Acetylenic quinoxalinoporphyrazines as photosensitisers for photodynamic therapy

Article abstract of DOI:10.1002/chem.200390140

A range of lipo- and hydrophilic derivatives of the new class of octaalkynyl tetra-[6,7]-quinoxalinoporphyrazines (TQuiPors), analogues of the naphthalocyanines, were prepared in two steps starting from functionalised hexa-1,5-diyne-3,4-diones. Divalent zinc and magnesium ions were introduced into the macrocyclic core. Whereas the triisopropylsilyl-, 3,5-di-tert-butylphenyl- and 4-triisopropylsilyloxyphenyl-terminated acetylenic TQuiPors are lipophilic and hence soluble in standard organic solvents, a polyethylene glycol-substituted derivative was found to dissolve in DMSO as well as in ethanol/water mixtures. The new chromophores are characterised by intense UV/Vis/NIR absorptions, most notably by bands at 770 nm with extinction coefficients exceeding 500000M^-1 cm^-1. With a view to possible photodynamic therapy applications, the potency of the chromophores to sensitise the formation of singlet oxygen was examined, both qualitatively using a 1,3-diphenylisobenzofuran assay, and quantitatively by the determination of the singlet oxygen quantum yields. It was found that all TQuiPors produce singlet oxygen when irradiated in the presence of air. In particular, the octaalkynyl Zn-TQuiPor generates singlet oxygen with a quantum yield of 56%, thereby rivalling, and, in conjunction with its absorption profile, even exceeding the standards set by established PDT agents. The photostabilities of the TQuiPors were assessed and generally found to be satisfactory, but dependent on the solvent and the wavelength of the incident light.

Full text of DOI:10.1002/chem.200390140

FULL PAPER
Acetylenic Quinoxalinoporphyrazines as Photosensitisers for
Photodynamic Therapy
Frieder Mitzel,[a, b] Simon FitzGerald,[c] AndrewBeeby, [c] and R¸diger Faust*[a]
Abstract: A range of lipo- and hydro-
philic derivatives of the new class of
octaalkynyl tetra-[6,7]-quinoxalinopor-
phyrazines (TQuiPors), analogues of
the naphthalocyanines, were prepared
in two steps starting from functionalised
hexa-1,5-diyne-3,4-diones. Divalent zinc
and magnesium ions were introduced
into the macrocyclic core. Whereas the
triisopropylsilyl-, 3,5-di-tert-butylphen-
yl- and 4-triisopropylsilyloxyphenyl-ter-
minated acetylenic TQuiPors are lip-
ophilic and hence soluble in standard
organic solvents, a polyethylene glycol-
substituted derivative was found to dis-
solve in DMSO as well as in ethanol/
water mixtures. The new chromophores
are characterised by intense UV/Vis/
NIR absorptions, most notably by bands
at 770 nm with extinction coefficients
exceeding 500000mÀ1 cmÀ1. With a view
to possible photodynamic therapy appli-
cations, the potency of the chromo-
phores to sensitise the formation of
singlet oxygen was examined, both qual-
itatively using a 1,3-diphenylisobenzo-
furan assay, and quantitatively by the
determination of the singlet oxygen
quantum yields. It was found that all
TQuiPors produce singlet oxygen when
irradiated in the presence of air. In
particular, the octaalkynyl Zn-TQuiPor
generates singlet oxygen with a quantum
yield of 56%, thereby rivalling, and, in
conjunction with its absorption profile,
even exceeding the standards set by
established PDTagents. The photosta-
bilities of the TQuiPors were assessed
and generally found to be satisfactory,
but dependent on the solvent and the
wavelength of the incident light.
Keywords: alkynes ¥ photodynamic
therapy ¥ photooxidation ¥ phthalo-
cyanines ¥ singlet oxygen
new developments in areas such as gene therapy[12] and blood
sterilisation.[13]
Introduction
Photodynamic therapy (PDT) is defined as the combined
action of a photosensitiser, light and molecular oxygen to
generate reactive oxygen species, notably singlet oxygen,
which then reacts with biomolecules to treat certain medical
conditions.[1, 2] The most prominent PDT application arguably
lies in the treatment of various forms of cancer, in particular
those of hollow organs (colon, oesophagus, etc.) and the
skin.[3 7] Increasingly, however, the principles of PDTare also
used to battle other diseases, among them age-related macular
degeneration,[8] the major cause for blindness in the elderly,
The successful realisation of any PDT concept crucially
depends on the nature of the photosensitiser,[14] whose
efficiency is determined among other things by its (bio-)-
availability, its potency as a singlet oxygen producer and its
accessibility by external light in a biological matrix. While the
sensitiser×s bioavailability in the target tissue can be optimised
by adjusting its solubility profile, the photophysical require-
ments define an optical window for sensitiser excitation
between 600 and 800 nm. Due to the enhanced light
penetration of biological tissue at longer wavelengths chro-
mophores with absorbances at the low-energy end of this
region are preferred (Figure 1). Most clinical efforts currently
focus on porphyrin-based sensitisers such as the haematopor-
phyrin 1 (commercialised as a mixture of porphyrins under
the brand name Photofrin),[7] the protoporphyrin prodrug
11]
and arteriosclerosis.[9 In addition, PDTis at the centre of
[a] Dr. R. Faust, Dr. F. Mitzel
Christopher-Ingold-Laboratories
Department of Chemistry
5-aminolaevulinic acid (e.g. Levulan)[15, 16] and meso-tetra-
University College London
20 Gordon Street, London WC1H 0AJ (UK)
E-mail: r.faust@ucl.ac.uk
19]
kis(m-hydroxyphenyl)chlorin 2 (Foscan)[17
despite their
low-intensity absorbance maxima around 630 and 650 nm
(Figure 1). To address this point phthalocyanines (e.g. 3),[20]
porphyrin isomers such as the porphycenes[22 24] and expanded
[b] Dr. F. Mitzel
Laboratorium f¸r Organische Chemie
ETH Z¸rich, Hˆnggerberg HCI G306
Wolfgang-Pauli-Strasse 10
27]
porphyrins[21] such as the texaphyrins (e.g. 4)[25 have been
8093 Z¸rich (Switzerland)
developed and are currently being tested for PDTapplications.
We have contributed to this area by designing phthalocya-
nines and phthalocyanine analogues with peripheral acetylene
[c] Dr. A. Beeby, Dr. S. FitzGerald
Department of Chemistry
South Road
30]
substitution.[28 These chromophores not only benefit from
Durham DH1 3LE (UK)
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R. Faust et al.
FULL PAPER
HO
Results and Discussion
Me
NH
Me
OH
Synthesis: The backbone of the tetra-[6,7]-quinoxalinopor-
phyrazines, octaaza-analogues of the naphthalocyanines, is
conveniently assembled by a base-induced cyclotetramerisa-
tion of dicyanoquinoxalines, which in turn are obtained from
the condensation of 1,2-diones with 1,2-diamino-4,5-dicyano-
benzene (Scheme 1). This short, two-step protocol ensures a
high degree of synthetic flexibility, as porphyrazine construc-
tion is limited only by the availability of suitably functional-
ised diketones. Peripheral acetylene substitution of the target
chromophores can therefore be achieved starting from the
corresponding acetylenic 1,2-diones, namely the hexa-1,5-
diyne-3,4-diones 6. We have earlier developed the copper-
mediated two-fold alkynylation of oxalyl chloride[35] as a route
to these diacetylenic building blocks and have prepared
diones 6a[35] and 6c.[29] The second building block, 1,2-
diamino-4,5-dicyanobenzene (7), is described with conflicting
analytical data in the literature,[36] and was prepared for this
work by the reaction of 1,2-diamino-4,5-dibromobenzene[37, 38]
with CuCN in DMF. Hence, condensation of 6a and 6c,
respectively, with 7 in acetic acid at room temperature
afforded the dicyanoquinoxalines 8a and 8c as crystalline
solids that can be easily purified by recrystallisation
(Scheme 1). The base-induced cyclotetramerisation of 8a
and 8c using magnesium butanolate in refluxing butanol
generated, with 5a and 5c, the first (lipophilic) members of
the class of the tetra-[6,7]-quinoxalinoporphyrazines. The
introduction of Zn2‡ into the central core of the porphyrazines
as in 5b succeeds by the cyclotetramerisation of the dicyano-
quinoxaline 8a with LiOPent in refluxing pentanol[39, 40] and
the subsequent addition of Zn(OAc)2.
