Synthesis and characterization of novel flavonoid-substituted phthalocyanines using (±)naringenin

Article abstract of DOI:10.1016/j.jorganchem.2009.09.012

In this study, novel unsymmetrical mono- and di-substituted metal free and metallo phthalocyanines containing peripheral naringeninoxy moieties have been prepared. The naringenin-substituted phthalonitrile was synthesized from 4-nitrophthalonitrile and (±

Full text of DOI:10.1016/j.jorganchem.2009.09.012

Journal of Organometallic Chemistry 694 (2009) 4152–4161
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis and characterization of novel flavonoid-substituted phthalocyanines
using ( )naringenin
*
S. Zeki Yıldız , Mustafa Küçükislamog˘lu, Murat Tuna
Sakarya University, Faculty of Arts and Sciences, Department of Chemistry, 54187 Sakarya, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 June 2009
Received in revised form 29 August 2009
Accepted 3 September 2009
Available online 11 September 2009
In this study, novel unsymmetrical mono- and di-substituted metal free and metallo phthalocyanines
containing peripheral naringeninoxy moieties have been prepared. The naringenin-substituted phthalo-
nitrile was synthesized from 4-nitrophthalonitrile and ( )naringenin in dimethylsulfoxide. Preparation of
unsymmetrical mono- and di-substituted phthalocyanines, 2-naringenin-7-O-phthalocyaninatozinc, 2,9-
bis-naringenin-7-O-phthalocyaninatozinc, 2,9-bis-naringenin-7-O-phthalocyaninatocobalt and 2,9-bis-
naringenin-7-O-phthalocyanine was performed at 120–140 °C using the corresponding phthalonitrile
in the presence of N,N-dimethylethanolamine (DMAE), ZnCl2, CoCl2 and LiCl, respectively. Synthesized
new phthalocyanine compounds have been characterized by elemental analysis and 1H NMR, 13C NMR,
FT-IR, MS and UV–vis spectroscopy. These are the first known examples of flavonoid-substituted
phthalocyanines.
Keywords:
Flavonoid
Naringenin
Substituted phthalocyanine
Synthesis
Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction
Flavonoids are classified with the rings named as A, B and C,
and/or the positions numbered. Based on the flavanone structure,
Since their first synthesis in 1928, phthalocyanines (Pcs) have
gained considerable industrial importance for use in dyestuffs,
paints, colorants for metal surfaces, fabrics and plastics [1]. Appli-
cations in the fields of chemical sensors, liquid crystals, semicon-
ductors, nonlinear optics, and photodynamic therapy (PDT) have
been demonstrated the increase due to the importance of these
macrocyclic coordination compounds [2].
Flavonoids are a group of natural products present in a wide
variety of plants. They are ubiquitous in photosynthesizing cells
and therefore occur widely in the plant kingdom. They are found
in flowers, vegetables, nuts, seeds, citrus fruits, olive oil, tea and
red wine and are commonly consumed with the human diet
[3,4]. Flavonoids, with several phenolic hydroxyl groups, exhibit
a broad range of biological activities, including antiviral, anti-
inflammatory, antioxidant, anti-allergic and anti-tumoral proper-
ties [5–7]. Furthermore, these compounds are used in bacteriology,
pharmacology and medicine due to their bactericidal activities [8].
It is also known that amino-substituted flavone derivatives exhibit
strong antitumour activity in breast cancer cells [9]. Moreover, fla-
vone imines show antimicrobial and antimalarial activities [10,11].
The basic structural feature of flavonoid compounds is the 2-
phenylchroman or flavane nucleus, which consists of two benzene
rings (A and B), linked through a heterocyclic pyrane ring (C)
(Fig. 1).
all other flavonoid species can be generated, including flavanols,
anthocyanidins, flavonols, flavonones and flavones [12]. Naringe-
nin is a member of the flavonoid family. It bears three hydroxyl
groups at the 5, 7 and 40 positions and may exhibit protective
effects against several types of cancers. Cell culture experiments
have shown inhibitory effects of naringenin on tumor growth in
human cancer cell lines deriving from breast, colon, liver, cervix,
and pancreas or stomach cancers [13].
Phthalocyanine derivatives have attracted much interest as PDT
candidates because they possess certain advantages over their por-
phyrin analogues. Phthalocyanines generally have larger extinction
coefficients, absorptions in the therapeutically convenient 650–
800 nm range and they have no dark toxicity. The photosensitizing
properties of aluminum, gallium, zinc, and silicon phthalocyanines
and naphthalocyanines have been investigated, as well as a series
of hydroxy-phthalocyanines. The latter was prepared by Leznoff’s
group as both single isomers and as statistical mixtures of the
isomers, and their efficacy as sensitizers for PDT was examined
in vitro and in vivo on some tumor species [14]. Some unsymmet-
rical benzylic-hydroxysubstituted phthalocyanines were prepared
in 2003 by Cosimelli and co-workers and their photodynamic
activity was tested against Candida albicans [15]. Hydroxyphenyl
porphyrins have been found to be among the most active com-
pounds in photodynamic therapy studies. Another porphyrin-
based substance, PhotofrinÒ, a mixture of porphyrin oligomers, is
currently in use as an effective treatment against esophageal and
endobronchial cancer [16].
* Corresponding author. Fax: +90 264 295 59 50.
