Phthalocyanines and related compounds: XXXVII. Synthesis of covalent conjugates of carboxy-substituted phthalocyanines with α-amino acids

Article abstract of DOI:10.1023/B:RUGC.0000030404.00492.d1

Methods of synthesis of covalent conjugates of metal complexes of octa-4,5-carboxy- and tetra-4-carboxyphthalocyanine, as well as of octa-6,7-carboxy-2,3-naphthalocyanine with α-amino acids, glycine and sarcosine, were developed and certain properties of

Full text of DOI:10.1023/B:RUGC.0000030404.00492.d1

Russian Journal of General Chemistry, Vol. 74, No. 3, 2004, pp. 451 459. Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 3, 2004,
pp. 496 505.
Original Russian Text Copyright
2004 by Mikhalenko, Solov’eva, Luk’yanets.
Phthalocyanines and Related Compounds:
XXXVII.1 Synthesis of Covalent Conjugates
of Carboxy-substituted Phthalocyanines with -Amino Acids
S. A. Mikhalenko, L. I. Solov’eva, and E. A. Luk’yanets
Research Institute of Organic Intermediate Products and Dyes, Moscow, Russia
Received March 7, 2002
Abstract Methods of synthesis of covalent conjugates of metal complexes of octa-4,5-carboxy- and tetra-
4-carboxyphthalocyanine, as well as of octa-6,7-carboxy-2,3-naphthalocyanine with -amino acids, glycine
and sarcosine, were developed and certain properties of the products were studied. The prepared conjugates
are soluble in organic solvents and water.
In recent years water-soluble derivatives of phthalo- plexes of octa-4,5-carboxyphthalocyanine with glycine
cyanine (Pc) have found wide practical use, specifi-
cally, as catalysts for generation of active oxygen
species whose cytotoxic activity is exploited in photo-
dynamic and catalytic (dark) cancer therapy [2 5].
(I, II) and sarcosine (III, IV) and studied their pro-
perties. -Amino acids with primary amino groups,
specifically glycine, react with o-phthaloyl group to
form cyclic amides thus giving a series of tetracar-
boxy-substituted tetraimides of octa-4,5-carboxy-
phthalocyanines, while -amino acids with secondary
amino groups (sarcosine) give their octacarboxy-
substituted octaamides. It is important that in both
cases the high symmetry of the starting octa-4,5-car-
boxyphthalocyanine (the same as in unsubstituted Pc),
i.e. D4h for M(II) metal complexes and C4v for
M(III)X complexes with an axially coordinated
ligand X.
Structural modification of porphyrins, specifically
chlorins, by introduction in their molecules of
-amino acid fragments by way of covalent linking
by methods of peptide synthesis [2] or even as counter
ions [6] enhances their efficiency as photosensitizers
for generation of singlet oxygen.
The aim of the present study was to develop con-
venient methods of synthesis of an almost unknown
group of phthalocyanine derivatives, i.e. covalent
conjugates with -amino acids. Among other possible
base structures for preparing such compounds we
chose the presently fairly well-studied tetra-4- and
octa-4,5-carboxy-substituted phthalocyanines. As an
example, sodium salt of cobalt octa-4,5-carboxy-
phthalocyanine can be mentioned, which is now under
clinical tests as a remedy for catalytic therapy [5].
The starting dinitriles, N-(ethoxycarbonylmethyl)-
4,5-dicyanophthalimide (VI) and N,N -bis(ethoxycar-
bonylmethyl)-N,N -dimethyl-4,5-dicyanophthalamide
(VII), were prepared by reactions of 4,5-dibromo-
phthaloyl dichloride (V) with ethyl esters of amino-
acetic and methylaminoacetic acids and subsequent
substitution of the bromine atoms in the resulting N-
(ethoxycarbonylmethyl)-4,5-dibromophthalimide
(VIII) and N,N -bis(ethoxycarbonylmethyl)-N,N -di-
methyl-4,5-dibromophthalamide (IX) by cyano groups
by the Rosenmund Brown reaction.
Introduction into carboxy-substituted phthalo-
cyanines of -amino acid fragments can be achieved
by two approaches: either starting from phthalic acid
derivatives, primarily o-dinitriles, that already contain
desired fragments, or by structural modification of
carboxy groups in the existing macroring via their
activation by transformation, for instance, into an-
hydrides or acyl halides.
By reacting dinitriles VI and VII with metal salts
in a solvent or without it and ammonium molybdate
as catalyst and subsequent hydrolysis of esters Ia Ic,
Ie, IIIa, and IIIb to free acids we obtained copper,
zinc, cobalt, and aluminum complexes of tetra(N-
carboxymethyl)imides of octa-4,5-carboxyphthalo-
cyanines (IIa IIc, IIe) and copper and zinc complexes
In the course of the present study we have syn-
thesized a new series of conjugates of metal com-
of
octakis-4,5-(N-carboxymethyl-N-methyl)carba-
For communication XXXVI, see [1].
moylphthalocyanines (IVa, IVb).
1070-3632/04/7403-0451 2004 MAIK Nauka/Interperiodica

452
MIKHALENKO et al.
The obtained compounds are rather readily soluble
corresponding tetraanhydrides of octa-4,5-carboxy-
phthalocyanines (XIb, XIc) with equimolar amount
of phthaloyl chloride in the presence of anhydrous
zinc chloride at 210 215 C. By refluxing octaacyl
chlorides Xb, Xc with ethyl N-methylaminoacetate in
chloroform followed by hydrolysis of the ester groups
we obtained zinc and cobalt octakis-4,5-[(N-methyl-N-
carboxymethyl)carbamoyl]phthalocyanines (IVb, IVc).
