Synthesis of novel alkylamino zinc(II) phthalocyanines

Article abstract of DOI:10.1002/jhet.5570380212

The synthesis of tetramethyl-tetraphthalimidomethyl-phthalocyaninato zinc(II) (6) and tetramethyl-tetraaminomethyl-phthalocyaninato zinc(II) (7) is described.

Full text of DOI:10.1002/jhet.5570380212

Mar-Apr 2001
Synthesis of Novel Alkylamino Zinc(II) Phthalocyanines
387
Myriam E. Rodríguez [a], Cristian A. Strassert [a],
Lelia E. Dicelio [b] and Josefina Awruch*[a]
[a] Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica,
UBA, Junín 956, 1113 Buenos Aires, Argentina
[b] Laboratotio de Fotoquímica, INQUIMAE, Departamento de Química Inorgánica,
Analítica y Química Física, Facultad de Ciencias Exactas y Naturales, UBA,
Pabellón II, Ciudad Universitaria, 1428 Buenos Aires, Argentina
Received August 31, 2000
The synthesis of tetramethyl-tetraphthalimidomethyl-phthalocyaninato zinc(II) (6) and tetramethyl-
tetraaminomethyl-phthalocyaninato zinc(II) (7) is described.
J. Heterocyclic Chem., 38, 387 (2001).
Photodynamic therapy (PDT) is a treatment based on the
extensively studied due to their high fluorescence and
triplet quantum yield, and their efficiency of singlet
oxygen photoproduction [6,7].
ability of certain photosensitizers to absorb light and, via
an excited state, cause damage to the neoplastic area. If the
photosensitizer concentrates selectively in the tumor,
activation with light of appropriate wavelength induces its
destruction [1,2].
In the last few years several photosensitizers have
been studied for application in PDT [3]. Among them,
phthalocyanines have been found to be promising dyes
[4] with high molar extinction coefficients, red-shifted
absorption and generation of singlet oxygen, the active
species being responsible for the cytotoxic effect [5].
Zinc and aluminium phthalocyanines have been
As unsubstituted phthalocyanines are extremely
insoluble in most common solvents, improving the water
solubility of the dye has been the main reason for the
synthesis of sulphonated derivatives [6,8]. However, a
correlation has been found between amphiphilicity of the
dye and its uptake in cells. The amphiphilic character is
accentuated through the addition of sulphonated groups
and alkyl groups [9,10], alkylamino groups and quaternary
alkylammonium salts [11] as well as alkylhydroxy
substituents [12].

388
M. E. Rodríguez, C. A. Strassert, L. E. Dicelio and J. Awruch
Vol. 38
EXPERIMENTAL
We regulated the amphiphilic character of zinc(II) phthalo-
cyaninates by introducing alkyl and amino groups [13,14] to
the macrocycle. We also reported their phototoxic properties,
which showed the importance of the amphiphilicity of the
dye, improving its cell association and photodynamic
activity [15]. On the basis of the above results, we investi-
gated the synthesis of two novel octasubstituted zinc(II)
phthalocyanines whose amphiphilic properties were
regulated by the introduction of alkylamino groups.
As shown in Scheme 1, the sequence begins with the
reaction of o-xylene (1) with bromine to give 1,2-dibromo-
4,5-dimethylbenzene (2). There are several reports for aryl
bromination of o-xylene [16-22]. The synthesis reported
by Y. Orihashi et al. [21] has been employed herein with
minor modifications.
The reaction of compound 2 with N-bromosuccin-
imide in carbon tetrachloride afforded the tribromo
derivative 3. The reaction of 3 with potassium phtha-
limide in N,N-dimethylformamide gave compound 4,
that was subsequently reacted with copper (I) cyanide in
the same solvent, to yield the required phthalonitrile 5.
A mixture in the order of 2% yield of 1-bromo-2-cyano-
4-phthalimidomethyl-5-methylbenzene and 1-bromo-2-
cyano-4-methyl-5-phthalimidomethylbenzene were
obtained as side products. Phthalocyanine 6 was readily
prepared by the cyclotetramisation of phthalonitrile 5
with powdered zinc at 230° [13,23]. Attempts to obtain
6 by employing 1,8-diazabicyclo[5,4,0]undec-7-ene in
butanol and zinc acetate yielded only traces of
compound 6 [7].