E-mail address: szy@sakarya.edu.tr (S.Z. Yıldız).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.09.012

S.Z. Yıldız et al. / Journal of Organometallic Chemistry 694 (2009) 4152–4161
4153
3) was added to adjust the pH ꢀ 3 and the mixture was stirred until
all the ice had melted. The precipitated crude product was collected
by vacuum filtration, washed with distilled water until pH 7, and
then dried under vacuum. The crude product was treated with
hot diethyl ether (3 ꢁ 20 mL) to remove some oily residues, and
than it was re-crystallized from acetone. The yield was 1.48 g
(84%), m.p. 153–158 °C. Anal. Calc. for C22H14N2O5: C, 69.34; H,
3.54; N, 7.03. Found: C, 69.17; H, 3.73; N, 6.85%. FT-IR (PIKE MIRa-
3'
2'
4'
5'
8
B
6'
O
7
6
2
3
A
C
4
5
O
cleTM ATR) max, cmꢂ1: 3421, 3085, 2955, 2927, 2233, 1774, 1693,
m
Fig. 1. The skeleton structure of favonoids (Flavanone).
1616, 1592, 1249, 1200, 1126. 1H NMR (DMSO): d, ppm 12.14
(1H, s, Ar–OH), 10.92 (1H, s, Ar–OH), 8.15 (1H, d, Ar–H), 7.81 (1H,
s, Ar–H), 7.65 (2H, d, Ar–H), 7.48 (1H, d, Ar–H), 7.23 (2H, d, Ar–H),
5.95 (2H, d, Ar–CH), 5.85 (1H, d, Alip–CH), 3.30 (2H, d, Alip–CH2)
and 2.78 (2H, d, Alip–CH2), 13C (DMSO): d, ppm 207.22, 196.58,
167.41, 164.18, 163.35, 161.48, 154.60, 137.02, 129.75, 123.57,
122.90, 121.02, 117.43, 116.59, 116.07, 109.08, 102.45, 96.68,
95.73, 78.53, 31.38. MS(FAB) (m/z): 437 (Calc. for [M+2H2O+3]+
437), 417 (Calc. for [M+H2O+1]+ 417), 399 (Calc. for [M+1]+ 399)
and 269.
In this work, we report the synthesis, characterization and
investigation of some spectroscopic properties of novel phthalocy-
anines containing naringenin groups as substituents. The phthalo-
cyanines were prepared as both metal free and metalated
compounds, substituted either mono- or di-peripherally. To our
knowledge, these are the first examples of naringenin-substituted
phthalocyanine compounds which may poses unique biological
activity properties.
2. Experimental
2.2.1.2. 40,5-Dibenzyl-naringenin-7-O-4-phtalonitrile (4). Compound
3 (0.398 g, 1 mmol) was dissolved in 50 mL acetone. Benzoyl chlo-
ride (0.260 mL, 2 mmol), potassium iodide (0.015 g, 0.09 mmol)
and potassium carbonate (1.380 g, 10 mmol) were added to the
solution. The reaction mixture was refluxed for 48 h and then
poured into distilled water (250 mL). Dilute HCl was added to
the mixture until pH ꢀ 4. The aqueous phase was extracted with
CH2Cl2 (3 ꢁ 25 mL). The extracts were combined, washed with
water until pH ꢀ 7, dried over anhydrous sodium sulfate, and then
filtered. The solvent was evaporated and the product was purified
by column chromatography on silica gel using THF/hexane (4/3) as
mobile phase. Compound 4 is solid; yield 0.167 g (34%). Anal. Calc.
for C30H20N2O5: C, 73.76; H, 4.13; N, 5.73. Found: C, 75.85; H, 4.02;
2.1. Materials and characterization techniques
( )Naringenin 1 was purchased from Sigma–Aldrich Company.
Deuteriated solvents (CDCl3 and DMSO-d6) for NMR spectroscopy
and the following chemicals were obtained from Merck; hexane,
MeOH, N,N-dimethylaminoethanol (DMEA), anhydrous ZnCl2,
anhydrous CoCl2, LiCl, THF, DMSO, HCl (37% sol.), CH2Cl2, K2CO3.
All other reagents and solvents were reagent grade quality and
were obtained from commercial suppliers. All solvents were dried
and purified as described by Perrin et al. [17], and the solvents
stored over molecular sieves (4 Å). 4-Nitro phthalonitrile 2 was
prepared according to literature procedure [18]. All reactions were
carried out under an atmosphere of argon, using standard Schlenk
techniques. Thin-Layer chromatography (TLC) was performed
using silica gel 60 HF254 as an adsorbent. Hot solvent extraction
was performed using a Soxhlet extractor. Flash silica with particle
N, 5.49%. FT-IR (PIKE MIRacleTM ATR) max/cmꢂ1: 3066, 3030, 2922,
m
2850, 2235, 1720, 1633, 1591, 1485, 1247, 1150, 1090, 833. 1H
(CDCl3) d = 12.15 (1H, s, Ar–OH), 7.84–6.22 (14H, m, Ar–H), 5.43
(1H, d, cyclic-CH), 5.15 (2H, s, benzylic-CH2), 3.20–2.82 (2H, m,
cyclic-CH2). 13C (DMSO): d, ppm 225.92, 195.02, 188.89, 187.46,
185.17, 177.14, 175.16, 166.45, 159.39, 157.06, 146.00, 134.86,
128.99, 127.70, 123.91, 121.25, 118.35, 114.87, 113.85, 110.00,
101.41, 99.69, 94.07, 65.39, 52.19, 29.95. MS(FAB) (m/z): 527 (Calc.
for [M+2H2O+3]+ 527), 489 (Calc. for [M+1]+ 489), 438, 413 and
400.
