The synthesis and photophysical properties of polyether substituted phthalocyanines of potential use in photodynamic therapy

Article abstract of DOI:10.1039/a701079f

The synthesis, photophysical properties and singlet oxygen yields of a range of polyether substituted metallo and free-base phthalocyanines are reported and discussed in the context of the potential use of these compounds as alternatives to haematoporphyrin derivatives (HpD) in the photodynamic therapy (PDT) of cancer. The triplet states of the phthalocyanines have been studied in benzene and methanol using nanosecond laser flash photolysis and pulse radiolysis. Triplet state absorption maxima occur at ca. 510 to 525 nm and the quantum yields of triplet formation (φ_T) lie in the range 0.14 to 0.32. Triplet state lifetimes are in the range 26 to 155 μs. Energy transfer from the triplet state (T₁) of the phthalocyanines to ground state molecular oxygen O₂ ³Σ^-_g to produce singlet oxygen O₂ ¹Δ_g is efficient and evidence is presented for the establishment of an equilibrium in perdeuterated benzene, eqn. (a). Pc(T₁) + O₂(³Σ^-_g) ? Pc(S_o) + O₂(¹Δ_g) (a) Singlet oxygen quantum yields (φΛ), determined by time resolved near infrared luminescence, are comparable with the triplet yield suggesting a high proportion of quenching encounters result in the formation of singlet oxygen. The photophysical properties of the metallophthalocyanines are dependent on the relative atomic mass and the magnetic properties of the central metal ion.

Full text of DOI:10.1039/a701079f

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The synthesis and photophysical properties of polyether substituted
phthalocyanines of potential use in photodynamic therapy
Sarah Foley,a Gurnos Jones,a Raffaelle Liuzzi,b David J. McGarvey,a
Martin H. Perrya and T. George Truscott *,a
a
Department of Chemistry, Keele University, Keele, Staffordshire, UK ST5 5BG
b Departimento di Biologia e Patologia, Cellulare e Molecolare ‘L. Califano’
Universitá di Napoli, Via S Pansini 5–80131 Napoli, Italy
The synthesis, photophysical properties and singlet oxygen yields of a range of polyether substituted
metallo and free-base phthalocyanines are reported and discussed in the context of the potential use of
these compounds as alternatives to haematoporphyrin derivatives (H pD ) in the photodynamic therapy
(PD T) of cancer. The triplet states of the phthalocyanines have been studied in benzene and methanol
using nanosecond laser flash photolysis and pulse radiolysis. Triplet state absorption maxima occur at ca.
510 to 525 nm and the quantum yields of triplet formation (öT) lie in the range 0.14 to 0.32. Triplet state
lifetimes are in the range 26 to 155 ìs. Energy transfer from the triplet state (T1) of the phthalocyanines to
ground state molecular oxygen O2 3ÓgϪ to produce singlet oxygen O2 1Äg is efficient and evidence is presented
for the establishment of an equilibrium in perdeuterated benzene, eqn. (a).
Pc(T1) ϩ O2(3ΣgϪ)
Pc(So) ϩ O2(1∆g)
(a)
Singlet oxygen quantum yields (öÄ), determined by time resolved near infrared luminescence, are
comparable with the triplet yield suggesting a high proportion of quenching encounters result in the
formation of singlet oxygen.
The photophysical properties of the metallophthalocyanines are dependent on the relative atomic mass
and the magnetic properties of the central metal ion.
of phthalocyanines as photosensitisers for the selective and
Introduction
effective destruction of animal and human malignant
tumours. Photosensitisation with a variety of tetrapyrrole
compounds has been shown to be an effective method for
killing a wide variety of cells including cancerous and bac-
terial cells. The transfer of electronic energy from the triplet
state of large molecules such as phthalocyanines to molecular
oxygen has increasingly been investigated by the biomedical
community as it is now widely believed that singlet molecular
oxygen may be the principal cytotoxic species in tumour
necrosis.5–7
There is at present considerable interest in the synthesis and
application of ‘new generation’ photosensitisers that contain
tetrapyrrole units such as porphyrins, chlorins, phthalocyanines
and bacteriochlorins.4,8–10 The medical application of these
tetrapyrrole compounds has given rise to a search for photo-
sensitisers that are more effective than the previously used
haematoporphyrin derivative. Such currently used ‘second
generation’ sensitisers must fulfil certain criteria if they are to
act efficiently.11
The photosensitiser should exhibit strong absorption in the
red region. Due to lower scattering and weak absorption by
natural chromophores red light is able to penetrate tissue to
a greater extent than light of shorter wavelengths. Photo-
physically, the photosensitiser should possess a high inter-
system crossing yield giving rise to the population of a
long-lived triplet state, and concomitant efficient generation of
singlet oxygen.
