Syntheses and properties of octa-, tetra-, and di-hydroxy-substituted phthalocyanines

Article abstract of DOI:10.1016/j.tet.2009.02.012

The synthesis and photophysical properties of a new series of zinc(II) phthalocyanines (ZnPcs) bearing multiple hydroxy and tert-butyl groups are reported. The X-ray structures of two phthalonitriles and one ZnPc are presented. All hydroxy-substituted ZnP

Full text of DOI:10.1016/j.tet.2009.02.012

Tetrahedron 65 (2009) 3357–3363
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Syntheses and properties of octa-, tetra-, and di-hydroxy-substituted
phthalocyanines
*
Hairong Li, Ngan Nguyen, Frank R. Fronczek, M. Graça H. Vicente
Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and photophysical properties of a new series of zinc(II) phthalocyanines (ZnPcs) bearing
multiple hydroxy and tert-butyl groups are reported. The X-ray structures of two phthalonitriles and one
ZnPc are presented. All hydroxy-substituted ZnPcs show low fluorescence quantum yields in DMSO and
complete fluorescence quenching in aqueous solutions, but high singlet oxygen quantum yields in DMSO
(0.2–0.7). Our results suggest that the tetra- and octa-hydroxy ZnPcs might find application as photo-
sensitizers in the PDT treatment of cancer.
Received 19 December 2008
Received in revised form 30 January 2009
Accepted 4 February 2009
Available online 11 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
phosphonates,10 carboranyls,11 and tert-butyl12 groups have been
introduced at either the Pc periphery or as axial ligands on metallo-
Phthalocyanines (Pcs) are promising photosensitizers for ap-
plication in the photodynamic therapy (PDT) of cancers,1,2 and
a few Pc derivatives are currently undergoing clinical evaluations.
PDT is a binary treatment modality that involves the activation of
a tumor-localized photosensitizer with red light.3,4 The electroni-
cally excited photosensitizer in the triplet state (formed via in-
tersystem crossing from a short-lived excited singlet state) reacts
with triplet molecular oxygen to generate in situ singlet oxygen, as
well as other cytotoxic reactive oxygen species (ROS), that destroy
malignant tissues. PDT has several advantages over other cancer
treatments, including its minimal invasiveness and highly tumor-
localized nature upon careful light delivery and availability of
tumor-specific photosensitizers. One porphyrin derivative, Photo-
frinÒ, is FDA-approved for the PDT treatment of melanoma, early
and advanced stage cancer of the lung, digestive tract, genitouri-
nary tract, and Barret’s esophagus. However this drug absorbs only
weakly in the red region of the optical spectrum where light
penetrates deepest into human tissues, and therefore has limited
application in the treatment of large and/or deep-seated tumors.
Since Pcs have characteristic intense absorptions in the red region
of the optical spectrum (ca. 700 nm), high photochemical stability,
and are effective generators of singlet oxygen, they have been found
to be highly promising PDT photosensitizers.2,5 However, their
well-known tendency for aggregation, mainly in aqueous media,
and subsequent reduction of their photosensitizing ability has
limited their application in PDT.6 Water-solubilizing and
bulky groups, such as carboxylates,7 pyridyls,8 sulfonates,9
Pcs as a means to minimize Pc aggregation. In particular bulky
substituents (such as tert-butyl groups) and neutral water-solubi-
lizing groups (such as hydroxy and PEG) at the photosensitizer
periphery can potentially increase the amphiphilicity and perme-
ability across cellular membranes of Pcs, while decreasing macro-
cycle aggregation. Our group12,13 and others14 have reported the
synthesis and properties of PEG-substituted porphyrins and Pcs,
and discovered that multiple PEG groups at the macrocycle
periphery can in fact induce aggregation and/or singlet oxygen
inactivation. On the other hand multi-hydroxy-substituted
macrocycles based on porphyrin,15,16 chlorin,17,18 pheophorbide,19
and Pc20,21 have been reported and shown to be promising pho-
tosensitizers for PDT. One such compound, meso-tetra-hydroxy-
phenylchlorin (mTHPC) known as Foscan, is currently undergoing
clinical investigations for application in PDT.22 Herein we report the
synthesis and photophysical properties of a new series of hydroxy-
substituted ZnPcs, bearing either two, four or eight hydroxy groups,
as well as bulky tert-butyl groups.
2. Results and discussion
Three different strategies were employed for the synthesis of
octa-, tetra-, and di-hydroxy Pcs, as pure compounds, as shown in
Schemes 1–3, respectively. The key precursor to the di- and octa-
hydroxy-substituted Pcs, 4,5-di(2,5-di-tert-butyl-4-methoxy)ph-
thalonitrile 1, was prepared in 77% yield from commercially
available 4,5-dichlorophthalonitrile and 2,5-di-tert-butyl-4-
methoxyphenol in the presence of potassium carbonate.23 Two
different methods were investigated for the macrocyclization re-
action of phthalonitrile 1. The first method involved the reaction of
* Corresponding author. Tel.: þ1 225 578 7405; fax: þ1 225 578 3458.