size 20–45 lm was used as solid phase dispersion during extrac-
tion. Melting points (mp) were determined using a Barnstad-Elec-
trotermel 9200 apparatus and are uncorrected. Electronic spectra
were recorded on a Shimadzu UV-2401 Pc-spectrophotometer
using a 1 cm quartz cell. Infrared spectra were recorded on a Shi-
madzu FTIR IRPrestige-21 spectrophotometer equipped with PIKE
MIRacleTM diamond ATR and corrected by applying IR solution soft-
ware’s ATR-correction function. 1H and 13C NMR spectra were re-
corded as CDCl3 and DMSO-d6 solutions on a Varian Mercury
Plus 300 MHz spectrometer. Mass analyses were measured on a
Micro-Mass Quatro LC/ULTIMA LC–MS/MS spectrometer. For Mal-
di-TOF spectra, the experiments were carried out using a Bruker
micrOTOF (Germany) electrospray ionisation-mass spectrometer
(ESI-MS). Samples were run in positive ion mode (ESI+). Chem-
Draw Ultra version 7.0 was also used to calculate and examine
the mass fragments.
2.2.2. Synthesis of phthalocyanines
2.2.2.1. 2-Naringenin-7-O-phthalocyaninatozinc (5). Substituted
phthalonitrile 3 (24 mg, 0.06 mmol) or 4 (32 mg, 0.06 mmol),
anhydrous ZnCl2 (14 mg, 0.1 mmol) and phthalonitrile (0.128 g
1 mmol) were dissolved in dry DMAE (10 mL). The reaction mix-
ture was heated at 135 °C for 4 h under an Ar atmosphere. The
resulting green reaction mixture was cooled to room temperature
and precipitated by pouring into 1:1 MeOH/H2O mixture. The pre-
cipitate was collected by centrifuge and washed with 1:1 MeOH/
H2O and then distilled water. The precipitate was dried under vac-
uum. The crude product was dissolved in THF (10 mL), adsorbed
onto silica gel (20 g) and then Soxhlet-extracted with hot THF
(125 mL) for 12 h. The solvent was evaporated and the product
was chromatographed by preparative TLC on silica gel using THF/
hexane (3/2) as mobile phase. Compound 5 was obtained as a
blue-green solid in both cases, with the melting point >300 °C
and the yield 0.025 g (48%) or 0.030 g (55%), respectively. Anal.
Calc. for C47H26N8O5Zn: C, 66.56; H, 3.09; N, 13.21. Found: C,
2.2. Synthesis
2.2.1. Synthesis of substituted phthalonitriles
2.2.1.1. Naringenin-7-O-4-phtalonitrile (3). ( )Naringenin 1 (0.602 g,
4.43 mmol) and 4-nitro phthalonitrile 2 (0.808 g, 4.67 mmol) were
dissolved in 40 mL dry DMSO. After stirring for 15 min at 30–40 °C,
finely powdered anhydrous potassium carbonate (0.555 g, 4 mmol)
was added portion wise over 12 h with efficient stirring and the sys-
tem was kept under vacuum. The reaction was stirred for 72 h and
monitored by TLC using THF/hexane (3/4) as eluent. The reaction
mixture was poured into ice-distilled water (200 g), dilute HCl (1/
66.27; H, 3.15; N, 13.54%. FT-IR (PIKE MIRacleTM ATR) max/cmꢂ1
m :
3186, 3060, 2953, 2922, 2855, 1720, 1605, 1483, 1330, 1285,
1088, 725. MS(FAB) (m/z): 843 (Calc. for [Mꢂ3]+ 843), 718, 507,

4154
S.Z. Yıldız et al. / Journal of Organometallic Chemistry 694 (2009) 4152–4161
129. UV–vis (THF): k, nm (log
e) 667.5 (5.46), 638.0 (4.55), 602.0
2.2.2.4. 2,9-Bis-naringenin-7-O-phthalocyanine (8). Substituted pht-
(4.60), 341.5 (4.91), 238.5 (4.83).
halonitrile 3 (48 mg, 0.12 mmol), phthalonitrile (0.128 g 1 mmol)
and LiCl (78 mg, 1 mmol) were dissolved in dry DMAE (4 mL).
The reaction mixture was heated at 120 °C for 4 h under an Ar
atmosphere. The progress of the reactions was monitored by UV–
vis spectroscopy according to the previously motioned method
for 6. The resulting green reaction mixture was cooled to room
temperature and precipitated by pouring into H2O (50 mL). The
precipitate was collected by centrifuge and washed with 1:3
MeOH/H2O solution until no-yellow colored washing solution re-
mained. The precipitate was dried under vacuum. The crude prod-
uct was dissolved in THF (10 mL), adsorbed onto silica gel (20 g)
and then Soxhlet-extracted with hot THF (125 mL) for 12 h. The
solvent was evaporated and the slurry was chromatographed by
preparative TLC on silica gel using THF/hexane (3/2) as mobile
phase. The purified compound 8 was collected as a frontier phase
and re-precipitated with methanol. After collected by centrifuge
and dried under vacuum, the compound 8 could be obtained as a
greenish-blue solid with the melting point > 300 °C and the yield
0.027 g (42%). Anal. Calc. for C62H38N8O10: C, 70.58; H, 3.63; N,
10.62. Found: C, 70.52; H, 4.26; N, 10.31%. FT-IR (PIKE MIRacleTM
2.2.2.2. 2,9-Bis-naringenin-7-O-phthalocyaninatozinc (6). (Reaction
with L/M: 1/10 ratio): Substituted phthalonitrile (40 mg,
0.1 mmol), anhydrous ZnCl2 (0.136 g, 1 mmol) and phthalonitrile
(0.128 g, 1 mmol) were dissolved in dry DMAE (4 mL). The reaction
mixture was stirred at 130–140 °C for 2.5 h under an Ar
atmosphere.