The determination of the photophysical properties of these
phthalocyanines is therefore desirable in assessing their suit-
ability as photosensitisers for PDT. This paper describes the
synthesis and photophysics of polyether substituted phthalocy-
anines with substitution being in the β position. The function
of the peripheral polyether groups is to enhance the solubility
of the phthalocyanines in water, rendering them easier to
administer in medical applications.
Phthalocyanines are synthetic substances related to the natur-
ally occurring porphyrins. They consist of a macrocycle made
up of four isoindole units linked by aza nitrogen atoms in
contrast to the methine carbon atoms in porphyrins. Phthalo-
cyanines are stable compounds both chemically and photo-
chemically. Typically they are blue or green in colour and are
used as pigments in printing inks, paints and plastics. They also
have applications in semiconductors, oxidation catalysts,
photochemical solar energy conversion systems and in laser
technology.1
RO
OR
β
α
N
N
N
RO
RO
OR
OR
N
N
M
N
N
N
RO
OR
R = CH2CH2OCH2CH3 (OE)
R = CH2CH2OCH2CH2OCH3 (OM)
M = 2H+, Ni2+, Pb2+, Zn2+
Polyether substituted phthalocyanine structure
Because of their structural resemblance to porphyrins and
their superior absorption in the red region of the spectrum 2–4
there has been increasing interest in the last decade in the use
J. Chem. Soc., Perkin Trans. 2, 1997
1725

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Table 1 Photophysical properties of polyether substituted phthalocyanines in benzene and methanol
Benzene
Methanol
∆εT /a
∆εT /c
103 dm3
molϪ1 cmϪ1
103 dm3
molϪ1 cmϪ1
b
d,e
Phthalocyanine
OMPcH2
OMPcNi
OMPcPb
OMPcZn
OEPcH2
λTmax/nm
515
τT /µs
50
φT(±20%)
0.15
φ∆
λTmax/nm
520
τT /µs
32
φT(±20%)
0.16
—
φ∆
28.5
—
0.13
0.0
9.0
—
0.06
(0.06)
0.0
(0.0)
0.17
(0.18)
0.16
(0.22)
0.10
525
—
—
520
—
520
7.21
28.2
29.3
28.0
32
0.30
0.25
0.20
0.10
0.14
520
—
—
—
515
105
50
0.32
520
23.5
6.2
64
0.16
0.15
0.14
525
0.15
520
26
(0.05)
0.14
OEPcZn
525
155
0.28
510
21.5
39
(0.19)
a
Determined using the energy transfer method. b Relative to φ∆ phenazine = 0.88.27 c Determined using the singlet depletion method. d Relative to φ∆
methylene blue = 0.58.28 e In monodeuterated methanol (CH3OD). φ∆ values given in parentheses are for acetonitrile solutions.
Fig. 1 Ground state electronic absorption spectra of OMPcZn in both
polar and non-polar solvents
Fig. 2 Dimer spectra of polyether substituted phthalocyanines in
benzene (the Zn derivatives show evidence of a monomer peak due to
discrepancies in the subtraction of the high and low temperature
spectra)
Results and discussion
Solubility considerations
Unsubstituted phthalocyanines are poorly soluble in most
common solvents. However, the addition of polyether groups
enhances the solubility of the phthalocyanines and conveys
solubility in a range of solvents, both protic polar (methanol
and water), aprotic polar (dichloromethane) and non-polar
such as benzene.12 Only those phthalocyanines substituted with
the longer polyether side chains are soluble in water. Whilst
solubility in the aforementioned solvents is enhanced by the
addition of polyether substituents, the phthalocyanines exhibit
a degree of aggregation (probably a monomer–dimer equi-
librium) in all solvents except dichloromethane.
Ground state absorption spectra
The UV–VIS absorption spectra of the phthalocyanines in
benzene have Q-bands (0, 0) ranging from 666 nm for OMPcNi
to 714 nm for OMPcPb. The position of λmax is independent of
the type of polyether substituent. Alongside the red Q-band
additional peaks are present in the regions 640–660, 390–400
and 300–350 nm.
