recrystallization to attain 41% of the desired 2(3), 9(10),
16(17),23(24)-tetrakis[(3-acetyl-sulfanyl)propoxy]phthalocyani-
natozinc(II) (5). Treatment of 5 in an alkaline solution at room tem-
perature, followed by addition of Dowex 50 W-X2 to neutralize the
solution, in order to prevent zinc loss, gave the desired phthalocy-
anine 6 in 30% yield.10b
On the other hand, when the benzoyl group was applied to pro-
tect the thiol group, thiobenzoic acid S-(3-hydroxy-propyl) ester
(7) was obtained. Reaction of 7 with 4-nitrophthalonitrile gave 8
* Corresponding author. Tel.: +54 11 4964 8252; fax: +54 11 4508 3645.
E-mail address: jawruch@ffyb.uba.ar (J. Awruch).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.201

2468
M. C. García Vior et al. / Tetrahedron Letters 50 (2009) 2467–2469
in 64% yield. However, deprotection of 8 at room temperature as
1.2
1.0
0.8
0.6
0.4
0.2
0.0
well as by heating in an alkaline solution failed.12 The desired
Normalized absorption spectrum of 5
Normalized emission spectrum of 5
dinitrile
9 precursor of phthalocyanine 6 was not obtained
(Scheme 2). In contrast, synthesis of phthalocyanine 6 could be
easily carried out through the sequence depicted in Scheme 1.
With regard to the solubility of the new phthalocyanines, both
dyes have markedly different solubility properties while 5 is solu-
ble in almost all organic solvents, 6 is fully soluble in methanol and
tetrahydrofuran and is partially soluble in water.
Intermediates were characterized by mass spectrometry
employing an APPI/APCI dual ionization technique. Over the last
few years, HPLC–MS using the electrospray (ESI) ionization mode
has become the choice method for the analysis of thiol-com-
pounds. Alternatively, atmospheric pressure chemical ionization
(APCI) and more recently, atmospheric pressure photospray ioniza-
tion (APPI) interfaces were also introduced. This technique shows
several advantages over ESI such as the possibility of detecting
more apolar compounds and lowering the ion suppression phe-
nomena. Besides, it was demonstrated13 that APPI is more sensitive
than ESI or APCI for non-polar compounds and has shown higher
300
400
500
600
700
800
λ / nm
1.2
1.0
0.8
0.6
0.4
0.2
0.0
a
b
HSCH2CH2CO2CH3
CH3COSCH2CH2CO2CH3
1
2
CN
c
d
CH3COSCH2CH2CH2OH
R
CN
3
4
R= OCH2CH2CH2SCOCH3
R
300
400
500
600
700
800
λ / nm
Figure 1. Absorption and fluorescence spectra of 5 and 6 in THF.
R= OCH CH CH SCOCH
3
N
N
N
5:
2
2
2
signal-to-noise ratios essentially due to lower chemical back-
ground noise. Also, it was impossible to achieve the molecular
ion under the GC/MS/EI ionization conditions for synthetic inter-
mediates; therefore, in order to solve that issue, an APPI/APCI dual
ionization technique was used. Phthalocyanines 5–6 were charac-
terized by electrospray ionization-quadrupole time-of-flight (ESI-
QTOF) mass spectrometry. The isotopic cluster ions and the frag-
mentation patterns were consistent with the structures proposed.
The UV–vis absorption spectra of phthalocyanines 5–6 showed
a Soret band of 358 nm and 360 nm and a Q band at 684 nm and
686 nm, respectively. Such bathochromic shift into the therapeutic
window could be useful for biomedical applications such as tissue
imaging and photodynamic therapy.2 Typical fluorescence emis-
sion spectra of zinc phthalocyanines were also observed (Fig. 1).