HO
OH
N
N
N
N
Me
NH
H
HN
HN
Me
CO2H
OH
H
H
H
OH
CO2H
1
2
R
HO
Me
AcO
OAc
N
N
N
N
Al
N
Cl
Et
Et
OPEG
OPEG
N
R
N
Lu
N
N
R
N
N
N
N
Me
PEG =(CH2CH2O)3Me
R = SO3H, H
HO
R
3
4
Figure 1. PDTphotosensitisers currently in use or in clinical development.
an expanded p-system and the associated batho- and hyper-
chromically shifted absorption profile in comparison to non-
alkynylated congeners, but, in addition, offer a convenient
handle to modulate their solubility properties by varying the
terminal acetylene substituents. We present here an example
of the versatility of this approach and describe the synthesis of
lipo- and hydrophilic octaalkynyltetra-[6,7]-quinoxalinopor-
phyrazines 5. These systems are characterised by intense
absorptions around 770 nm and efficiently produce singlet
oxygen in the presence of light and air. As far as we are aware,
the tetra-[6,7]-quinoxalinoporphyrazines 5, structural isomers
of the known tetra-[2,3]-quinoxalinoporphyrazines,[31, 32] are
the first members of a new class of phthalocyanine-based
chromophores,[33] which we aim to develop into viable PDT
agents. A preliminary communication describing our first
efforts towards this goal has appeared.[34]
R
R
R
R
N
N
CN
CN
O
O
H2N
H2N
CN
CN
a)
+
6a, c, d
7
8a, c, d
b)
a, b: R = Si(i Pr)3
for 5a, c, d
R
R
c:
d:
R = 3,5-di(tert-butyl)phenyl
R = 4-[(i Pr)3SiO]phenyl
5a-d
or c)
for 5b
N
N
Scheme 1. Synthesis of octaalkynyltetra-[6,7]-quinoxalinoporphyrazines
5a d. a) AcOH, room temp. 8a: 66%, 8c: 75%, 8d: 80%. b) Mg(OBu)2,
BuOH, reflux. 5a: 43%, 5c: 29%, 5d: 35%. c) LiOPent, PentOH, reflux,
then Zn(OAc)2. 5b: 39%.
R
R
R
R
N
N
N
M
N
N
N
N
N
N
N
In order to access more hydrophilic derivatives of 5 the
introduction of hydroxyl groups at the aryl termini of the
acetylenes of 5 was explored. As a first example, we prepared
the silyloxyphenyl-terminated dione 6d along the route
depicted in Scheme 2 starting from commercially available
4-iodophenol 9. Thus, conversion of 9 into its corresponding
triisopropysilyl ether 10 was followed by the alkynylation of
10 with 2-methylbut-3-yn-2-ol under Sonogashira condi-
tions.[41, 42] Subsequent liberation of the terminally free
acetylene 11 was achieved using potassium hydroxide in
refluxing benzene. The arylacetylene 11 was then converted to
N
N
N
N
R
R
5
5a: M = Mg, R = Si(i Pr)3
5b: M = Zn, R = Si(i Pr)3
5c: M = Mg, R = 3,5-di(tert-butyl)phenyl
5d: M = Mg, R = 4-[(i Pr)3SiO]phenyl
5e: M = Mg, R = 2,6-Me2-4-PEGO-phenyl
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Photosensitisers
1233 1241
Me
Me
Me
Me
b)
RO
a)
I
(iPr)3SiO
H
d)
b)
RO
I
PEGO
R
9: R = H
11
10: R = Si(iPr)3
12: R = H
14: R = SiEt3
15: R = H
a)
c)
(iPr)3SiO
13: R = PEG
O
O
c)
PEGO
Me
PEGO
Me
O
O
N
N
CN
CN
e)
Me
Me
Me
Me
(iPr)3SiO
6d
Scheme 2. Synthesis of dialkynyl-1,2-dione 6d. a) (iPr)3SiCl, imidazole,
CH2Cl2, RT, 14 h, 93%. b) 1) 2-Methylbut-3-yn-ol, [PdCl2(PPh3)2], CuI,
PhMe, Et3N, RT, 30 min; 2) PhH, KOH, reflux, 3 h, 68%. c) 1) BuLi;
2) LiBr, CuBr; 3) (COCl)2, T HF, 08C, 15 min, 46%.
PEGO
f)
Me
PEGO
Me
6e
8e
5e
PEG = (CH2CH2O)3Me
dione 6d using the copper-mediated alkynylation of oxalyl
chloride. Finally, 6d was converted via quinoxaline 8d to the
corresponding quinoxalinoporphyrazine 5d using the proto-
col outlined in Scheme 1.
Scheme 3. Synthesis of PEGylated octaalkynyltetra-[6,7]-quinoxalinopor-
phyrazine 5e. a) 2-[(methoxyethoxy)ethoxy]ethyl bromide, K2CO3,
ꢀ
CH3CN, reflux, 15 h, 75%. b) Et3SiC CH, [PdCl2(PPh3)2], CuI, Et3N,
reflux, 2 h, 83%. c) Bu4NF, moist THF, RT, 15 min, 100%. d) 1) BuLi;
2) LiBr, CuBr; 3) (COCl)2, T HF, 08C, 15 min, 40%. e) 7, AcOH, RT,
20 min, 85%. f) Mg(OBu)2, BuOH, reflux, 1.5 h, 18%.
Although siloxyphenyl-substituted quinoxalinoporphyra-
zine 5d continues to be a lipophilic chromophore, it was
expected that the solubility of 5d could be modified by
exploring the chemistry of the latent phenolate groups.
However, attempted desilylations using tetrabutylammonium
fluoride at either the dione or the dicyanoquinoxaline stage
were ill-fated as the phenolate intermediates generated
proved to be exceedingly unstable and decomposed rapidly.
The chemical manipulation of 5d itself was deemed unprac-
tical as the conversion of eight functional groups at a time
would result in low yields and/or complex reaction mixtures.
Moreover, a putative protodesilylated derivative of 5d was
expected to be quite insoluble.[43]
from hexacosa-13,14-dione[46] via the corresponding quinoxa-
line 17.
n-C12H25 n-C12H25
N
N
N
N
N
n-C12H25
n-C12H25
N
N
N
N
n-C12H25
n-C12H25
Mg
N
N
N
N
N
The strategy to obtain hydrophilic derivatives of 5 was
therefore slightly adjusted and, in analogy to texaphyrin 4,
solubilising polyethyleneglycol (PEG) chains were imple-
mented on the aryl-termini of the dialkynyl-1,2-diones
(Scheme 3). In a further structural modification the aryl
acetylene moiety was equipped with two methyl groups
flanking the CC triple bonds. This substitution pattern was
thought to enforce a porphyrazine conformation in which the
planes of the aryl groups of two vicinal arylethynyl units are
perpendicular to that of the main chromophore. The methyl
substituents will thus protrude above and below that plane
and should at least diminish chromophore aggregation.[43]
Hence, the reaction of 4-iodo-3,5-dimethylphenol (12)[44] with
2-[(methoxyethoxy)ethoxy]ethyl bromide[45] in the presence
of potassium carbonate afforded aryl iodide 13 which was
alkynylated with triethylsilylacetylene under Sonogashira
conditions to give 14. Protodesilylation of 14 with tetrabutyl-
ammonium fluoride afforded the free terminal acetylene 15
which was converted to dialkynyl-1,2-dione 6e using the
copper-mediated alkynylation of oxalyl chloride. Condensa-
tion of 6e with 1,2-diamino-4,5-dicyanobenzene 7 led to the
dicyanoquinoxaline 8e, and subsequent cyclotetramerisation
yielded the corresponding octaalkynyltetra-[6,7]-quinoxalino-
porphyrazine 5e.
N
N
n-C12H25 n-C12H25
16
The octaalkynyltetra-[6,7]-quinoxalinoporphyrazines are
deep blue (5a, b) or dark green (5c, d) solids with the
exception of green, waxy 5e. All chromophores are soluble in
common organic solvents (CH2Cl2, CHCl3, T HF, EOt ,
2
EtOAc) and are easily purified by chromatography on silica
gel and subsequent gel permeation chromatography on cross-
linked polystyrene (eluting with THF). Gratifyingly, PEGy-
lated 5e shows appreciable solubility in methanol, ethanol,
ethanol/water mixtures (up to 1:1 v/v) and DMSO, which
represent typical formulation systems currently in use with
other PDT-active chromophores. More lipophilic PDT
agents are commonly administered using colloidal delivery
systems such as liposomes.[47, 48]
[1]
Photophysical properties: The absorption profiles of the new
acetylenic chromophores are of particular interest, as this
parameter serves as a first measure by which to gauge the
potential of the compounds in future PDTapplications. As
For comparison purposes, the alkyl-substituted derivative
16 was prepared by the route depicted in Scheme 1 starting
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R. Faust et al.