Fig.
3
Triplet minus singlet difference absorption spectrum for
OMPcZn in methanol
for several polyether substituted phthalocyanines obtained in
this way.
In protic polar solvents such as methanol and water the main
spectral Q-bands are blue shifted compared with benzene and
are relatively broad due to extensive aggregation. In water the
presence of higher associates (trimers etc.) is not discounted. In
the absorption spectra of the metallophthalocyanines a red
shift in the absorption maxima is observed with increasing mass
of the central metal ion, irrespective of the solvent.
Fig. 1 shows the absorption spectra of OMPcZn in different
solvents where different degrees of aggregation are evident. The
position of equilibrium is temperature dependent and by
recording the spectrum at different temperatures and subtract-
ing the two spectra (after scaling) the resolved monomer and
dimer spectra are obtained. Fig. 2 illustrates the dimer spectra
Triplet state yields and lifetimes
Laser excitation of the phthalocyanines gives rise to a transient
absorption in the visible region of the spectrum which is identi-
fied as the triplet state since it is quenched by molecular oxygen
giving singlet oxygen. Table 1 gives a summary of the triplet
state properties for each of the phthalocyanines studied. The
maxima in the difference absorption spectra range from 510–
525 nm and all exhibit a broad, featureless spectrum as shown
in Fig. 3 for OMPcZn. Values of φT range from 0.14 to 0.32,
with triplet lifetimes τT in deaerated solutions ranging from 26–
155 µs for OMPcPb and OEPcZn respectively. Such variations
are due to enhanced intersystem crossing promoted by heavier
metal ions.
1726
J. Chem. Soc., Perkin Trans. 2, 1997

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Table 3 Equilibrium constants and triplet energy levels for polyether
substituted phthalocyanines in perdeuterated benzene
Table 2 Polyether substituted phthalocyanine triplet state quenching
by O2
Methanol
[2H6]Benzene
Phthalocyanine
Keq
ET /kJ molϪ1
Phthalocyanine
kq/109 dm3 molϪ1 sϪ1
kq /109 dm3 molϪ1 sϪ1
OMPcH2
OMPcPb
OMPcZn
OEPcH2
OEPcZn
0.31
0.12
0.54
0.29
0.51
96.5
94.3
97.9
96.3
97.8
OMPcH2
OMPcPb
OMPcZn
OEPcH2
OEPcZn
0.79
—
1.1
1.2
1.2
1.7
2.2
2.0
1.7
1.8
Fig. 4 Decay profiles of triplet OEPcH2 in [2H6]benzene solutions
saturated with air and 5% O2. (Insert shows the mono-exponential
decay of OEPcH2 in [2H6]benzene when saturated with N2.)
Triplet state quenching by O2
Quenching of the phthalocyanine triplet state by ground state
molecular oxygen results in the formation of singlet molecular
oxygen. In methanol the quenching rate constants (kq) are ca.
1–2 × 109 dm3 molϪ1 sϪ1 which is typical for porphyrin like
compounds14 (see Table 2). However, in perdeuterated benzene
a biexponential decay is observed (see Fig. 4) that is indicative
of the establishment of an energy transfer equilibrium. Such
observations are similar to observations reported by Rodgers et
al.15,16 of reversible energy transfer involving a phthalocyanine
triplet state and singlet oxygen (Scheme 1).
Fig. 5 (a) Time profile of the absorbance change at 660 nm of air
saturated OEPcH2 in [2H6]benzene using a short timescale. (b) Time
profile of the absorbance change at 660 nm of air saturated OEPcH2 in
[2H6]benzene using a long timescale.
kf
Pc(T1) ϩ O2(3ΣgϪ)
Pc(So) ϩ O2(1∆g)
kb
exponential kinetics is clearly observable and the effects of
increasing the oxygen concentration on the rate of decay of the
first component and the equilibrium triplet state concentration
are also apparent. The equilibrium constant may be determined
from triplet state absorption measurements using eqn. (1),
kT
k∆
Pc(So)
O2(3ΣgϪ)
Scheme 1
(A0 Ϫ A∞)/A∞ = Keq([O2]/[Pc])
(1)
Supporting evidence for the existence of such an equilibrium
comes from the mono-exponential decay kinetics observed
when the solutions are nitrogen saturated (see insert Fig. 4) and
the fact that the lifetime of singlet oxygen measured from time-
resolved near infrared emission matches the lifetime of the
second component of the phthalocyanine triplet state decay. In
addition the amplitude of the second component in the triplet
state absorption data is sensitive to the oxygen concentration.