Phthalocyanines 5–6 are excellent singlet oxygen generators with
e
R
Zn
N
R
N
N
N
N
6: R= OCH2CH2CH2SH
R
Scheme 1. Reagents and conditions: (a) Ac2O, reflux, 3 h, 94%; (b) B2H6, THF, rt,
48 h, 63%; (c) 4-nitrophthalonitrile, K2CO3, DMF, 60 °C, 24 h, 55%; (d) Zn(AcO)2,
DBU, BuOH, reflux, 1 h, 41%; (e) NaOMe 0.1 M, rt, 12 h, Dowex 50 W-X2, 30%.
CN
a high value of quantum yield of singlet oxygen production (UD
)
of 0.59–0.6114 as well as a fluorescence quantum yield (UF) pro-
duction of 0.34,15 basic conditions for further biological testing.
In summary, we have prepared and characterized two tetrasub-
stituted zinc(II) phthalocyanines. One of them, that having the free
thiol group, is likely to be a promising second-generation photo-
sensitizer for biological purposes, on account of its significant
solubility.
C6H5COSCH2CH2CH2OH
X
R
CN
8
7
R= OCH2CH2CH2SCOC6H5
CN
CN
6
R
Acknowledgments
9
R= OCH2CH2CH2SH
This work was supported by grants from the Universidad de
Buenos Aires, Consejo Nacional de Investigaciones Científicas y
Scheme 2.

M. C. García Vior et al. / Tetrahedron Letters 50 (2009) 2467–2469
2469
H, Ar), 7.55 (s, 1 H, Ar), 7.71 (d, 1 H, Ar); MS (APPI/APCI): m/z (%) = [M+H]+ calcd
for C13H12N2O2S: 261.0985; found: [M+H]+ 261.0997. Anal. Calcd for
C13H12N2O2S: C, 59.98; H, 4.65; N, 10.76. Found: C, 60.15; H, 4.67; N, 10.80.
9. Dei, D.; Chiti, G.; De Filippis, M. P.; Fantetti, L.; Giuliani, F.; Giuntini, F.; Soncin,
M.; Jori, G.; Roncucci, G. J. Porphyrins Phthalocyanines 2006, 10, 147–150.
Técnicas (CONICET), and the Agencia Nacional de Promoción
Científica y Tecnológica. We wish to thank Ms. Juana Alcira Valdez
for technical assistance regarding chromatography. Language
supervision by Professor Rex Davis is also appreciated.
10. (a)
2(3),
9(10),
16(17),
23(24)-tetrakis[(3-acetylsulfanyl)-
mixture of (0.05 g, 0.19 mmol),
propoxy]phthalocyaninatozinc(II) (5).
A
4
References and notes
anhyd Zn(OAc)2 (0.05 g, 0.22 mmol), and DBU (0.1 mL, 0.67 mmol) in anhyd
BuOH (5 mL) was stirred and heated at reflux temperature under Ar for 1 h.
After evaporation in vacuo, the residue was treated with CH2Cl2 (5 mL) and
centrifuged to eliminate the Zn(OAc)2 excess. The organic solution was
evaporated in vacuo leaving a blue- green solid which was then dissolved in
CH2Cl2 and filtered through a column of silica-gel packed and pre-washed with
the same solvent. The title compound was eluted with CH2Cl2–MeOH (9:1).
