Synthesis and photosensitizing properties of fluoroalkoxyl phthalocyanine metal complexes

Article abstract of DOI:10.1016/S0022-1139(01)00539-5

Nine fluoroalkoxyl phthalocyanine metal complexes (Zn, AlCl, Mg, Co, Cu, FeCl) were synthesized from 4-(polyfluoroalkoxyl) phthalic anhydride. The fat-soluble phthalocyanines were characterized by elemental analysis, IR, ¹H NMR and fast-atom-bo

Full text of DOI:10.1016/S0022-1139(01)00539-5

Journal of Fluorine Chemistry 113 )2002) 161±165
Synthesis and photosensitizing properties of ¯uoroalkoxyl
phthalocyanine metal complexes
Lindong Gaoa, Xuhong Qianb,*
aInstitute of Pharmaceuticals & Pesticides, East China University of Science & Technology, Shanghai 200237, China
bState Key Laboratory of Fine Chemicals, Dalian University of Technology, P.O. Box 40, 158 Zhongshan Rd., Dalian 116012, China
Received 19 January 2001; accepted 14 September 2001
Abstract
Nine ¯uoroalkoxyl phthalocyanine metal complexes )Zn, AlCl, Mg, Co, Cu, FeCl) were synthesized from 4-)poly¯uoroalkoxyl) phthalic
anhydride. The fat-soluble phthalocyanines were characterized by elemental analysis, IR, 1H NMR and fast-atom-bombardment mass
spectroscopy. Zinc and aluminum chloride complexes show higher photooxidation ability in solution containing 20% per¯uorocarbons than
in hydrocarbon solvents. # 2002 Published by Elsevier Science B.V.
Keywords: Phthalocyanine; Synthesis; Photosensitizers
1. Introduction
drugs such as 5-¯uorouracil, we have now designed and
synthesized some new ¯uorine-containing phthalocyanines
in order to ®nd better photosensitizers which will be
expected to be used in PDT. Compared to typical phthalo-
cyanines, these tetra)¯uoroalkoxyl) phthalocyanine metal
complexes show good fat solubility. Synthetic routes to
phthalocyanine metal complexes may involve either the
initial synthesis of the metal free phthalocyanine derivatives,
followed by metalization with metal salts or may incorporate
the metal ion concurrently with the synthesis of the phtha-
locyanine ring system from a simple benzenoid precursor.
The precursor may be a phthalic anhydride or a phthaloni-
trile derivative.
PDT dyes are recognized as ef®cient sensitizers of
singlet oxygen and the involvement of singlet oxygen in
the PDT process is now widely accepted, thus, the relative
photooxidation rate by singlet oxygen catalyzed by these
dyes have been examined. The Diels±Alder reaction and
the ene reaction are two widely used application of singlet
oxygen with ole®ns [10,11]. Here we have examined the
structural effects of the synthesized dyes as sensitizers by
using the Diels±Alder reaction with furan-2-carboxylic
acid )10) as a model reaction )Scheme 1). Per¯uorocar-
bons have shown that they can dissolve substantial
amounts of oxygen and other gases )CO2, F2), and have
also been reported to enhance the photosensitized oxida-
tion of histidine [12,13], so we also examined the photo-
oxidation ability of these compounds in solvent containing
per¯uorocarbons.
For many years, phthalocyanines have attracted great
interest in research ®elds such as chemical sensors, electro-
chromism, batteries, semiconductors, molecular metals,
catalysts, liquid crystals and nonlinear optics [1]. As the
second generation photosensitizers for photodynamic ther-
apy )PDT) in the treatment of cancer, phthalocyanines,
particularly the aluminum and zinc derivatives, are the most
recently studied [2]. Although some of these materials show
excellent PDT behavior and low general toxicity in animal
models, they still have yet to ®nd widespread clinical
acceptance. There is still a clear need to explore in greater
depth relationships between the structure of phthalocyanine
sensitizers and their PDT behavior.
