Synthesis and singlet oxygen generation of pyrazinoporphyrazines containing dendrimeric aryl substituents

Article abstract of DOI:10.1039/c6nj03886g

Pyrazinoporphyrazines and tribenzopyrazinoporphyrazines were synthesized and studied towards their potential applications in photodynamic therapy. The macrocycles were obtained via Linstead macrocyclization with good yields. The expansion of the porphyraz

Full text of DOI:10.1039/c6nj03886g

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Goslinski and E. Tykarska, New J. Chem., 2017, DOI: 10.1039/C6NJ03886G.
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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Synthesis and singlet oxygen generation of pyrazinoporphyrazines
containing dendrimeric aryl substituents
Adam Tilloa, Dariusz T. Mlynarczyka, Lukasz Popendab, Barbara Wichera, Michal Kryjewski*c,
Wojciech Szczolkoa, Stefan Jurgab,d, Jadwiga Mielcarekc, Maria Gdaniece, Tomasz Goslinskia, Ewa
Tykarska*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Pyrazinoporphyrazines and tribenzopyrazinoporphyrazines were synthesized and studied towards their potential
applications in photodynamic therapy. The macrocycles were obtained via Linstead macrocyclization with good yields. The
expansion of the porphyrazine periphery with hyperbranched aryl substituents was beneficial in terms of purification and
isolation of compounds, effectively hampering their aggregation tendency in different concentrations. The obtained
macrocycles were assessed for their singlet oxygen generation quantum yields and revealed far better efficacies for
tribenzopyrazinoporphyrazines than pyrazinoporphyrazines. Comparison of crystal packing of two 2,3-dicyanopyrazine
derivatives revealed that recurring motif of supramolecular architecture is a dimer formed by π-π stacking interactions
between aromatic pyrazine and phenyl rings of the inversion center related molecules.
physicochemical properties make them possible candidates for
photosensitizers in photodynamic therapy (PDT),7–9 radiation
therapy,10 boron neutron capture therapy and in bioimaging.3
Introduction
Porphyrazines (Pzs) are synthetic macrocycles, which are
analogues of naturally occurring porphyrinoids like heme or
chlorophyll. In the Pz macrocycle the pyrrole rings are bound
together by aza bridges, in contrast to methine groups found
in porphyrins.1
In PDT, photosensitizer is delivered to the tumor tissue, where
upon irradiation with light of an appropriate wavelength it
generates reactive oxygen species, including singlet oxygen.
These species have the ability to kill tumor cells leading further
to their necrosis or apoptosis. Currently used photosensitizers
are still far from being ideal. Improvement in their biophysical
properties, while maintaining high singlet oxygen generation
yield is still a subject of research.8 One of the main factors,
hampering effective biological activity of porphyrinoids is their
poor solubility in water and tendency to form aggregates
resulting from high molecular mass and π-bond stacking
interactions. Aggregation tendency can lead to efficient non-
radiative energy relaxation, thereby reducing macrocycles
triplet-state population and consequently significantly
decreasing their photosensitizing efficacy.11
Benzene-fused derivatives of porphyrazines - phthalocyanines
have been used for decades as dyes and pigments in textile
and paper industry.2 Recently, they have been extensively
studied for their possible use in a broad range of both
technical and medical applications.2,3 Some of the modern
research areas for their further use are industrial catalytic
systems, semiconductors, chemical sensors, materials for
electrophotography, and advanced functional materials.2,4,5
Peripherally substituted tetrapyrazinoporphyrazines have
become one of the most easily accessible phthalocyanine
analogues.6
Pz molecule can be modified by peripheral functionalization
and/or insertion of a metal ion into the macrocycle core. These
structural changes can effectively improve the macrocycle
solubility, as well as prevent the aggregation of its molecules.12
One of the most common synthetic routes to octakis-
functionalized porphyrazines is the cyclization of the
functionalized maleonitrile derivatives in the presence of
magnesium alkoxide (Linstead macrocyclization).13 Various
dicyano derivatives of N-heterocycles themselves have been a
subject of interest for chemical industry, as well as food,
agricultural and medicinal chemistry.14,15 2,3-Dicyanopyrazine
derivatives are most commonly used substrates for
Porphyrazines raise a lot of interest for their possible use in
biomedical
sciences.