As judged from the elemental analyses and IR and UV
spectra, complexes IVb, IVc prepared by this method
are identical to those obtained from dinitrile VII.
not only in organic solvents, but in water, too, even
at room temperature. The best soluble in water, much
better than the starting octa-4,5-carboxyphthalocya-
nines, are metal octakis-4,5-[(N-carboxymethyl-N-
methyl)carbamoyl]phthalocyanines (IV). As the above-
described method of synthesis of these compounds is
rather elaborate, we tried a new synthetic approach,
starting from zinc and cobalt octakis-4,5-(chlorocar-
bonyl)phthalocyanines (Xb, Xc). The latter were
prepared in quantitative yields by reactions of the
COCl
Br
Br
COCl
V
H2NCH2COOC2H5
NH(CH3)CH2COOC2H5
CO
Br
Br
CON(CH3)CH2COOC2H5
CON(CH3)CH2COOC2H5
Br
Br
NCH2COOC2H5
CO
VIII
IX
CuCN/HCON(CH3)2
CuCN/HCON(CH3)2
CON(CH3)CH2COOC2H5
CO
NC
NC
NC
NC
NCH2COOC2H5
CON(CH3)CH2COOC2H5
CO
VI
VII
ROOCCH2(CH3)NCO
NCH2COOR
CON(CH3)CH2COOR
CON(CH3)CH2COOR
CO
CO
CO
ROOCCH2N
N
ROOCCH2(CH3)NCO
N
CO
N N
N N
M
N
N
M
N
N
N
N
N
N
ROOCCH2(CH3)NCO
ROOCCH2(CH3)NCO
N
CON(CH3)CH2COOR
CON(CH3)CH2COOR
N
CO
ROOCCH2N
CO
CO
NCH2COOR
CO
I, II
III, IV
R = C2H5 (I, III), H (II, IV); M = Cu (a), Zn (b), Co (c), Fe (d), AlOH (e).
To simplify the route to conjugates like glycine
derivatives II, by reactions of zinc, cobalt, iron, and
hydroxyaluminum octa-4,5-carboxyphthalocyanine
tetraanhydrides (XIb XIe) with ethyl glycinate in
methylpyrrolidone under an inert gas followed by
hydrolysis of the ester groups in the resulting tetra(N-
ethoxycarbonylmethyl)imides Ib Ie we prepared zinc,
cobalt, iron, and hydroxyaluminum octa-4,5-carboxy-
phthalocyanine tetra(N-carboxymethyl)imides (IIb
IIe) in yields of 15 60%. The moderate yields of
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PHTHALOCYANINES AND RELATED COMPOUNDS: XXXVII.
453
Absorption maxima in the UV spectra of aqueous solutions of sodium salts of octa-4,5-carboxyphthalocyanines
PcM(COONa)8, octakis-4,5-[(N-carboxymethyl-N-methyl)carbamoyl]phthalocyanines PcM[CON(CH3)CH2COONa]8, and
octa-4,5-carboxyphthalocyanine tetra(N-carboxymethyl)imides PcM[(CO)2NCH2COONa]4
Comp. no.
IVa
Compound
max, nm
Relative intensity
PcCu(COONa)8
685, 655 sh, 615, 348
685, 650 sh, 617, 349
674, 650 sh, 356
686, 656 sh, 618, 354
686, 655 sh, 619, 354
657, 654, 358
2.25: 0 45: 0.45: 1
2.34: 0.40: 0.45: 1
1.05: 1.03: 1
2.20: 0 45: 0.40: 1
1.95: 0.45: 0.40: 1
1.10: 1.08: 1
PcCu[CON(CH3)CH2COONa]8
PcCu[(CO)2NCH2COONa]4
PcZn(COONa)8
PcZn[CON(CH3)CH2COONa]8
PcZn[(CO)2NCH2COONa]4
PcCo(COONa)8
IIa
IVb
IIb
675, 608, 333
1.40: 0.40: 1
IVc
IIc
PcCo[CON(CH3)CH2COONa]8
PcCo[(CO)2NCH2COONa]4
PcFe(COONa)8
675, 619, 331
674, 600 sh, 328
682, 612, 340
1.50: 0.45: 1
0.85: 0.45: 1
1.50: 0.35: 1
IId
IIe
PcFe[(CO)2NCH2COONa]4
PcAlOH(COONa)8
PcAlOH[(CO)2NCH2COONa]4
678, 610, 335
690, 650 sh, 614, 361
688, 650 sh, 618, 360
1.25: 0.30: 1
2.22: 0.45: 0.40: 1
1.42: 0.48: 0.55: 1
certain conjugates can be explained by rather rigid
conditions of their synthesis.
The position of the long-wave absorption band (Q
band) in the UV spectra of aqueous solutions of
complexes IV containing eight sarcosine moieties is
almost the same as in the spectra of octa-4,5-carboxy-
phthalocyanines (see table). The long-wave absorption
maxima in the spectra of complexes II containing
cyclic imide groups are shifted hypsochromically (by
about 10 nm) and have lower intensities, which is
explained by aggregation like that observed with tetra-
4-carboxyphthalocyanine complexes [7]. Thus, con-
sidering published and our present data on the effect
of carboxy groups on the UV spectra of phthalo-
cyanines we can conclude that the number of carboxy
groups in the molecule is a key factor controlling its
aggregation in solutions.
COX
R
R
N
XOC
N N
N
N
M
N
N
R
XOC
COX
N
R
X, XIII XVI
We also tried to synthesize similar conjugates of
2,3-naphthalocyanines.
X = Cl, R = COCl (X); R = H, X = OH (XIV), Cl (XV),
N(CH3)CH2COOH (XIII), N(CH3)CH2COOC2H5 (XVI);
M = Zn (b), Co (c), Fe (d), AlOH (e).