FULL PAPER
with other typical phthalocyanine-type chromophores, the
spectra of the tetra-[6,7]-quinoxalinoporphyrazines 5 and 16
are dominated by a higher-energy B-band (around 400 nm)
and a lower-energy Q-band (around 750 nm) (Figure 2,
Table 1), both of which are characterised by high extinction
coefficients. For example, the absorption spectrum of silyl-
ethynyl-derivative 5a at room temperature in THF features a
affecting their beneficial optical properties. However, the
notable drop in the B- and Q-band intensities of 5d and
freshly prepared solutions of 5e in particular, points to an
increasing aggregation of these large aromatic macrocycles, a
behaviour that also prevented the accumulation of NMR data
for these compounds. It is therefore clear that any further
structural variations on 5 need to consider the impact of such
hydrophobic effects on these systems. All tetra-[6,7]-quinox-
alinoporphyrazines are fluorescent, showing small Stokes
shifts of about 20 nm upon excitation at wavelengths corre-
sponding to either their B- or Q-bands.
Singlet oxygen generation and photostability: The potential of
the quinoxalinoporphyrazines to induce photooxidation was
first established qualitatively using the oxidative degradation
of 1,3-diphenylisobenzofuran (DPBF). This established sin-
glet oxygen quencher undergoes a cycloaddition reaction with
1O2 to produce an endoperoxide which, in protic solvents,
converts swiftly to 1,2-dibenzoylbenzene.[49, 50] The photoox-
idative degradation of DPBF can be monitored using its
absorption maximum at 413 nm, a region in which 1,2-
dibenzoylbenzene does not show any absorption. Figure 3
illustrates the outcome of one such experiment. Hexanol
solutions of DPBF and sensitisers were prepared such that the
absorption at 413 nm was approximately A ˆ 1. The concen-
tration of the photosensitiser was [PS] ˆ 5.0  10À7 m in each
experiment. The time-dependent absorption at 413 nm was
monitored while the solutions were irradiated in quartz
cuvettes at room temperature using an ordinary slide-
projector halogen lamp (24 V, 250 W) with a fluence rate of
50 mWcmÀ1. High-energy wavelengths (< 550 nm) were
filtered out by passing the incident beam through an
appropriate cut-off filter. As can be seen from Figure 3, the
DPBF absorption maximum at 413 nm decays exponentially
in the presence of photosensitiser 5b, air and light (trace d).
Control experiments reveal that the presence of the quinox-
alinoporphyrazine sensitisers is essential for an oxidative
DPBF degradation (trace b). However, some degree of
photobleaching, that is DPBF decay in the absence of oxygen,
is also observed (trace c). Similar profiles were obtained for
Figure 2. UV/Vis/NIR-spectra of 5a (a) and 16 (b) in THF at room
temperature.
Table 1. UV/Vis/NIR-absorption maxima of tetra-[6,7]-quinoxalinopor-
phyrazines.[a]
B-band/ nm (e/mÀ1 cmÀ1
)
Q-band/ nm (e/mÀ1 cmÀ1
)
5a
5b
5c
5d
5e[b]
16
389 (288000)
380 (249000)
394 (305500)
397 (264000)
397 (172000)
364 (133100)
771 (510700)
770 (507000)
770 (516800)
772 (411000)
774 (233200)
735 (431000)
[a] All measurements in THF at RT. [b] B- and Q-band values in DMSO at
RT: 400 nm (140400 mÀ1 cmÀ1), 787 nm (38500mÀ1 cmÀ1).
B-band at 389 nm (e ˆ 288000mÀ1 cmÀ1) and a Q-band at
771 nm (e ˆ 510000mÀ1 cmÀ1). A comparison between the
UV/Vis/NIR spectra of alkyl-substituted 16 and triisopropyl-
silyl-substituted 5a (Figure 2) reveals that the introduction of
eight acetylene groups leads to bathochromically and hyper-
chromically shifted absorption maxima of both, the B- and the
Q-band. As the long wavelength maxima of all acetylenic
chromophores 5 peak beyond the visible at around 770 nm,
their absorption profile is ideally suited for addressing these
compounds in a biological environment and for efficient
singlet oxygen generation. It is interesting to note in this
context that the PDT-relevant absorption maxima of haema-
toporphyrin 1 and texaphyrin 4, established PDTagents of the
first and the second generation, are at 630 nm (e ˆ
5000mÀ1 cmÀ1) and 732 nm (e ˆ 42000mÀ1 cmÀ1), respective-
ly.[1]
There is virtually no difference in the Q-band positions of
the silyl-terminated octaalkynylquinoxalinoporphyrazines
5a,b on one hand and the aryl-terminated porphyrazines 5c
and 5d; this, however, suggests that the chromophores×
effective p-systems do not extend to the peripheral phenyl
rings. The aryl substituents can therefore be used to fine-tune
the compound×s pharmacological profile without, principally,
Figure 3. Photooxidation of 1,3-diphenylisobenzofuran (DPBF) with 5b in
aerated hexanol at room temperature (d). The DPBF absorption at 413 nm
was monitored. a) In the absence of light; b) in the absence of 5b; c) in the
absence of oxygen.
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1233 1241
5a, although in this case the rate of DPBF degradation was
somewhat slower. The PEGylated derivative 5e, however,
showed little photooxidising potential in the qualitative assay
with DPBF a finding that we attribute to the high degree of
aggregation of 5e in this solvent. In contrast, quinoxalinopor-
phyrazines 5a and 5b show little aggregation at this concen-
tration range in hexanol.
The efficiency with which the tetra-[6,7]-quinoxalinopor-
phyrazines can generate singlet oxygen was also assessed
quantitatively by determining their singlet oxygen quantum
yields using 1O2-phosphorescence measurements in THF
(Table 2). The results of these experiments reveal notable
differences. Compared with the non-acetylenic reference
a fluorescence at 500 nm. Efforts to elucidate the nature of the
photodegradation product of 5e by mass spectrometry were
unsuccessful, but the loss of the original emission at 790 nm
points to the disrupture of the macrocyclic porphyrazine
framework of 5e. Interestingly, derivatives 5a d are photo-
stable under these conditions. It appears that the higher
photostability of 5e in hexanol as compared to THF is a result
of chromophore aggregation in the former solvent whereas in
the latter the reduced degree of aggregation seems to
facilitate photo-induced decomposition. However, we have
currently no satisfying explanation for the differing photo-
stabilities of 5e and 5a d in THF, a solvent in which all
quinoxalinoporphyrazines prevail in non-aggregated form at
the concentrations used.[51]
Table 2. Fluorescence lifetimes tf, fluorescence quantum yields Ff, and
singlet oxygen quantum yields FD for selected tetra-[6,7]-quinoxalinopor-
phyrazines.[a]
Conclusion
[c]
tf/ns
Ff[b]
FD
We have devised a flexible and concise synthetic route to a
new class of photosensitiser, the octaalkynyltetra-[6,7]-quin-
oxalinoporphyrazines 5. Starting from appropriately func-
tionalised dialkynyl-1,2-diones lipophilic and hydrophilic
derivatives of these chromophores are readily prepared. The
title compounds feature intense absorptions in the near
infrared, efficiently photosensitise the generation of singlet
oxygen and, with the exception of the more hydrophilic
derivative 5e, possess satisfactory photostability. Based on the
flexibility of our approach, an elaboration of these systems
into bioavailable, target-specific PDTagents seems therefore
warranted and work towards this goal is currently underway.
5a
5b
5e
16
4.3 Æ 0.1
2.4 Æ 0.1
4.0 Æ 0.1
5.3 Æ 0.1
0.46
0.25
0.43
0.59
0.19
0.56
0.37[d]
0.15
[a] All measurements in aerated THF at RT. [b] Absolute values (Æ10%)
relative to cresyl violet in MeOH (Ff ˆ 0.54) and disulfonated phthalo-
cyanine standards in H2O (Ff ˆ 0.40) standards. [c] Obtained by time-
resolved phosphorescence measurements using excitation at lex ˆ 355 nm.
Values are relative to perinaphthenone (FD ˆ 0.97) and have an error of
Æ10%. [d] Due to photodegradation we estimate the error margin to be ca.
Æ20%.
compound 16 (FD ˆ 0.15), all acetylenic tetra-[6,7]-quinoxa-
linoporphyrazines sensitise the formation of singlet oxygen
more efficiently, albeit to various degrees. Whereas the singlet
oxygen quantum yield FD of Mg-coordinated 5a amounts to
only 0.19, that of PEGylated 5e is increased to 0.37, and is
surpassed by that of Zn-derivative 5b with a FD value of 0.56.