Their
unique
spectral
and
pyrazinoporphyrazine
synthesis.6
2,3-Dicyanopyrazine
heterocycle comprises two strong electron withdrawing cyano
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groups, which results in its specific properties. Despite the (Scheme 1). The use of pyridine hydrochloride24 was found to
small chromophoric system of dicyanopyrazine, it shows be more efficient (90% yield) for demethylation of anisil to
strong fluorescence, even in the solid state15. Highly dihydroxy derivative
, comparing to the originally published
functionalized 2,3-dicyanopyrazine derivatives have been procedure with aqueous HBr (69% yield).15 Alkylation reaction
recently extensively studied for their possible use as a of 2,3-dicyanopyrazine derivative with benzyl bromide and
functional dyes, electroluminescence materials and 3,5-bis(benzyloxy)benzyl bromide led to compounds 5b and 5c
amorphous molecular glass.15,16
wide range of respectively. Known alkylating agent, 3,5-bis(benzyloxy)benzyl
2
3
4
,
A
aminoporphyrazine derivatives, possessing heterocyclic bromide was prepared in a four step process. Briefly, 3,5-
diazepine,17,18 pyrrole,19,20 or pyrazine rings21,22 have been dihydroxybenzoic acid was converted to methyl ester25, which
synthesized. The nature of the substituent strongly influenced was subsequently alkylated with benzyl bromide, leading to
electronic and optical properties of the macrocycle. Moreover, methyl 3,5-bis(benzyloxy)benzoate.26,27 Obtained ester was
tetrapyrazinoporphyrazines have been studied as potential reduced to alcohol28 and converted to bromide following the
photosensitizers in PDT.23
Hawker procedure.29
In the present study, pyrazinoporphyrazines and Dicyanopyrazine derivatives 5a-c were applied in the Linstead
tribenzopyrazinoporphyrazines were designed and studied macrocyclization reaction, employing magnesium n-butanolate
towards their potential application in photodynamic therapy. solution in n-butanol13 towards symmetrical macrocycle
The expansion of the porphyrazine periphery with derivatives (Scheme 2). In addition, in analogous conditions,
hyperbranched aryl substituents was found to be beneficial as 2,3-dicyanopyrazines 5a-c and excess of 1,2-dicyanobenzene
its ensure easier purification and prevents its aggregation. The were subjected to macrocyclization reaction towards
effect of symmetry and peripheral expansion on singlet oxygen tribenzoporphyrazine derivatives.30. Massive aggregation of
generation yields and aggregation was extensively studied in products obtained in macrocyclization reactions in which 2,3-
both macrocycle types.
dicyanopyrazine derivative 5b was used, hampered their
effective isolation as pure products (see discussion and
characterization in Supplementary data). When 5a and 5c were
used as substrates, it was possible to isolate with good yields
Results and discussion
symmetrical porphyrazine derivatives 6,
tribenzoporphyrazine derivatives and
7 as well as
Molecular design and synthesis
8
9.
The aim of our study was to design novel
pyrazinoporphyrazines with hyperbranched peripheral
substituents. We have synthesized, isolated and characterized
novel porphyrazines containing annulated pyrazine rings. The
peripheries of the obtained macrocycles were equipped with
dendritic wedges and represent both pyrazinoporphyrazines
(A4) as well as tribenzopyrazinoporphyrazines (A3B).
Scheme 1. Reagents and conditions: (i) pyridine hydrochloride, 220 °C, 1.5 h; (ii) p-
toluenesulfonic acid, CH3OH, reflux, 18 h; (iii) K2CO3, DMF, 60 °C, 18 h.
Scheme 2. Synthetic route leading to porphyrazines 6-9. Reagents and conditions: (i)
Mg(n-OBu)2, n-BuOH, reflux, 20 h.