E-mail address: vicente@lsu.edu (M.G.H. Vicente).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.012

3358
H. Li et al. / Tetrahedron 65 (2009) 3357–3363
1 and anhydrous zinc acetate in dry NMP as a solvent at 150 ꢀC for 1
day,23,24 and afforded Zn-Pc 4 in only 9% yield after chromato-
graphic purification. In the second method, precursor 1 was treated
with lithium metal in dry pentanol followed by zinc acetate to
afford the octamethoxy-substituted Zn-Pc 4 in 31% yield. The
metal-free Pc 3 was subsequently isolated in 30% yield upon
treatment of Zn-Pc 4 with acetic acid. The molecular structure of
Zn-Pc 4 is shown in Figure 1. The structure contains two in-
dependent molecules, both lying on inversion centers. Only one of
them is shown in the figure. Since the coordination of the Zn atom
in each molecule is square pyramidal, with Zn lying slightly (0.28(2)
and 0.43(2) Å) out of the plane of the four coordinated basal N
atoms, the Zn atoms are disordered into half-populated sites. In
one of the two independent Zn complexes, the apical ligand is
coordinated solvent methanol. In the other, the apical position
appears to be water, but since this site is disordered, sharing a site
with solvent dichloromethane, that is uncertain. In both Zn com-
plexes, the 24-atom Pc core is reasonably planar, with mean
deviations being 0.06 and 0.03 Å.
The tetra-hydroxy Zn-Pc 7 was synthesized and isolated as the
pure C4h isomer, as indicated in Scheme 2. The precursor 3-(2,5-di-
tert-butyl-4-hydroxyphenoxy)phthalonitrile 6 was prepared in 38%
yield by reacting 3-nitrophthalonitrile with 2,5-di-tert-butyl-hy-
droquinone. A side product isolated from this reaction, in 46% yield,
was the corresponding diphthalonitrile species, which might be
a valuable precursor in the preparation of Pc dimers. The X-ray
structure of phthalonitrile 6 is shown in Figure 2, and that of the
diphthalonitrile is shown in Figure 3. In 6, the CN distances are
1.144(2) and 1.146(2) Å, and the two six-membered rings form
a dihedral angle of 71.23(4)ꢀ. The conformations of the tert-butyl
groups are such that the methyl group anti to the oxygen sub-
stituent is eclipsed with the phenyl plane (C–C–C–C torsion angle
OH
OH
OH
NO2
O
K2CO3, DMF
NC
CN
NC
CN
6
1. Li, octanol, 70 °C
2. Zn(OAc)2
HO
OH
O
O
N
N
N
Zn
N
N
N
N
N
O
O
HO
7
OH
Scheme 2. Synthesis of tetra-hydroxy-Zn-Pc 7.
RO
OR
OH
OR
O
O
NC
NC
O
O
Cl
Cl
CN
CN
OR
1. 1 or 2 , n-pentanol
DBU, 140 °C
K2CO3, DMF
N
N
N
M
N
CN
CN
N
N
2. Li, ZnBr2, DCM/DMF, 40 °C
3. NaSEt, DMF, 135 °C
1: R = CH3
2: R = H
OR
N
N
RO
OR
1. Li, Zn(OAc)2, 140 °C
2. NaSEt, DMF, 135 °C
8: M = 2H, R = CH3
9: M = Zn, R = CH3
10: M = Zn, R = H
O
O
Scheme 3. Synthesis of di-hydroxy-Pc 10.
RO
RO
OR
magnitudes 0.5(2) and 1.1(2)ꢀ). In the two independent, centro-
symmetric molecules of the diphthalonitrile, the CN distances are
in the range 1.143(2)–1.148(2) Å. The dihedral angle formed by the
central phenyl ring and each phthalonitrile plane is 64.25(3)ꢀ in
one molecule and 59.87(3)ꢀ in the other. The tert-butyl conforma-
tions are quite similar to those in 6, with relevant torsion angle
magnitudes 0.9(2) and 9.6(2)ꢀ.
N
N
N
M
N
O
O
O
O
N
N
N
N
OR
Several reagents were investigated for the demethylation of
O
O
Pc 4, including boron tribromide,25,26 boron tribromide dime-
3: M = 2H, R = CH3
4: M = Zn, R = CH3
5: M = Zn, R = H
thylsulfide
complex,27
pyridine
hydrochloride,28
iodo-
trimethylsilane (TMSI),29,30 and sodium ethanethiolate.31,32 In the
presence of BBr3 at ꢁ78 ꢀC for 24 h, one, two or three of the
tert-butyl groups of Pc 4 were also cleaved, as was indicated by
MALDI-TOF mass spectrometry, and only 1% of Pc 5 was isolated
RO
OR
Scheme 1. Synthesis of octa-hydroxy-Pc 5.

H. Li et al. / Tetrahedron 65 (2009) 3357–3363
3359
The macrocyclization of phthalonitrile 6 under the same con-
ditions as 1 and 2 led to the expected mixture of four possible ZnPc
isomers that were difficult to separate.33,34 Using optimized re-
action conditions (vide infra) the major C4h isomer 7 was isolated in
15% yield. The formation of the C4h over the C2v, Cs and D2h struc-
tural isomers was favored by a low reaction temperature (70 ꢀC
rather than 150 ꢀC normally used in this type of macrocyclization),
a longer reaction time (3 days rather than 1 day) and the presence
of the bulky tert-butyl group at the
a position of phthalonitrile 6, as
previously observed.35,36
The pure A3B-type Pc 8 was synthesized from condensation of 1
with a 40-fold excess of phthalonitrile in dry pentanol, using DBU
as the catalyst, as shown in Scheme 3. We have previously shown
that using such a large excess of phthalonitrile minimizes the
formation of the A2B2-type Pc products.11 Under these conditions
only the A3B-type Pc 8 and the unsubstituted A4-type Pc were
obtained, as indicated by MALDI-TOF mass spectrometry of the
crude reaction mixture. Since the unsubstituted A4-type Pc is highly
insoluble, it is conveniently removed by filtration, thus greatly
simplifying the purification process. The A3B-type Pc 8 was isolated
in 12% yield, after chromatographic purification. The metalation of
Pc 8 using zinc(II) dibromide in dry DMF did not afford Pc 9, due to
the poor solubility of the free-base in DMF. However, at reflux in
dichloromethane for 2 h and in the presence of zinc(II) dibromide,
the ZnPc 9 was obtained in quantitative yield. The deprotection of
the methoxy groups of Pc 9 using sodium ethanethiolate under our
above optimized conditions produced a mixture of metalated and
unmetalated di-hydroxy Pcs. Re-metalation of the soluble di-hy-
droxy Pcs with zinc(II) dibromide in dry DMF gave the target ZnPc
10 in 10% overall yield. ZnPc 10 was also obtained via condensation
of 2 with a 40-fold excess of phthalonitrile in the presence of
a catalytic amount of DBU, at 140 ꢀC in dry pentanol. The free-base
Pc was identified by MALDI-TOF mass spectrometry (m/z 954.90),
and upon metalation using zinc(II) dibromide in DMF at 40 ꢀC
afforded ZnPc 10 in 6% overall yield.