The superiority of Zn2‡ coordinated to the macrocyclic core of
phthalocyanine-type photosensitisers in inducing singlet oxy-
gen has been noted before and is attributed to their high
triplet quantum yields and their long triplet state lifetimes.[14]
The values obtained for 5b and 5e compare favourably with
the singlet oxygen quantum yields of other sensitisers
currently in use in photodynamic therapy (e.g. protoporphy-
rin: FD ˆ 0.57 in benzene; texaphyrin 4: FD ˆ 0.11 in
MeOH).[1]
We have also examined the photostability of the novel
tetraquinoxalinoporphyrazines 5 by irradiating aerated hex-
anol solutions under conditions identical to those described
for the DPBF experiments (slide projector halogen lamp:
24 V, 250 W, fluence rate: 50 mWcmÀ1, cut-off filter <
550 nm) and by monitoring the Q-band absorption of the
chromophore. Sensitisers 5b and 5e display remarkable
photostabilities (less than 6% degradation after irradiation
for 4 h). In contrast, porphyrazine 5a is less photostable under
these conditions and undergoes 45% photodegradation with-
in four hours. The situation is quite different when an aerated
THF solution of 5e is irradiated at 355 nm in the spectro-
fluorimeter. In this case, complete chromophore degradation
occurs within 7 min to yield an unspecified photoproduct with
Experimental Section
General: All reactions were conducted in oven-dried glassware under an
argon atmosphere. Unless otherwise indicated, all reagents were purchased
from commercial suppliers and were used as received. Known starting
materials that were not commercially available were prepared according to
literature procedures cited in the text. Solvents were purified and dried
according to customary procedures:[52] THF was distilled from sodium/
benzophenone under a nitrogen atmosphere; toluene was distilled from
sodium under a nitrogen atmosphere; dichloromethane, acetonitrile and
triethylamine were distilled from calcium hydride under
a nitrogen
atmosphere; butanol and pentanol were heated under reflux with
magnesium, activated by iodine, distilled and stored under argon over
molecular sieves (4 ä). Lithium bromide was dried at 1608C at 0.1 mm Hg
for 2 h. Analytical thin-layer chromatography was carried out using
precoated, aluminium-backed, silica gel 60 F254 plates (E. Merck) and the
spots visualised by UV light. Flash column chromatography was performed
under positive pressure from a compressed air line using silica gel 60,
supplied by BDH (230 400 mesh). Gel permeation chromatography was
performed using a polystyrene resin cross-linked with divinylbenzene (Bio-
beads 1-SX, Bio-Rad, Munich), preswollen in THF. Melting points were
1
determined on a Reichert hotstage and are uncorrected. H NMR spectra
were recorded on a Bruker AMX400 instrument in CDCl3, [D6]-acetone or
THF/CDCl3 and are reported as follows: chemical shift d (ppm), [multi-
plicity, number of protons, coupling constant J [Hz] and assignment].
Residual protic solvent CHCl3 (dH ˆ 7.24) and CD3C(O)CD2H (dH ˆ 2.04)
was used as internal reference. 13C NMR spectra were recorded on the
same instrument operating at a frequency of 100.5 MHz using the central
signals of CDCl3 (dc ˆ 77.0) or [D6]-acetone (dc ˆ 29.8) as reference signal.
IR spectra were taken on a Perkin Elmer 1600 FT-IR or a Shimadzu
FTIR-8700 spectrometer either as KBr-discs or as film. UV/Vis/NIR-
spectra were taken on a Perkin Elmer Lambda40 instrument; absorption
Chem. Eur. J. 2003, 9, No. 5
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0905-1237 $ 20.00+.50/0
1237

R. Faust et al.
FULL PAPER
maxima (lmax) in nm; extinction coefficients e in mÀ1 cmÀ1. Mass spectra
were recorded on a VGZABSE instrument (EI and FAB ionisation) or a
Micromass Quattro LC instrument (ES). MALDI-TOF mass spectrometry
was carried out on a Fisons VG TOF Spec or a Bruker Biflex III Reflectron
MALDI-TOF mass spectrometer using trans-3-indoleacrylic acid as a
matrix. Microanalyses were carried out on a Perkin Elmer 2400 CHN
machine.
[2,3,11,12,20,21,29,30-Octakis(4-(triisopropylsilyloxy)phenylethynyl)tetra-
[6,7]-quinoxalinoporphyrazinato]-magnesium(ii) (5d): Tetraquinoxalino-
porphyrazine 5d was prepared from dicyanoquinoxaline 8d (160 mg,
0.22 mmol) analogous to 5a. To enhance solubility of the starting material,
toluene (1 mL) was added to the reaction mixture. The crude product was
purified by flash chromatography (eluting first with CH2Cl2, then with
THF) followed by gel-permeation chromatography (THF), giving the pure
product as a dark green solid (56 mg, 19 mmol, 35%). IR (KBr): nÄ ˆ 2943
Fluorescence spectra were recorded using a Jobin Yvon Fluorolog FL3-22
spectrofluorimeter. Fluorescence quantum yields were determined from
the integrated emission spectra relative to cresyl violet in methanol (Ff ˆ
0.54)[53] and disulfonated aluminium phthalocyanine in water (Ff ˆ 0.40).[54]
Fluorescence lifetimes were recorded by time-correlated single photon
counting using a pulsed 635 nm laser as the excitation source. The
equipment used for this measurement has been fully described else-
where.[55] Singlet oxygen quantum yields were recorded by time-resolved
phosphorescence measurements using the method described by Nonell and
Braslavsky[56] using 355 nm excitation and perinapthenone as a standard
(FD ˆ 0.97).[57]
(CH), 2866 (CH), 2202 cmÀ1 (C C); UV (THF): lmax (e) ˆ 397 (264000),
ꢀ
548 (22000), 693 (43000), 705 (45000), 732 (46000), 772 nm (411000);
‡
MALDI-TOF-MS: m/z: isotopic cluster peaking at 2924 [M ]; elemental
analysis calcd (%) for C176H208N16O8Si8Mg  2H2O (2960.71): C 71.39, H
7.22, N 7.57; found: C 71.55, H 7.14, N 7.44.
[2,3,11,12,20,21,29,30-Octakis[4-(((methoxyethoxy)ethoxy)ethoxy)-2,6-di-
methyl-phenylethynyl]tetra-[6,7]-quinoxalinoporphyrazinato]magnesium-
(ii) (5e): Tetraquinoxalinoporphyrazine 5e was prepared from dicyano-
quinoxaline 8e (55 mg, 73 mmol) analogous to 5a. The crude product was
purified by flash chromatography (impurities were eluted first with Et2O/
CH2Cl2, the product was then eluted with THF/MeOH 4:1), followed by
gel-permeation chromatography, yielding the title compound as a dark
[2,3,11,12,20,21,29,30-Octakis(triisopropylsilylethynyl)tetra-[6,7]-quinoxa-
linopor-phyrazinato]-magnesium(ii) (5a):
A mixture of Mg turnings
(39 mg, 1.6 mmol), one small crystal of iodine and butanol (5 mL) was
heated under reflux for 4 h. The mixture was then cooled to room
temperature and dicyanoquinoxaline 8a (216 mg, 0.4 mmol) was added in
one portion. The reaction was quickly re-heated to reflux for 1 h. The
mixture was cooled to room temperature, the solvent removed in vacuo
(Kugelrohr), yielding the crude product as a dark blue solid. This was
purified by flash chromatography (5% EtOAc/hexane ! 40% EtOAc/
hexane) followed by gel permeation chromatography using THF as eluent,
giving the title compound as a dark blue solid (95 mg, 43 mmol, 43%).
1H NMR (THF/CDCl3, 400 MHz): d ˆ 10.03 (s, 8H, aryl CH), 1.29 (s,
168H, Si(CH(CH3)2)3); 13C NMR (THF/CDCl3, 100.5 MHz): d ˆ 152.3,
139.6, 138.8, 138.6, 121.5, 103.3, 97.4, 17.3, 10.2; IR (KBr): nÄ ˆ 2943 cmÀ1
green waxy solid (10 mg, 3.3 mmol, 18%). IR (KBr): nÄ ˆ 2922 (CH), 2191
À1
ꢀ
(C C), 1134 cm (C-O); UV (DMSO): lmax (e) ˆ 266 (159000), 273
(159000), 287 (157000), 584 (13000), 788 nm (38000); MALDI-TOF-MS:
‡
m/z: isotopic cluster peaking at 3066 [M ]; elemental analysis calcd (%) for
C176H192N16O32Mg  2H2O (3103.87): C 68.11, H 6.36, N 7.22; found: C
65.78, H 6.09, N 6.85.
1,6-Bis[4-(triisopropylsilyloxy)phenyl]hexa-1,5-diyne-3,4-dione (6d): BuLi
(2.25 mL of a 1.6m solution in hexane, 3.6 mmol) was added to a cooled
(08C) solution of the phenylacetylene 11 (1.0 g, 3.6 mmol) in THF (10 mL).
The reaction mixture was stirred for 10 min and then transferred through a
cannula to a to a cooled (08C) solution of LiBr (625 mg, 7.2 mmol) and
CuBr (517 mg, 3.6 mmol) in THF (20 mL). The reaction mixture was
stirred for 15 min at that temperature after which time a cooled (08C)
solution of oxalyl chloride (208 mg, 1.64 mmol) in THF (10 mL) was added
dropwise. Stirring was continued for an additional 15 min and the reaction
mixture was quenched by the addition of saturated aqueous ammonium
chloride solution (20 mL) and 1m hydrochloric acid (4 mL). The organic
layer was separated and the aqueous layer extracted with Et2O (30 mL).