After evaporation of the solvent, the dye was recrystallized from CH2Cl2–
hexane. Yield: 0.022 g (41%); IR (KBr): 3099, 2933, 1727, 1697, 1446, 1359,
1. (a)Leznoff, C. C., Lever, A. B. P., Eds.; VCH: New York, 1989, 1992, 1993, 1996;
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1324,1265, 1206, 1106, 984, 844, 739, 527 cmÀ1 1H NMR (500 MHz, CDCl3): d
;
1.60 (br s, 12 H, CH3), 2.15 (m, 8 H, CH2CH2CH2), 3.23 (m, 8 H, CH2O), 4.19 (m, 8
H, SCH2), 7.22 (br s, 4 H, Ar), 7.61 (br s, 4 H, Ar), 7.74 (br s, 4 H, Ar); ESI-TOF MS:
m/z [M+] calcd for C52H48N8O8S4Zn: 1106.1763; found: [M+] 1106.1861; UV–vis
(THF): kmax
kmax = 688 nm; Singlet oxygen quantum yields
quantum yields UF): 0.35. (b) 2(3), 9(10), 16(17), 23(24)-tetrakis[(3-
mercapto)propoxy]phthalocyaninatozinc(II) (6). Phthalocyanine (0.005 g,
(e
, MÀ1 cmÀ1) = 684 nm (142035); Fluorescence emission (THF):
(UD): 0.59; Fluorescence
(
5
0.0045 mmol) was suspended in anhyd MeOH (1 mL). 0.1 M NaOMe soln
(1 mL) was added and the solution was stirred for 12 h. Dowex 50 W-X2 was
added to neutralize the solution and then the ion exchanger was filtered off.
After evaporation of the solvent in vacuo, the residue was dissolved in a small
volume of MeOH and filtered through a column of silica-gel packed and pre-
washed with the same solvent. A blue-green residue was obtained after the
evaporation of the solvent in vacuo; this was recrystallized from CH2Cl2–
hexane. Yield: 0.0013 g (30%); IR (KBr): 3409, 2929, 2317, 1617, 1436, 1294,
6. (a) Konan, Y. N.; Chevallier, J.; Gurny, R.; Allémann, E. Photochem. Photobiol.
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Evans-Gowing, R.; FitzGerald, S.; Beeby, A.; Chambrier, I.; Cook, M. J.; Russell, D.
A. Langmuir 2002, 18, 2985–2987.
1258, 1046, 667 cmÀ1 1H NMR (500 MHz, DMSO-d6): d 1.52 (br s, 4 H, SH),
;
2.05 (m, 8 H, CH2CH2CH2), 2.58 (m, 8 H, SCH2), 4.01 (m, 8H, CH2O), 6.83 (br s, 4
H, Ar), 6.94 (br s, 4 H, Ar), 7.19 (br s, 4 H, Ar); ESI-TOF MS: m/z [M+] calcd for
C44H40N8O4S4Zn: 938.1347; found: [M+] 938.1425; UV–vis (THF): kmax
(e,
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M
À1 cmÀ1) = 686 nm (137419); Fluorescence emission (THF): kmax = 690 nm;
8. Thioacetic acid S-[3-(3,4-dicyano-phenoxy)-propyl] ester (4). A mixture of 3
(0.40 g, 2.98 mmol), 4-nitrophthalonitrile (0.10 g, 0.58 mmol), and K2CO3
(0.61 g, 4.4 mmol) in anhyd DMF (5 mL) was heated at 60 °C and stirred
under Ar for 24 h. After cooling down, the mixture was poured into H2O and
then extracted with CH2Cl2 (4 Â 30 mL). The combined extracts were washed
with H2O (3 Â 30 mL) and dried over Na2SO4, and then evaporated in vacuo.
The solid residue was dissolved in a small volume of CH2Cl2, and filtered
through a silica-gel column packed and pre-washed with the same solvent.
After evaporation of the solvent, the residue was recrystallized from EtOH.
Yield: 0.083 g (55%); mp 106–108 °C; IR (KBr): 3081, 2923, 2573, 2228, 1737,
1598, 1582, 1562, 1492, 1468, 1390, 1360, 1342, 1283, 1258, 1192, 1167, 1019,
Singlet oxygen quantum yields (UD): 0.61; Fluorescence quantum yields (UF):
0.34.
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;
962, 871, 833, 718, 622, 594 cmÀ1 1H NMR (300 MHz, CDCl3): d = 1.56 (s, 3 H,
CH3), 2.26 (m, 2 H, CH2CH2CH2), 3.24 (t, 2 H, CH2O), 4.20 (t, 2 H, SCH2), 7.23 (d, 1