Synthesis and characterization of 1,8(11),15(18),22(25)-tetraglycosylated zinc(II) phthalocyanines

Article abstract of DOI:10.1142/S1088424610002343

In continuation of our work on glycosylated phthalocyanines, a new series of 1,8(11),15(18),22(25)-tetraglycosylated zinc(II) phthalocyanines (PcZns) have been synthesized and characterized. 3-glycosylated phthalonitriles were synthesized through nitrite

Full text of DOI:10.1142/S1088424610002343

Journal of Porphyrins and Phthalocyanines
J. Porphyrins Phthalocyanines 2010; 14: 494–498
DOI: 10.1142/S1088424610002343
Published at http://www.worldscinet.com/jpp/
Synthesis and characterization of 1,8(11),15(18),22(25)-tetra-
glycosylated zinc(II) phthalocyanines
Zafar Iqbala, Alexey Lyubimtseva,b, Michael Hanack*a◊ and Thomas Ziegler*a
a Institut für Organische Chemie der Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
b Ivanovo State University of Chemistry and Technology, F. Engels str. 7, 15300 Ivanovo, Russia
Received 9 November 2009
Accepted 28 January 2010
ABSTRACT: In continuation of our work on glycosylated phthalocyanines, a new series of
1,8(11),15(18),22(25)-tetraglycosylated zinc(II) phthalocyanines (PcZns) have been synthesized and
characterized. 3-glycosylated phthalonitriles were synthesized through nitrite displacement in 3-nitro-
phthalonitrile with anomerically deprotected glycoses. The anomerically glycosylated phthalonitriles
were then treated with hexamethyldisilazane (HMDS), trimethylsilyltriflate (TMSOTf) and zinc salt
in DMF to form the corresponding acetyl-protected PcZns, followed by deprotection of acetyl groups
by NaOMe in methanol/DMSO mixture. The formed unprotected tetraglycosylated PcZns are highly
soluble in water, which is a necessary condition for potential biological applications.
KEYWORDS: 3-glycosylated phthalonitriles, PDT, glycosylated phthalocyanines, synthesis.
primary prerequisite for potential biological applica-
tions. In addition to the tetraglucosylated PcZn other
peripherally tetraglycosylated PcZns with D-glucose,
INTRODUCTION
Recently, we published a series of papers dealing
with the syntheses of phthalocyanine (Pc) zinc and
naphthalocyanine (Nc) zinc carbohydrate conjugates
[1–4]. We investigated phthalocyanine-carbohydrate
1-thio-β-D-glucopyranose, β-D-galactopyranose, 1-thio-
β-D-cello- and lactobiose were synthesized [2]. The tetra-
substituted PcZns were obtained as mixtures of structural
conjugates because of the potential of other substituted
isomers.
Pcs and Ncs in photodynamic therapy (PDT) [5–18].
We also prepared a structural uniform octaglycosy-
This is due to their ability to photosensitize the for-
mation of highly reactive singlet oxygen via transfer
lated PcZn with 1,2:3,4-di-O-isopropylidene-α-D-galacto-
pyranose attached to the Pc macrocycle via its position
of energy from the triplet-excited state of the Pc or
6 [3].
Nc macrocycle to the triplet-ground state of oxygen.
In addition we synthesized anomerically glycosy-
Conjugates of carbohydrates and Pcs were synthesized
lated octasubstituted PcZns in which the sugar part is
assuming that the presence of carbohydrate substituents
protected by acetyl groups as well as deprotected gly-
will improve the membrane activity of these Pcs and
cosylated PcZns. The sugars glucose, galactose, lactose,
thereby increase their tumor selectivity when applied
cellobiose and maltose were anomerically attached either
in PDT [19, 20].
via oxygen or sulfur to the Pc ring [21].