(Reaction with L/M: 1/3 ratio): Substituted phthalonitrile 3
(40 mg, 0.1 mmol), anhydrous ZnCl2 (41 mg, 0.3 mmol) and pht-
halonitrile (38.5 mg, 0.3 mmol) were dissolved in dry DMAE
(4 mL). The reaction mixture was stirred at 130 °C for 3.5 h under
an Ar atmosphere.
(Reaction with L/M: 1/1 ratio): Substituted phthalonitrile 3
(40 mg, 0.1 mmol), anhydrous ZnCl2 (14 mg, 0.1 mmol) and pht-
halonitrile (13 mg, 0.1 mmol) were dissolved in dry DMAE
(3 mL). The reaction mixture was stirred at 130 °C for 4 h under
an Ar atmosphere.
3
The progress of the reactions was monitored by UV–vis spec-
troscopy for the samples prepared dissolving 5 lL reaction media
in 25 mL THF. Upon completion, the reaction mixtures were cooled
to room temperature and precipitated by pouring into 1:3 MeOH/
H2O. For each reaction, the precipitate was collected by centrifuge
and washed with 1:2 MeOH/H2O and then distilled water. The pre-
cipitate was dried under vacuum. The crude product was adsorbed
onto silica gel (20–50 g) and then purified by Soxhlet extraction
with hot THF (150–200 mL) according to the previously described
method for 5. The solvent was evaporated to dryness and the prod-
uct was chromatographed by preparative TLC on silica gel using
THF/hexane (3/2) as mobile phase. After re-precipitated by metha-
nol, collected by centrifuge and dried under vacuum, the phthalo-
cyanine 6 was obtained as statistical mixture of isomers with
different yield for each reaction condition. The product is a blue-
green solid, melting point > 300 °C and the yield for 1/10 reaction
ratio 0.042 g (63%), for 1/3 reaction ratio 0.036 g (54%) and for 1/
1 reaction ratio 0.020 g (30%). Anal. Calc. for C62H36N8O10Zn: C,
66.58; H, 3.24; N, 10.02. Found: C, 66.65; H, 3.18; N, 9.95%. FT-IR
ATR) m
max/cmꢂ1: 3289, 3150, 3071, 2950, 2914, 2870, 1741, 1699,
1595, 1506, 1437, 1302, 1275, 1238, 1163, 1007, 741, 716.
MS(MALDI-TOF) (m/z): 1074 (Calc. for [M+H2O]+, 1074), 950, 799,
544. UV–vis (THF): k, nm (log e) 689.0 (5.21), 652.5 (5.16), 635.5
(4.74), 593.0 (4.51), 338.0 (5.02), 236.5 (4.97).
2.3. Spectroscopic measurement
Stock solutions were prepared in 1 ꢁ 10ꢂ4 mol dmꢂ3 by dissolv-
ing 30 mg, 2,9-bis-naringenin-7-O-phthalocyaninatozinc (6) in
250 mL THF, EtOH and DMSO, respectively. The solutions were di-
luted to 7.5 ꢁ 10ꢂ5 mol/dm3, 5.0 ꢁ 10ꢂ5 mol/dm3, 2.5 ꢁ 10ꢂ5 mol/
dm3, 1.0 ꢁ 10ꢂ5 mol/dm3, 7.5 ꢁ 10ꢂ6 mol/dm3, 5.0 ꢁ 10ꢂ6 mol/
dm3, 1.0 ꢁ 10ꢂ6 mol/dm3 and 5.0 ꢁ 10ꢂ7 mol/dm3 by adding re-
lated solvent. UV–vis spectra of the prepared solutions were taken
in a 1 ꢁ 1 cm quartz tub at the range of 850–200 nm. UVPC39 soft-
ware program was used to record the results. The collected results
were plotted as absorptions against to concentration on the graph-
ics to examine the changes of the aggregation properties with the
varying concentration.
(PIKE MIRacleTM ATR)
m
max/cmꢂ1: 3196, 3059, 2953, 2924, 2855,
1717, 1651, 1605, 1483, 1385, 1333, 1284, 1116, 1088, 1053,
738. MS(MALDI-TOF) (m/z): 1116 (Calc. for [M]+ 1116), 1026,
830, 753, 864. UV–vis (THF): k, nm (log e) 665.5 (5.57), 637.5
(4.71), 601.5 (4.76), 341.5 (5.01), 239.0 (4.78).