Compounds
4
and 5a have been previously synthesized and
was
to give 5a
characterized by Cristiano et al.15 Diaminomaleonitrile
1
Porphyrazines 6-9 were isolated and characterized by means
of HRMS spectrometry and studied in detail by NMR
subjected to condensation reaction with anisil
2
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Fig.
1.
NMR
analysis
of
macrocycles
6
(left)
and
7
(right).
spectroscopy. The spectra of all of the compounds
6
-9
sphere protons were found at 6.65 ppm, 6.77 ppm. Moreover,
displayed characteristic peaks around 7.0 ppm and 7.5 ppm, signals of outer peripheral sphere protons were found at 7.28-
corresponding to the protons of the phenyl rings directly 7.40 ppm (Fig. 1). Chemical structures of synthesized
attached to the porphyrazine core annulated pyrazines. In macrocycles were further studied in detail by analysis of two-
general, porphyrazines bearing peripheral methoxy (
6,
8)
dimensional 1H - 13C HMBC and 1H - 1H COSY spectra.
substituents displayed unresolved and overlapped signals,
even at elevated temperatures (Fig. 1). Broad and complex X-ray structural analyses
proton signals present in NMR spectra of these macrocycles
indicate an increased π-π bond stacking.31 What is interesting,
Single crystals of dicyanopyrazine derivatives 5b and 5c
suitable for X-ray analysis were obtained by slow evaporation
of ethyl acetate:hexane 2:1 and dichloromethane:hexane 2:1
solutions, respectively. Crystals of 5b belong to the P21/n
space group and have one molecule in the asymmetric part of
the unit cell (Fig. S25). Compound 5c crystallizes as a solvate in
the C2/c space group and the molecule is located around
an improved solubility and lack of aggregation of dendrimeric
porphyrazines
7 and 9 resulted in improved NMR spectral
data. For 7 separate but broadened signals were found at 7.04
ppm and 7.79 ppm for phenyl rings attached to the pyrazine
ring. Better resolved peaks corresponding to inner peripheral
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In 5b the two 4-(benzyloxy)phenyl substituents adopt different
conformations resulting from the rotation about single bonds
presented in Fig. 2a. The inner A and C rings are twisted by
45.0(1)º and 39.1(1)º, respectively, in the same direction
against planar pyrazine ring. Similar twist of the benzene rings
was
observed
in
2,3-dicyano-5,6-bis(4-
methoxyphenyl)pyrazine.15 The -O-CH2- groups bridging the
inner and the outer benzene rings are in trans and gauche
conformations (Table S8). Thus one of the benzyloxyphenyl
branches adopts elongated and the other one sharply bent
shapes. The pyrazine and the B rings (Fig. 2a) are oriented
nearly parallel [the dihedral angle 6.24(8)
In the more branched dicyanopyrazine derivative 5c (Fig. 2b),
the conformation of zero-generation (G0) branch of
°] (Table S9).
a
substituted 4-(benzyloxy)phenyl moiety (ring A-O-CH2-ring B) is
similar to the corresponding group of 5b. The dihedral angles
between the best planes of the pyrazine and ring A, and
pyrazine and ring B are 39.7(1)º and 0.6(2)°, respectively. The
G1 branches of 4-[3,5-bis(benzyloxy)benzyloxy]phenyl
substituent also have the -O-CH2- groups in trans
conformation, however, they differ in the rotation of the
terminal phenyl group about a single C-C bond (Table S8). The
terminal B1 phenyl group is virtually parallel and coplanar with
B ring [dihedral angle 3.5(2)
ring [dihedral angle 3.7(2) ], whereas the ring B2 is strongly
twisted (ca. 68 , Table S9).
°] and parallel with the pyrazine
°
°
Fig. 2. Caped-stick representation of 5b and 5c.
twofold symmetry axis. The asymmetric unit consist of one
half of the dicyanopyrazine derivative and one
dichloromethane molecule (Fig. S25).