However, in contrast to Rodgers et al.15,16 the equilibrium lies
further to the right, and the equilibrium concentration of
phthalocyanine triplet under these experimental conditions is
very small, although by monitoring the ground state depletion
of the phthalocyanine the short and long-lived components can
be seen clearly [see Figs. 5(a) and 5(b)]. A detailed study of
oxygen quenching under these circumstances permits the equi-
librium constant (Keq = kf /kb) to be determined and from this
the phthalocyanine triplet state energy, ET. In these experiments
the concentration of oxygen was varied whilst the phthalo-
cyanine concentration was kept constant. Time profiles of the
absorption changes at 520 nm showing the decay of the
phthalocyanine triplet state at two different oxygen concen-
trations are reproduced in Fig. 4. A departure from mono-
where A0 is the initial triplet state absorbance and A∞ is the
equilibrium triplet state absorbance extrapolated to t = 0. The
values of Keq can then be used to evaluate triplet state energies
1
–
(ET, see Table 3) using eqn. (2) where the (9) accounts for the
spin statistical factor.15,17
1
–
ET Ϫ E∆ ϩ RT ln(9) = RT ln Keq
(2)
Singlet oxygen quantum yields and lifetimes
The measured values of φ∆ for the series of phthalocyanines in
acetonitrile, benzene and monodeuterated methanol are col-
lected in Table 1. In all experiments the emission observed at
1270 nm decayed exponentially with a solvent dependent rate
constant. The average lifetimes (τ∆) observed for singlet oxygen
in acetonitrile (55 µs) and benzene (28 µs) are comparable with
the published values of 54–68,18 27–33 µs19 for these two sol-
vents. However, in monodeuterated methanol the singlet oxy-
gen lifetimes are reduced to 16.5 and 15 µs in the presence of
OMPcH2 and OEPcH2 respectively from which O2 1∆g quench-
ing rate constants of 7.5 × 108 and 3.8 × 108 dm3 molϪ1 sϪ1 are
deduced in this solvent. No singlet oxygen formation was
J. Chem. Soc., Perkin Trans. 2, 1997
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Table 4 Efficiency of singlet oxygen formation of polyether substi-
tuted phthalocyanines in benzene and methanol
photometer for solutions in CDCl3. Mass spectra were deter-
mined using an AE1 MS12 mass spectrophotometer.
S∆
Methods
Triplet state absorption coefficients (ÄåT) and triplet state
quantum yield (öT). Triplet state absorption coefficients were
obtained using the energy transfer and singlet depletion tech-
niques.22 In the energy transfer method, a triplet state of
unknown ∆εT is compared with a standard triplet state of ∆εT.
In the energy transfer experiments pulse radiolysis was used
Phthalocyanine
Benzene
Methanol
OMPcH2
OMPcNi
OMPcPb
OMPcZn
OEPcH2
OEPcZn
0.87
—
0.83
0.63
0.67
0.5
0.38
—
—
1.0
0.67
1.0
and the standard was biphenyl for which ∆εT360 = 27 100 dm3
molϪ1 cmϪ1
.
Solutions of biphenyl (0.1 mol dmϪ3) were sub-
23
jected to pulse radiolysis in benzene in the presence and absence
of the polyether substituted phthalocyanines (10Ϫ4 mol dmϪ3).
The singlet depletion technique depends upon measuring the
ground state depletion in a region where it is assumed that
εT = 0 [see eqn. (4)].
observed for OMPcNi in any of the solvents studied. The φ∆/φT
ratio (S∆) gives the efficiency of O2 1∆g formation under condi-
tions of complete triplet state quenching by oxygen. As can be
seen from Table 4 the values of S∆ vary from 1.0 to 0.38. Thus,
for all the polyether substituted phthalocyanines studied as
potential new sensitisers for PDT, triplet state quenching by
O2 leads to efficient O2 1∆g formation, even though the triplet
energies are rather close to that of O2 1∆g.