2.2.2.3. 2,9-Bis-naringenin-7-O-phthalocyaninatocobalt (7). Substi-
3. Results and discussion
tuted phthalonitrile
3 (48 mg, 0.12 mmol), anhydrous CoCl2
(0.130 g, 1 mmol) and phthalonitrile (0.128 g 1 mmol) were dis-
solved in dry DMAE (4 mL). The reaction mixture was heated at
135 °C for 4 h under an Ar atmosphere. The resulting green reac-
tion mixture was cooled to room temperature and precipitated
by pouring into ice-distilled water (50 g). The precipitate was col-
lected by centrifuge and washed with 1:1 MeOH/H2O solution until
no-yellow colored washing solution remained. After drying under
vacuum, the crude product was dissolved in THF (10 mL), adsorbed
onto silica gel (20 g) and then Soxhlet-extracted with hot THF
(125 mL) for 12 h. The solvent was evaporated and the product
was chromatographed by TLC on silica gel using THF/hexane (3/
2) as mobile phase to check the purity of the compound. Without
future purification, compound 7 was obtained pure enough as a
greenish-blue solid with the melting point > 300 °C and the yield
0.025 g (38%). Anal. Calc. for C62H36N8O10Co: C, 66.97; H, 3.26; N,
10.08. Found: C, 66.32; H, 3.16; N, 10.54%. FT-IR (PIKE MIRacleTM
Naringeninoxy-substituted phthalonitrile 3 was synthesized
from ( )naringenin 1 and 4-nitrophthalonitrile 2 via displacement
of the nitro group with the 7-hydroxy group on ( )naringenin as
shown in Scheme 1. This reaction was performed in the presence
of K2CO3 and DMF using a well established procedure and gave
one product almost exclusively, and in very good yield due to the
higher reactivity of the hydroxyl group at the 7 position compared
to those at the 5 and 40 positions [18–20]. Water was added to the
reaction mixture to precipitate the crude phthalonitrile 3, but the
alkaline constitution of the reaction mixture resulted in emulsions
due to the formation of partially-soluble phenolate salts. The crude
product was eventually isolated by simply adjusting the pH of the
mixture to ꢀ3. Substituted phthalonitrile 3 was purified by crystal-
lization from acetone to obtain a light brownish micro-crystalline
product. After investigating various protecting groups for the free
hydroxyls on 3, it was found that only the benzylated derivative
could be prepared. Refluxing compound 3 with benzyl chloride in
acetone for 48 h gave compound 4, but in poor yield. A mixture
of mono-benzyl and di-benzyl derivatives was obtained, and was
separated by column chromatography on silica gel using THF/hex-
ATR) m
max/cmꢂ1: 3194, 3061, 2955, 2918, 2870, 1736, 1605, 1475,
1427, 1333, 1163, 1121, 1094, 736. MS(MALDI-TOF) (m/z): 1135
(Calc. for [M+Na]+, 1134), 901, 579. UV–vis (THF): k, nm (log
e)
655.5 (5.31), 594.0 (4.65), 323.5 (5.05), 238.0 (4.87).

S.Z. Yıldız et al. / Journal of Organometallic Chemistry 694 (2009) 4152–4161
4155
OH
OH
HO
O
NC
NC
O
O
O
CN
CN
DMF/K2CO3
+
RT, 72 h.
O2N
O
1
OH
OH
2
3
Acetone
Reflux, 48h.
Cl
OR
NC
NC
O
O
O
OH
4
R:Benzyl
Scheme 1. Preparation steps of substituted phthalonitrile.
ane (4/3) as eluent. Due to the di-benzyl derivative of 3 was ob-
tained in very low yield, it is unaccepted as product.
the benzyl protecting groups of 4 unexpectedly cleaved under
these reaction conditions, therefore only the free-hydroxyl
naringeninoxy-substituted zinc-phthalocyanines were prepared.
Mono-substituted Zn-Pc 5 could be obtained under dilute reaction
conditions, when the ratio of 3 or 4 to phthalonitrile was applied as
1:17 or higher, respectively. On the other hand, using ratios of 1:1,
1:3, or 1:10 3 to phthalonitrile, the same di-substituted Zn-Pc 6
was obtained each time (Scheme 2). It was found that the highest
yield was achieved using a ratio of 1:10. This reaction was found to
be essentially complete within 30 min, but when left to heat for
extended periods of time, lower yields were obtained. In the prep-
aration of the other di-substituted phthalocyanines 7 and 8, the
same 1:10 ratio was applied by using phthalonitrile 3. Reaction
completion was monitored by UV–vis spectroscopy with samples
taken at half hour intervals. The samples were diluted to prepare
Preparation of the corresponding metallo phthalocyanines (5–
7) was achieved by fusing of phthalonitrile and the naringenin-
oxy-substituted phthalonitrile in different ratios in the presence
of DMAE and the related MCl2 salt at 120–140 °C for 2–4 h. In
the preparation of the metal free phthalocyanine 8, LiCl was used
as metal salt and the lityum phthalocyanine PcLi2 was obtained ini-
tially, and than it hydrolyzed to metal free species, PcH2, with
water during work up. Naringeninoxy-phthalonitrile 3 and its ben-
zyl derivative 4 were both combined with phthalonitrile in various
ratios to determine the optimum reaction conditions of either the
mono- or di- substituted zinc-phthalocyanines. It was found that
2.5 ꢁ 10ꢂ6 M solutions in THF (5
lL/25 mL THF) and the Q band
OR
absorptions at 600–700 nm region were checked to establish the
optimal reaction time. For all phthalocyanines 5–8, a slightly long-
er reaction time was necessary (2–4 h) to reach completion. A
number of attempts were made to synthesize the tetrasubstituted
phthalocyanines by self tetramerization of 3 using a variety of con-
ditions, but unfortunately all attempts were unsuccessful. The
reaction conditions and yields are summarized in Table 1.
Separation of the substituted Pcs from un-substituted Pc was
able to achieve due to the higher solubility of naringeninoxy-
substituted Pcs in organic solvents. The crude products were dis-
solved in THF and adsorbed onto flash silica gel (1 mg/1 g) and
then isolated by Soxhlet extraction using THF as the solvent. The
extracted naringeninoxy-substituted phthalocyanines were
purified by preparative TLC on silica gel using THF/hexane (3/2)
as mobile phase except Co-Pc 7.