First, we synthesized an anomerically tetraglucosy-
Naphthalocyanines (Ncs) have also been used as pho-
lated zinc(II) phthalocyanine (Fig. 1) by tetramerization of
tosensitizers in PDT. Ncs are of particular interest due
4-(2,3,4,6-tetra-O-acetyl-α/β-D-glucopyranosyl)-phthalo-
nitrile [1] which exhibited high solubility in water, the
to their absorption maxima in the range of 750–800 nm,
where light penetration through skin and tissues is
approximately twice that of Pcs (∼630 nm) [22]. There-
fore, we extended our work on glycoconjugated Pcs to
SPP full member in good standing
Ncs and reported recently about a peripherally tetraglu-
cose-substituted Zn(II) naphthalocyanine linked via the
anomeric carbon to the macrocycle [4].
*Correspondence to: Michael Hanack, email: hanack@uni-
tuebingen.de, tel: +49 7071-29-72432, fax: +49 7071-29-5268
and Thomas Ziegler, email: thomas.ziegler@uni-tuebingen.de
Copyright © 2010 World Scientific Publishing Company

SyntheSIS Of 1,8(11),15(18),22(25)-tetraglyCOSylateD zInC(II) PhthalOCyanIneS
495
O
NO2
HO
Y
O
CN
Y
AcO
CN
CN
i
CN
1
N
N
+
N
O
O
HO
O
Y
N
Zn
N
Y
YH
OH
AcO
3a-e
O
OAc
2a-e
ii
N
N
Y
N
Glycoses
Y
2a glucose
2b galactose O
O
N
O
O
HO
2c maltose
2d glucose
2e galactose
O
S
S
Y
Y
OAc
N
N
N
Fig. 1. Anomerically tetraglycosylated zinc(II) phthalocya-
nines. The glycosyl moieties represent glucose, galactose, cel-
lobiose and lactose residues. Y = O or S
N
N
Zn
4a-e
N
N
In the first published tetraglycosylated PcZns (Fig. 1),
the sugar molecules are linked to the Pc macrocycle in
positions 2,9(10),16(17),23(24).
O
O
iii
Y
Y
AcO
OAc
For PDT studies, a structural diversity of the up to now
prepared glycosylated PcZns is essential. Therefore, we
have now also synthesized the 1,8(11),15(18),22(25)-tet-
raglycosylated PcZns 4a–4e and 5a–5e (Scheme 1).
O
OH
Y
N
O
Y
EXPERIMENTAL
OH
N
N
N
Commercially available reagents were purchased at
highest commercial quality and used without further
purification. Organic solutions were concentrated by
rotary evaporation below 50 °C. Reactions were car-
ried out under anhydrous conditions using flame-dried
glassware in anhydrous, freshly distilled solvents,
unless otherwise noted. Thin-layer chromatography
(TLC) was performed on Macherey & Nagel Polygram
SIL G/UV254 plastic plates precoated with 0.2 mm of
silica gel containing fluorescent indicator. Detection
of spots on TLC was carried out by UV light whereas
sugar-containing compounds were visualized by spray-
ing the TLC with 5% H2SO4 solution in EtOH and heat-
ing the plate. Silica gel 60 (particle size 0.040–0.063
mm) was used for column chromatography. NMR
spectra were measured on a Bruker Avance 400 (400
MHz) spectrometer. UV-vis spectra were recorded on a
PerkinElmer Lambda 25 using a 1 cm quartz cell. Melt-
ing points were taken on a Büchi B-540 and are uncor-
rected. Optical rotation measurements were obtained
by using a PerkinElmer Model 341 polarimeter. High-
resolution mass spectra were recorded on a Bruker
Autoflex MALDI-TOF mass spectrometer, with 2,5-
dihydroxybenzoic acid or α-cyano-4-hydroxycinnamic
acid as matrix. Elemental analyses were carried out by a
HEKAtech Euro EA instrument using sulfanylamide as
standard. Preparative RP-HPLC was performed on an
aqueous system using a GROM-SIL 120 ODS-4HE; 10
mm; 250 × 20 mm (C-18 column); H2O and acetonitrile
were used as eluents.