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Fig. 3. π-π stacking interactions between the pyrazine ring and the phenyl group B (top) and two phenyl groups B and B1 (bottom) in 5b and 5c. Lines connecting
centroids are shown in red.
assess their consistence with the Lambert-Beer law. For the
macrocycles bearing smaller peripheral substituents (6, 8), the
Parallel arrangement of some of the aromatic rings within the
dicyanopyrazine derivative molecules (Table S9) is related to
the molecular self-assembly in the crystals of 5b and 5c. In the
absence of other functional groups able to form stronger
intermolecular interactions only weak forces govern crystal
packing of the analyzed compounds. In both crystals the
dimers are formed by π-π stacking interactions between the
pyrazine and B rings of the inversion center related molecules
(Fig. 3 top). The distances between the ring centroids are 3.61
Å in 5b and 3.47 Å in 5c. In 5b the dimers further interact via C-
H∙∙∙O and C-H∙∙∙N weak hydrogen bonds (Fig. S26, Table S10).
In 5c, the centrosymmetric dimers form larger 3D aggregates
via π-π stacking interactions between the virtually coplanar B
and B1 rings (centroid∙∙∙centroid distance 3.74 Å) (Fig. 3
bottom). The 3D network of 5c contains centrosymmetric
voids occupied by two dichloromethane molecules.
obtained plots significantly deviated from linearity, what
indicates their tendency to aggregation (Fig. 4, Tables S11,
S12). Our visual observations indicate that porphyrazines
bearing methoxy groups (6, 8) quickly form aggregates in
concentrated solutions (Fig. 5). Expanding the macrocycle core
with polyaryl substituents seem to be an effective way to
prevent its aggregation. For the macrocycles
concentrated solutions could be prepared.
7 and 9 stable
Aggretation studies
The aggregation tendency of the obtained porphyrazines was
checked in DMF and DMSO as solvents, as aggregation may
decrease singlet oxygen quantum yields and fluorescence
yields. Absorbance of a series of solutions with increasing
concentrations of porphyrazine were measured. Subsequently,
absorbance - concentration graphs were plotted in order to
Fig. 4. Absorbance – concentration graphs of porphyrazines 6 and 7 in DMF.
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to moderate values of fluorescence quantum yields, highest
for compound , and lowest for (Table 1). These valuse are
9
8
significantly lower than ΦF = 0.50 (in pyridine), which has been
previously reported by Morkved et al.32 for magnesium
pyrazinoporphyrazine peripherally substituted with phenyl
moieties. Excitation spectra superimpose well with absorbance
plots (Fig. S39-42). The Stokes shifts are minor, which confirms
a small difference between geometry of the molecule in its
ground and singlet S1 state. No emissions from higher singlet
states were observed.
Fig. 5. Comparison of 2∙10-4 mol/L dichloromethane solutions of methoxy (
6) and
polyaryl (7) substituted porphyrazines after 40 min at ambient temperature.
Absorption and fluorescence studies
Porphyrazines researched in our study have the magnesium(II)
ion in the central cavity. The UV-Vis spectra were analyzed
taking into account the effects of the peripheral groups and
symmetry of the macrocycles. Absorbance maxima (Table 1)
Fig. 6. UV-Vis spectra of symmetrical A4 7 (green) and A3B type 9 (red) porphyrazines in
DMF.
Singlet oxygen generation
for the A4 macrocycles 6 and 7 correspond well with published
data32; λmax = 659 nm has been reported for magnesium
pyrazinoporphyrazine peripherally substituted with phenyl
Effective singlet oxygen generation is a key feature of a
successful PDT photosensitizer. In our studies, the designed
macrocycles were assessed for their singlet oxygen generation
quantum yields in DMF and DMSO, according to a previously
described literature procedure.35-37 The comparative method
was used, employing 1,3-diphenylisobenzofuran (DPBF) as a
singlet oxygen chemical quencher and zinc(II) phthalocyanine
(ZnPc) as a reference (quantum yields 0.56 and 0.67 in DMF
and DMSO, respectively).34,37 The prepared solutions of the
macrocycle and DPBF were exposed to the monochromatic
light of the wavelength adjusted to the maximum absorbance
of the macrocycle Q-band. The decrease of the DPBF
concentration was determined by measurement of its
absorption maximum at 417 nm (Fig. 7).