The new compounds are characterized by a combination of ele-
mental analysis and spectroscopic data involving FT-IR, 1H NMR,
13C NMR, ESI MS-MS and UV–vis spectra. The data for all the
new compounds appear to be consistent with the proposed
structures.
The elemental analysis result of the starting materials 3, 4 and
the phthalocyanines 5, 6, 7 and 8 show good agreements with
the calculated values (Table 2). Comparison of the IR spectral data
clearly indicates the formation of 3 and 4 with the appearance of
absorption bands at 3421 cmꢂ1 (Ar–OH), 3085 cmꢂ1 (Ar–H),
2927 cmꢂ1 (C–H), 2233 cmꢂ1 (C„N), 1774 cmꢂ1 (C@O) and
1200 cmꢂ1 (C–O–C) for compound 3, and at 3066–3030 cmꢂ1
(Ar–H), 2922–2850 cmꢂ1 (C–H), 2235 cmꢂ1 (C„N), 1720 cmꢂ1
NC
NC
O
O
O
OH
3
4
R:H
R: Benzyl
DMAE
MCl
120-140 °C
2-5h.
CN
CN
+
HO
O
O
O
N
M
N
OH
N
N
N
N
N
N
R'
OH
5
M: Zn, R':H
M: Zn. R':
M: Co, R':
M: 2H. R':
O
O
O
6
7
8
OH
Scheme 2. Synthesis of naringeninoxy-substituted Pcs.

4156
S.Z. Yıldız et al. / Journal of Organometallic Chemistry 694 (2009) 4152–4161
Table 1
Preparation conditions of substituted phthalocyanines and their yields.
Metal salt (mmol) Substituted PN (mmol)
PNa (mmol)
Reaction time (h)
Reaction temp. (°C)
Pc
Yield (%)
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
CoCl2
LiCl
17
3
4
3
3
3
3
3
3
1
1
1
1
1
4
1
1
20
20
10
3
1
–
4
4
2.5
3.5
4
12
4
4
130–140
130–140
135–140
130–135
130–135
135–140
135–140
120–125
5
5
6
6
6
–
7
8
48
55
63
54
30
–
17
10
3
1
3
10
10
10
10
38
42
a
PN: phthalonitrile.
Table 2
the IR results of the substituted phthalonitriles and the phthalocy-
anines are in good agreement with the previous literature
[15,16,20–23].
Elemental analysis results of the substituted phthalonitriles (3, 4) and the phthal-
ocyanines (5–8).a
The 1H NMR of the compound 3 in deuterated DMSO indicates
two different D2O exchangeable phenolic Ar–OH protons appeared
at d 12.14 ppm and 10.92 ppm with 1H integrated values. The
intra-molecular hydrogen bond between the phenolic proton at 5
position and the carbonyl group at 4 in the flavanone ring made
the Ar–OH group more acidic, and the peak shifted to lower field.
As well as, all the aromatic protons appeared in between d 8.15
and 5.95 ppm with the 9H integrated values and the identified
splitting, the aliphatic protons belong to the heterocyclic ring ap-
peared at d 5.85 ppm, 3.30 ppm and 2.78 ppm as doublets due to
geminal and vicinal interactions with the justifying integrals. In
the 1H NMR spectra of 4, as the benzylated product of 3, the singlet
at d 10.92 ppm disappeared. The aromatic proton region became
more complicated with the addition of the benzyl group, and the
–CH2– protons of this group appeared as singlet at d 5.15 ppm. Be-
cause of the extremely low solubility of naringeninoxy-substituted
phthalocyanines (5–8), we were unable to record their 1H and 13C
NMR spectra. However, appeared decoupled peaks in the 13C NMR
spectra of 3 and 4 support the proposed structures. Some charac-
teristic shifts which belong to the compounds can be seen at Table
3. In addition, the 1H and 13C NMR results of the compound 3 and 4
are in good agreement with the published literature [24–26].
ESI MS-MS and MALDI-TOF spectra identify the structures of the
prepared compounds. Interpretation of MS spectra of 3 has been
done according to peaks which appeared at m/z 437, 417, and
399. Corresponding molecular ion and the fragment ions were
calculated as [M+2H2O+3]+, [M+H2O+1]+ and [M+1]+. Additionally,
the basic peak of the spectrum, which appears at 269, could be
commented as three hydrogen lost naringenin moiety. The MS
spectra of 4 were interpreted according to peaks which appeared
at m/z 527, 489, 413 and 400. The molecular ion and the frag-
ment ion molecules were calculated as [M+2H2O+3]+, [M+1]+,
[MꢂBzyl+H2O-2] and [MꢂBzyl+3], respectively. The peak appear-
Compound
C%
H%
N%
3
4
5
6
7
8
69.17(69.34)
75.85(73.76)
66.27(66.56)
66.65(66.58)
66.52(66.97)
70.52 (70.58)
3.73(3.54)
4.02(4.13)
3.15(3.09)
3.18(3.24)
3.16(3.26)
4.26 (3.63)
6.85(7.03)
5.49(5.73)
13.54(13.21)
9.95(10.02)
10.54(10.08)
10.31(10.62)
a
Theoretical calculated values are given in parentheses.
(O–H–O) 1683 cmꢂ1 (C@O) and 1150 cmꢂ1 (C–O–C) for compound
4.