Phthalocyanine 6 was purified by chromatography,
followed by recrystallization to attain 25% of the desired
tetramethyl-tetraphthalimidomethyl-phthalocyaninato zinc
(II). Treatment of 6 with hydrazine in tetrahydrofuran at
room temperature [13,24] gave phthalocyanine 7 in
quantitative yields.
With regard to the solubility of the new phthalo-
cyanines, though tetrakis(1,1-dimethyl-2-phthalimido)-
ethylphthalocyaninato zinc (II) [13] is soluble in almost
all organic solvents, 6 shows the influence of a minor
lipophilicity owing to the presence of both a methyl and
a methylene chain. On the other hand, phthalocyanine 7
is insoluble in tetrahydrofuran and soluble in dimethyl
sulfoxide, N,N-dimethylformamide and pyridine.
Phthalocyanine 6 and 7 were characterized by their
uv-visible spectra. Both compounds 6 and 7 showed the
Melting points were determined on a Thomas Hoover capillary
1
13
1
melting point apparatus and are uncorrected. The H nmr and
C
nmr were recorded on a Bruker MSL 300 spectrometer. The H
nmr of phthalocyanine 7 was recorded on a Bruker AM 500.
Mass Spectra were obtained with a TRIO 2 (electronic ionization
70 eV) spectrometer. Phthalocyanines FAB-ms were measured
using 3-nitrobenzylalcohol as a matrix for 6 and glycerol for 7,
with a ZAB SEQ (VG, Fisons) spectrometer. Electronic
absorption spectra were determined using a Shimadzu UV-160A
spectrophotometer. Infrared spectra were performed with an
FT-IR Nicolet 510P spectrometer. Microanalyses were performed
using a Carlo Erba EA 1108 elemental analyzer.
The silica gel used in column chromatography was tlc
Kiesegel (Merck). N,N-Dimethylformamide was dried over 3 Å
molecular sieves during 72 hours, filtered and freshly distilled
[25] before using.
1,2-Dibromo-4-bromomethyl-5-methylbenzene (3).
To a solution of 1.18 g (4.47 mmol) of 1,2-dibromo-4,5-
dimethylbenzene in 17 mL of carbon tetrachloride, 0.816 g
(4.58 mmol) of N-bromosuccinimide was added. The mixture
was stirred under reflux during 16 hours. After cooling, the
precipitate was filtered, washed with carbon tetrachloride and the
filtrate evaporated in vacuo to eliminate the solvent. The residue
was dissolved in a small volume of hexane and filtered through a
tlc silica gel column packed and pre-washed with the same
solvent. The elution fractions containing 3 were monitored using
tlc. The solvent was evaporated to dryness affording a thick oil
+
+
0.540 g (35%); ms: m/z 343 (M , 2.47%), 345 (M + 2, 1.47%),
+
1
341 (M - 2, 1.90%), 263 (100%); H nmr (deuteriochloroform):
δ 2.34 (s, 3H, CH ), 4.38 (s, 2H, CH ), 7.45, 7.54 (s, s, 2H, Ar);
3
2
ir (film CCl ): 2359, 1723, 1466, 1350, 1212, 1123, 905, 721,
4
-1
652, 565 cm .
Anal. Calcd for C H Br : C, 28.02; H, 2.06. Found: C, 28.10,
8
7
3
H, 2.20.
1,2-Dibromo-4-phthalimidomethyl-5-methylbenzene (4).
A mixture of 1.08 g (3.15 mmol) of 3, 0.582 g (3.16 mmol) of
potassium phthalimide and 30 mL of N,N-dimethylformamide
was stirred at 65° during 7 hours. The mixture was poured over
ice-water, the precipitate was filtered, dried and crystallized from
methylene chloride-hexane, 1.140 g (89% yield), mp 172-173°;
+
+
ms: m/z 409 (M , 26.57%), 411 (M + 2 , 11.66%), 407
+
1
(M - 2, 13.07%), 160 (100%); H nmr (deuteriochloroform): δ
2.42 (s, 3H, CH ), 4.76 (s, 2H, CH ), 7.43, 7.48 (s, s, 2H, Ar),
3
2
7.82 (m, 4H, phthalimide); ir (potassium bromide): 1713, 1479,
-1
1420; 1395, 1364, 1113, 951, 725, 713 cm .
Anal. Calcd. for C H NBr O : C, 46.97; H, 2.71; N, 3.42.
16 11
2 2
Found: C, 47.00; H, 2.85; N, 3.22.