By condensation of fumaroyl chloride with ethyl
glycinate we prepared N,N -bis(ethoxycarbonylmethyl)-
fumaramide (XVII). The latter was reacted with bis-
4,5-(dibromomethyl)phthalonitrile [8] to obtain N,N -
bis(ethoxycarbonylmethyl)-6,7-dicyanonaphthalene-
2,3-dicarboxamide (XVIII). Condensation of the latter
with anhydrous cobaltous chloride in 1-bromona-
phthalene followed by hydrolysis of the ester groups
in the resulting cobalt octakis-6,7-(ethoxycarbonyl-
methylaminocarbonyl)-2,3-naphthalocyanine (XIXc)
by refluxing with dilute hydrochloric acid gave cobalt
octakis-6,7-(carboxymethylaminocarbonyl)]-2,3-na-
phthalocyanine (XXc) soluble in aqueous alkali and
aprotic solvents. The UV spectra of complex XXc in
both cases show a broad band with its maximum near
In a similar way, by a one-step reaction of cobalt
octa-4,5-carboxyphthalocyanine tetraanhydride (XIc)
with tert-butyl -aminopropanoate (L-alanine) hydro-
chloride in an aprotic solvent in the presence of tri-
ethylamine we obtained cobalt octa-4,5-carboxyphtha-
locyanine tetra(N-carboxyethyl)imide (XIIc). By re-
actions of acyl chlorides XVb, XVc of zinc and cobalt
tetra-4-carboxyphthalocyanines (XIVb, XIVc) with
ethyl ester of sarcosine, followed by hydrolysis of the
ester groups in the resulting tetrakis-4-[N-(ethoxy-
carbonylmethyl)-N-methylcarbamoyl]phthalocyanines
(XVIb, XVIc) we obtained zinc and cobalt complexes
XIIIb, XIIIc.
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MIKHALENKO et al.
H2NCH2COOC2H5
ClOCCH
HCCOCl
H5C2OOCCH2HNOCC
HCCONHCH2COOC2H5
XVII
CN
CONHCH2COOC2H5
1,2-(CN)2C6H2-4,5-(CHBr2)2
CoCl2
HCl
XIX
XX
CN
CONHCH2COOC2H5
R
XVIII
R
R
R
N
N N
N
N
Co
N
N
N
R
R
R
R
XIX, XX
R = CONHCH2COOC2H5 (XIX), CONHCH2COOH (XX).
740 nm, which is evidence for aggregation of the
complex.
of ethyl glycinate in 3 ml of absolute ethanol was
added dropwise at 8 to 10 C. The mixture was
stirred for 3 h at this temperature, then for 2 h at 5
to 7 C and then heated to room temperature. The
solvent was removed, and the residue was subjected
to chromatography on silica gel (eluent benzene) to
isolate 0.54 g (89%) of compound VIII, mp 120
121 C. Found, %: C 36.85, 36.67; H 2.23, 2.27; Br
39.95, 39.79; N 3.35, 3.65. C12H10Br2NO4. Cal-
culated, %: C 36.76; H 2.58; Br 40.76; N 3.57.
The compounds obtained in the present work ex-
tend the range of water-soluble phthalocyanines con-
taining in the macroring active functional groups
capable of forming stable covalent bonds with
proteins and oligonucleotides [9].
EXPERIMENTAL
The UV spectra were measured on an HP-8453 in-
strument. The IR spectra were taken on an FSM-1201
instrument.
N,N -Bis(ethoxycarbonylmethyl)-N,N -dimethyl-
4,5-dibromophthalamide (IX) was obtained si-
milarly to compound VIII by the reaction of 4.03 g
of diacyl chloride V in 50 ml of dry ethyl ether with a
solution of 6.58 g ethyl ester of sarcosine in 20 ml of
anhydrous ethanol followed by purification by
chromatography on alumina (eluent benzene).
Yield 4.89 g (85%), oily eventually crystallizing
material, mp 98 99 C. Found, %: C 41.78, 41.65; H
4.22, 4.24; Br 30.38, 30.48; N 5.13, 5.01. C18H22
Br2N2O6. Calculated, %: C 41.37; H 4.25; Br 30.60;
N 5.36.
4,5-Dibromophthaloyl dichloride (V) was pre-
pared in 91% yield, mp 48 50 C, by fusing 4,5-di-
bromophthalic anhydride with phosphorus penta-
chloride at a temperature gradually raised from 150 to
250 C and simultaneous distillation of the phosphorus
oxychloride formed. The starting 4,5-dibromophthalic
anhydride was prepared by bromination of o-xylene
with molecular bromine [10] to 4,5-dibromo-o-xylene,
its subsequent oxidation with potassium permanganate
in aqueous pyridine [11] to 4,5-dibromophthalic acid,
and refluxing the latter with acetic anhydride.
N-(Ethoxycarbonylmethyl)-4,5-dicyanophthal-
imide (VI). A mixture of 1.18 g of dibromide VIII
and 0.81 g of CuCN in 30 ml of DMF was refluxed
for 4 h with stirring, cooled, and a solution of 2.8 g
of FeCl3 6H2O in 20 ml of 5% hydrochloric acid
N-(Ethoxycarbonylmethyl)-4,5-dibromophthal-
imide (VIII). To a solution of 0.56 g of diacyl chlo-
ride VII in 7 ml of dry ethyl ether, a solution of 0.8 g
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PHTHALOCYANINES AND RELATED COMPOUNDS: XXXVII.
455
were added. The mixture was stirred for 10 min at
45 C, cooled, diluted with water, and extracted with
ether. The ether extracts were washed with water to
neutral reaction, the solvent was removed, and the
residue was subjected to chromatography on silica gel
(eluent chloroform) to isolate 0.33 g (39%) of dinitrile
benzene, methanol, and water, squeezed, and dried.