Zinc and aluminum phthalocyanines because of their poor
water and fat solubility are utilized in liposomal form and
have shown suf®cient PDT activity to justify their commer-
cialization [3,4]. Some polar derivatives that have received
attention include sulfonated derivatives, amino substituted
derivatives and octahydroxy derivatives [5,6]. Non-polar
derivatives of PDT interest have included octa-n-butoxyl
and tetra)dibenzobarrelene)-octabutoxyl derivatives [7±9],
etc. Owning to the effects of ¯uorine-containing anti-tumor
* Corresponding author. Tel.: ‡86-411-3673466/3631333x3244/
21-64253589/2945; fax: ‡86-411-3673466/21-64251386.
E-mail addresses: xhqian@dlut.edu.cn, xhqian@ecust.edu.cn )X. Qian).
0022-1139/02/$ ± see front matter # 2002 Published by Elsevier Science B.V.
PII: S 0 0 2 2 - 1 1 3 9 ) 0 1 ) 0 0 5 3 9 - 5

162
L. Gao, X. Qian / Journal of Fluorine Chemistry 113 92002) 161±165
Table 1
Photooxidation of furan-2-carboxylic acid
Compound Solvent Time )h)
Yielda
11
10
95.8
Scheme 1.
4a
CH3OH
5
12
5
4.2
13.4
4.9
86.6
95.1
70.6
87.7
85.5
4ab
CH3OH/C6F14
12
5
29.4
12.3
15.5
0
2. Results and discussion
7a
CH3OH
CH3OH/C6F14
CH3OH
7ab
5ac
5
12
100
The desired compounds were prepared according to the
route shown in Scheme 2. The nucleophilic substitution of
the dimethyl-4-nitrophthalate with 2,2,2-tri¯uoro-ethanol or
2,2,3,3,4,4,4-hepta¯uorobutanol in N,N-dimethylformamide
using sodium hydride as base at room temperature for 24 h
gave compounds 2a or b in about 80% yield. 2a and b were
base hydrolyzed and neutralized to give 4-¯uoroalkoxy
phthalic acid, which was heated to melting to give 3a or
b as a solid in more than 90% yield. The condensation
reaction of 3a and b with urea and a metal salt may be
carried out in a high boiling point solvent )nitrobenzene,
trichlorobenzene, etc.) or in the melt. In our experiments, the
latter is better. The condensation products were puri®ed by
different methods according to their physical properties. For
instance, zinc 4,8,12,16-tetra)tri¯uroethoxyl) phthalocyani-
nate )4a) can be dissolved in most organic solvents such as
ethyl acetate, acetone, chloroform, methanol etc., it could be
puri®ed by column chromatography followed by re-crystal-
lization from ethyl acetate/petroleum ether. Cobalt and
copper complexes are less soluble in organic solvents and
can be puri®ed by re-crystallization from concentrated
a Dye:furan-2-carboxylic acid ˆ 1:200 )molecular ratio), yield based
on gas chromatography.
b Perfluorohexane:methanol ˆ 4:1 )volume ratio).
c Compounds 5b, 6a, 6b, 8a, 8b included show the same result, i.e.
11:10 ˆ 0:100.
sulfuric acid and water. The structure of these compounds
1
were identi®ed by elemental analysis, IR, H NMR, FAB-
MS, etc.
Photolysis of the acid )10) in methanol in the presence of
0.5 mol% of compounds 4a and b or 7a )zinc and aluminum
centered phthalocyanines), with a 300 W tungsten lamp,
gave the lactone )11) in >10% yield. The other dyes )cobalt,
magnesium, iron and copper centered phthalocyanines) do
not show such activity. The photooxidation yield catalyzed
by 4a was increased from 13.4% )in methanol) to 26.4%
)with 20% per¯uorohexanes in methanol) for 12 h )Table 1),
the results may be explained that per¯uorocarbons could
dissolve more oxygen which is favorable to the production
of singlet oxygen.
Scheme 2. )a) CF3CH2OH or CF3CF2CF2CH2OH/NaH, DMF, room temperature; )b) NaOH/H2O; )c) HCl; )d) heat and )e) H2NCONH2, MX, NH4Cl,
)NH4)6Mo7O24Á4H2O.