Figure 1. One of the two independent, centrosymmetric molecules of ZnPc 4. Only one
of the disordered Zn positions is shown, and H atoms are omitted.
Figure 2. Molecular structure of phthalonitrile 6.
The structures of all Pcs were confirmed by UV–vis, MS, and 1H
NMR spectroscopy. While the octa- and tetra-hydroxy Pcs 5 and 7
are highly soluble in polar organic solvents, such as dichloro-
methane, THF, acetone, methanol, acetonitrile, DMF, and DMSO, the
di-hydroxy-Pc 10 is less soluble and has higher tendency for ag-
gregation, even in polar organic solvents such as dichloromethane
and methanol (vide infra). In the mass spectrum (ESI) of Pc 5 the
molecular ion was observed at m/z 2338.2421 ([MþH]þ) and the
double-negative molecular ion at m/z 1168.6159 ([Mꢁ2H]2ꢁ),
according to its assigned structure. Similarly for Pcs 7 and 10 the
molecular ions were observed at m/z 1459.6721 ([MþH]þ) and m/z
1016 ([MþH]þ) on their mass spectra (ESI), respectively.
Figure 3. Molecular structure of diphthalonitrile showing only one of the two in-
dependent molecules.
after chromatographic purification. When the dimethylsulfide
complex BBr3$SMe2 was used under similar conditions no Pc 5 was
formed even after 2 days, as indicated by MALDI-TOF mass spec-
trometry. The same result was observed when pyridine hydro-
chloride or iodotrimethylsilane was used. However, an excess of
sodium ethanethiolate in dry DMF under argon at 135 ꢀC for 1 day
afforded Pc 5 in 25% yield (5% overall from the commercially
available 4,5-dichlorophthalonitrile). The reaction was followed by
MALDI-TOF mass spectrometry and partial cleavage of the di(tert-
butyl)phenoxy groups was also observed to occur under these
conditions, leading to the low yield. Pc 5 can also be synthesized
directly by cyclotetramerization of the di-hydroxy-substituted
phthalonitrile 2 in the presence of lithium metal in dry pentanol,
followed by zinc acetate in 9% overall yield (2% from 4,5-dichloro-
phthalonitrile). Phthalonitrile 2 was obtained in 27% yield from
reaction of 2,5-di-tert-butyl-hydroquinone with 4,5-dichloroph-
thalonitrile. Although the overall yield for Pc 5 using the latter
synthetic strategy is lower, this methodology involves only two
rather than three steps and therefore can be completed within
a shorter time period.
The 1H NMR spectrum of Pc 5 in deuterated acetone shows three
sharp downfield signals at 8.8 ppm (singlet), 7.06 ppm (doublet),
and 7.03 ppm (doublet), due to, respectively, the Pc backbone and
the phenoxy protons at the macrocycle periphery. The OH protons
gave a broad signal at 8.1 ppm, while the two types of tert-butyl
protons appeared upfield at 1.5 and 1.3 ppm, according to the
assigned structure. On the other hand, the 1H NMR spectrum for Pc
7 of C4h symmetry is in agreement with previously reported values
for C4h Pcs,37,38 with the phenoxy protons appearing between 7.2
and 7.3 ppm. In addition, as seen in Figure 4, the OH protons of Pc 7
appear at 8.4 ppm, as indicated by the disappearance of this signal
upon addition of one drop of D2O to the NMR solution. The
presence of D2O also caused a more clear slitting (triplet) of the
hydrogen at the
g position of the Pc backbone, which suggests that
in acetone solution intermolecular hydrogen bonding occurs
between the OH groups of different Pc molecules. Such in-
termolecular hydrogen bonding has been previously observed in
the case of a hydroxy-substituted porphyrin.39 The 1H NMR spec-
trum of Pc 10 in deuterated DMF shows the aromatic signals

3360
H. Li et al. / Tetrahedron 65 (2009) 3357–3363
Table 1
Spectral properties of ZnPcs 5, 7, and 10 in DMSO at room temperature
c
Pc Absorption lmax (nm) Emissiona lmax (nm) Ffb
Stokes’ shift (nm) FD
5
7
686, 618
710, 638
689
713
679
0.004
0.003
0.20
3
3
3
0.692
0.693
0.201
10 676, 609
a
Excitation at 620 nm.
Calculated using ZnPc as the standard.