N
N
Zn
N
5a-e
N
O
O
Y
Y
HO
OH
Scheme1. Synthesisof1,8(11),15(18),22(25)-tetraglycosylated
zinc(II) phthalocyanines. Reagents and conditions (i) K2CO3,
DMF, rt, 24 h (ii) TMSOTf, HMDS, DMF, Zn(OAc)2·2H2O,
115–120 °C, 15 h (iii) MeOH, DMSO, NaOMe, rt, 15 h
Syntheses of phthalonitriles 3a–3e
3-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-
phthalonitrile (3a). K2CO3 (5.80 g, 42 mmol) was added
to a mixture of 3-nitrophthalonitrile (1) (1.0 g, 5.78 mmol)
and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranose (2a) (2.44 g,
7 mmol) in dimethylformamide (DMF) (50 mL). The
reaction mixture was stirred at room temperature for 12 h.
After completion the reaction mixture was poured into
water. Precipitates formed were filtered, washed with
water, dried and purified by column chromatography on
silica gel using toluene/acetone (5:1) as eluent to afford
2.10 g of 3a in 77% yield. mp: 142–144 °C. [α]D20 + 13.9
1
(c 0.5, CHCl3). H NMR (400 MHz, CDCl3): δ, ppm
7.68–7.63 (m, 1H, HAr), 7.53–7.48 (m, 2H, HAr), 5.83
(d, J1,2 = 3.8 Hz, 1H, H-1), 5.66 (t, J 2,3 = J3,4 = 9.8 Hz,
1H, H-3), 5.17 (t, J4,3 = J4,5 = 9.8 Hz, 1H, H-4), 5.03 (dd,
J2,1 =3.8Hz, J2,3 =9.8Hz, 1H, H-2), 4.23(dd, J5,6a =4.6Hz,
Copyright © 2010 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2010; 14: 495–498

496
z. Iqbal et al.
J6a,6b = 12.2 Hz, 1H, H-6a), 4.16–4.12 (m, 1H, H-5), 4.10
(dd, J5,6b = 2.0 Hz, J6a,6b = 12.2 Hz, 1H, H-6b), 2.09 (s, 3H,
CH3), 2.02 (s, 9H, CH3). 13C NMR (100 MHz, CDCl3): δ,
ppm 170.7, 170.5, 170.0, 169.7 (4C, C=O), 159.1 (1C,
O-CAr), 135.1 (1C, H-CAr), 128.3 (1C, H-CAr), 121.2 (1C,
H-CAr), 117.7 (1C, H-CAr), 115.2 (1C, CN), 112.4 (1C,
NC-CAr), 107.6 (1C, NC-CAr), 96.9 (1C, C-1), 70.5 (1C,
C-2), 69.9 (1C, C-3), 69.6 (1C, C-5), 68.2 (1C, C-4),
61.7 (1C, C-6), 21.1, 21.0, 21.0, 20.9 (4C, CH3). HRMS
(FTICR): m/z 497.1169 (calcd. for [M + Na]+ 497.1166).
Anal. calcd. for C22H22N2O10: C 55.70, H 4.67, N 5.90%.
Found: C 55.34, H 4.94, N 5.80.
(1C, C-2′), 69.6 (1C, C-3′), 69.0 (1C, C-5), 68.4 (1C,
C-4′), 62.6 (1C, C-6), 61.9 (1C, C-6′), 21.8, 21.2, 21.2,
21.1, 21.0, 21.0, 20.9 (7C, CH3). HRMS (FTICR): m/z
785.2007 (calcd. for [M + Na]+ 785.2011). Anal. calcd.
for C34H38N2O18: C 53.54, H 5.02, N 3.67%. Found: C
53.48, H 5.14, N 3.75.