Cyclotetramerizations of the dinitriles 3 and 4 to obtain mono-
substituted phthalocyanine 5 and di-substituted phthalocyanines
6, 7 and 8 were confirmed by the disappearance of the sharp –
C„N vibrations at 2233 cmꢂ1 and 2235 cmꢂ1, respectively. In the
IR spectra of mono-substituted phthalocyanine 5 and di-substi-
tuted phthalocyanines 6, 7 all the peaks are located the same,
but the intensities have some differences. The stretching vibration
which belongs to free –OH group at 40 position of the naringenin
moiety appears at 3196–3184 cmꢂ1 as broad band and the intra-
molecular hydrogen bond at 1717 cmꢂ1. Because of this hydrogen
bond, the stretching vibration of the C@O group shifted to
1651 cmꢂ1 in all phthalocyanines. Weak bands at above
3000 cmꢂ1 and the absorptions at 2953–2855 cmꢂ1are due to the
aromatic @C–H stretchings of the substituted phthalocyanines
and the anti-symmetric C–H stretching vibrations of the heterocy-
clic ring of the naringenin substituent, respectively. In the range of
1605–1284 cmꢂ1, the pyrrole, benzene, isoindol ring and aza group
stretching of the molecules are prominent, and the in-place C–H
bending vibrations are in between 1116 and 1053 cmꢂ1 in the
spectra. Additionally, the resonances at 3289 and 1006 cmꢂ1 are
assigned to the N–H stretching and bending vibrations for 8. All
Table 3
Some characteristic 13C NMR shifts of 3 and 4.
Molecular structures
Carbon num.
Cn
Comp. 3
d (ppm)
Comp. 4
d (ppm)
18
C1, C2
C3–C20
C3–C26
C27
C28
C29
116.59, 116.07
196.58–95.73
–
207.22
31.38
78.53
–
114.87, 113.85
–
195.02–94.07
225.92
29.95
52.19
OR
20
17
6
12
19
O
29
13
14
NC
8
9
4
3
O
15
2
16
27
28
10
7
NC
11
5
1
C30
65.39
O
OH
30
R:
23
26
21
24
22
25

S.Z. Yıldız et al. / Journal of Organometallic Chemistry 694 (2009) 4152–4161
4157
ing at m/z 413 was the basic peak of the spectrum, as well. ESI MS-
MS spectra of mono-substituted zinc-phthalocyanine were
molecular ions of the phthalocyanines (5–8) and their fragments
were determined using ChemDraw Ultra version 7.0.
5
examined in detail and the peaks appeared at m/z 843, 718, 507
and 129 were determined to be molecular ion peak and derived
fragment peaks. The MS spectra of 5 and the structures of the cor-
responding molecular ion and the fragment ions can be seen in
Fig. 2. The basic peak of the spectrum appeared at m/z 129 belongs
to an iminoisoindoline moiety. MALDI-TOF spectra of 6 were also
interpreted and the chemical structures of the molecular ion and
the fragment ions were determined from the peaks which ap-
peared at m/z 1116, 1026, 830, 753 and 663. The considered MS
peaks in the determination of the structures and the molecular
species matched with are given in Fig. 3. The molecular ion peak
of the di-substituted zinc-phthalocyanine 6 appeared at m/z 1116
was expanded to see the distributions of the peaks in the region.
It is obvious that the main peak fractionated in to the five due to
the isotopes of the zinc ion bearing in the tetrabenzo-
tetraazaporphyrin ring [19]. Zinc has five stable isotopes with the
mass numbers 64, 66, 67, 68 and 70, and their abundances are
48.6%, 27.9%, 4.1%, 18.8%, and 0.6%, respectively [27–29]. However,
MS spectra of Co-Pc 7 is simpler due to, the stable isotope of cobalt
is only one [30]. Accordingly, in the MALDI-TOF spectra of 7, the
molecular ion peak emerged at m/z 1135 was calculated as
[M+Na]+. Finally, the MS spectra of PcH2 8 was examined as
MALDI-TOF and the peak appeared at m/z 1074 was interpreted
as the molecular ion ([M+H2O]+). The chemical structures of the
UV–vis spectra of 6 were recorded from 1 ꢁ 10ꢂ5 M solutions in
THF, DMSO and ethanol (Fig. 4). The significant wavelengths and
the calculated extinction coefficients of the prepared compound
are given in Table 4. As shown in Table 4, the molar extinction coef-
ficients of 6 in THF solutions have prominently higher values at the
Q and B band regions than those found in DMSO and ethanol solu-
tion due to less aggregation effects in non polar solvents. However,
the aggregation properties of 6 changing with the increased con-
centrations were examined by using mentioned solvents in
5 ꢁ 10ꢂ5–5 ꢁ 10ꢂ7 mol/L concentration range. The increase of the
aggregation properties with the rising concentration in the related
solvents was determined in the order of THF > DMSO > EtOH, and
the Q band appeared at 665 nm was found as the much affected
one (Fig. 5). The typical Q and B bands correspond to the transi-
tions a1u ? eg or HOMO–LUMO and a2u-LUMO at wavelengths
around 700 nm and 380 nm, respectively [31]. The single Q bands
observed for THF solutions 6 at 667.5 and 665.0 nm are character-
istic of metallo phthalocyanines. The nature and the symmetrical
positions of the peripheral substituents and the molecular environ-
ment of the Pc macro-ring affect the Q and B bands of the elec-
tronic spectrum by splitting or shifting the peaks [32,33].