Determined using ZnPc as reference and DPBF as scavenger.
b
c
presence of at least two types of Pc aggregates in aqueous solution.
Fluorescence quenching was observed for all Pcs in aqueous solu-
tion, as a result of Pc aggregation.
Figure 4. 1H NMR spectra of ZnPc 7 (aromatic region only) in (a) acetone-d6 and in (b)
acetone-d6 with one drop of D2O.
3. Conclusions
downfield at about 7 ppm and aliphatic protons around 3 ppm. The
Pc macrocycle protons on the three identical isoindole subunits
appear in the downfield region between 8.13 and 9.61 ppm along
with two kinds of substituted phenyl ring protons at 7.32 (singlet)
and 7.28 (singlet) ppm, respectively.
The total syntheses of an octa-, a tetra-, and a di-hydroxy-
substituted ZnPcs as pure compounds, using different strategies are
reported. NMR and spectrophotometric data suggest that these
hydroxy-substituted Pcs may undergo intermolecular hydrogen
bonding in polar organic solvents, such as DMSO and acetone. The
octa- and tetra-hydroxy Pcs have very low fluorescence quantum
yields in DMSO (w0.003) and complete fluorescence quenching in
aqueous solution; however they were found to have high singlet
oxygen quantum yields w0.7 in DMSO. On the other hand, the
di-hydroxy-Pc shows moderate (w0.2) quantum yields in DMSO
and similar fluorescence quenching in aqueous solution. Our results
suggest that hydroxy-substituted Pcs, in particular tetra and octa-
hydroxy Pcs, may have application as photosensitizers in the PDT
treatment of cancer, and are worthy of further biological
investigation.
The absorption spectra of the octa-, tetra-, and di-hydroxy-Pcs 5,
7, and 10 in acetone show characteristic strong and sharp Q bands
with 3
>105 L molꢁ1 cmꢁ1, as shown in Figure 5. As expected, the
lmax for the Q bands of Pcs 5, 7, and 10 were found to be 679, 698
and 668 nm, respectively. The significant red-shift observed in the
case of Pc 7 is due to its substitution at the a (rather than b) position
of the macrocycle, as we have previously observed.40
Table 1 summarizes the spectral properties observed for Pcs 5, 7,
and 10 in DMSO. All Pcs showed similar Stokes’ shifts in DMSO and
other polar organic solvents (w3 nm), and 7–12 nm red-shifted Q
bands in DMSO compared with other solvents, e.g., acetone. In-
terestingly, the fluorescence quantum yields of Pcs 5 and 7 were
almost two orders of magnitude lower than that found for Pc 10 and
other neutral Pcs,8 maybe as a result of intermolecular hydrogen
bonding and assembly of these hydroxy Pcs, as has been previously
observed in the case of mTHPC photoproducts.41 On the other hand,
Pcs 5 and 7 showed significantly higher singlet oxygen quantum
yields (of the order of 0.7) than the di-hydroxy-Pc 10 (of the order
of 0.2) and other previously reported positively charged Pcs.8 In
phosphate buffer at pH 7.4, all Pcs showed significantly less intense
Q band absorptions, broadened and red-shifted by 3–12 nm as
shown in Figure 5, indicating aggregation. In addition, Pc 10 shows
a split absorption with lmax at 628 and 680 nm, suggesting the
4. Experimental
4.1. Syntheses
Silica gel 60 (230ꢂ400 mesh, Sorbent Technologies) and
alumina gel (50–200
mm, neutral, standard activity _, Sorbent
Technologies) were used for column chromatography. Analytical
thin-layer chromatography (TLC) was carried out using polyester
backed TLC plates 254 (precoated, 200
mm) from Sorbent Tech-
nologies. Prep alumina and silica TLC plates (w/UV 254, 1000
mm)
were purchased from Sorbent Technologies Inc. All chemicals were
purchased from commercial sources and used directly without
further purification. NMR spectra were recorded on a DPX-250,
ARX-300 or AV-400 Bruker spectrometers (250 MHz, 300 MHz or
400 MHz for 1H, 63 MHz, 75 MHz or 100 MHz for 13C). The chemical
shifts are reported in d ppm using the following deuterated solvents
as internal references: CD2Cl2 5.32 ppm (1H), 54.00 ppm (13C);
CDCl3 7.24 ppm (1H), 77.23 ppm (13C); CD3OD 4.87 ppm (1H);
CD3COCD3 2.04 ppm (1H), 29.92 ppm (13C); DMF-d 2.92 ppm (1H),
34.89 ppm
(
13C); THF-d 3.58 ppm (1H). Electronic absorption
spectra were measured on a Perkin–Elmer Lambda 35 UV–vis
spectrometer. High-resolution ESI mass spectra were obtained on
an Agilent Technologies 6210 Time-of-Flight LC/MS. HPLC separa-
tion and analyses were carried out on a Dionex system equipped
with a P680 pump and a UVD340U detector. Semi-preparative
column was Luna C18 100 Å, 5
USA. Analytical HPLC was carried out on a Delta Pak C18 300 Å,
m, 3.9ꢂ150 mm (Waters, USA) column; flow rate 1.0 mL/min;
injected volume 20 L; wavelength detection 350 nm; solvent
mm, 10ꢂ250 mm from Phenomenex,
5
m
m
methanol. The singlet oxygen quantum yields, determined with an
accuracy of w10%, were obtained in DMSO at room temperature,
using ZnPc (FD¼0.67) as reference and 1,3-diphenylisobenzofuran
Figure 5. Absorption spectra of ZnPcs 5 (dashed line), 7 (dotted line), and 10 (solid
line) at 8
mM solution in acetone (black) and buffer pH¼7.4 (red).