∆ATλ = ϪεSλ[3M*]l
(4)
Triplet quantum yields (φT) were obtained by the comparative
method 24 using methylene blue in methanol for which
φT = 0.5224 and ∆εT = 14 000 dm3 molϪ1 cmϪ1 at 420 nm.13
Deaerated solutions of the polyether-substituted phthalo-
cyanines and methylene blue were optically matched at the laser
excitation wavelength, and the yields were obtained using eqn.
(5).
Conclusion
The synthesis of a range of polyether substituted phthalo-
cyanines has been described and their photophysical properties
and singlet oxygen quantum yields have been measured in ben-
zene and methanol. The polyether substituted phthalocyanines
show intense absorption in the red region of the spectrum and
the presence of the polyether groups improves the solubility of
these compounds in common solvents including water. With
respect to triplet quantum yields and singlet oxygen quantum
yields it has been shown that those phthalocyanines which con-
tain a diamagnetic metal centre (Zn and Pb) exhibit greater
photoactivity. The efficiency of singlet oxygen formation has
been shown to be substantial.
∆ODTPc × ∆εTRef
∆ODTRef × ∆εTPc
(5)
φTPc = φTRef ×
Oxygen quenching rate constants (kq) measurements. The rate
constants (kq) for oxygen quenching of the triplet states of the
polyether substituted phthalocyanines were determined in
methanol by kinetic absorption measurements on various
O2/N2 mixtures. Five single shot kinetic absorption traces
were signal-averaged for each measurement and good single
exponential fits were obtained for all the phthalocyanines in
methanol. However, in perdeuterated benzene there is a depart-
ure from monoexponential kinetics and biexponential kinetics
are observed (see Results and discussion). The oxygen concen-
trations in air saturated solvents were taken to be 2.1 × 10Ϫ3 and
1.9 × 10Ϫ3 mol dmϪ3 in methanol and benzene, respectively.25
Singlet oxygen quantum yield measurements (öÄ). Air equili-
brated solutions of polyether substituted phthalocyanines
were optically matched at the laser excitation wavelength, along
with that of a reference standard for which the singlet oxygen
quantum yield has previously been determined. Solutions were
prepared in 1 × 1 cm quartz cells with absorbances of 0.5 at 694
or 355 nm.
For the determination of φ∆ values time-resolved lumines-
cence at 1270 nm was recorded following laser excitation. At
each laser intensity the recorded luminescence trace was
obtained by signal-averaging ten single shots. The averaged
traces were fitted with a single exponential which was extra-
polated to t = 0. Plots of I0 (the extrapolated signal intensity at
t = 0) versus laser intensity were found to be linear up to a laser
intensity of 4 mJ pulse Ϫ1. Within this laser intensity range eight
data points were obtained for each plot. Since the gradient of
the I0 versus laser intensity plots are proportional to φ∆, the
values of φ∆ may be obtained by comparison with the gradient
obtained for the reference standard. The standards employed
for the three solvents are as follows.
Experimental
Materials
Methylene blue (British Drug Houses Ltd) was used as re-
ceived. Phenazine (Lancaster) was recrystallized from ethanol.
Acetonitrile (spectroscopic grade, Rathburn Chemicals Ltd),
benzene(spectroscopicgrade, FisonsScientific), methanol(spec-
troscopic grade, Rathburn Chemicals Ltd), monodeuterated
methanol (CH3OD) (Cambridge Isotope Laboratories, CIL)
and perdeuterated benzene (Aldrich), were used as received.
Instrumentation
Kinetic absorption measurements were made using a JK system
2000 Q switched ruby laser operating on the fundamental (694
nm) and the third harmonic (355 nm) of a Spectron Q switched
Nd-YAG laser as described previously.20 Time resolved singlet
oxygen luminescence (1270 nm) was detected via the (0, 0)
phosphorescence band eqn. (3), centred at 1270 nm using a
O2(1∆g) → O2(3ΣgϪ) ϩ hv (1270 nm)
(3)
Judson germanium diode (G-050, active diameter = 0.5 cm)
coupled to a Judson preamplifier. Pulse radiolysis measure-
ments were made using a 9–12 MeV Vickers linear accelerator
as described previously21 with pulses of 50 ns duration and
doses of between 7 and 8 Gy. Irradiation was in quartz flow-
through cells with internal volumes of 2.5 cm3 and a monitor-
ing optical path length of 2.5 cm.