L. Gao, X. Qian / Journal of Fluorine Chemistry 113 92002) 161±165
163
3. Experimental
xide )10%, 5 ml) was heated under re¯ux for 30 min. The
mixture was then cooled to room temperature, hydrochloric
acid was added to pH ˆ 1±2, extracted with ethyl ether
)3 ml  20 ml), dried over anhydrous sodium sulfate. Ethyl
ether was evaporated and the resulting solid was heated to
melting for 20 min, cooled and solidi®ed to give a light
yellow solid )1.5 g, 94%), mp 78±80 8C. IR )KBr): nmax
1855, 1782, 1623, 1601, 1498, 1458, 1309, 1280, 1185,
Infrared spectra were recorded on a Nicolet Magna-IR550
infrared spectrophotometer, using potassium bromide pel-
1
lets of solids. H NMR spectra with TMS as the internal
standard were recorded on a Brucker AM-500 nuclear
magnetic resonance spectrometer. Electron ionization mass
spectra were recorded on a Hitachi M-80 mass spectrometer.
Fast-atom-bombardment mass spectra with m-nitrobenzyl
alcohol as a matrix were recorded on a Jeol JMS-HX 110
mass spectrometer. Combustion analysis for elemental com-
position was carried out on an Italian MOD-1106 analyzer
run by the analysis center of the East China University of
Science & Technology. Gas chromatography was carried out
on a 1102G gas chromatograph. Methyl-4-nitrophthalate
was prepared by the reference method [14].
900 cmÀ1
.
3.4. Synthesis of 4-heptafluorobutoxyphthalic anhydride
93b)
The procedure is similar to that of 3a on a 10 mmol scale,
3b was formed as a light yellow solid in 97% yield, mp 62±
64 8C. IR )KBr): nmax 1855, 1782, 1623, 1601, 1498, 1458,
1309, 1280, 1185, 900 cmÀ1
.
3.1. Synthesis of dimethyl-4-trifluoroethoxyphthalate 92a)
3.5. Synthesis of zinc 4,8,12,16-tetra9trifluoroethoxy)
phthalocyaninate 94a)
2,2,2-Tri¯uoroethanol)1 ml,1.37 g,13.7 mmol)wasadded
dropwise to a mixture of sodium hydride )60%, 0.6 g, 15
mmol) and N,N-dimethylformamide )18 ml) )over 4& mole-
cule sieve) over 20 min at room temperature, hydrogen was
evolved. The mixture was stirred for another 20 min, and then
dimethyl-4-nitrophthalate )2 g, 8.37 mmol) was added and
the reaction mixture was stirred for 24 h at room temperature.
After addition of hydrochloric acid )5%, 36 ml), the
mixture was extracted with ethyl ether )3 ml  30 ml),
washed with water )3 ml  30 ml), dried over anhydrous
sodium sulfate. The solvent was removed under reduced
pressure, the residue crude oil product was puri®ed by
column chromatography on silica gel with petroleum ether:-
ethyl acetate )8:1±4:1, v/v) as eluant to give a light yellow
solid )1.9 g, 79%), mp 48±50 8C. IR )KBr): nmax 2952, 1725,
A mixture of tri¯uoroethoxyphthalic anhydride )1.5 g,
6.10 mmol), urea )2.9 g, 48.33 mmol), zinc acetate )0.55 g,
2.51 mmol),ammoniumchloride)0.24 g,4.49 mmol),ammo-
nium molybdate )0.034 g, 0.03 mmol) was ground, heated
with stirring at 135 8C for 40 min, then heated to 180 8C for
1 h, and then heated to 200±210 8C for 4 h. The reaction
mixture was cooled to room temperature, hydrochloric acid
)1N, 100 ml) was added and the mixture was heated with
re¯ux for 1 h. The resulting black-green precipitate was
®ltered while hot, the ®ltered residue was washed with hot
water, and the solid was again treated with 10% sodium
hydroxide solution once by the same procedure.