H. Li et al. / Tetrahedron 65 (2009) 3357–3363
3361
(DPBF) as scavenger, according to a procedure previously de-
scribed.8,42 The DPBF absorption decay was followed at 417 nm.
the filtrate was colorless. The product was dried under vacuum at
70 ꢀC to afford a green solid (0.15 g, 30%). 1H NMR (CD2Cl2,
300 MHz): d 8.90 (s, 8H, Ar-H), 7.09 (s, 8H, Ar-H), 7.07 (s, 8H, Ar-H),
4.1.1. 4,5-Bis(2,5-di-tert-butyl-4-methoxyphenoxy)phthalo-
nitrile (1)
3.97 (s, 24H, OCH3), 1.52 (s, 72H, C(CH3)3), 1.27 (s, 72H, C(CH3)3),
ꢁ0.35 (s, 2H, NH). 13C NMR (CD2Cl2, 75 MHz):
d 154.7, 152.2, 149.3,
4,5-Dichlorophthalonitrile (1 g, 5 mmol) and 2,5-di-tert-butyl-
4-methoxyphenol (4 g, 16.4 mmol) were dissolved in 30 mL of dry
DMF at 95 ꢀC under argon. Potassium carbonate (4.5 g, 32.8 mmol)
was added to the reaction solution in 8 portions every 5 min. After
1 day, another portion (2 g, 14.5 mmol) of 2,5-di-tert-butyl-4-
methoxyphenol was added to the reaction mixture. The reaction
was followed by 1H NMR until complete disappearance of mono-
chloro-substituted phthalonitrile. After 24 h, the reaction mixture
was cooled to room temperature and poured into 250 mL of ice
water. After filtration under vacuum, the crude product was
purified by silica gel column chromatography using hexane/
dichloromethane 4:1 for elution. The title compound was obtained
138.7, 137.6, 132.8, 118.3, 113.4, 111.9 (Ar-C), 56.0 (OCH3), 35.1, 34.8,
30.4, 29.9 (C(CH3)3). MS (MALDI-TOF) m/z 2388.37 [M]þ, calcd for
C152H194N8O16 2388.46.
4.1.4. Octamethoxy-Zn-Pc (4)
Method I. Phthalonitrile 1 (0.26 g, 0.4 mmol) and anhydrous zinc
acetate (73 mg, 0.4 mmol) were dissolved in dry NMP (5 mL). The
solution was heated to 150 ꢀC under argon for 1 day. The solid was
collected by filtration and purified by column chromatography on
silica gel using hexane/dichloromethane 2:1 for elution, affording
Pc 4 in 9% yield. Method II. Phthalonitrile 1 (0.38 g, 0.64 mmol) was
dissolved in 3 mL of dry pentanol at 135 ꢀC under argon. Lithium
(0.1 g, 14 mmol) was carefully added in small pieces to the reaction
solution. After 2 min, the reaction solution turned green. After 3 h,
anhydrous zinc acetate (400 mg) was added and the solution was
refluxed for another 3 h. The solvent was removed under reduced
pressure. The dry residue was washed three times with methanol/
H2O (1:1) and extracted with hexane (100 mL). The crude product
was purified by column chromatography on silica gel using hexane/
dichloromethane (2:1) for elution to afford a green solid (0.12 g,
as a white solid (2.3 g, 77%). 1H NMR (CD2Cl2, 300 MHz):
d 7.18
(s, 2H, Ar-H), 7.04 (s, 2H, Ar-H), 6.95 (s, 2H, Ar-H), 3.95 (s, 6H, OCH3),
1.42 (s, 18H, C(CH3)3), 1.40 (s, 18H, C(CH3)3). 13C NMR (CD2Cl2,
75 MHz): d 156.3, 153.3, 145.6, 140.4, 138.6, 120.9, 120.6, 116.0, 111.8,
109.7 (Ar-C, CN), 55.8 (OCH3), 35.1, 35.0, 30.6, 29.9 (C(CH3)3). LRMS
(MALDI-TOF) m/z 596.87 [M]þ, calcd for [C38H48N2O4]þ 596.36.
HRMS-MALDI m/z 619.3491 [MþNa]þ, calcd for [C38H48N2O4Na]þ
619.3512.
31%). 1H NMR (CD2Cl2, 300 MHz):
Ar-H), 7.05 (s, 8H, Ar-H), 3.95 (s, 24H, OCH3), 1.50 (s, 72H, C(CH3)3),
1.25 (s, 72H, C(CH3)3). 13C NMR (CD2Cl2, 75 MHz):
154.5, 153.4,
d 8.89 (s, 8H, Ar-H), 7.06 (s, 8H,
4.1.2. 4,5-Bis(2,5-di-tert-butyl-4-hydroxyphenoxy)phthalo-
nitrile (2)
d
2,5-Di-tert-butyl-hydroquinone (2.3 g, 10.3 mmol) and potas-
sium carbonate (0.7 g, 5.1 mmol) were dissolved in DMF (30 mL).
The solution was heated to 50 ꢀC under argon. 4,5-Dichloroph-
thalonitrile (0.5 g, 2.6 mmol) was dissolved in DMF (10 mL) and
added dropwise over a period of 30 min to the reaction mixture.