moieties. For the symmetric porphyrazine
7 an intensive
absorption band (beta-band), followed by a weaker one
(alpha-band) was observed in the Q-band region. In the UV-Vis
spectrum of unsymmetrical porphyrazine
9 the main band
accompanied by two smaller alpha-bands was found.
Introduction of the asymmetry factor to the macrocycle
resulted in approximate 20 nm shifting of the absorption band
towards the red (Fig. 6). Q-Band of the A3B-type porphyrazines
8
and 9 was broadened in comparison to the A4-type, which is
typical for A3B porphyrazines and phthalocyanines33, however
no splitting of the Q-band was observed. Our studies did not
show any significant correlations between the size of
peripheral side-chains present in studied compounds and their
UV-Vis absorption maxima.
Comparison of DPBF oxidation kinetic parameters of
porphyrazines 6-9 and ZnPc allowed calculation of the singlet
oxygen generation yield (Table 1).
Fluorescence studies were conducted using zinc(II)
phthalocyanine as a reference of known values34 revealed low
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Table 1. Singlet oxygen generation and fluorescence quantum yields of porphyrazines 6-9.
Absorbance maximum at Q-
band λmax [nm]
Fluorescence maximum λF
[nm]
Fluorescence quantum yields
ΦF
Singlet oxygen generation
quantum yields ΦΔ
Pz
DMF
660
658
666
677
DMSO
658
DMF
DMSO
664
DMF
0.07
0.11
0.07
0.18
DMSO
0.26
0.27
0.02
0.29
DMF
0.04
0.04
0.22
0.09
DMSO
0.07
0.08
0.26
0.13
6
7
8
9
662
658
662
665
667
676
677
678
676
680
For the symmetrical porphyrazines
6,
7
low quantum yields
(0.04-0.08) of singlet oxygen generation were measured.
However, improved values were obtained by implementing
the attribute of asymmetry to the photosensitizer.
Tribenzopyrazinoporphyrazines 8, 9 exhibited low to moderate
singlet oxygen generating yields (0.09-0.26). The highest
singlet oxygen generation was recorded for the methoxy-
substituted A3B porphyrazine 8. This observation is in contrast
to our previous studies performed for phthalocyanines,38
where introduction of dendrimeric moieties increased singlet
oxygen quantum yields. However, this is consistent with very
low fluorescence quantum yields measured for this compound.
Value of ΦΔ = 0.249 has been reported for previously
mentioned magnesium pyrazinoporphyrazine peripherally
substituted with phenyl moieties.32 This may be attributed to
the influence of the solvent, as pyridine is known to coordinate
central metal ion and prevent aggregation.
Fig. 7. Changes in the UV-Vis spectra of solutions of DPBF and porphyrazines 8 and 9 (in
DMSO) during irradiation.
Conclusions
Novel symmetrical (A4) as well as asymmetric (A3B type)
porphyrazines structures were obtained. The macrocycles
were obtained in good yields, provided easy purification
method and did not decompose during their prolonged
storage. The compounds were studied towards key features
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aiming for their use in photodynamic therapy. Expansion of the NMR resonances were unambiguously assigned on the basis of
1
1
porphyrazine periphery with aryl substituents was intended to 1H–1H COSY, H–13C HSQC and H–13C HMBC spectra. All NMR
prevent the aggregation tendency, a common drawback of experiments were carried out at 298 K, except for samples
macrocyclic photosensitizers. Obtained porphyrazines were and where data were collected at 353 K. Mass spectra (ES,
subsequently assessed for their singlet oxygen generation MALDI TOF, HRMS) were carried out by the Advanced
quantum yields. Chemical Equipment and Instrumentation Facility at the
7
8
In the crystalline state, G0 branches of 5c adopt a Faculty of Chemistry and the Wielkopolska Center for
conformation similar to that of the 4-(benzyloxy)phenyl Advanced Technologies at Adam Mickiewicz University in
substituent of 5b having the terminal phenyl ring parallel with Poznan. Melting points were obtained on a “Stuart” Bibby
the pyrazine ring. This arrangement of the aromatic rings apparatus and are uncorrected.