The combined organic layers were dried (Na2SO4), filtered and the solvents
evaporated in vacuo leaving a brownish oil. This was subjected to flash
chromatography (5% EtOAc in hexane) giving the title compound as a
yellow solid (456 mg, 0.75 mmol, 46%). An analytically pure sample was
obtained by recrystallisation from hexane at À208C. M.p. 83 858C;
1H NMR (CDCl3, 400 MHz): d ˆ 7.57 (d, 4H, J ˆ 8.6 Hz, aryl CH), 6.86 (d,
4H, J ˆ 8.6 Hz, aryl CH), 1.23 (m, 6H, CH(CH3)2), 1.07 (d, 36H, J ˆ 7.4 Hz,
CH(CH3)2); 13C NMR (CDCl3, 100.5 MHz): d ˆ 172.6, 159.7, 136.1, 120.5,
ˆ
(CH), 2866 (CH), C C absorption not visible; UV (THF): lmax (e) ˆ 244
(175000), 249 (210000), 255 (226000), 389 (288000), 553 (18000), 703
(58000), 731 (54000), 771 nm (510700); MALDI-TOF-MS: m/z: isotopic
‡
cluster peaking at 2187 [M ]; elemental analysis calcd (%) for
C128H176N16Si8Mg (2187.90): C 70.27, H 8.11, N 10.24; found: C 70.25, H
8.43, N 10.00.
2,3,11,12,20,21,29,30-Octakis(triisopropylsilylethynyl)tetra-[6,7]-quinoxali-
noporphyrazinato]-zinc(ii) (5b):
A suspension of Li metal (1.2 mg,
1.7 mmol) in pentanol (1 mL) was heated to 1008C until all the lithium
had dissolved. The solution was cooled to room temperature, dicyanoqui-
noxaline 8a (100 mg, 0.19 mmol) was added, the reaction reheated to
1308C and held at that temperature for 1 h. To the reaction mixture was
then added Zn(OAc)2 (60 mg, 0.33 mmol) and heating was continued for
another 3 h. After cooling to room temperature, the solvent was distilled in
vacuo (Kugelrohr) and the residue purified by flash chromatography (5%
EtOAc/hexane ! 40% EtOAc/hexane) followed by gel-permeation chro-
matography, giving the pure title compound as a dark blue solid (41 mg,
18 mmol, 39%). 1H NMR (THF/CDCl3, 400 MHz): d ˆ 10.03 (s, 8H, aryl
CH), 1.31 (s, 168H, Si(CH(CH3)2)3); 13C NMR (THF/CDCl3, 100.5 MHz):
d ˆ 152.4, 139.6, 138.7, 138.0, 121.6, 103.4, 97.5, 17.2, 10.2; IR (KBr): nÄ ˆ 2943
111.2, 101.5, 86.8, 17.8, 12.6; IR (KBr): nÄ ˆ 2945 (s, CH), 2866 (s, CH), 2187
À1
ꢀ
ˆ
(s, C C), 1657 cm (s, C O); UV (CH2Cl2): lmax (e) ˆ 266 (27700), 366 nm
‡
‡
(26700); EI-MS (70 eV): m/z (%): 602 (2.5) [M ], 546 (48.0) [M À 2CO],
‡
301 (100) [1³2M ]; elemental analysis calcd (%) for C36H50O4 (602.96): C
71.71, H 8.36; found: C 71.99, H 8.43.
(CH), 2866 cmÀ1 (CH), C C absorption not visible; UV (THF): lmax (e) ˆ
ˆ
1,6-Bis[4-[[(methoxyethoxy)ethoxy]ethoxy]-2,6-dimethylphenyl]hexa-1,5-
diyne-3,4-dione (6e): Dione 6e was prepared analogous to dione 6d
starting from acetylene 15 (2.17 g, 7.43 mmol). After hydrolysis, the layers
were separated and the aqueous layer was extracted with CH2Cl2 (100 mL).
The combined organic layers were dried (MgSO4), the solution then
filtered through a pad of silica gel, followed by the removal of the solvent in
vacuo which left a brown oil. This was subjected to flash chromatography
(EtOAc/CH2Cl2 1:1), yielding the product as a yellow solid (870 mg,
1.36 mmol, 40%). An analytically pure sample was obtained by recrystal-
lisation from hexane. M.p. 79 808C; 1H NMR (CDCl3, 400 MHz): d ˆ 6.62
(s, 4H, CH), 4.12 (t, 4H, J ˆ 4.8 Hz, OCH2), 3.82 (t, 4H, J ˆ 4.8 Hz, OCH2),
3.70 (m, 4H, OCH2), 3.63 (m, 8H, OCH2), 3.52 (m, 4H, OCH2), 3.35 (s, 6H,
OCH3), 2.49 (s, 12H, CH3); 13C NMR (CDCl3, 100.5 MHz): d ˆ 173.3,
161.3, 146.5, 113.6, 111.6, 100.0, 94.3, 71.9, 70.8, 70.6, 70.5, 69.5, 67.4, 59.0,
380 (249000), 547 (27000), 702 (58000), 731 (56000), 770 nm (507000);
‡
MALDI-TOF-MS: m/z: isotopic cluster peaking at 2228 [M ]; elemental
analysis calcd (%) for for C128H176N16Si8Zn (2228.97): C 68.98, H 7.96, N
10.05; found: C 68.62, H 8.22, N 9.87.
[2,3,11,12,20,21,29,30-Octakis(3,5-di(tert-butyl)phenylethynyl)tetra-[6,7]-
quinoxalinoporphyrazinato]magnesium(ii) (5c): Tetraquinoxalinoporphyr-
azine 5c was prepared from dicyanoquinoxaline 8c (242 mg, 0.4 mmol)
analogous to 5a. To enhance solubility of the starting material, toluene
(2 mL) was added to the reaction mixture. The crude product was purified
by flash chromatography (eluting first with CH2Cl2, then with 20% Et2O in
CH2Cl2) followed by gel permeation chromatography (THF), yielding the
pure product as a dark green solid (70 mg, 29 mmol, 29%). IR (KBr): nÄ ˆ
2960 (CH), 2204 cmÀ1 (C C); UV (THF): lmax (e) ˆ 244 (196000), 249
ꢀ
ꢀ
ˆ
(232000), 255 (244000), 261 (200000), 286 (139000), 394 (305500), 571
(26100), 704 (59400), 730 (59400), 770 nm (516800); MALDI-TOF-MS:
21.2; IR (KBr): nÄ ˆ 2895 (CH), 2180 (C C), 1656 (C O), 1140 (C-O); UV
(CH2Cl2): lmax (e) ˆ 273 (25400), 383 nm (31000); EI-MS (70 eV): m/z (%):
‡
‡
‡
‡
m/z: isotopic cluster peaking at 2442 [M ]; elemental analysis calcd (%) for
610 (0.6) [M À CO], 582 (18.1) [M À 2CO], 319 (59.3) [1³2M ], 59 (100)
‡
C168H176N16Mg ¥ 2H2O (2479.69): C 81.38, H 7.32, N 9.04; found: C 81.65, H
7.20, N 8.59.
[(CH3OCH2CH2) ]; elemental analysis calcd (%) for C36H46O10 (638.75): C
67.69, H 7.26; found: C 67.49, H 7.15.
1238
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0905-1238 $ 20.00+.50/0
Chem. Eur. J. 2003, 9, No. 5

Photosensitisers
1233 1241
1,2-Diamino-4,5-dicyanobenzene (7):[36]
A
mixture of 1,2-diamino-4,5-
calcd (%) for C44H52N4O2Si2 (725.09): C 72.89, H 7.23, N 7.73; found: C
73.08, H 7.08, N 7.65.
dibromobenzene[37, 38] (2.0 g, 7.5 mmol) and CuCN (2.7g, 30.0 mmol) in
DMF (15 mL) was heated to 1408C for 15 h. After this time, the reaction
was cooled to room temperature and poured into an aqueous ammonia
solution (conc. NH3 (60 mL), water (140 mL)). The resulting suspension
was filtered, the collected solid was washed with the same ammonia
solution until the filtrate was colourless and the crude product was then
washed out with acetone. Removal of the solvent yielded a brownish solid
which was recrystallised from H2O/EtOH (3:1), to give the title compound
as off-white needles (300 mg, 1.90 mmol, 25%). M.p. 272 2758C (de-
comp.; lit.:[36] 193 1958C). Due to this discrepancy, the product was further
characterised: 1H NMR ([D6]-acetone, 400 MHz): d ˆ 7.03 (s, 2H, CH),
5.38 (broad s, 4H, NH2); 13C NMR ([D6]-acetone, 100.5 MHz): d ˆ 140.0,
118.0, 117.7, 104.4; IR (KBr): nÄ ˆ 3444 (NH2), 3334 (NH2), 2218 cmÀ1
6,7-Dicyano-2,3-bis[4-[[(methoxyethoxy)ethoxy]ethoxy]-2,6-dimethylphe-
nylethynyl]-quinoxaline (8e): Dione 6e (59.4 mg, 0.093 mmol) was added
to a suspension of 1,2-diamino-4,5-dicyanobenzene 7 (14.7 mg, 0.093 mmol)
in AcOH (2 mL). The reaction mixture was warmed until all compounds
had dissolved and further stirred at room temperature for 20 min.