The final mixture was heated at 100 ꢀC for three days. The solution
was cooled to room temperature and concentrated under vacuum
to a volume of 10 mL. The residue was poured into ice water
(100 mL) and acidified upon dropwise addition of 1 N HCl solution,
until pH¼5. The precipitate was collected by filtration and further
purified by column chromatography on silica gel using hexane/
dichloromethane 1:1 and methanol/dichloromethane 2:98 for
elution. The title compound was obtained as a white solid (0.4 g,
151.6,149.5,138.6,137.4, 134.4, 118.1,113.4,111.9 (Ar-C), 56.0 (OCH3),
35.1, 34.8, 30.3, 29.8 (C(CH3)3). MS (MALDI-TOF) m/z 2451.80 [M]þ,
calcd for C152H192N8O16Zn 2451.38.
4.1.5. Octa-hydroxy-Zn-Pc (5)
Method I. Pc 4 (60 mg, 0.024 mmol) and sodium ethanethiolate
(900 mg, 9.6 mmol) were dissolved in dry DMF (35 mL). The so-
lution was refluxed at 135 ꢀC for 24 h under argon and the reaction
followed by MALDI-TOF mass spectroscopy. The solution was
poured into 150 mL of water and the product was extracted with
ethyl acetate (50 mLꢂ3) and dried over anhydrous sodium sulfate.
The crude product was purified by Sephadex LH-20 eluting with
methanol. After purification by HPLC with methanol as the mobile
phase, a green solid was obtained (15 mg, 25%). Method II. Phtha-
lonitrile 2 (0.08 g, 0.14 mmol) was dissolved in pentanol (3 mL) in
a 25 mL three-necked flask. The solution was heated at 135 ꢀC
under argon. Lithium (30 mg, 4.3 mmol) was added in small por-
tions and the mixture was heated for another 10 h. The solution
was cooled to room temperature, zinc(II) acetate (0.1 g, 0.55 mmol)
was added, and the final mixture refluxed at 135 ꢀC for 2 h. The
solvent was evaporated under vacuum and the residue was tritu-
rated in 100 mL of water. The suspension was kept in the re-
frigerator for 3 h, then filtered under vacuum, and the green solid
washed with water. The crude product was purified by column
chromatography on alumina using methanol/dichloromethane
2:98 for elution. The final product was purified by HPLC using
methanol as the mobile phase to afford a green solid (8 mg, 9%). 1H
27%). 1H NMR (CD2Cl2, 400 MHz):
Ar-H), 6.79 (s, 2H, Ar-H), 5.01 (s, 2H, OH), 1.37 (s, 18H, C(CH3)3), 1.31
(s, 18H, C(CH3)3). 1H NMR (acetone-d, 400 MHz):
8.66 (s, 2H, OH),
7.27 (s, 2H, Ar-H), 6.99 (s, 2H, Ar-H), 6.85 (s, 2H, Ar-H), 1.34 (s, 18H,
C(CH3)3), 1.31 (s, 18H, C(CH3)3). 13C NMR (CD2Cl2, 100 MHz):
153.0,
d 7.09 (s, 2H, Ar-H), 6.84 (s, 2H,
d
d
144.8, 139.7, 135.4, 120.8, 120.1, 115.5, 115.4, 109.1 (Ar-C, CN), 34.2,
34.0, 29.9, 28.9 (C(CH3)3). HRMS-ESI: m/z 567.3219 [MꢁH]ꢁ,
568.3245 [M]ꢁ, 1135.6526 [2MꢁH]ꢁ, calcd for [C36H43N2O4]ꢁ
567.3228, [C36H44N2O4]ꢁ 568.3261, [C72H87N4O8]ꢁ 1135.6524. FTIR
(solid): 3463.7 (br, OH), 2236.0 (CN) cmꢁ1
.
4.1.3. Octamethoxy-Pc (3)
Phthalonitrile 1 (0.5 g, 0.84 mmol) was placed in a 25 mL three-
necked flask and the flask was evacuated and filled with argon
three times. Pentanol (5 mL) was added via syringe and the solution
was heated to 120 ꢀC. Lithium (0.048 g, 6.8 mmol) was added and
the final reaction mixture was heated to 120 ꢀC for 17 h. The mix-
ture was cooled to room temperature, acetic acid (15 mL) was
added, and the mixture stirred for 30 min. The mixture was poured
into 200 mL of ice-cold water/methanol 10:1. This mixture was
stirred vigorously for 1 h. The precipitate was collected by filtration
and re-dissolved in 100 mL of hexane. The impurities were
removed by filtration and the solution was dried over anhydrous
sodium sulfate overnight. The solvent was evaporated under
vacuum and the resulting residue was washed with methanol until
NMR (acetone-d, 250 MHz):
7.06 (s, Ar-H, 8H), 7.03 (s, Ar-H, 8H), 1.46 (s, 9H, C(CH3)3), 1.31 (s, 9H,
C(CH3)3). 13C NMR (methanol-d, 63 MHz):
154.5, 153.0, 152.8,
d 8.82 (s, 8H, Ar-H), 8.09 (br, 8H, OH),
d
149.5, 139.9, 135.9, 134.6, 119.6, 116.4, 113.2 (Ar-C), 35.4, 35.3, 31.0,
30.1 (C(CH3)3). MS (MALDI-TOF) m/z 2338.71 [M]þ, calcd for
C144H176N8O16Zn 2339.25. HRMS-ESI: m/z 1168.6159 [Mꢁ2H]2ꢁ
,
calcd for [C144H174N8O16Zn]2ꢁ 1168.6194. tR¼11.227 min (MeOH).