The crude product was dried, dissolved in acetone, and the
solution was ®ltered to remove the insoluble precipitate,
which was washed with acetone, the ®ltrate was condensed
under reduced pressure. The residue was puri®ed twice by
column chromatography on silica gel using chloroform:-
methanol )15:1±10:1, v/v) as eluant. The product was further
puri®ed by re-crystallization from a mixed solvent of ethyl
acetate:petroleum ether )50:1, v/v) to give a blue-green solid,
160 mg )11%). C40H20F12N8O4Zn requires: C, 49.52; H,
2.08; N, 11.55. Found: C, 49.78; H, 2.35; N, 11.49%. IR
)KBr): nmax 3030 )=C±H), 2905 )CH2), 1605, 1490 )C=C),
1405 )CH2), 1340, 1280 )C±O), 1175 )C±F), 1125 )ring),
1613, 1582, 1448, 1381, 1285, 1230, 1159, 1083, 978 cmÀ1
.
1H NMR )CDCl3): d ˆ 3:88 )s, 3H, CH3), 3.92 )s, 3H, CH3),
4.41 )q, 2H, CH2), 7.06 )q, 1H, Ar±H5), 7.16 )d, 1H, Ar±H6),
7.81 )d, 1H, Ar±H3). EI-MS )m/z, %): 292 )M ‡, 52), 262
)M À 2 Â CH3, 27), 261 )M À 1 À 2 Â CH3, 100).
3.2. Synthesis of dimethyl-4-heptafluorobutoxyphthalate
92b)
The procedure is similar to that of 2a using a 10 mmol
scale. 2b was produced as a light yellow thick liquid in 87%
yield. IR )KBr): nmax 2952, 1725,1613, 1582, 1448, 1381,
1090 )C±O), 975, 820, 750 cmÀ1. H NMR )CD3COCD3):
1
1285, 1230, 1159, 1083, 978 cmÀ1
.
1H NMR )CDCl3):
d ˆ 4:93 )s, br, 8H, 4  OCH2CF3), 7.46 )s, br, 4H, Ar±H),
8.08 )s, br, 4H, Ar±H), 8.54 )s, br, 4H, Ar±H). FAB-MS
)m/z, %): 971 )M ‡ 1, 100), 970 )M ‡, 50), 888 )M ‡ 1À
CH2CF3, 55), 872 )M ‡ 1À OCH2CF3, 38).
d ˆ 3:87 )t, 3H, CH3), 3.90 )t, 3H, CH3), 4.52 )t, 2H,
CH2), 7.05 )m, 1H, Ar±H5), 7.14 )t, 1H, Ar±H6), 7.80
)q, 1H, Ar±H3). EI-MS )m/z, %): 392 )M ‡, 25), 362
)M À 2 Â CH3, 20), 361 )M À 1 À 2 Â CH3, 100).
3.6. Zinc 4,8,12,16-tetra9heptafluorobutoxy)
phthalocyaninate 94b)
3.3. Synthesis of 4-trifluoroethoxyphthalic anhydride 93a)
A mixture of dimethyl-4-tri¯uoroethoxyphthalate )1.9 g,
6.51 mmol), methanol )5 ml), and aqueous sodium hydro-
The synthesis procedure is similar to that for 4a, 4 mmol
3b was used to give 4b as a dark blue solid in 8% yield.

164
L. Gao, X. Qian / Journal of Fluorine Chemistry 113 92002) 161±165
C48H20F28N8O4Zn requires: C, 42.07; H, 1.47; N, 8.18.