Subsequently the solvent was removed in vacuo. The residual brown oil
was purified by flash chromatography (CH2Cl2/EtOAc 2:1 ! 1:2) to yield
the title compound as an orange solid (60.0 mg, 0.079 mmol, 85%). An
analytically pure sample was obtained by recrystallisation from EtOH. M.p.
97 998C; 1H NMR (CDCl3, 400 MHz): d ˆ 8.37 (s, 2H, quinoxaline CH),
6.56 (s, 4H, phenyl CH), 4.07 (t, 4H, J ˆ 4.8 Hz, OCH2), 3.80 (t, 4H, J ˆ
4.8 Hz, OCH2), 3.67 (m, 4H, OCH2), 3.61 (m, 8H, OCH2), 3.49 (m, 4H,
OCH2), 3.31 (s, 6H, OCH3), 2.36 (s, 12H, CH3); 13C NMR (CDCl3,
100.5 MHz): d ˆ 160.0, 144.9, 143.9, 140.8, 135.9, 114.9, 114.1, 113.4, 112.9,
98.9, 93.4, 71.9, 70.8, 70.6, 70.5, 69.5, 67.3, 59.0, 21.2; IR (KBr): nÄ ˆ 2872
‡
ꢀ
(C N); EI-MS (70 eV): m/z (%): 158 (100) [M ]; elemental analysis calcd
(%) for C8H6N4 (158.63): C 60.75, H 3.82, N 35.42; found: C 61.02, H 3.60, N
35.42.
(CH), 2193 (C N), 1136 cmÀ1 (C-O); UV (CH2Cl2): lmax (e) ˆ 228 (22700),
ꢀ
6,7-Dicyano-2,3-bis(triisopropylsilylethynyl)quinoxaline (8a): 1,2-Diami-
no-4,5-dicyanobenzene (7; 153 mg, 0.85 mmol) was added in one portion at
room temperature to a solution of 1,6-bis(triisopropylsilyl)hexa-1,5-diyne-
3,4-dione (6a)[35] (355 mg, 0.85 mmol) in AcOH (20 mL). The resulting
solution was stirred for 20 min at this temperature, before the solvent was
removed in vacuo, to yield a brown oil. This was subjected to flash
chromatography (10% EtOAc in hexane) giving the product as a colourless
solid (304 mg, 0.56 mmol, 66%). An analytically pure sample was obtained
by recrystallisation from pentane. M.p. 91 938C; 1H NMR (CDCl3,
400 MHz): d ˆ 8.46 (s, 2H, aryl CH), 1.24 1.13 (m, 42H, Si(CH(CH3)2)3);
13C NMR (CDCl3, 100.5 MHz): d ˆ 143.4, 140.7, 136.1, 114.62, 114.58, 105.0,
275 (42200), 351 (19200), 432 nm (23800); ES-MS: m/z (%): 761 (100)
‡
[MH ]; elemental analysis calcd (%) for C44H48N4O8 (760.88): C 69.46, H
6.36, N 7.36; found: C 69.06, H 6.29, N 7.37.
1-Iodo-4-(triisopropylsilyloxy)benzene (10): Chlorotriisopropylsilane
(4.84 mL, 4.38 g, 22.7 mmol) was added at room temperature to a solution
of 4-iodophenol (9; 5.0 g, 22.7 mmol) and imidazole (3.87 g, 56.8 mmol) in
CH2Cl2 (40 mL). The reaction mixture was then stirred for 24 h at the same
temperature. Subsequently the solvent was evaporated in vacuo and the
residue was filtered through a pad of silica gel (hexane) to yield the product
1
as a colourless oil (7.99 g, 21.2 mmol, 93%). H NMR (CDCl3, 400 MHz):
ꢀ
102.4, 18.6, 11.2; IR (KBr): nÄ ˆ 2943 (CH), 2866 (CH), 2237 (C N),
d ˆ 7.47 (d, 2H, J ˆ 8.7 Hz, aryl CH), 6.63 (d, 2H, J ˆ 8.7 Hz, aryl CH), 1.21
(m, 3H, CH(CH3)2), 1.07 (d, 18H, J ˆ 7.2 Hz, CH(CH3)2); 13C NMR
(CDCl3, 100.5 MHz): d ˆ 156.0, 138.2, 122.3, 83.2, 17.8, 12.6; IR (film): nÄ ˆ
2151 cmÀ1 (C C); UV (CH2Cl2): lmax (e) ˆ 250 (28100), 288 (48800), 370
ꢀ
‡
(16000), 390 nm (20000); EI-MS (70 eV): m/z (%): 540 (1.2) [M ], 498
‡
‡
‡
2943 (CH), 2866 cmÀ1 (CH); EI-MS (70 eV): m/z (%): 376 (54.6) [M ];, 333
(21.3) [M À C(CH3)2], 456 (100) [M À 2C(CH3)2]; elemental analysis
calcd (%) for C32H44N4Si2 (540.90): C 71.06, H 8.20, N 10.36; found: C 71.14,
H 8.39, N 10.41.
‡
(100) [M À CH(CH3)2], 305 (33.4), 277 (51.2), 263 (26.9); HR-MS (FAB):
calcd for C15H25IOSi: 376.0719; found: 376.0732.
6,7-Dicyano-2,3-bis[3,5-di(tert-butyl)phenylethynyl]quinoxaline (8c):
A
1-Ethynyl-4-(triisopropylsilyloxy)benzene (11): A solution of 1-iodo-4-
(triisopropylsilyloxy)benzene (10; 2.83 g, 7.5 mmol) in toluene (20 mL) was
purged with Ar for 5 min. To this solution was added Et3N (3.5 mL),
2-methyl-but-3-yn-2-ol (0.89 mL, 0.76 g, 9.0 mmol), [PdCl2(PPh3)2]
(100 mg, 0.14 mmol) and CuI (30 mg, 0.16 mmol) at room temperature.
The reaction mixture was stirred for 30 min at the same temperature, after
which time a black suspension was obtained. The volatile components were
removed in vacuo. The residue was filtered through a pad of silica gel (30%
EtOAc in hexane) to give a brown oil, which was dissolved in PhH (30 mL).
Subsequently crushed pellets of KOH (0.9 g, 16.1 mmol) were added. The
reaction mixture was heated to reflux for 3 h, cooled to room temperature
and the solvent was removed in vacuo. The residue was filtered through a
pad of silica gel (hexane), yielding the title compound as a colourless oil
(1.42 g, 5.1 mmol, 68%). 1H NMR (CDCl3, 400 MHz): d ˆ 7.34 (d, 2H, J ˆ
suspension of 1,6-bis[3,5-di(tert-butyl)phenyl]hexa-1,5-diyne-3,4-dione
(6c)[29] (412 mg, 0.85 mmol) in AcOH (20 mL) and THF (10 mL) was
heated until all the material had dissolved. To this solution was added 1,2-
diamino-4,5-dicyanobenzene (7; 153 mg, 0.85 mmol) in one portion and the
resulting solution was stirred for 20 min at room temperature during which
time a yellow precipitate formed. The solvents were evaporated in vacuo
and the resulting yellow solid was recrystallised from hexane/toluene (2:1),
giving the title compound as a fluffy yellow solid (350 mg). The mother
liquor was evaporated in vacuo and the obtained solid recrystallised, giving
a second crop (35 mg) of the product (overall 385 mg, 75%). M.p. 275
1
2798C (decomp.); H NMR (CDCl3, 400 MHz): d ˆ 8.47 (s, 2H, quinoxa-
line CH), 7.50 (t, 2H, J ˆ 1.7 Hz, phenyl CH), 7.47 (d, 4H, J ˆ 1.7 Hz, phenyl
CH), 1.24 (s, 36H, CH3; 13C NMR (CDCl3, 100.5 MHz): d ˆ 151.4, 145.1,
140.8, 136.1, 126.7, 125.4, 119.6, 114.8, 114.6, 102.3, 85.1, 34.8, 31.2; IR
ꢀ
8.6 Hz, aryl CH), 6.79 (d, 2H, J ˆ 8.6 Hz, aryl CH), 2.97 (s, 1H, C CH), 1.24
(KBr): nÄ ˆ 2963 (CH), 2208 cmÀ1 (C N); UV (CH2Cl2): lmax (e) ˆ 249
(m, 3H, CH(CH3)2), 1.07 (d, 18H, J ˆ 7.3 Hz, CH(CH3)2); 13C NMR
(CDCl3, 100.5 MHz): d ˆ 156.7, 133.6, 119.9, 114.4, 83.8, 75.8, 17.8, 12.6; IR
ꢀ
(30700), 280 (35600), 296 (31800), 409 nm (21000); EI-MS (70 eV): m/z
‡
‡
‡
(film): nÄ ˆ 3317 (acetylenic CH), 2945 (CH), 2866 (CH), 2108 cmÀ1 (C C);
(%): 604 (19.0) [M ], 548 (65.1) [M À C(CH3)3‡H], 533 (45.0) [M
À
ꢀ
‡
‡
‡
C(CH3)3 À CH3‡H], 287 (31.8), 57 (100) [C(CH3)3 ]; elemental analysis
calcd (%) for C42H44N4 (604.84): C 83.40, H 7.33, N 9.26; found: C 83.34, H
7.54, N 9.21.