HRMS-ESI: m/z 2338.2421 [MꢁH]ꢁ, 1168.6159 [Mꢁ2H]2ꢁ, calcd for
[C144H175N8O16Zn]ꢁ 2338.2455, [C144H174N8O16Zn]2ꢁ 1168.6194.
tR¼11.227 min (MeOH). UV–vis (acetone): lmax (log
3) 678.8 (5.3),
612.0 (4.5) nm.

3362
H. Li et al. / Tetrahedron 65 (2009) 3357–3363
4.1.6. 3-(2,5-Di-tert-butyl-4-hydroxyphenoxy)phthalonitrile (6)
2,5-Di-tert-butyl-hydroquinone (3.2 g, 14 mmol) was dissolved
in DMF (100 mL) under nitrogen. Potassium carbonate (2 g,
14 mmol) was added to the solution in five portions. The mixture
was heated to 50 ꢀC. 3-Nitrophthalonitrile (2 g, 11 mmol) was dis-
solved in DMF (40 mL) and added dropwise during a 30 min period
to the reaction mixture. The temperature was raised to 100 ꢀC and
kept for 20 h. After cooling to room temperature, the mixture was
concentrated to 20 mL and poured into water (100 mL). The pre-
cipitate was separated by filtration and the solution was evaporated
to dryness and further purified by column chromatography on silica
gel using methanol/dichloromethane 2:98 for elution. The title
compound was obtained as a light yellow solid (1.5 g, 38%). 1H NMR
remove excess salt. The residue was purified by column chroma-
tography on silica gel using dichloromethane/THF 20:1 for elution.
The title Pc was obtained as a bluish green solid (0.067 g, 96%). 1H
NMR (THF-d, 250 MHz):
d 9.32–9.27 (m, 4H, Ar-H), 9.22–9.19
(m, 2H, Ar-H), 9.04 (s, 2H, Ar-H), 8.11–8.08 (m, 4H, Ar-H), 8.05–8.02
(m, 2H, Ar-H), 7.31 (s, 2H, Ar-H), 7.17 (s, 2H, Ar-H), 4.01 (m, 6H,
Ar-H), 1.61 (s, 18H, C(CH3)3), 1.38 (s, 18H, C(CH3)3). MS (MALDI-TOF)
m/z 1044.84 [M]þ, calcd for C62H60N8O4Zn 1044.40.
4.1.10. Di-hydroxy-Zn-Pc (10)
Method I. Pc 8 (60 mg, 0.057 mmol) and sodium ethanethiolate
(534 mg, 5.7 mmol) were dissolved in dry DMF (20 mL). The same
procedure was followed as reported above for the synthesis of Pc 5.
Re-metalation took place with zinc bromide (0.08 g, 0.35 mmol) in
DMF (10 mL) to yield a bluish green solid (6 mg, 10%). Method II.
(CD2Cl2, 400 MHz):
d 7.58–7.54 (m, 1H, Ar-H), 7.43–7.41 (m, 1H,
Ar-H), 7.04–7.02 (m, 1H, Ar-H), 6.84 (s, 1H, Ar-H), 6.77 (s, 1H, Ar-H),
1.34 (s, 9H, C(CH3)3), 1.30 (s, 9H, C(CH3)3). 13C NMR (CD2Cl2,
Phthalonitrile
2 (0.1 g, 0.176 mmol) and phthalonitrile (1.9 g,
100 MHz):
d
162.3, 152.6, 145.1, 140.9, 136.2, 134.9, 126.7, 120.9,
15 mmol) were dissolved in dry pentanol (50 mL) and heated to
140 ꢀC under argon. DBU (0.2 mL) was added and the solution stir-
red at 140 ꢀC for 24 h. The solvent was evaporated to dryness under
vacuum. The residue was dissolved in acetone and the byproduct A4-
type Pc was removed by filtration. The crude Pc was purified by
alumina column chromatography using methanol/dichloromethane
5:95 for elution to afford the free-base A3B-type Pc as a blue solid.
LRMS (MALDI-TOF) m/z 954.90 [M]þ, calcd for C60H58N8O4 954.46.
The free-base Pc was dissolved in DMF (20 mL), zinc dibromide
(0.16 g, 0.7 mmol) was added, and the mixture was heated to 40 ꢀC
for 24 h. The solvent was evaporated under vacuum and the crude
product was purified by alumina column chromatography using
methanol/dichloromethane 2:98 for elution. Further purification
using alumina preparative TLC plates afforded the title Pc as
120.3, 117.4, 116.4, 115.9, 113.7, 105.6 (Ar-C, CN), 34.7, 34.5, 30.5, 29.5
(C(CH3)3). HRMS-ESI: m/z 347.1766 [MꢁH]ꢁ, 348.1791 [M]ꢁ,
695.3580 [2MꢁH]ꢁ, calcd for [C22H23N2O2]ꢁ 347.1766,
[C22H24N2O2]ꢁ 348.1838, [C44H47N4O4]ꢁ 695.3597. FTIR (solid):
3440.9 (br, OH), 2243.0 (CN) cmꢁ1
.