3-(2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyrano-
syl)-phthalonitrile (3d). Prepared from 2,3,4,6-tetra-O-
acetyl-1-thio-β-D-glucopyranose (2d, 2.54 g, 7 mmol)
and 3-nitrophthalonitrile (1, 1 g, 5.78 mmol) as described
for compound 3a. Column chromatography was carried
out by using toluene/acetone mixture (5:1) to afford 2.27
20
3-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-
phthalonitrile (3b). Prepared from 2,3,4,6-tetra-O-
acetyl-α-D-galactopyranose (2b, 2.44 g, 7 mmol) and
3-nitrophthalonitrile (1, 1 g, 5.78 mmol) as described for
compound 3a. Purification was carried out by column
chromatography using toluene/acetone mixture (5:1)
as eluent to afford 2.29 g product as white solid; yield
g of white solid; yield (80%). mp: 137–139 °C. [α]D
1
-3.0 (c 0.25, CHCl3). H NMR (400 MHz, CDCl3): δ,
ppm 8.05 (dd, J = 1.0 Hz, J = 8.1 Hz, 1H, HAr), 7.78
(dd, J = 1.0 Hz, J = 7.9 Hz, 1H, HAr), 7.68 (t, J = 1.0
Hz, J = 7.9 Hz, 1H, HAr), 5.22 (t, J3,4 = J3,2 = 9.4 Hz, 1H,
H-3), 4.99 (t, J4,3 = J4,5 = 9.4 Hz, 1H, H-4), 4.87 (t, J2,1
=
9.9 Hz, 1H, H-2), 4.786 (d, J1,2 = 9.9 Hz, 1H, H-1), 4.25
(dd, J6a,5 = 5.1 Hz, J6a,6b = 12.5 Hz, 1H, H-6a), 4.16 (dd,
J6b,5 = 2.3 Hz, J6b,6a = 12.5 Hz, 1H, H-6b), 3.78–3.72 (m,
1H, H-5), 2.11, 2.07, 2.00, 1.96 (4s, 4 × 3H, CH3). 13C
NMR (100 MHz, CDCl3): δ, ppm 170.8, 170.3, 169.7,
169.9, 169.8 (4C, C=O), 139.0 (1C, O-CAr), 138.1 (1C,
H-CAr), 133.5 (1C, H-CAr), 133.1 (1C, H-CAr), 121.1 (1C,
H-CAr), 117.9 (2C, CN), 115.3 (1C, NC-CAr), 114.1 (1C,
NC-CAr), 84.8 (1C, C-1), 76.7 (1C, C-2), 73.9 (1C, C-3),
69.6 (1C, C-4), 68.2 (1C, C-5), 62.2 (1C, C-6), 21.1 21.1,
20.9 (4C, CH3). HRMS (FTICR): m/z 513.0943 (calcd.
for [M + Na]+ 513.0938). Anal. calcd. for C22H22N2O9S:
C 53.87, H 4.52, N 5.71, S 6.54%. Found: C 53.83, H
4.65, N 5.69, S 6.47.
3-(2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyrano-
syl)-phthalonitrile (3e). Prepared from 2,3,4,6-tetra-O-
acetyl-1-thio-β-D-galactopyranose (1e, 2.54 g, 7 mmol)
and 3-nitrophthalonitrile (1, 1 g, 5.78 mmol) as described
for compound 3a. Purification was carried out by col-
umn chromatography using toluene/acetone (5:1) to pro-
duce 2.74 g of white solid; yield (97%). mp: 139–141 °C.
[α]D20 -0.23 (c 0.4, CHCl3). 1H NMR (400 MHz, CDCl3):
δ, ppm 8.09 (dd, J = 1.0 Hz, J = 7.9 Hz, 1H, HAr), 7.75 (dd,
J = 1.0 Hz, J = 7.9 Hz, 1H, HAr), 7.66 (t, J = 1.0 Hz, J =
7.9 Hz, 1H, HAr), 5.42 (d, J4,5 = 2.8 Hz, 1H, H-4), 5.15 (t,
20
(84%). mp: 192–194 °C. [α]D +14.7 (c 0.3, CHCl3).