Repeated chromatography on silica gel (eluent chlo-
roform methanol, 30:1) gave 0.6 g (ca. 20%) of
complex Ib. UV spectrum (chloroform), max, nm:
357, 699 (relative intensity 1:1.85). Further elution
with pyridine gave 0.03 g of the complex with partly
hydrolyzed ester groups. IR spectrum (Vaseline oil),
VI, mp 164 165 C. IR spectrum (Vaseline oil),
,
1
1
cm : 1715, 1730, 1778 (C=O), 2225 (C N). Found,
%: C 59.76, 59.79; H 3.35, 3.35; N 14.12, 14.29.
C14H10N3O3. Calculated, %: C 59.14; H 3.55; N
14.78.
, cm : 1695, 1715, 1740, 1765 (C=O).
Cobalt octa-4,5-carboxyphthalocyanine tetra(N-
ethoxycarbonylmethyl)imide (Ic). A mixture of
0.29 g of dinitrile VI, 0.09 g of anhydrous cobalt
acetate, and 0.01 g of ammonium molybdate were
heated for 2 h under helium at 205 210 C, cooled,
and subjected to chromatography on silica gel (eluent
chloroform methanol, 10:1) to isolate 0.04 g (ca.
Further elution with a chloroform methanol (10:1)
mixture gave 0.14 g (15.5%) of copper octa-4,5-car-
boxyphthalocyanine tetra(N-ethoxycarbonylmethyl)-
imide (Ia).
13%) of complex Ic. UV spectrum (chloroform),
,
max
N,N -Bis(ethoxycarbonylmethyl)-N,N -dimethyl-
4,5-dicyanophthalamide (VII) was prepared si-
milarly to compound VI by the reaction of 2.4 g of
dibromide IX with 1.26 g of CuCN in 72 ml of DMF.
Yield 0.59 g (31%), mp 93 94 C. IR spectrum
nm: 339, 689 (relative intensity 1:1.15). IR spectrum
1
(Vaseline oil), , cm : 1700, 1728, 1765 (C=O).
Copper octa-4,5-carboxyphthalocyanine tetra(N-
carboxymethyl)imide (IIa). A mixture of 0.05 g of
compound Ia and 1 ml of 10% HCl was refluxed for
4 h, cooled to 4 5 C, and filtered. The solid material
was washed with 10% HCl, squeezed, and dried at
100 105 C to obtain 0.04 g (95%) of water-soluble
complex IIa. UV spectrum, max, nm: (H2O +
1% NH4OH) 347, 611, 681 (relative intensity 1:0.85:
1.41); (H2O): 350, 633 (relative intensity 1:1.08);
(H2O + 0.5% NaOH): 355, 633, 674 (relative intensity
1
(Vaseline oil), , cm : 1635 1645, 1728 (C=O),
2225 (C N). Found, %: C 57.24, 57.32; H 5.27, 5.18;
N 13.07, 13.21. C20H22N4O6. Calculated, %: C 57.95;
H 5.36; N 13.52.
Along with dinitrile VII, further elution with a
chloroform methanol (10:1) mixture gave 0.43 g of
the dinitrile with partly hydrolyzed ester groups. IR
1
spectrum (Vaseline oil), , cm : 1630 1640, 1730
1
1:1:1.06). IR spectrum (Vaseline oil), , cm : 1695,
(C=O), 2230 (C N), 3610 (OH).
1765 (C=O), 3350 (OH). Found, %: C 54.16, 54.03;
H 2.24, 1.99. C48H20CuN12O16. Calculated, %: C
53.16; H 1.86.
Copper octa-4,5-carboxyphthalocyanine tetra(N-
ethoxycarbonylmethyl)imide (Ia). A mixture of
0.25 g of dinitrile VI, 0.05 g of CuCl, and 0.01 g of
ammonium molybdate in 1 ml of anhydrous trichloro-
benzene was stirred for 3 h at 200 205 C, cooled, and
subjected to repeated chromatography on silica gel
(eluent methanol chloroform, 1:10) to isolate 0.05 g
(ca. 20%) of complex Ia. IR spectrum (Vaseline oil),
Zinc octa-4,5-carboxyphthalocyanine tetra(N-
carboxymethyl)imide (IIb) was prepared similarly
to compound IIa from compound Ib. UV spectrum,
max, nm: (H2O) 352, 646 (relative intensity 1:0.90);
(H2O + 1% NH4OH): 352, 620.5, 689 (relative inten-
1
1
sity 1:0.41:2.23). IR spectrum (KBr), , cm : 1695,
, cm : 1700 1715, 1730, 1765 (C=O). UV spectrum
1760 (C=O), 3390 (OH).
(chloroform), max, nm: 360.5, 694.5 (relative in-
tensity 1:1.95).
Metal complexes of octa-4,5-carboxyphthalo-
cyanine tetraanhydride XIb XIe. A mixture of
0.3 mmol of metal octa-4,5-carboxyphthalocyanine
and 6 ml of acetic anhydride was refluxed for 6 h. The
resulting suspension was cooled and filtered. The
solid material was washed with a little acetic an-
hydride, squeezed, and dried in a vacuum at 115
120 C. Yield > 90%. IR spectrum (Vaseline oil), ,
Further elution with pyridine gave 0.02 g of a
partly hydrolyzed complex. Found, %: C 56.46, 56.42;
H 3.05, 3.14; N 14.02,14.12. C56H36CuN12O16. Cal-
culated, %: C 56.21; H 3.04; N 14.05.
Zinc octa-4,5-carboxyphthalocyanine tetra(N-
ethoxycarbonylmethyl)imide (Ib). A mixture of
0.29 g of dinitrile VI, 0.09 g of anhydrous zinc
acetate, and 0.01 g of ammonium molybdate in 0.9
ml of 1-bromonaphthalene was stirred for 3 h under
helium at 210 215 C, cooled, and diluted with
methanol. The resulting suspension was filtered, and
the solid material was washed successively with
1
cm : 1760, 1830 (C=O).