Soret band at λ
347 nm and the Q band at 676 nm in
max
1,2-Dicyano-4-phthalimidomethyl-5-methylbenzene (5).
tetrahydrofuran ε = 134,000 M-1 cm-1 (c = 1x 10-7 M) and
686 nm in dimethyl sulfoxide ε = 40,000 M-1 cm-1 (c = 8x
10-8 M) respectively. The low extinction coefficient and
the non-linearity of the Lambert-Beer law obtained is
evidence that 7 remains aggregated even at low
concentrations (i.e. 8 x 10-8 M). Photophysical and
photobiological studies of compounds 6 and 7 are in
progress.
A solution of 1.07 g (2.62 mmol) of 4 and 1.00 g cuprous
cyanide in N,N-dimethylformamide (35 mL) was heated at 150°
during 9 hours under nitrogen. The solution adquired a light
brown color. After cooling, it was poured into a concentrated
ammonia solution (35 mL) and stirred during 4 hours. The solid
residue obtained was separed by centrifugation, washed twice
with cold water and then dried. The residue was dissolved in
methylene chloride and filtered through a tlc silica gel column.

Mar-Apr 2001
Synthesis of Novel Alkylamino Zinc(II) Phthalocyanines
389
After evaporation of the solvent the solid residue R 0.3 was
Acknowledgement.
f
recrystallized from methylene chloride-hexane, 0.197 g (25%),
mp 225-226°; ms: m/z 301 (M , 100%), 160 (22.77%); H nmr
This work was supported by grants from the National Research
Council of Argentina (CONICET) and Agencia Nacional de
Promoción Científica y Tecnológica (BID 802/OC-AR). C. A. S.
is a recipient of a student fellowship from the University of
Buenos Aires (UBACyT). We thank the technical assistance as
regards chromatography of Ms. Juana Alcira Valdez. FAB-ms
assistance of Mr. Gustavo Arabehety is also appreciated.
+
1
(deuteriochloroform): δ 2.60 (s, 3H, CH ), 4.88 (s, 2H, CH ),
3
2
7.63, 7.64 (s, s, 2H, Ar), 7.80 (m, 4H, phthalimide); ir (potassium
bromide): 2238, 1773, 1715, 1420, 1397, 1384, 1356, 1335,
-1
1111, 953, 727, 715, 635, 534 cm .
Anal. Calcd. for C H N O : C, 71.75; H, 3.68; N, 13.95.
18 11
3 2
Found: C, 71.68; H, 3.81; N, 13.74.
13
The C nmr spectrum of 5 shows four new signals at δ 113.65,
REFERENCES AND NOTES
113.65, 114.85, 115.18 corresponding to the two nitriles and the
two adjacent aromatic carbons, instead of the signals at δ 121.89
and 123.58 observed in 4.
[1] B. W. Hendersen and T. J. Dougherty , eds, Photodynamic
Therapy. Marcel Dekker, Inc., New York, 1992.
2,9,16,23-Tetramethyl-3,10,17,24-tetraphthalimidomethyl-
phthalocyaninato Zinc (II) (6).
[2] G. Jori, Photochem. Photobiol. A: Chem., 62, 371 (1992).
[3] M. G. Henriques Vicente, Rev. Port. Quím., 3, 47 (1996).
[4] I. Rosenthal, Photochem. Photobiol., 53, 859 (1991).
[5] D. A. Fernández, J. Awruch and L. E. Dicelio, Photochem.
Photobiol., 63, 784 (1996).
[6] R. W. Boyle, B. Paquette and J. E. van Lier, Br. J. Cancer, 65,
813 (1992) and references therein.
[7] M. Hu, N. Brasseur, S. Zeki Yildiz, J. E. van Lier and C. C.
Leznoff, J. Med. Chem., 41, 1789 (1998) and references therein.
[8] S. Kudrevich, N. Brasseur, C. La Madeleine, S. Gilbert and J.
E. van Lier, J. Med. Chem., 40, 3897 (1997).
A mixture of 0.100 g ( 0.33 mmol ) of 5 and 0.050 g of
powdered zinc was heated at 230° in a closed vessel during
16 hours. It was allowed to cool, methylene chloride (500 mL)
was added and the remaining zinc filtered under suction. The
solution was evaporated in vacuo, leaving a green solid. This
residue was dissolved in methylene chloride and filtered through
a tlc silica gel column packed and pre-washed with the same
solvent. The band eluted corresponded to compound 5. The title
dye was eluted with methylene chloride-acetone-methanol
(5:0.5:0.25). After evaporation, the deep green solid was
recrystallized from methylene chloride-hexane, 0.026 g (25%);
[9] B. Paquette, H. Ali and J. E. van Lier, J. Chim. Phys., 88, 1113
(1991).