1H NMR (400 MHz, CDCl3): δ, ppm 7.67–7.63 (m, 1H,
HAr), 7.55–7.48 (m, 2H, HAr), 5.88 (d, J1,2 = 3.8 Hz, 1H,
H-1), 5.58 (d, J4,5 = 2.8 Hz, 1H, H-4), 5.51 (dd, J3,4 = 3.3
Hz, J3,2 = 10.9 Hz, 1H, H-3), 5.27 (dd, J2,1 = 3.8 Hz, J2,3
= 10.9 Hz, 1H, H-2), 4.37 (t, J5,6a = J5,6b = 6.6 Hz, 1H,
H-5), 4.10 (d, J6,5 = 6.6 Hz, 2H, H-6), 2.15, 2.12, 2.01,
1.96 (4s, 4 × 3H, CH3). 13C NMR (100 MHz, CDCl3): δ,
ppm 170.4, 170.3, 170.2, 169.9 (4C, C=O), 159.4 (1C,
O-CAr), 135.1 (1C, H-CAr), 128.2 (1C, H-CAr), 121.3 (1C,
H-CAr), 117.7 (1C, H-CAr), 115.3 (1C, CN), 112.5 (1C,
NC-CAr), 107.6 (1C, NC-CAr), 97.6 (1C, C-1), 70.7 (2C,
C-2,3), 67.7 (2C, C-4,5), 61.7 (1C, C-6), 21.2, 21.0 (4C,
CH3). HRMS (FTICR): m/z 497.1170 (calcd. for [M +
Na]+ 497.1166). Anal. calcd. for C22H22N2O10: C 55.70, H
4.67, N 5.90%. Found: C 55.98, H 5.04, N 5.74.
3-(2,2′,3,3′,4′,6,6′-hepta-O-acetyl-α-D-maltose)-
phthalonitrile (3c). Prepared from 2,3,6,2′,3′,4′,6′-hepta-
O-acetyl-α-D-maltose (2c, 4.45 g, 7 mmol) and 3-ni-
trophthalonitrile (1, 1 g, 5.78 mmol) as described for
compound 3a. Purification was carried out by column
chromatography using toluene/acetone (4:1) mixture to
form 3.80 g white solid; yield (86%). mp: 188–190 °C.
[α]D20 + 12.2 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3):
δ, ppm 7.68–7.63 (m, 1H, HAr), 7.53–7.49 (m, 2H, HAr),
5.74–5.69 (m, 2H, H-1,1′), 5.42 (d, J = 4.1, 1H, H-2′),
5.35–5.26 (m, 1H, H-5′), 5.03 (t, J3,2 = J3,4 = 9.9 Hz, 1H,
H-3), 4.92 (dd, J2,3 = 9.9 Hz, J2,1 = 3.8 Hz, 1H, H-2), 4.85
(dd, J = 10.4 Hz, 1H, H-3′), 4.48 (dd, J = 2.6 Hz, J = 12.4
Hz, 1H, H-6b), 4.22 (dd, J = 3.6 Hz, J = 12.4 Hz, 2H,
H-6a′,b′), 4.14–3.94 (m, 4H, H6a, H-4, H-5), 2.08, 2.07,
2.06, 2.03, 2.01, 1.98, 1.97 (7s, 7 × 3H, CH3). 13C NMR
(100 MHz, CDCl3): δ, ppm 171.2, 171.0, 170.9, 170.5,
170.2, 169.8, 169.7 (7C, C=O), 159.1 (1C, O-CAr), 135.1
(1C, H-CAr), 128.6 (1C, H-CAr), 121.6 (1C, H-CAr), 117.7
(1C, H-CAr), 115.3 (1C, CN), 112.4 (1C, NC-CAr), 107.9
(1C, NC-CAr), 96.9 (1C, C-1′), 96.0 (1C, C-1), 72.7 (1C,
C-3), 71.9 (1C, C-5), 71.5 (1C, C-4), 70.6 (1C, C-2), 70.3
J2,1 = J2,3 = 9.9 Hz, 1H, H-2), 5.05 (dd, J3,4 = 3.3 Hz, J3,2
9.9 Hz, 1H, H-3), 4.78 (d, J1,2 = 9.9 Hz, 1H, H-1), 4.17 (dd,
J6a,5 = 6.9 Hz, J6a,6b = 11.4 Hz, 1H, H-6a), 4.10 (dd, J6b,5
=
=
6.1 Hz, J6b,6a = 11.4 Hz, 1H, H-6b), 3.96 (t, J5,6a = 6.9, 1H,
H-5), 2.11, 2.10, 2.02, 1.94 (4s, 4 × 3H, CH3). 13C NMR
(100 MHz, CDCl3): δ, ppm 170.8, 170.3, 170.2, 170.0,
(4C, C=O), 139.4 (1C, O-CAr), 138.1 (1C, H-CAr), 133.2
(1C, H-CAr), 132.9 (1C, H-CAr), 120.2 (1C, H-CAr), 117.8
(2C, CN), 115.4 (1C, NC-CAr), 114.1 (1C, NC-CAr), 85.7
(1C, C-1), 75.4 (1C, C-5), 72.0 (1C, C-3), 67.4 (1C, C-2),
66.7 (1C, C-4), 61.8 (1C, C-6), 21.1 21.1, 21.0, 20.9 (4C,
CH3). HRMS (FTICR): m/z 513.0941 (calcd. for [M + Na]+
513.0938). Anal. calcd. for C22H22N2O9S: C 53.87, H 4.52,
N 5.71, S 6.54%. Found: C 53.74, H 4.69, N 5.63, S 6.37.