Conjugates of octa-4,5-carboxyphthalocyanines
with glycine IIb IIe. To a solution of 0.15 mmol of
tetraanhydride XIb XIe in 8 ml of anhydrous N-
methyl-2-pyrrolidone, 0.8 mmol of ethyl glycinate
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456
MIKHALENKO et al.
was added, and the mixture was stirred for 6 h under
an inert gas at 180 185 C, 0.5 mmol more ethyl
glycinate was added,2 and stirring was continued for
an additional 8 h at the same temperature. The reac-
tion mixture was cooled, diluted with 5% HCl to pH
1, and stirred for 15 20 min. The resulting suspension
was filtered, and the solid material was washed
successively with dilute HCl and water, squeezed, and
dried to obtain tetra(ethoxycarbonylmethyl)imide
Ib Ie.
Cobalt octa-4,5-carboxyphthalocyanine tetra(N-
-carboxyethyl)imide (XIIc). To a solution of
0.1 mmol of tetraanhydride XIc in 10 ml of anhydrous
N-methyl-2-pyrrolidone, 1.1 mmol of L-alanine tert-
butyl ester hydrochloride and 1.1 mmol of triethyl-
amine were added. The mixture was stirred for 6 h
under an inert gas at 175 185 C, an additional ester
and triethylamine, 3.7 mmol each, were added, the
mixture was heated for 5 h at this temperature and
then cooled and diluted with 5% HCl to pH 1. The
suspension was filtered, the solid material was
successively washed with water and chloroform,
squeezed, and dried. The product was purified by
reprecipitation from 0.1% aqueous NaOH with HCl.
Yield 0.08 g (71%). The complex is soluble in water,
Compound Ib. UV spectrum (chloroform),
,
max
nm: 357, 646, 699 (relative intensity 1:0.60:1.80). IR
1
spectrum (Vaseline oil), , cm : 1695, 1715, 1735,
1768 (C=O). Compound Ic. UV spectrum (chloro-
form), max, nm: 334, 689 (relative intensity 1:1.10).
1
especially when heated. IR spectrum (KBr), , cm :
1
IR spectrum (Vaseline oil), , cm : 1700, 1715, 1730,
1695 (carboxyl C=O), 1755 (C=O), 2900 (C H). UV
spectrum, max, nm (relative intensity): (DMSO) 348,
610, 684 (1:0.45:1.66); (0.1 NaOH): 332, 610, 674
(1:0.43:1.34). Found, %: C 54.27, 54.35; H 2.63,
2.78; N 14.62, 14.58. C52H28CoN12O16. Calculated,
%: C 54.98; H 2.49; 14.80.
1760 (C=O). Compound Id. UV spectrum (chloro-
form methanol, 20:1), max, nm: 335, 628, 695
(relative intensity 1:0.90:1.55). IR spectrum (Vase-
1
line oil), , cm : 1705, 1735, 1768 (C=O). Com-
pound Ie. UV spectrum (chloroform), max, nm:
353, 611, 704 (relative intensity 1:0.50:1.80). IR
1
spectrum (Vaseline oil), , cm : 1710, 1740, 1770
Copper octakis-4,5-[N-(ethoxycarbonylmethyl)-
N-methylcarbamoyl]phthalocyanine (IIIa). A mix-
ture of 0.37 g of dinitrile VII, 0.05 g of CuCl, and
0.01 g of ammonium chloride in 1 ml of anhydrous
trichlorobenzene was stirred for 3 h at 200 205 C and
cooled. Repeated chromatography on silica gel (eluent
methanol chloroform, 1:10) gave 0.08 g (ca. 20%) of
complex IIIa. UV spectrum (chloroform), max, nm:
348.5, 613.5, 631.5, 679.5 (relative intensity 1:0.43:
(C=O).
Compounds Ib Ie were refluxed in 10% HCl for
4 h, the hot suspension was filtered, the solid material
was washed with hot water to neutral reaction,
squeezed, and treated with 0.1% aqueous NaOH to
pH 8.5. The resulting solution was subjected to chro-
matography on alumina [eluent phosphate buffer (pH
6.75)]. The eluate (blue band) was acidified with
dilute HCl, the resulting suspension was filtered, and
the precipitate of tetra(carboxymethyl)imide IIb IIe
was washed with 5% HCl and cold water to neutral
reaction, squeezed, and dried.
1
0.32:2.08). IR spectrum (KBr), , cm : 1635, 1730
(C=O), 2815 2930 (C H).
Further elution with pyridine gave 0.03 g of partly
hydrolyzed complex IIIa, whose IR spectrum (KBr)
1
shows an additinal band at 3400 cm (OH).