facilitates
centrosymmetric dimers that are a common supramolecular
motif for 5c and 5b
Far better singlet oxygen generation efficacies for the
tribenzoporphyrazines were found. Our laboratory
π-π stacking interactions leading to the formation of Synthesis
Compounds 4 and 5a have been previously synthesized and
characterized by Cristiano et al.15
2,3-Dicyano-5,6-bis-[4-(benzyloxy)phenyl]pyrazine (5b)
.
Compound
4 (0.720 g, 2.25 mmol) and K2CO3 (0.930 g, 6.75
observations indicate that all of the synthesized methoxy- and
benzoxy-substituted macrocycles strongly aggregate and they
are hardly soluble in any common organic solvents. As
previously reported,38 attachment of the dendritic-like
substituents can successfully improve the solubility of
porphyrazines and phthalocyanines. Despite large structures of
molecules and strong hydrophobic nature, solutions of
mmol) were heated in DMF (20 mL) at 60 °C for 30 min.
Afterwards, benzyl bromide (0.8 mL, 6.75 mmol) was added
and the reaction mixture was vigorously stirred at 60 °C for 18
h. Next, the reaction mixture was cooled down and poured
into 10% NaOH solution (100 mL). The oily precipitate was
stirred for 30 min, then Celite filtered. After washing with
water, the product was rinsed down with acetone. The
obtained solution was concentrated, brine was added and
mixture was extracted with CH2Cl2 (3 × 50 mL). Combined
organic layers were dried with MgSO4 and vaporized. Obtained
yellow oil was purified by means of column chromatography
(CH2Cl2/n-hexane 1:5 to 1:2) to give 5b as a yellow powder
(0.320 g, 28%). Mp. 190-192°C (AcOEt/n-hexane). Rf (CH2Cl2/n-
porphyrazines
7 and 9 remained stable in broad concentration
range. Similarly, introduction of polyaryl substituents improves
fluorescence quantum yields.
Tribenzoporphyrazine
9 with its dendrimeric periphery shows
promising properties as a potential PDT photosensitizer,
considering its solubility, the lack of aggregation and moderate
singlet oxygen generation yield. Further functionalization of
the peripheral side chain could bring the photosensitizer well
soluble in polar solvents.
1
hexane 1:1) 0.24. H NMR (800 MHz, DMSO-d6) δ, ppm: 7.49
(d, J = 7.5 Hz, 4H), 7.45 (d, J = 7.5 Hz, 4H), 7.40 (t, J = 7.5 Hz,
4H), 7.34 (t, J = 7.5 Hz, 2H), 7.06 (d, J = 7.0 Hz, 4H), 5.14 (s, 4H).
13C NMR (201 MHz, DMSO-d6) δ, ppm: 160.3, 153.8, 136.4,
131.3, 129.0, 128.4, 128.1, 128.0, 127.8, 115.0, 114.3, 69.4.
HRMS (MALDI) Found: [M+Na]+ 517.1626; molecular formula
C32H22N4O2+Na requires [M+Na]+ 517.1640.