Found: C, 42.44; H, 1.56; N, 8.78%. IR )KBr): nmax 3015
)=C±H), 2905 )CH2), 1610, 1495 )C=C), 1395 )CH2), 1340,
1230 )C±O), 1180 )C±F), 1125 )ring), 1015 )C±O), 950, 820,
3.11. Aluminum chloride 4,8,12,16-tetra9trifluoroethoxy)
phthalocyaninate 97a)
The synthesis procedure was similar to that for 4a on
a 5 mmol scale, but the reaction mixture was not treated
with hot dilute acidic or alkali solution, to give a dark
blue microcrystalline solid, yield 8%. C40H20F12N8O4AlCl
requires: C, 49.67; H, 2.09; N, 11.59. Found: C, 49.13; H,
2.34; N, 11.93%. IR )KBr): nmax 3035 )=C±H), 2905 )CH2),
1610, 1490 )C=C), 11402 )CH2), 1340, 1230 )C±O), 1170
750 cmÀ1
.
3.7. Synthesis of cobalt 4,8,12,16-tetra9trifluoroethoxy)
phthalocyaninate 95a)
A mixture of tri¯uoroethoxyphthalicanhydride )2.0 g, 8.13
mmol), urea )3.9 g, 65 mmol), cobaltous acetate )1.05 g,
4.22 mmol),ammoniumchloride)0.32 g,5.98mmol),ammo-
nium molybdate )0.04 g, 0.03 mmol) was ground and treated
as above to give a dark blue solid. The crudeproduct was dried
and dissolved in concentrated sulfuric acid at room tempera-
ture.Theresultingsolutionwasslowlypouredintowaterwhile
stirring, the precipitate was collected by suction. The product
was re-crystallized twice from concentrated sulfuric acid and
water as above to give a dark blue solid with purple re¯ection,
500 mg )26%). C40H20-F12N8O4Co requires: C, 49.85; H,
2.10; N, 11.63. Found: C, 49.90; H, 2.18; N, 12.10%. IR
)KBr): nmax 3030 )=C±H), 2900 )CH2), 1610, 1490 )C=C),
1395 )CH2), 1230 )C±O), 1180 )C±F), 1125 )ring), 1100
)C±F), 1125 )ring), 1085 )C±O), 950, 820, 750 cmÀ1
.
3.12. Magnesium 4,8,12,16-tetra9trifluoroethoxy)
phthalocyaninate 98a)
Prepared on a 5 mmol scale as cited for 4a to give a dark
blue solid, yield 7%. C40H20F12N8O4Mg requires: C, 51.71;
H, 2.17; N, 12.06. Found: C, 51.76; H, 2.29; N, 11.94%. IR
)KBr): nmax 3085 )=C±H), 2900 )CH2), 1610, 1490 )C=C),
1390 )CH2), 1285, 1230 )C±O), 1170 )C±F), 1125 )ring),
1010 )C±O), 980, 820, 750 cmÀ1
.
3.13. Iron chloride 4,8,12,16-tetra9trifluoroethoxy)
phthalocyaninate 99a)
)C±O), 970, 820, 750 cmÀ1
.
3.8. Cobalt 4,8,12,16-tetra9heptafluorobutoxy)
phthalocyaninate 95b)
Prepared on a 5 mmol scale as cited for 7a to give a dark
blue solid, yield 4%. C40H20F12N8O4FeCl requires: C,
48.25; H, 2.03; N, 11.26. Found: C, 48.45; H, 2.23; N,
11.72%. IR )KBr): nmax 3035 )=C±H), 2900 )CH2), 1605,
1490 )C=C), 1402 )CH2), 1340, 1235 )C±O), 1180 )C±F),
The synthesis procedure is similar to that for 5a on a
5 mmol scale. 5b is a dark blue solid with purple re¯ection,
yield 23%. C48H20F28N8O4Co requires: C, 42.27; H, 1.48;
N, 8.22. Found: C, 41.47; H, 1.52; N, 8.59%. IR )KBr): nmax
3015 )=C±H), 2905 )CH2), 1610, 1495 )C=C), 1390 )CH2),
1350, 1230 )C±O), 1180 )C±F), 1125 )ring), 1020 )C±O),
1125 )ring), 1080 )C±O), 980, 820, 750 cmÀ1
.
3.14. General procedure for photooxidation of furan-2-
carboxylic acid with metal phthalocyanates
950, 820, 750 cmÀ1
.