Polyhydroxyl-containing substituents such as glucose and
phenol derivatives cause blue-shifting in the Q bands and shorter
wavelength shifting in the
B
bands owing to the electron
OH
OH
O
O
O
O
N
N
O
OH
OH
O
N
N
N
N
N
N
N
N
N
N
Zn
N
N
Zn
N
N
Chemical Formula:
39H22N6O5Zn••
Chemical Formula: C47H26N8O5Zn
Exact Mass: 846,13
C
••
Chemical Formula: C8H4N2
Exact Mass: 128,04
Exact Mass: 718,09
m/z: 846,13 (100,0%)
m/z: 718,09 (100,0%)
m/z: 128,04 (100,0%)
Fig. 2. (a) ESI MS-MS spectra of 5 and (b) molecular ion and some fragment ions structures of 5 examined by using ChemDraw Ultra 7.0 version.

4158
S.Z. Yıldız et al. / Journal of Organometallic Chemistry 694 (2009) 4152–4161
OH
O
O
O
N
N
HO
N
N
N
N
N
N
N
N
Zn
N
N
Zn
N
N
HO
N
N
O
O
O
O
OH
Chemical Formula: C38H17N8OZn•••
Exact Mass: 665,08
Chemical Formula: C62H36N8O10Zn
Exact Mass: 1116,18
m/z: 665,08 (100,0%)
m/z: 1116,18 (100,0%)
Fig. 3. (a) MALDI-TOF spectra of 6 and (b) molecular ion and basic fragment ion structures of 6 examined by using ChemDraw Ultra 7.0 version.
Fig. 4. UV–vis spectra of Pc–Zn 6 in THF (—), DMSO (ꢃ ꢃ ꢃ) and ethanol (– –).

S.Z. Yıldız et al. / Journal of Organometallic Chemistry 694 (2009) 4152–4161
4159
Table 4
withdrawing properties of the substituents. The same effect was
observed with the substitutions of the naringenin groups as poly-
phenolic species, thus the bands appeared at lower wavelengths
when they compared with the un-substituted phthalocyanines
[16,34,35]. Addition of a second naringenin group to the macro-
ring did not appreciably affect the electronic spectrum. However,
approximately 2.5 nm shifts were observed in the Q bands as well
as a decrease in the intensity in the B bands due to the increasing
aggregation effects by the rising of the number of the substituted
hydroxyl groups. These changes can be seen in the UV–vis spectra
of 3, 5 and 6, which were recorded from 1.3 ꢁ 10ꢂ6 M solutions in
Wavelengths and the extinction coefficients of 1 ꢁ 10ꢂ5 M solutions of 6 in THF,
DMSO and ethanol.
Solution(1x10ꢂ5M) THF
DMSO
Ethanol
Peaks
kmax
log
e
kmax
log
e
kmax
log e
(nm)
(nm)
(nm)
1
2
3
4
5
665.0
637.5
601.5
341.5
239.0
5.48 671.5
4.71 606.0
4.76 345.0
5.01 281.0
4.78 253.0
5.43 665.5
4.66 637.5
4.88 602.0
4.53 341.5
4.49 282.0
4.99
4.15
4.18
4.46
4.24
Fig. 5. The aggregation properties of Zinc Pc 6 in (a) THF, (b) DMSO and (c) EtOH.

4160
S.Z. Yıldız et al. / Journal of Organometallic Chemistry 694 (2009) 4152–4161
Fig. 6. UV–vis spectra of 3 (ꢃ ꢃ ꢃ), 5 (- - -) and 6 (—) in THF.
Fig. 7. UV–vis spectra of Pc–Zn 6 (ꢃ ꢃ ꢃ), Pc–Co 7 (—) and Pc–H2 8 (- - -) in THF.
THF (Fig. 6). The extinction coefficients of the intense Q bands of 5
and 6 are also higher than known many symmetrical and unsym-
metrical phthalocyanines [24]. Mono-substituted zinc-phthalocya-
nine 5 gives rise to a single Q band at 667.5 nm, similar to some
other mono-functional phthalocyanines due to the degeneracy of
the LUMO (eg) in the molecules with D4h symmetry [15,33–37].
Steric hindrance of the naringeninonxy group gives opposite type
di-substituted phthalocyanines. However, the metallo phthalocya-
4. Conclusion
Novel naringenin-substituted zinc-phthalocyanines have been
prepared by reacting 4-naringeninoxyphthalonitrile 3 and its
benzylated derivative 4 with an excess of phthalonitrile in the
presence of DMAE and ZnCl2. By varying the amount of phthalonit-
rile, either the mono-substituted ZnPc 5 or the di-substituted ZnPc
6 could be obtained. During this tetramerization reaction protect-
ing group (benzyl) cleaved. Therefore, in the preparation of the
other phthalocyanines 7 and 8, phthalonitrile 3 was used directly
in the same reaction conditions together with CoCl2 and LiCl,
respectively. The starting naringenin-substituted phthalonitrile 3
was prepared by reacting 4-nitrophthalonitrile with naringenin
in DMSO in the presence of K2CO3. Due to the substantially higher
nines 6 and 7 consist of the mixture of isomers (C2v, Cs and D2h
)
and give single Q bands at 665 and 655 nm, respectively. Com-
pound 8 has split Q absorption bands which appear at 689 and
652 nm as shown in Fig. 7. These results are consistent with the
published literature [38–40]. The UV–vis spectra of 6, 7 and 8
which were taken in THF can be seen at Fig. 7.

S.Z. Yıldız et al. / Journal of Organometallic Chemistry 694 (2009) 4152–4161
4161
reactivity of the 7-hydroxy group, as compared to the 5 or 40-hy-
droxy groups on naringenin, this nucleophilic aromatic displace-
ment was performed selectively without the need for protecting
groups. To our knowledge, these are the first known examples of
flavonoid-substituted phthalocyanines.
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