EI-MS (70 eV): m/z (%): 274 (34.9) [M ], 231 (100) [M À CH(CH3)2], 203
(39.4), 175 (89.8), 161 (63.0); HR-MS (FAB): calcd for C17H26OSi‡H:
275.1831; found: 275.1834.
6,7-Dicyano-2,3-bis[4-(triisopropylsilyloxy)phenylethynyl]quinoxaline
(8d): A suspension of dione 6d (200 mg, 0.33 mmol) in AcOH (6 mL) was
heated until all the material had dissolved. To this solution was added 1,2-
diamino-4,5-dicyanobenzene (7; 53 mg, 0.33 mmol) in one portion and the
reaction mixture was stirred for 20 min at room temperature. Removal of
the solvent in vacuo yielded a brownish solid which was recrystallised from
iPrOH/MeOH/EtOAc, giving the title compound as yellow needles
(191 mg, 0.26 mmol, 80%). M.p. 232 2348C; 1H NMR (CDCl3,
400 MHz): d ˆ 8.42 (s, 2H, quinoxaline-CH), 7.58 (d, 4H, J ˆ 8.6 Hz,
phenyl-CH), 6.89 (d, 4H, J ˆ 8.6 Hz, phenyl-CH), 1.27 (m, 6H, CH(CH3)2),
1.10 (d, 36H, J ˆ 7.3 Hz, CH(CH3)2); 13C NMR (CDCl3, 100.5 MHz): d ˆ
158.8, 144.9, 140.7, 136.0, 134.6, 120.5, 114.9, 114.4, 112.8, 101.6, 86.2, 17.8,
1-Iodo-4-[[(methoxyethoxy)ethoxy]ethoxy]-2,6-dimethylbenzene
(13):
Anhydrous potassium carbonate (6.26 g, 45.4 mmol) was added at room
temperature to a solution of 2-[(methoxyethoxy)ethoxy]ethyl bromide[45]
(5.15 g, 22.7 mmol) and 4-iodo-3,5-dimethylphenol (12)[44] (9.03 g,
27.2 mmol) in CH3CN (30 mL). The reaction mixture was heated to reflux
for 15 h. After this time, the mixture was cooled to room temperature,
poured into water (150 mL), neutralised with 1m HCl and extracted with
EtOAc (2 Â 100 mL). The combined organic extracts were dried (MgSO4)
and filtered. The solvents were removed in vacuo to leave a brown oil,
which was subjected to flash chromatography (EtOAc/hexane 1:1) to yield
the product as a pale yellow oil (6.73 g, 17.1 mmol, 75%). 1H NMR (CDCl3,
400 MHz): d ˆ 6.65 (s, 2H, CH), 4.06 (t, 2H, J ˆ 4.9 Hz, OCH2), 3.80 (t, 2H,
J ˆ 4.9 Hz, OCH2), 3.70 (m, 2H, OCH2), 3.64 (m, 4H, OCH2), 3.52 (m, 2H,
OCH2), 3.35 (s, 3H, OCH3), 2.40 (s, 6H, CH3); 13C NMR (CDCl3,
100.5 MHz): d ˆ 158.3, 142.7, 113.5, 97.2, 71.9, 70.8, 70.6, 70.5, 69.6, 67.3,
59.0, 29.7; IR (film): nÄ ˆ 2876 (CH), 1111 cmÀ1 (C-O); EI-MS (70 eV): m/z
12.7; IR (KBr): nÄ ˆ 2945 (CH), 2866 (CH), 2203 cmÀ1 (C N); UV (CH2Cl2):
ꢀ
lmax (e) ˆ 254 (36600), 279 (38300), 302 (34000), 339 (38400), 421 nm
‡
‡
(30600); EI-MS (70 eV): m/z (%): 724 (100) [M ], 681 (54.0) [M
À
‡
CH(CH3)2], 639 (23.1) [M À CH(CH3)2 À C(CH3)2]; elemental analysis
Chem. Eur. J. 2003, 9, No. 5
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0905-1239 $ 20.00+.50/0
1239

R. Faust et al.
FULL PAPER
‡
‡
(%): 394 (41.9) [M ], 248 (32.2), 103 (27.7), 59 (100) [(CH3OCH2CH2) ];
HR-MS (FAB): calcd for C15H23O4I‡H: 395.0719; found: 395.0735.
[1] R. Bonnett, Chemical Aspects of Photodynamic Therapy, Gordon &
Breach, Amsterdam, 2000.
[2] R. Bonnett, Chem. Soc. Rev. 1995, 19 33.
1-[[(Methoxyethoxy)ethoxy]ethoxy]-3,5-dimethyl-4-(triethylsilylethynyl)-
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103 112.
benzene (14):
A solution of compound 13 (6.22 g, 15.8 mmol) and
triethylsilylacetylene (2.21 g, 2.82 mL, 15.8 mmol) in Et3N (40 mL) was
purged with Ar for 5 min. To this solution was added (PPh3)2PdCl2 (240 mg,
0.34 mmol) and the reaction mixture was heated to reflux. To the refluxing
reaction mixture was added CuI (130 mg, 0.68 mmol) and reflux was
continued for 2 h. After this time, the reaction mixture had turned black. It
was cooled to room temperature, the solvent was removed in vacuo and the
residue was filtered through a pad of silica gel (Et2O) yielding the product
as a pale yellow oil (5.29 g, 13.0 mmol, 83%). 1H NMR (CDCl3, 400 MHz):
d ˆ 6.57 (s, 2H, CH), 4.07 (t, 2H, J ˆ 4.9 Hz, OCH2), 3.81 (t, 2H, J ˆ 4.9 Hz,
OCH2), 3.70 (m, 2H, OCH2), 3.65 (m, 4H, OCH2), 3.53 (m, 2H, OCH2),
3.35 (s, 3H, OCH3), 2.38 (s, 6H, CH3), 1.03 (t, 9H, J ˆ 7.9 Hz, Si(CH2CH3)3),
0.65 (q, 6H, J ˆ 7.9 Hz, Si(CH2CH3)3); 13C NMR (CDCl3, 100.5 MHz): d ˆ
158.1, 142.3, 115.8, 112.9, 103.9, 98.2, 71.9, 70.8, 70.6, 70.5, 69.6, 67.2, 59.0,
À1
ˆ
21.3, 7.6, 4.6; IR (film): nÄ ˆ 2954 (CH), 2876 (CH), 2145 (C C), 1126 cm
[13] M. Wainwright, Chem. Soc. Rev. 2002, 31, 128 136.
[14] H. Ali, J. E. van Lier, Chem. Rev. 1999, 99, 2379 2450.
[15] Q. Peng, T. Warloe, K. Berg, J. Moan, M. Kongshaug, K. E. Giercksky,
J. M. Nesland, Cancer 1997, 79, 2282 2308.
[16] Q. Peng, K. Berg, J. Moan, M. Kongshaug, J. M. Nesland, Photochem.
Photobiol. 1997, 65, 235 251.
‡
(C-O); EI-MS (70 eV): m/z (%): 406 (52.3) [M ], 59 (100)
‡
[(CH3OCH2CH2) ]; HR-MS (FAB): calcd for C23H38O4Si‡H: 407.2618;
found: 407.2634.