The experiments in Table 1 were carried out as described
below. A mixture of furan-2-carboxylic acid )224 mg,
2.00 mmol) and zinc phthalocyanine )9.7 mg, 0.01 mmol)
in methanol )20 ml) was irradiated with a water-cooled
300 W halogen tungsten lamp from a distance of 5 cm,
while oxygen was passed through the reaction mixture for
5±12 h. The internal temperature was 15±20 8C. A simple
was analyzed by gas chromatography to determine the
conversion yield. The reaction mixture was concentrated
under reduced pressure below 50 8C and puri®ed by ¯ash
column chromatography )petroleum ether:ethyl acetate
10:1±4:1, v/v) to verify the structure of the photooxidation
product [15].
3.9. Copper 4,8,12,16-tetra9trifluoroethoxy)
phthalocyaninate 96a)
Prepared on a 5 mmol scale as cited for 5a to give a dark
blue solid with purple re¯ection, yield 24%. C40H20F12N8-
O4Cu requires: C, 49.62; H, 2.09; N, 11.58. Found: C,
49.87; H, 2.30; N, 12.00%. IR )KBr): nmax 3045 )=C±H),
2895 )CH2), 1605, 1490 )C=C), 1402 )CH2), 1340, 1230
)C±O), 1160 )C±F), 1125 )ring), 1095 )C±O), 980, 820,
750 cmÀ1
.
3.10. Copper 4,8,12,16-tetra9heptafluorobutoxy)
phthalocyaninate 96b)
Prepared on a 5 mmol scale as cited for 5a to give a dark
blue solid, yield 21%. C48H20F28N8O4Cu requires: C, 42.13;
H, 1.48; N, 8.19. Found: C, 42.06; H, 1.47; N, 8.44%. IR
)KBr): nmax 3015 )=C±H), 2905 )CH2), 1610, 1490 )C=C),
1410 )CH2), 1350, 1230 )C±O), 1180 )C±F), 1125 )ring),
References
[1] C.C. Leznoff, A.B.P. Lever, Phthalocyanines, Properties and
Applications, Vols. I±III, VCH, Weinheim, 1993.
[2] I. Rosenthal, Photochem. Photobiol. 53 )1991) 859.
[3] C. Milanesi, Br. J. Cancer 61 )1990) 846.
1020 )C±O), 970, 820, 760 cmÀ1
.

L. Gao, X. Qian / Journal of Fluorine Chemistry 113 92002) 161±165
165
[4] R.W. Boyle, B. Paquette, J.E. van Lier, Br. J. Cancer 65 )1992) 813.
[5] N. Brasseur, H. Ali, R. Langlois, J.E. van Lier, Photochem.
Photobiol. 47 )1988) 705.
[9] M.J. Cook, I. Chambrier, S.J. Cracknell, D.A. Mayes, D.A. Russell,
Photochem. Photobiol. 62 )1995) 542.
[10] L.M. Stephenson, M.J. Gradina, M. Orfanopoulos, Acc. Chem. Res.
13 )1980) 419.
[6] C.C. Leznoff, S. Vigh, P.I. Svirskaya, S. Greenberg, D.M. Drew, E.
Ben-Hur, I. Rosenthal, Photochem. Photobiol. 49 )1989) 279.
[7] W.E. Ford, B.D. Rihter, M.E. Kenney, M.A.J. Rodgers, Photochem.
Photobiol. 50 )1989) 277.
[11] T. Hidetoshi, N. Eiichi, J. Org. Chem. 59 )1994) 1135.
[12] L.C. Clark, F. Golan, Science 152 )1966) 1755.
[13] D.C. Richard, S. Graham, S. Aneela, Synth. Commun. 26 )1996) 1861.
[14] R.L. Williams, S.W. Shalaby, J. Heterocycl. Chem. 10 )1973) 891.
[15] J.D. White, J.P. Carter, H.S. Kezar, J. Org. Chem. 47 )1982) 929.
[8] B.D. Rihter, M.D. Bohorquez, M.A.J. Rodgers, M.E. Kenney,
Photochem. Photobiol. 55 )1992) 677.