Acetonitrile: methylene blue in air equilibrated acetonitrile
for which φ∆ = 0.52.26
Absorption spectra were recorded using a Perkin-Elmer
Lambda 2 UV–VIS spectrophotometer. Melting points were
determined on a heated stage, and are uncorrected. NMR
spectra were recorded on a Jeol GS × 270 MHz spectro-
Benzene: phenazine in air equilibrated benzene for which
φ∆ = 0.88.27
Methanol: methylene blue in air equilibrated monodeuter-
ated methanol for which φ∆ = 0.58.28
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J. Chem. Soc., Perkin Trans. 2, 1997

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Syntheses
hexane, mp 86–87 ЊC (Found: C, 62.98; H, 6.51; N, 9.37.
The phthalocyanines (4a and 4b) were synthesised as illustrated
in Scheme 2.
C16H20N2O4 requires C, 63.14; H, 6.62; N, 9.20%) m/z 304 (Mϩ,
7%), 73 (CH3CH2 OCH2CH2ϩ, 95%), 45 (CH3CH2Oϩ, 100%).
δH 1.23 (6H, t), 3.60 (4H, q), 3.84 (4H, t), 4.23 (4H, t), 7.25 (2H,
s). δC 15.06 (CH3), 66.99 (CH2), 68.41 (CH2), 69.43 (CH2),
108.74 (CN), 115.75 (C1, C2), 116.90 (C3, C6), 152.38 (C4, C5).
νmax /cmϪ1 2233 (CN).
Br
Br
OH
OH
1
4,5-Bis(3,6-dioxaheptyloxy)phthalonitrile 3b.—Obtained in
21% yield, mp 47 ЊC (from CCl4) (Found: C, 59.28; H, 6.57; N,
i
7.81. C18H24N2O6 requires C, 59.33; H, 6.64; N, 7.69%). m/z 364
ϩ
,
(Mϩ, 2.6%), 103 (CH3OCH2CH2ϩ, 28%), 59 (CH3OCH2CH2
Br
OR
OR
CN
CN
OR
OR
100%). δH 3.39 (6H, s), 3.56 (4H, t), 3.72 (4H, t), 3.91 (4H, t),
4.27 (4H, t), 7.28 (2H, s). δC 58.99 (CH3), 69.27 (CH2), 69.37
(CH2), 70.83 (CH2), 71.83 (CH2), 108.71 (CN), 115.69 (C1, C2),
117.05 (C3, C6), 152.31 (C4, C5). νmax /cmϪ1 (CHCl3) 2234.
(c) General procedure for making phthalocyanines 4. The
dinitrile 3 (3.45 mmol) and lithium carbonate (17.16 mmol)
were dissolved in hot stirred n-pentanol (10 cm3) and the solu-
tion boiled (66 h). The alcohol was removed (50 ЊC, water
pump, then 75 ЊC, 0.01 mmHg), the residue treated with
dichloromethane, and then filtered. The crude phthalocyanine
was purified by Chromatotron, (neat CH2Cl2, then 2% ethanol).
In some cases further chromatography was necessary, on a silica
gel column, loaded in ethanol and eluted with ethanol–CH2Cl2,
(8:2).
2,3,9,10,16,17,23,24-Octakis(2-ethoxyethoxy)phthalocyanine
4a.—This was obtained in 32% yield (Found: C, 63.25; H,
6.77; N, 9.03. C64H82N8O16 requires C, 63.04; H, 6.78; N,
9.19%). δH 1.45 (24H, t), 3.89 (16H, q), 4.16 (16H, t), 4.44 (16H,
t), 7.63 (8H, s). δC 15.41 (CH3 ), 66.96 (CH2), 68.66 (CH2), 69.10
(CH2), 104.27 (CH), 128.99, 150.26. λmax/nm (C6H6) (ε/dm3
molϪ1 cmϪ1) 344.2 (29.0 × 103), 391.5 (11.4 × 103), 660.7
(26.3 × 103) and 699.99 (25.1 × 103).
ii
Br
3
2
iii
RO
OR
N
N
N
N
RO
OR
OR
NH
HN
RO
N
N
RO
OR
4a R = CH2CH2OCH2CH3
4b R = CH2CH2OCH2CH2OCH3
2,3,9,10,16,17,23,24-Octakis(3,6-dioxaheptyloxy)phthalo-
cyanine 4b.—This was obtained in 34% yield (Found: C, 59.25;
H, 6.86; N, 7.64. C72H98N8O24 requires C, 59.25; H, 6.77; N,
7.68%). δH 3.53 (24H, s), 3.78 (16H, s), 4.04 (16H, s), 4.31 (16H,
s), 8.24 (8H, s). δC 59.16 (CH3), 69.06 (CH2), 69.95 (CH2), 71.08
(CH2), 72.27 (CH2), 104.88 (CH), 129.64, 150.87. λmax/nm
(C6H6) (ε/dm3 molϪ1 cmϪ1) 350.9 (33.7 × 103) 391.5 (11.5 × 103),
660.7 (35.9 × 103) and 699.9 (37.5 × 103).