Compound IIb. Yield 25%. UV spectrum (H2O +
NaOH), max, nm: 358, 657, 680 sh (relative intensity
1:0.95:1.15). IR spectrum (Vaseline oil), , cm :
Copper octakis-4,5-[N-(carboxymethyl)-N-
methylcarbamoyl]phthalocyanine (IVa) was pre-
pared by refluxing compound IIIa in 10% HCl (re-
agent ratio 1:10), yield 90%. It is soluble in water,
alkali solutions, and aprotic solvents. IR spectrum
1
1695, 1765 (C=O), 3380 (OH). Compound IIc. Yield
61%. UV spectrum (H2O + NaOH), max, nm: 330,
674 (relative intensity 1:0.95). IR spectrum (Vaseline
1
1
oil), , cm : 1695, 1755 (C=O), 3380 (OH). Found
(KBr), , cm : 1610 1640, 1690 (C=O), 2815 2920
N, %: 14.14, 14.40. C48H20CrN12O16. Calculated N,
%: 15.57. Compound IId. Yield 15%. UV spectrum
(H2O + NaOH), max, nm: 335, 678 (relative intensity
(C H), 3400 (OH). UV spectrum (H2O), max, nm:
340.5, 616.0 (relative intensity 1:1.10). UV spectrum,
max, nm: (H2O + NOH) 349, 617.5, 685 (relative
intensity 1:0.40:2.34); (DMSO): 351, 614, 683 (re-
lative intensity 1:0.80:3.45)
1
1:1.25). IR spectrum (Vaseline oil), , cm : 1690,
1755 (C=O), 3400 (OH). Compound IIe. Yield
27%. UV spectrum (H2O + NaOH), max, nm: 360,
618, 688 (relative intensity 1:0.55:1.45). IR spectrum
Complex IVb was prepared similarly to complex
IIIa by the reaction of dinitrile VII with anhydrous
zinc acetate. Yield 22%. UV spectrum (chloroform),
max, nm: 360.5, 695 (relative intensity 1:1.95). IR
1
(Vaseline oil), , cm : 1695, 1760 (C=O), 3370 (OH).
1
2
Excess ethyl glycinate is taken in view of the possible forma-
spectrum (KBr), , cm : 1640, 1730 (C=O), 2815
tion of diketopiperazine.
2925 (C H). The product is readily soluble in aro-
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PHTHALOCYANINES AND RELATED COMPOUNDS: XXXVII.
457
matic (benzene) and aliphatic solvents, alcohols, and
ketones (acetone).
refluxed with stirring for 25 h, the solvent was then
removed in a vacuum, the residue was agitated in a
chloroform methanol (5:1) mixture, the precipitate
was filtered off and washed on the filter with the same
solvent mixture to a colorless filtrate. The filtrate was
evaporated to dryness, and the reside was subjected to
chromatography on silica gel first in methanol chlo-
roform, 1:10, and then in methanol chloroform, 1:5,
to obtain 0.69 g of octaester IIIb. IR spectrum (KBr),
Hydrolysis of compound IIIb, as described above
for compound IIIa, gave 90% of compound IVb. IR
1
spectrum (KBr), , cm : 1610 1640, 1690 (C=O),
2815 2920 (C H), 3400 (OH). UV spectrum,
,
max
nm: (H2O) 344, 636 (relative intensity 1:0.95);
(H2O + N OH): 353.5, 618, 635, 687 (relative in-
tensity 1:0.40:0.35:1.85); (DMSO): 354, 618, 683
(relative intensity 1:0.63:2.09).
1
, cm : 1616, 1721 (C=O), 2854, 2925 (C H).
Octaester IIIb was refluxed with 0.5 h in 5% HCl.
The subsequent reprecipitation from 0.1% NaOH gave
ca. 30% of complex IVb identical to that prepared
Cobalt octakis-4,5-[(N-carboxymethyl-N-me-
thylcarbamoyl]phthalocyanine (IVc). A mixture of
0.41 g of dinitrile VII, 0.09 g of anhydrous cobalt
acetate, 0.06 g of ammonium molybdate, and 1 ml of
anhydrous nitrobenzene was heated for 4.5 h at 190 C
with stirring under an inert gas. Purification by chro-
matography on silica gel (eluent chloroform methanol,
5:1) gave 0.12 g of octaester IIIc. IR spectrum (KBr),
1
from dinitrile VII. IR spectrum (KBr), , cm : 1615,
1712 (C=O), 2850, 2930 (C H). UV spectrum,
,
max
nm: (H2O) 643, 680 sh (aggregated); (0.1% NaOH):
354, 615, 683. Found, %: C 50.91, 50.93; H 3.86,
3.82; N 14.49, 14.47. C64H56N16O24Zn. Calculated,
%: C 51.28; H 3.72; N 14.96.
1
, cm : 1630, 1750 (C=O), 2845, 2922, 2945 (C H).
UV spectrum (chloroform), max, nm: 338, 614, 673
(relative intensity 1:0.60:1.55).
Cobalt octakis-4,5-[(N-carboxymethyl-N-methyl-
carbamoyl]phthalocyanine (IVc). Octaester IIIc was
prepared similarly compound IVb by the reaction of
1.06 g of octaacyl chloride Xc with 2.34 g of sar-
cosine ethyl ester in 50 ml of absolute chloroform.
Yield 0.15 g. IR spectrum (KBr), , cm : 1616,
1721 (C=O), 2854, 2925 (C H).
Refluxing of compound IVc with 10 ml of 10%
HCl for 4 h gave 24% of acid IVc. IR spectrum (KBr),
1
, cm : 1627, 1698 (C=O), 2852, 2923, 2957 (C H).
1
UV spectrum (H2O), max, nm: 319, 632, 675 (relative
intensity 1:0.65:1.05).
A suspension of acid IVc in water was diluted with
0.1% aqueous NaOH to pH 8.5, filtered, the filtrate
was evaporated to dryness in a vacuum (20 mm), and
further dried at 110 C to constant weight. The yield of
the sodium salt is quantitative. UV spectrum (0.01 M
NaOH), max, nm: 331, 619, 675 (relative intensity
1:0.40:1.35). Found, %: C 45.89, 45.96; H 2.67,
2.72; N 12.84, 12.88. C64H48CoN16Na8O24. Calcu-
lated, %: C 46.07; H 2.91; N 13.44.
Octaester IIIc was hydrolyzed with 5% HCl, as
described for compound (IIIb), to obtain complex IVc
identical to that prepared from dinitrile VII. IR spec-
1
trum (KBr), , cm : 1620, 1703 (C=O), 2850, 2925
(C H). UV spectrum, max, nm: (H2O) 630, 675 sh
(0.1% NaOH): 330, 618:675 (relative intensity
1:0.45:1.30). Found, %: C 51.84, 51.86; H 3.24,
3.31; N 14.17, 14.19. C64H56CoN16O24. Calculated, %:
C 51.50; H 3.73; N 15.02.