4.1.7. Tetra-hydroxy-Zn-Pc (7)
Lithium (0.033 g, 4.6 mmol) was dissolved in octanol (5 mL) and
the solution heated to 170 ꢀC. After 1 h, the solution was cooled to
40 ꢀC. Phthalonitrile 6 (50 mg, 0.14 mmol) in dichloromethane
(1 mL) was added to the reaction mixture via syringe. After 4 h an-
hydrous zinc acetate (0.2 g, 1.0 mmol) was added and the reaction
mixture was heated at 70 ꢀC for 3 days. Ethanol (10 mL) was added
and the solutionwas concentrated byazeotropic distillation. Hexane
(10 mL) was added to the residue and the suspension was centri-
fuged to afford the crude solid product. The residue was purified by
column chromatography on silica gel using methanol/dichloro-
methane 2:98 for elution. The product was further purified by
preparative TLC silica plates eluted with hexane/dichloromethane
1:4 and methanol/dichloromethane 2:98. After purification by HPLC
using methanol, the title Pc was obtained as a dark green solid (8 mg,
a greenish blue solid (10 mg, 6%). 1H NMR (DMF-d, 400 MHz):
d 9.61
(s, 2H, Ar-H), 9.35–9.17 (m, 6H, Ar-H), 8.95 (br, 2H, OH), 8.23–8.13 (m,
6H, Ar-H), 7.32 (s, 2H, Ar-H), 7.28 (s, 2H, Ar-H), 1.60 (s, 18H, C(CH3)3),
1.46 (s, 18H, C(CH3)3). 13C NMR (DMF-d, 100 MHz):
d 162.9, 154.1,
154.0, 153.9, 153.8, 153.20, 152.3, 147.9, 139.8, 139.1, 139.0, 138.9,
135.3, 134.2, 123.2, 122.9, 122.8, 120.0, 116.2, 111.7 (Ar-C), 29.8
(C(CH3)3, other carbon signals shielded by DMF-d). LRMS (MALDI-
TOF) m/z 1016.25 [M]þ, calcd for C60H56N8O4Zn 1016.37. UV–vis
15%). 1H NMR (acetone-d, 400 MHz):
8.35 (br, 4H, OH), 7.98 (t, J¼7.7 Hz, 4H, Ar-H), 7.39 (d, J¼7.1 Hz, 4H, Ar-
H), 7.32 (br, 4H, Ar-H), 7.20 (s, 4H, Ar-H),1.70 (s, 36H, C(CH3)3),1.42 (s,
36H, C(CH3)3). 1H NMR (acetone-d with one drop of D2O, 400 MHz):
d
9.08 (d, J¼7.5 Hz, 4H, Ar-H),
(acetone): lmax (log 3) 668.2 (5.3), 603.5 (4.5) nm.
4.2. Molecular structures
d
9.07 (d, J¼7.4 Hz, 4H, Ar-H), 7.99 (t, J¼7.7 Hz, 4H, Ar-H), 7.38 (d,
The crystal structures of Pc 4 and dimer 8 were determined
using data collected at low temperature with Mo Ka radiation on
a Nonius KappaCCD diffractometer. The structure of phthalonitrile
6 was determined using data collected at low temperature with Cu
J¼7.8 Hz, 4H, Ar-H), 7.29 (br, 4H, Ar-H), 7.22 (s, 4H, Ar-H),1.71 (s, 36H,
C(CH3)3), 1.40 (s, 36H, C(CH3)3). HRMS-ESI: m/z 1459.6721 [MþH]þ,
calcd for [C88H97N8O8Zn]þ 1459.6730. UV–vis (acetone): lmax (log
3)
698.2 (5.3), 628.4 (4.5) nm.
Ka radiation on a Bruker Apex-II CCD diffractometer. Compound Pc
4 was crystallized as a mixed CH2Cl2, CH3OH, H2O solvate, and
exhibits considerable disorder. Despite the low temperature of data
collection, T ¼ 115 K, the crystals scattered to low resolution (1.04
Å). Anisotropic refinement was possible for only Zn and Cl. The
structure contains two independent Zn-phthalocyanine complexes,
each lying on an inversion center, with the Zn atom lying slightly
out of plane and disordered. For Pc 4, R¼0.138 for 9492 observed
data of 14,648 unique data. Phthalonitrile exhibited no disorder,
and gave high-resolution data at T¼90 K. For 6, R¼0.030 for 3034
observed data of 3289 unique data. The X-ray crystallographic data
for Pc 4, phthalonitrile 6, and corresponding diphthalonitrile can be
found in supplementary publications CCDC-713859, CCDC-713860,
and CCDC-713860 respectively, available from the Cambridge
Crystallographic Data Centre.
4.1.8. Dimethoxy-Pc (8)
Phthalonitrile 1 (0.3 g, 0.5 mmol) and phthalonitrile (7.6 g,
59.3 mmol) were dissolved in dry pentanol (50 mL) at 140 ꢀC under
argon. DBU (0.6 mL) was added dropwise and the reaction mixture
was refluxed for 9 h. After cooling to room temperature the solution
was poured into methanol (200 mL). The product was collected by
filtration and washed repeatedly with methanol and dichloro-
methane until the filtrate was colorless. The crude product was
purified by column chromatography on silica gel using dichloro-
methane for elution, giving the title Pc as a blue solid (0.06 g,12%).1H
NMR (CDCl3 with one drop of TFA-d, 300 MHz): d 7.98–7.87 (m,18H,
Ar-H), 4.11 (s, 6H, OCH3),1.72 (s,18H, C(CH3)3),1.46 (s,18H, C(CH3)3).
MS (MALDI-TOF) m/z 982.81 [M]þ, calcd for C62H62N8O4 982.49.
4.1.9. Dimethoxy-Zn-Pc (9)
Acknowledgements
Pc 8 (0.07 g, 0.7 mmol) and zinc dibromide (0.16 g, 0.7 mmol)
were dissolved in dichloromethane (20 mL). The solution was
refluxed for 2 h, cooled to room temperature, and filtered to
The work described was partially supported by the National
Science Foundation, grant number CHE-304833, and the National

H. Li et al. / Tetrahedron 65 (2009) 3357–3363
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