Scheme 2 Synthesis of the polyether-substituted phthalocyanines.
Reagents and conditions: i, RBr, KOH, EtOH; ii, CuCN, DMF; iii,
Li2CO3, pentanol, heat.
(a) General procedure for ethers 2. Dibromocatechol (0.12
mol) was dissolved in ethanol (300 cm3), KOH (0.27 mol) was
added, and the mixture stirred under nitrogen. The alkyl brom-
ide (0.1 mol) was added, and the solution heated under reflux
(15–24 h). The ethanol was removed, the residue extracted with
dichloromethane (3 × 80 cm3) and filtered. The filtrate was
washed with 2  NaOH (2 × 125 cm3) and water, and the
organic layer dried (Na2SO4) and evaporated.
4,5-Dibromo-1,2-bis(2-ethoxyethoxy)benzene 2a.—Obtained
as an oil in 75% yield. m/z 414 (Mϩ ϩ 4, 1.74%), 412 (Mϩ ϩ 2,
3.48%), 410 (Mϩ, 1.87%), 73 (EtOCH2CH2ϩ, 44%), 45(C2H5Oϩ,
100%). δH 1.26 (6H, t), 3.62 (4H, q), 3.82 (4H, t), 4.16 (2H, t),
7.18 (2H, s). δC 15.02 (CH3), 66.67 (CH2), 68.58 (CH2), 69.20
(CH2), 115.11 (C4, C5), 118.92 (C3, C6), 148.76 (C1, C2).
4,5-Dibromo-1,2-bis(3,6-dioxaheptyloxy)benzene 2b.—
Nickel phthalocyanine. The appropriate phthalonitrile (1.38
mmol), nickel chlorideؒ6H2O and quinoline (1 cm3) were heated
and stirred under nitrogen at 200–220 ЊC (6 h). Evaporation of
quinoline under reduced pressure was followed by extraction
with ethyl acetate, filtration and evaporation. The residue was
chromatographed on silica gel, then for analysis on a further
column, loading with ethanol, eluting with CH2Cl2–ethanol
mixtures. This procedure was applied to all metal phthalo-
cyanines.
Nickel phthalocyanine (4b–NiII).—This was obtained in 56%
yield (Found: C, 57.21; H, 6.66; N, 7.15. C72H96N8NiO24
requires C, 57.03; H, 6.38; N, 7.39%). λmax/nm (C6H6) (ε/dm3
molϪ1 cmϪ1) 286.0 (73.9 × 103), 391.5 (20.1 × 103), 618.7
(38.0 × 103) and 666.0 (38.9 × 103).
Obtained as an oil in 85% yield. m/z 472 (Mϩ ϩ 4, 19%), 470
(Mϩ ϩ 2, 37%), 468 (Mϩ, 19%), 103 (C5H11O2ϩ, 95%), 59
(CH3OCH2CH2ϩ, 100%), 45 (CH3OCH2ϩ, 50%). δH 3.38 (6H,
s), 3.55 (4H, m), 3.71 (4H, m), 4.14 (4H, m), 7.14 (2H, s). δC
59.05 (CH3), 69.51 (CH2), 69.73 (CH2), 70.93 (CH2), 72.14
(CH2), 115.53 (C4, C5), 119.38 (C3, C6), 148.05 (C1, C2).
(b) General procedure for synthesis of dinitriles 3. The ether 2
(5.78 mmol) in anhydrous dimethylformamide (DMF ) (4 cm3)
was added to a stirred solution of copper() cyanide (17.4 mmol)
in anhydrous DMF (60 cm3), and the mixture boiled (8 h). The
reaction was monitored by GLC. Removal of the DMF under
reduced pressure was followed by chromatography on silica gel,
eluting with CHCl3, first mixed with light petroleum, then neat,
then small amounts of methanol. In the case of 3a and 3b the
copper phthalocyanines were also formed, and were eluted after
the dinitrile.