Zinc octakis-4,5-(chlorocarbonyl)phthalocyanine
(Xb). A mixture of 0.86 g of tetraanhydride XIb,
0.812 g of phthaloyl chloride, and 0.19 g of an-
hydrous zinc chloride was stirred for 24 h at 210
215 C to obtain 1.06 g (95%) of compound Xb.
Zinc tetra-4-carboxyphthalocyanine (XIVb). A
mixture of 4.75 g of trimellitic acid (or its anhydride),
2.52 g of zinc acetate dihydrate, 0.3 g of ammonium
molybdate, 0.5 g of anhydrous sodium sulfate, and
13.5 g of urea in 5 ml of 1-bromonaphthalene was
stirred for 4 h at 200 205 C, cooled, diluted with
methanol, and the resulting suspension was filtered.
The solid material was successively washed with
methanol, chloroform, and acetone, thoroughly
squeezed, and ground, and refluxed for 1 h with 5%
HCl, after which it was filtered off, washed with water,
and dried. The reaction product was reprecipitated
from conc. H2SO4 (35 ml) to obtain 1.95 g of a com-
plex which was then treated for 2 h at 130 135 C
with a 15% solution of KOH in triethylene glycol
(9.2 g of KOH in 54 ml of triethylene glycol). Acidi-
fication with dilute HCl to pH 1 gave 0.76 g (ca.
Cobalt octakis-4,5-(chlorocarbonyl)phthalo-
cyanine (Xc). A mixture of 0.78 g of tetraanhydride
XIc, 0.82 g of phthaloyl chloride, and 0.16 g of an-
hydrous zinc chloride was stirred for 24 h at 210
215 C to obtain 1.06 g (98%) of crude octachloride
Xc as a running friable powder.
Zinc octakis-4,5-[(N-carboxymethyl-N-methyl-
carbamoyl]phthalocyanine (IVb). To a solution of
3.11 g of sarcosine ethyl ester in 70 ml of absolute
chloroform, 1.42 g of octaacyl chloride Xb was added
in portions over a period of 15 min. The mixture was
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458
MIKHALENKO et al.
18%) of complex XIVb. Found N, %: 14.74, 15.02.
C36H16N8O8Zn. Calculated N, %: 14.86.
to chromatography on alumina. Impurities were eluted
with benzene and chloroform, and acid XVIc, with
chloroform methanol, 10:1. Yield 0.31 (35%). IR
Cobalt tetra-4-carboxyphthalocyanine (XIVc).
A mixture of 2.6 g of trimellitic anhydride, 0.88 of
anhydrous CoCl2, 8.2 g of urea, 5.2 g of anhydrous
sodium sulfate, 0.3 g of ammonium molybdate, and
2.6 g of 1-bromonaphthalene was stirred for 4 h at
210 215 C, cooled, diluted with methanol, and the
resulting suspension was filtered. The solid material
was successively washed with methanol, chloroform,
and water, squeezed, and dried. The crude product
was purified by successive refluxing with 10 NaOH
(6 h) and 10 HCl (1 h). Yield 1.9 g (75%). Found, %:
C 57.64, 57.35; H 2.90, 2.63; N 15.11, 15.15. C36H16
CoN8O8. Calculated, %: C 57.83; H 2.16; N 14.99.
1
spectrum (KBr), , cm : 1641, 1743 (C=O), 2932,
2977 (C H). UV spectrum (chloroform), max, nm:
619, 670. Found, %: C 58.70, 58.52; H 4.88, 4.78; N
14.73, 14.71; ash 7.00, 6.73. C56H52CoN12O12. Cal-
culated, %: C 58.78; H 4.59; N 14.69; ash 7.02.
Cobalt tetrakis-4-[N-(carboxymethyl)-N-me-
thylcarbamoyl]phthalocyanin (XIIIc). A mixture of
0.23 g of ester XVIc and 5 ml of 10% HCl was re-
fluxed for 2 h, the precipitate was filtered off, washed
with 10% HCl and water, squeezed, and dried to
obtain 0.19 g (90%) of acid XIIIc. IR spectrum (KBr),
1
, cm : 1616, 1727 (C=O), 2900 2960 (C H). UV
spectrum (0.1% NaOH), max, nm: 630, 670 (aggrega-
ted). Found, %: C 56.12, 55.96; H 3.68, 3.73; N 15.98,
15.87, ash 7.08, 7.26. C48H36CoN12O12. Calculated,
%: C 55.87; H 3.52; N 16.29, ash 7.78.
Zinc and cobalt tetra-4-(chlorocarbonyl)phthalo-
cyanines (XVb, XVc). A mixture of 0.002 mmol of
zinc or cobalt tetra-4-carboxyphthalocyanine (XIVb
or XIVc), 30 ml of dry benzene, and 2 ml of thionyl
chloride was refluxed for 7 h, and the suspension was
cooled and filtered. The solid material was washed
with dry benzene and dried in a vacuum at room
temperature. The yields of complexes XVb and XVc
were 95 and 98%, respectively.