Copyright © 2010 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2010; 14: 496–498

SyntheSIS Of 1,8(11),15(18),22(25)-tetraglyCOSylateD zInC(II) PhthalOCyanIneS
497
Syntheses of acetyl protected phthalocyanines 4a–4e
remove all DMSO. The crude product was dissolved in a
small amount of water and repeatedly recrystallized with
acetone.
A mixture of phthalonitrile (2 mmol), Zn(OAc)2·2H2O
(440 mg, 2 mmol), DMF (1.5 mL), hexamethyldisila-
zane (HMDS) (65 mg, 0.40 mmol) and TMSOTf (77 mg,
0.35 mmol) in a sealed glass tube was stirred and heated
at 115–120 °C overnight. The semi-solid obtained was
cooled and precipitated with methanol water (1:2) mix-
ture. The precipitates obtained were dried and purified
with column chromatography using ethyl acetate con-
taining 0–3% methanol.
1
5a. Yield: 96%. H NMR (400 MHz, DMSO-d6): δ,
ppm 9.51–9.48 (m, 4H, HAr), 8.19–8.06 (m, 8H, HAr),
6.22 (bs, 4H, H1), 5.90 (bs, 4H), 5.47 (bs, 4H), 5.28 (bs,
4H), 4.69–4.64 (m, 8H), 4.13 (bs, 4H), 3.82–3.74 (m,
8H), 3.64 (bs, 4H), 3.51–3.47 (m, 4H). UV-vis (DMSO):
λ
max, nm (log ε) 702 (5.09), 633 (4.42), 352 (4.47). HRMS
(MALDI-TOF): m/z 1289.287 (calcd. for C56H57N8O24Zn
[M + H]+ 1289.2777).
4a. Yield: 65%. 1H NMR (400 MHz, CDCl3): δ, ppm
8.08–7.91 (m, 4H, HAr), 7.67–7.48 (m, 8H, HAr), 5.84 (d,
J = 3.8 Hz, 4H, H-1), 5.65 (t, J = 9.6, 4H), 5.42–5.37 (m,
8H), 5.18–5.00 (m, 4H), 4.26–4.00 (m, 8H), 2.10–2.00
(m, 48H, CH3). UV-vis (DCM): λmax, nm (log ε) 691
(5.11), 623(4.40), 362(4.50). HRMS(MALDI-TOF):m/z
1960.436 (calcd. for C88H88N8O40Zn [M]+ 1960.4389).
4b. Yield: 47%. 1H NMR (400 MHz, CDCl3): δ, ppm
8.32–8.03 (m, 4H, HAr), 7.83–7.40 (m, 8H, HAr), 5.98–
5.85 (m, 4H, H-1), 5.68–5.23 (m, 8H), 5.15–4.97 (m,
2H), 4.59–4.49 (m, 2H), 4.40–4.26 (m, 2H), 4.20–3.99
1
5b. Yield: 95%. H NMR (400 MHz, DMSO-d6): δ,
ppm 9.44–9.42 (m, 4H, HAr), 8.17–8.08 (m, 8H, HAr),
6.27 (bs, 4H, H1), 5.04–4.74 (m, 12H), 4.50–4.35 (m,
6H), 4.28–4.09 (m, 10H), 3.81–3.54 (m, 16H). UV-vis
(DMSO): λmax, nm (log ε) 704 (5.17), 633 (4.48), 333
(4.55). HRMS (MALDI-TOF): m/z 1289.267 (calcd. for
C56H57N8O24Zn [M + H]+ 1289.2777).