Zinc(II) phthalocyanines. A solution of phthalonitrile (1.74
mmol) and anhydrous zinc acetate (1.74 mmol) in DMF (5 cm3)
was boiled under nitrogen (72 h). The metal derivatives, isolated
by evaporation of the DMF, were purified as described above.
Zinc phthalocyanine (4a–ZnII).—This was obtained in 24%
yield (Found: C, 59.80; H, 6.06; N, 8.45. C64H80N8O16Zn
requires C, 59.93; H, 6.29; N, 8.74%). λmax/nm (ε/dm3 molϪ1
cmϪ1) 350.9 (36.8 × 103), 675.6 (42.4 × 103).
Zinc phthalocyanine (4b–ZnII).—This was obtained in 42%
yield (Found: C, 56.61; H, 6.06; N, 7.16. C72H96N8O24Zn
requires C, 56.78; H, 6.35; N, 7.36%). λmax/nm (C6H6) (ε/dm3
molϪ1 cmϪ1) 291.4 (54 × 103), 350.9 (68.1 × 103) and 676.9
(110.9 × 103).
4,5-Bis(2-ethoxyethoxy)phthalonitrile 3a.—Compound 3a
was obtained in 35% yield, colourless crystals from cyclo-
Lead phthalocyanine. Phthalonitrile (1.41 mmol) and lead()
oxide (1.41 mmol) in chloronaphthalene (4 cm3) were stirred at
J. Chem. Soc., Perkin Trans. 2, 1997
1729

View Article Online
10 K. R. Adams, M. C. Berenbaum, R. Bonnett, A. N. Nizhnik,
180–200 ЊC under nitrogen (66 h), and the product purified as
described above. Lead phthalocyanine (4b–PbII) was obtained
in 33% yield (Found: C, 51.70; H, 5.47; N, 6.46. C72H96N8O24Pb
requires C, 51.95; H, 5.81; N, 6.73%). λmax/nm (C6H6) (ε/dm3
molϪ1 cmϪ1) 401.0 (48.6 × 103) 640.4 (19.5 × 103) and 713.5
(112.8 × 103).
A. Salgado and M. A. Valles, J. Chem. Soc., Perkin Trans. 1, 1992,
1465.
11 J. Moan, J. Photochem. Photobiol., B: Biol., 1990, 5, 521.
12 M. J. Cook, A. J. Dunn, S. D. Howe, A. J. Thomson and
K. J. Harrison, J. Chem. Soc., Perkin Trans. 1, 1989, 2453.
13 I. Carmichael and G. L. Hug, J. Phys. Chem. Ref. Data, 1986, 15, 1.
14 R. Bonnett, A. A. Charalambides, E. J. Land, R. S. Sinclair, D. Tait
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15 B. D. Rhiter, M. E. Kenney, W. E. Ford and M. A. J. Rodgers,
J. Am. Chem. Soc, 1990, 112, 8064.
Acknowledgements
16 P. A. Firey, W. E. Ford, J. R. Sounik, M. E. Kennedy and
M. A. J. Rodgers, J. Am. Chem. Soc, 1988, 110, 7626.
17 W. E. Ford, B. D. Rhiter, M. E. Kenney and M. A. J. Rodgers,
Photochem. Photobiol, 1989, 50, 277.
18 A. A. Gorman, I. R. Gould, I. Hamblett and M. C. Standen, J. Am.
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19 M. A. J. Rodgers, J. Am. Chem. Soc., 1983, 105, 6201.
20 J. H. Tinkler, S. M. Tavender, A. W. Parker, D. J. McGarvey,
L. Mulroy and T. G. Truscott, J. Am. Chem. Soc., 1996, 118, 1756.
21 J. Butler, B. W. Hodgson, B. M. Hoey, E. J. Land, J. S. Lea,
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22 R. V. Bensasson, E. J. Land and T. G. Truscott, Flash photolysis
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This research was supported by the EEC PDT EURONET
(Grant ERBCHRXCT930178). We also thank the Nuffield
Foundation for financial support. The authors would also like
to thank Dr E. J. Land for his help with the pulse radiolysis
work at the Paterson Institute for Cancer Research, Christie
Hospital Manchester, UK.
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Paper 7/01079F
Received 14th February 1997
Accepted 15th April 1997
1730
J. Chem. Soc., Perkin Trans. 2, 1997