1-Ethynyl-4-[[(methoxyethoxy)ethoxy]ethoxy]-2,6-dimethylbenzene (15):
Tetrabutylammonium fluoride (3.50 mL of
a 1.0m solution in THF
containing ꢁ3% water, 3.50 mmol) was added at room temperature to a
solution of compound 14 (1.35 g, 3.33 mmol) in THF (20 mL) and the
reaction mixture was stirred for 15 min. After this time, the solvent was
evaporated in vacuo and the residue was filtered through a pad of silica gel
(EtOAc/hexane 1:1), giving the product as a pale yellow oil (970 mg,
3.33 mmol, 100%). 1H NMR (CDCl3, 400 MHz): d ˆ 6.57 (s, 2H, aryl CH),
4.07 (t, 2H, J ˆ 4.9 Hz, OCH2), 3.81 (t, 2H, J ˆ 4.9 Hz, OCH2), 3.70 (m, 2H,
OCH2), 3.63 (m, 4H, OCH2), 3.52 (m, 2H, OCH2), 3.39 (s, 1H, CCH), 3.35
(s, 3H, OCH3), 2.38 (s, 6H, CH3); 13C NMR (CDCl3, 100.5 MHz): d ˆ 158.3,
142.6, 114.4, 113.0, 83.7, 81.2, 71.8, 70.8, 70.6, 70.5, 69.6, 67.2, 59.0, 21.2; IR
[17] H. B. Ris, H. J. Altermatt, R. Inderbitzi, R. Hess, B. Nachbur, J. C. M.
Stewart, Q. Wang, C. K. Lim, R. Bonnett, M. C. Berenbaum, U.
Althaus, Br. J. Cancer 1991, 64, 1116 1120.
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C. K. Lim, R. Bonnett, U. Althaus, Int. J. Cancer 1993, 55, 245 249.
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[20] C. M. Allen, W. M. Sharman, J. E. van Lier, J. Porphyrins Phthalo-
cyanines 2001, 5, 161 169.
[21] J. L. Sessler, S. J. Weghorn, Expanded, Contracted
Porphyrins, Pergamon Press, New York 1997.
& Isomeric
(film): nÄ ˆ 3255 (acetylenic CH), 2877 (CH), 2095 (C C), 1152 cmÀ1 (C-O);
ˆ
[22] E. Vogel, Pure Appl. Chem. 1996, 68, 1355 1360.
[23] E. Vogel, J. Heterocycl. Chem. 1996, 33, 1461 1487.
[24] B. Franck, A. Nonn, Angew. Chem. 1995, 107, 1941 1957; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1795 1811.
[25] J. L. Sessler, R. A. Miller, Biochem. Pharmacol. 2000, 59, 733 739.
[26] S. W. Young, K. W. Woodburn, M. Wright, T. D. Mody, Q. Fan, J. L.
Sessler, W. C. Dow, R. A. Miller, Photochem. Photobiol. 1996, 63,
892 897.
[27] J. L. Sessler, G. Hemmi, T. D. Mody, T. Murai, A. Burrell, S. W. Young,
Acc. Chem. Res. 1994, 27, 43 50.
[28] R. Faust, C. Weber, J. Org. Chem. 1999, 64, 2571 2573.
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[30] R. Faust, Eur. J. Org. Chem. 2001, 2797 2803.
[31] S. V. Kudrevich, J. E. van Lier, Can. J. Chem. 1996, 74, 1718 1723.
[32] S. V. Kudrevich, M. G. Galpern, E. A. Luk×yanets, J. E. van Lier, Can.
J. Chem. 1996, 74, 508 515.
[33] While this work was in progress, a report about another tetra-[6,7]-
quinoxalinoporphyrazine appeared: J. Rusanova, M. Pilkington, S.
Decurtins, Chem. Commun. 2002, 2236 2237.
[34] F. Mitzel, S. FitzGerald, A. Beeby, R. Faust, Chem. Commun. 2001,
2596 2597.
[35] R. Faust, C. Weber, V. Fiandanese, G. Marchese, A. Punzi, Tetrahe-
dron 1997, 53, 14655 14670.
‡
EI-MS (70 eV): m/z (%): 292 (100) [M ], 146 (57.7), 59 (97.4); HR-MS
(FAB): calcd for C17H24O4‡Na: 315.1572; found: 315.1560.
[2,3,11,12,20,21,29,30-Octakisdodecyltetra-[6,7]-quinoxalinoporphyrazina-
to]-magnesium(ii) (16): Tetraquinoxalinoporphyrazine 16 was prepared
from dicyanoquinoxaline (17; 206 mg, 0.4 mmol) analogous to tetraqui-
noxalinoporphyrazine 5a. The crude product was purified by flash
chromatography (eluting first with CH2Cl2, then with 20% Et2O in
CH2Cl2) followed by gel permeation chromatography (THF), yielding the
pure product as a dark blue solid (64 mg, 31 mmol, 31%). IR (KBr): nÄ ˆ
2922 (CH), 2852 cmÀ1 (CH); UV (THF): lmax (e) ˆ 271 (81500), 310
(79400), 364 (133100), 483 (7300), 660 (52500), 700 (50400), 735 nm
‡
(431000); MALDI-TOF-MS: m/z: isotopic cluster peaking at 2091 [M ];
elemental analysis calcd (%) for C136H208N16Mg (2091.56): C 78.10, H 10.02,
N 10.72; found: C 77.76, H 10.22, N 10.67.
6,7-Dicyano-2,3-bisdodecylquinoxaline (17): Quinoxaline 17 was prepared
analogous to quinoxaline 8a from 4,5-diaminophthalonitrile (7) and
hexacosa-13,14-dione.[46] The crude product was recrystallised from EtOH,
giving the title compound as a colourless solid (319 mg, 0.62 mmol, 72%).
M.p. 77 808C; 1H NMR (CDCl3, 400 MHz): d ˆ 8.44 (s, 2H, aryl CH), 3.02
ˆ
(t, 4H, J ˆ 7.7 Hz, CH2CH2C N), 1.81 (quintet, 4H, J ˆ 7.6 Hz,
ˆ
CH2CH2CH2C N), 1.46 1.20 (m, 36H, alkyl chain), 0.86 (t, 6H, J ˆ
6.8 Hz, CH3); 13C NMR (CDCl3, 100.5 MHz): d ˆ 161.8, 141.6, 136.4,
[36] E. V. Kudrik, G. P. Shaposhnikov, E. A. Balakirev, Russ. J. Gen. Chem.
1999, 69, 1321 1324.
[37] G. W. H. Cheeseman, J. Chem. Soc. 1962, 1170 1176.
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Mo, Acta Chem. Scand. 1995, 49, 658 662.
115.2, 113.1, 35.4, 31.9, 29.65, 29.63, 29.61, 29.52, 29.50, 29.42, 29.34, 27.7,
22.7, 14.1; IR (KBr): nÄ ˆ 2916 (CH), 2848 (CH), 2235 cmÀ1 (C N); UV
ꢀ
(CH2Cl2): lmax (e) ˆ 225 (26800), 250 (60100), 321 (5200), 335 nm (5700);
‡
‡
EI-MS (70 eV): m/z (%): 516 (13.8) [M ], 362 (100) [M À 11CH2];
elemental analysis calcd (%) for C34H52N4 (516.81): C 79.02, H 10.14, N
10.84; found: C 78.71, H 10.33, N 10.71.
[39] P. A. Barrett, D. A. Frye, R. P. Linstead, J. Chem. Soc. 1938, 1157
1163.
[40] Z. Jin, K. Nolan, C. R. McArthur, A. B. P. Lever, C. C. Leznoff, J.
Organomet. Chem. 1994, 468, 205 212.
Acknowledgement
[41] K. Sonogashira in Metal-catalyzed Cross-coupling Reactions (Eds.: F.
Diederich, P. J. Stang), Wiley-VCH, Weinheimm, 1998, p. 203 229.
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1980, 627 630.
[43] F. Mitzel, Ph. D. Thesis, University College London (UK), 2001.
[44] S. H¸nig, H. Schwarz, Liebigs Ann. Chem. 1956, 599, 131 138.
We wish to acknowledge University College London for the provision of a
Provost Studentship to F.M. and the EPSRC for a studentship to S.F. We
thank Dr. A. J. MacRobert, National Medical Laser Centre, UCL, for
helpful discussions.
1240
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Chem. Eur. J. 2003, 9, No. 5

Photosensitisers
1233 1241
[45] T. W. Brockmann, J. M. Tour,J. Am. Chem. Soc. 1995, 117, 4437 4447.
[46] Hexacosa-13,14-dione has been reported before: E. Logemann, G.
Schill, C. Z¸rcher, H. Fritz, Chem. Ber. 1978, 111, 1019 1028. For this
work the compound was synthesised according to the method
described in F. Babrudi, V. Fiandanese, G. Marchese, A. Punzi,
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naphthalocyanines, see J. D. Spykes, J. E. van Lier, J. C. Bommer, J.
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[54] S. M. Bishop, Ph. D. Thesis, Imperial College, London (UK), 1993.
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566 569.
[56] S. Nonell, S. L. Braslavsky in Methods in Enzymology: Singlet UV
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Weinheim 1998.
Received: October 9, 2002 [F4335]
Chem. Eur. J. 2003, 9, No. 5
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/03/0905-1241 $ 20.00+.50/0
1241