1
5c. Yield: 91%. H NMR (400 MHz, DMSO-d6): δ,
ppm 9.51–9.25 (m, 4H, HAr), 8.18–8.03 (m, 8H, HAr), 6.28
(bs, 4H, H1), 5.26 (bs, 4H), 5.10–4.87 (m, 12H), 4.23 (bs,
8H), 3.93–3.71 (m, 16H). UV-vis (DMSO): λmax, nm (log
ε) 703 (5.03), 633 (4.29), 329 (4.41). HRMS (MALDI-
TOF): m/z 1937.482 (calcd. for C80H97N8O44Zn [M + H]+
1937.4890).
(m, 8H), 2.32–1.74 (m, 48H, CH3). UV-vis (DCM): λmax
,
nm (log ε) 689 (4.90), 622 (4.24), 362 (4.33). HRMS
(MALDI-TOF): m/z 1960.441 (calcd. for C88H88N8O40Zn
[M]+ 1960.4389).
1
5d. Yield: 94%. H NMR (400 MHz, DMSO-d6): δ,
4c. Yield: 29%. 1H NMR (400 MHz, CDCl3): δ, ppm
8.33–8.15 (m, 4H, HAr), 8.09–7.93 (m, 4H, HAr), 7.70–
7.42 (m, 4H, HAr), 6.72–6.49 (m, 4H), 5.61–5.19 (m,
6H), 5.11–4.75 (m, 6H), 4.36–3.79 (m, 12H), 2.22–1.86
(m, 48H, CH3). UV-vis (DCM): λmax, nm (log ε) 693
(4.92), 625 (4.14), 356 (4.27). HRMS (MALDI-TOF):
m/z 3115.808 (calcd. for C136H155N8O72Zn [M+3H]+
3115.8004).
ppm 9.33–9.27 (m, 4H, HAr), 8.27–8.12 (m, 8H, HAr),
5.47 (d, J = 10.2 Hz, 4H), 5.32 (bs, 4H), 5.15 (bs, 4H),
4.69 (bs, 4H), 3.85–3.74 (m, 6H), 3.70–3.61 (m, 6H),
3.52–3.40 (m, 16H). UV-vis (DMSO): λmax, nm (log ε)
710 (5.16), 639 (4.46), 336 (4.66), 260 (4.72). HRMS
(MALDI-TOF): m/z 1353.181 (calcd. for C56H56N8O20-
S4Zn [M + H]+ 1353.1863).
1
5e. Yield: 97%. H NMR (400 MHz, DMSO-d6): δ,
1
4d. Yield: 39%. H NMR (400 MHz, DMSO-d6): δ,
ppm 9.33–9.26 (m, 4H, HAr), 8.33–8.07 (m, 8H, HAr),
5.41 (d, J = 9.7 Hz, 4H), 5.27 (bs, 4H), 5.10 (bs, 4H),
4.80 (bs, 4H), 4.16–4.02 (m, 6H), 3.94–3.77 (m, 6H),
3.70–3.52 (m, 16H). UV-vis (DMSO): λmax, nm (log ε)
712 (5.15), 639 (4.42), 336 (4.63), 261 (4.72). HRMS
(MALDI-TOF): m/z 1353.187 (calcd. for C56H56N8O20-
S4Zn [M + H]+ 1353.1863).
ppm 9.35–9.05 (m, 4H, HAr), 8.09–7.96 (m, 8H), 5.70–
5.18 (m, 12H), 4.49–4.27 (m, 8H), 4.21–4.01 (m, 8H),
2.21–1.83 (m, 48H, CH3). UV-vis (DCM). λmax, nm (log
ε) 727 (4.73), 693 (5.09), 626 (4.47), 333 (4.65). HRMS
(MALDI-TOF): m/z 2024.348 (calcd. for C88H88N8O36-
S4Zn [M]+ 2024.3476).