[10] B. Paquette, R. W. Boyle, H. Ali, A. H. MacLennan, T. G.
Truscott and J. E. van Lier, Photochem. Photobiol., 53, 323 (1991).
[11] C. C. Leznoff, S. Vigh, P. I. Svirskaya, S. Greenberg, D. M. Drew, E.
Ben-Hur and I. Rosenthal, Photochem. Photobiol., 49, 279 (1989).
[12] R. W. Boyle, C. C. Leznoff and J. E. van Lier, Br. J. Cancer,
67, 1177 (1993).
[13] D. A. Fernández, L. E. Dicelio and J. Awruch, J. Heterocyclic
Chem., 32, 519 (1995).
[14] D. A. Fernández, J. Awruch and l. E. Dicelio, J. Photochem.
Photobiol., B: Biology, 41, 227 (1997).
+
1
FAB-ms: m/z 1269 (M ); H nmr (deuteriochloroform): δ 2.63
(s, 12H, CH ), 4.91 (s, 8H, CH ), 7.61, 7.68 (s, s, 8H, Ar), 7.86
3
2
(m, 16H, phthalimide); ir (potassium bromide): 1771, 1716
-1
(phthalimide CO), 1395, 1343, 1110, 951, 716 cm .
Anal. Calcd. for C
H N O Zn: C, 68.06; H, 3.49; N, 13.23.
72 44 12 8
Found: C, 68.38; H, 3.61; N, 13.39.
2,9,16,23-Tetraaminomethyl-3,10,17,24-tetramethylphthalo-
cyaninato Zinc (II) (7).
[15] E. Shai, D. A, Fernández, S. Gross, L. E. Dicelio, A. Scherz,
Y. Salomon and J. Awruch. VI ELAFOT, September 12-16, Teresópolis,
Brasil, 1999, pp P-11.
A solution of 0.056 g of 6 and 0.4 mL of hydrazine in 20 mL of
tetrahydrofuran was stirred during 17 hours at room temperature.
After evaporation of the solvent, the residue was sublimated at
140° and 50 microns to eliminate the phthalhydrazide obtained.
The residue was dissolved in a 0.1 M hydrochloric acid solution
and then adjusted to pH 7 with a 0.1 M sodium hydroxide
solution. After 18 hours the fine green powder was centrifuged
and dried to give 0.033 g of the titled compound (quantitative
[16] D. Jacobson , Chem. Ber., 17, 2372 (1984).
[17] C. Piechocki and J. Simon, Nouv. J. Chim., 3, 159 (1985) .
[18] E. Klingsberg, Synthesis, 29 (1972).
[19] G. Pawlowski and M. Hanack, Synthesis, 287 (1980).
[20] H. Hart, S. Shamouvillan and Y. Takehira, J. Org. Chem., 46,
4427 (1981).
[21] Y. Orihashi, M. Nishikawa, H. Ohno, E. Tsuchida, H.
Matsuda, H. Nakanishi and M. Kato, Bull. Chem. Soc. Jpn., 60, 3731
(1987).
[22] J. Vacus and J. Simon, Adv. Mater., 7, 797 (1995).
[23] G. Gaspard and P. Maillard, Tetrahedron, 43, 1083 (1987).
[24] T. Sasaki, K. Minamoto and H. Itoh, J. Org. Chem., 43, 2200
(1978).
[25] D. R. Burfield and R. H. Smithers, J. Org. Chem., 43, 3966
(1978).
+
1
yield) . FAB-ms: m/z 841(M + glycerol); H nmr (dimethyl
sulfoxide-d ): δ 2.55 (br, 12H, CH ), 4.85 (br, 8H, CH ), 7.82,
6
3
2
8.03 (brs, brs, 8H, Ar), 9.23 (br, 8H, NH ); ir (potassium
2
-1
bromide): 3419, 3421 (NH ), 2924, 1646, 1496, 1081, 793 cm .
2
Anal. Calcd. for C
H N Zn: C, 64.04; H, 4.84; N, 22.41.
40 36 12
Found: C, 63.78; H, 4.86; N, 22.50.