N,N -Bis(ethoxycarbonylmethyl)fumaramide
(XVII). To a cooled ( 12 C) solution of 3.24 g of
fumaroyl chloride in absolute ether, 10.4 g of ethyl
glycinate was added dropwise with stirring over a
period of 2.5 h. Stirring was continued for 1 h at the
same temperature, and then the temperature was raised
to 20 C. The solvent was removed, the residue was
mixed with water, the resulting suspension was fil-
tered, the solid material was washed with water, dried,
and subjected to chromatography on alumina (eluent
chloroform methanol, 10:1) to obtain 3.15 g (32.4%)
of diamide XVII, mp 202 203 C. IR spectrum (Va-
Zinc tetrakis-4-[N-(ethoxycarbonylmethyl)-N-
methylcarbamoyl]phthalocyanine (XVIb). A sus-
pension of 0.62 g of acyl chloride XVb and 0.88 g of
sarcosine ethyl ester in 30 ml of dry chloroform was
refluxed with stirring for 16 h. The solvent was then
removed in a vacuum, and the residue was subjected
to chromatography on alumina. Impurities were eluted
with bezene and chloroform, and zinc complex XVIb,
with chloroform methanol, 10:1. Yield 25%. IR
1
seline oil), , cm : 1615, 1725 (C=O). Found, %: C
50.22, 50.33; H 6.33, 6.34; N 9.86, 9.98. C12H18N2O6.
Calculated, %: C 50.34; H 6.35; N 9.79.
1
spectrum (KBr), , cm : 1643, 1742 (C=O), 2930,
N,N -Bis(ethoxycarbonylmethyl)-6,7-dicyano-
naphthalene-2,3-dicarboxamide (XVIII). A mixture
of 0.95 g of 4,5-bis(dibromomethyl)phthalonitrile [8],
0.63 g of diamide XVII, and 1.7 g of anhydrous
sodium iodide in 40 ml of dry DMF was stirred for
7 h at 85 87 C, cooled, poured into ice-cold water
and treated with sodium hydrosulfite. The precipitate
that formed was filtered off, dried, and subjected to
chromatography on silica gel (eluent chloroform
methanol, 5:1) to obtain 0.16 g (18.5%) of compound
XVIII, mp 220 222 C. IR spectrum (Vaseline oil), ,
2975 (C H). Found, %: C 58.61, 58.49; H 4.75, 4.52;
N 14.45, 14.52. C56H52N12O12Zn. Calculated, %: C
58.45; H 4.56; N 1 4.61.
Zinc tetrakis-4-[N-(carboxymethyl)-N-methyl-
carbamoyl]phthalocyanine (XIIIb). A mixture of
0.23 g of ester XVIb and 5 ml of 10% HCl was re-
fluxed for 2 h, the precipitate that formed was filtered
off, washed with 10% HCl and water, squeezed, and
dried to obtain 0.21 g (93%) of complex XIIIb. IR
1
spectrum (KBr), , cm : 1616, 1720 (C=O), 2900,
1
2950 (C H). Found N, %: N 15.79, 15.88. C48H36
N12O12Zn. Calculated N, %: 16.19.
cm : 1610, 1650, 1720, 1735 (C=O), 2230 (C N).
Cobalt octakis-6,7-[N,N-(carboxymethyl)car-
bamoyl]-2,3-naphthocyanine (XXc). A mixture of
0.13 g of dinitrile XVIII, 0.12 g of anhydrous CoCl2,
and 0.01 g of ammonium molybdate in 0.7 ml of
1-bromonaphthalene, and 0.02 ml of N-methyl-2-
pyrrolidone was stirred for 4.5 h under helium at
225 240 C, cooled, and diluted with methanol. The
Cobalt tetrakis-4-[N-(ethoxycarbonylmethyl)-N-
methylcarbamoyl]phthalocyanine (XVIc). A mix-
ture of 0.62 g of acyl chloride XIVc and 0.88 g of
sarcosine ethyl ester in 30 ml of dry chloroform was
refluxed for 16 h with stirring. The solvent was then
removed in a vacuum, and the residue was subjected
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PHTHALOCYANINES AND RELATED COMPOUNDS: XXXVII.
459
resulting suspension was filtered, the solid material
was successively washed with chloroform, acetone,
water, and again with acetone, squeezed, and dried
to obtain 0.07 g of crude compound XIXc. IR spec-
trum (Vaseline oil), , cm : 1590, 1645, 1695, 1745
(C=O). UV spectrum (DMSO), max, nm: 750.
5. Syrkin, A.B., Zhukova, O.S., Kikot’, B.S., Gatin-
skaya, L.G., Treshchalina, E.M., Yakubovskaya, R.I.,
Pankratov, A.A., Mikhailova, L.M., Kolesniko-
va, E.Yu., Oborotova, N.A., Polozkova, A.P., Gera-
simova, G.K., Kuz’min, S.G., Lukyanets, E.A., Ka-
liya, O.L., Vorozhtsov, G.N., and Trapeznikov, N.N.,
Ross. Khim. Zh., 1998, vol. 42, no. 5, p. 140.
1
By refluxing octaester XIXc in 10% HCl for 4 h,
followed by isolation of the reaction product by the
procedure described for conjugates II and IV, 63% of
complex XXc was obtained. The product is soluble in
aqueous alkali and aprotic solvents (DMSO, quinoline,
6. Ponomarev, G.V., Reshetnikov, A.V., Guseva-Don-
skaya, T.N., Shvets, V.I., Baum, R.F., and Ashmaro-
va, V.V., RU Patent no. 2144538, 2000, Byull.
Izobret., 2000, no. 2.
1
etc). IR spectrum (Vaseline oil), , cm : 1600 (NH),
7. Solov’eva, L.I., Lukyanets, E.A., Zh. Obshch. Khim.,
1695 (C=O), 3360 (OH). UV spectrum, max, nm:
(H2O + NaOH) 735; (DMSO): 743; (quinoline): 744
(always aggregated).
1980, vol. 50, no. 5, p. 1122.
8. Kovshev, E.I., Puchnova, V.A., and Lukyanets, E.A.,
Zh. Obshch. Khim., 1971, vol. 7, no. 2, p. 369.
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10. Jacobsen, O., Chem. Ber., 1884, vol. 17, p. 2732.
Izv. Ross. Akad. Nauk, Ser. Khim., 1998, no. 4, p. 836.
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