4e. Yield: 32%. 1H NMR (400 MHz, CDCl3): δ, ppm
9.55–9.33 (m, 4H, HAr), 8.32–8.03 (m, 4H, HAr), 7.79–
7.51 (m, 4H, HAr), 5.75–5.50 (m, 8H), 5.30–4.96 (m, 6H),
4.47–4.20 (m, 12H), 4.09–4.00 (m, 2H), 2.22–1.91 (m,
48H, CH3). UV-vis (DCM): λmax, nm (log ε) 727 (4.97),
695 (5.17), 333 (4.67). HRMS (MALDI-TOF): m/z
2024.348 (calcd. for C88H88N8O36S4Zn [M]+ 2024.3476).
RESULTS AND DISCUSSION
The syntheses of the anomerically glycosylated phtha-
lonitriles 3a–3e (Scheme 1) were carried out by our previ-
ously described method [23] through nitrite displacement
in 3-nitrophthalonitrile (1) with anomerically deprotected
glycoses 2a–2e. The obtained phthalonitriles 3a–3e were
characterized with various analytical techniques, e.g.
NMR, HRMS and elemental analysis.
Syntheses of PcZns 4a–4e turned out to be difficult.
Many conventional methods were tried until we found
a successful route for the syntheses of Pcs 4a–4e. First
of all, phthalonitrile 3a was subjected to acetyl depro-
tection in sugar part by Zemplen’s method [24, 25].
The deprotected phthalonitrile 3a was then treated with
Syntheses of deprotected phthalocyanines 5a–5e
Acetylated phthalocyanines 4a–4e (400 mg) were
dissolved in 2:1 mixture of DMSO/MeOH (15 mL).
Catalytic amount of NaOMe was added and the reac-
tion mixture was stirred at room temperature overnight.
Precipitation of the unprotected phthalocyanine was car-
ried out by adding excess of acetone. Precipitates formed
were filtered and extensively washed with acetone to
Copyright © 2010 World Scientific Publishing Company
J. Porphyrins Phthalocyanines 2010; 14: 497–498

498
z. Iqbal et al.
Zn(OAc)2·2H2O in DMAE at various temperatures
ranging from 110–135 °C, which resulted only in tarry
material from decomposition of the starting material.
Changing solvent from DMAE to DMF did not improve
the method.
Now, instead of 3a, the thioglucosylated phthalonitrile
3d was used assuming a higher reactivity for tetrameriza-
tion. After deprotection of the acetyl groups in 3d under
Zemplen’s conditions [24, 25], followed by evaporation
of the solvent, the obtained compound was heated at
110 °C in DMF. The solution turned green after some
time, zinc acetate was added and the mixture was further
heated at the same temperature for 12 h. The cooled solu-
tion was poured in a small amount of water and recrys-
tallized from excess acetone to afford PcZn 5d in 27%
yield. However, this method only worked for the phtha-
lonitriles containing the thiosugars 3d and 3e.
In another attempt, phthalonitrile 3a was treated with
hexamethyldisilazane (HMDS), p-toluenesulfonic acid
(p-TsOH) and Zn(OAc)2·2H2O in DMF at 110–115 °C
overnight [21], leading to the conversion of the phtha-
lonitrile 3a into the corresponding PcZn 4a. However,
the yield was low. In order to improve the yield, p-TsOH
was replaced by trimethylsilyltriflate (TMSOTf), which
proved to be successful. Finally, all the individual phtha-
lonitriles 3a–3e were heated with HMDS, TMSOTf,
Zn(OAc)2·2H2O and DMF sealed in a glass tube, at
115–120 °C to form the corresponding PcZns 4a–4e in
good yield. Purification of the formed Pcs 4a–4e was
carried out by column chromatography to obtain the Pcs
4a–4e, which were further recrystallized from DCM and
hexane.
Deprotection of acetyl groups in Pcs 4a–4e was
accomplished by catalytic amount of NaOMe in metha-
nol/DMSO mixture at room temperature to form PcZns
5a–5e in good yields. Pcs 5a–5e were purified by repeated
recrystallization from water and acetone and further puri-
fied by reverse phase HPLC. Pcs 5a–5e are completely
water-soluble.
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Financial support of the Deutsche Forschungsgemein-
schaft (DFG) (ZI: 338/8-1) is highly acknowledged.
Z. Iqbal thanks the Higher Education Commission
(HEC) of Pakistan, for generous grant of scholarship for
doctoral studies.
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