Experimental
Chemicals and instrumentation
2,3-Dicyano-5,6-bis-[4-[3,5-bis(benzyloxy)benzyloxy]
All reactions were conducted in oven dried glassware under
argon atmosphere using Radleys Heat-On heating system. All
solvents were rotary evaporated at or below 60 °C under
reduced pressure. All solvents and reagents were obtained
from commercial suppliers and used without further
purification, unless otherwise stated. Flash column
chromatography was carried out on Merck silica gel 60,
particle size 0.040 – 0.063 mm, Merck aluminum oxide 90,
particle size 0.063 – 0.2 mm, and reverse phase Fluka C18 silica
gel 90. Thin layer chromatography (TLC) was performed on
Merck Kieselgel 60 F 254 plates or Fluka aluminum oxide TLC
cards, 60 Å pore diameter and visualized with UV (λmax= 254 or
365 nm). UV–Vis spectra were recorded on a Hitachi UV/VIS U-
1900 and Shimadzu PC-160 spectrophotometers. The NMR
spectra were acquired on Agilent DD2 800 spectrometer
operating at resonance frequencies of 799.903 and 201.146
MHz for 1H and 13C, respectively. Chemical shifts (δ) are
quoted in parts per million (ppm) and are referred to a residual
solvent peak. Coupling constants (J) are quoted in hertz (Hz).
The abbreviations s, bs, d, t, and m refer to singlet, broad
phenyl]pyrazine (5c)
Compound
4 (0.359 g, 1.1 mmol) and K2CO3 (0.386 g, 2.8
mmol) were heated in DMF (8 mL) at 60 °C for 30 min.
Afterwards, 3,5-bis(benzyloxy)benzyl bromide (1.1 g, 2.8
mmol) was added and the reaction mixture was vigorously
stirred at 60 °C for 18 h. Next, the reaction mixture was cooled
down and Celite filtrated, which was rinsed with CH2Cl2. The
combined filtrates were evaporated to dryness with toluene.
Obtained crude product was purified on silica-gel column
(CH2Cl2 to CH2Cl2/MeOH 20:1) to give 5c as a yellow powder
(0.850 g, 84%). Mp. 148 °C (AcOEt/2-propanol). Rf (CH2Cl2/n-
1
hexane 1:1) 0.22. H NMR (800 MHz, DMSO-d6) δ, ppm: 7.49
(d, J = 7.5 Hz, 4H), 7.42 (d, J = 7.5 Hz, 8H), 7.37 (t, J = 7.5 Hz,
8H), 7.31 (m, 4H), 7.03 (d, J = 7.0 Hz, 4H), 6.70 (d, J = 2.4 Hz,
4H), 6.64 (t, J = 2.4 Hz, 2H), 5.07 (s, 8H), 5.06 (s, 4H). 13C NMR
(201 MHz, DMSO-d6) δ, ppm: 160.2, 159.6, 153.8, 138.8, 136.9,
131.3, 128.9, 128.4, 128.1, 127.8, 127.7, 115.0, 114.3, 106.6,
101.3, 69.3, 69.2. HRMS (MALDI) Found: [M+Na]+ 941.3280;
molecular formula C60H46N4O6+Na requires [M+Na]+ 941.3315.
1
singlet, doublet, triplet, and multiplet, respectively. H and 13C
8 | J. Name., 2012, 00, 1-3
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General procedure for preparation of
Magnesium(II) 2,3-bis(4-methoxyphenyl)-1,4-
(diaza)phthalocyanine (8)
6 and 7 were prepared according to Obtained product was purified by column chromatography
tetrapyrazinoporphyrazines (6 and 7)
Symmetrical macrocyclces
classical Linstead procedure.13 Magnesium turnings (1 equiv) using silica gel and eluents: CH2Cl2, n-hexane/THF (5:1),
were refluxed in n-butanol (7 mL for each mmol of substrate) CH2Cl2/MeOH (50:1) to give product as a deep green film (18%
1
with a catalytic amount of iodine for 3 hours. After cooling yield). Rf (CH2Cl2/MeOH 35:1) 0.43. H NMR (800 MHz, DMSO-
down of the slurry, 2,3-dicyanopyrazine derivative was added d6) δ, ppm: 9.38 (m, 4H), 8.24 (m, 4H), 7.90 (m, 6H), 7.17 (m,
and the mixture was refluxed for 20 hours. After cooling down, 6H), 3.96 (s, 3H), 3.95 (s, 3H). 13C NMR (201 MHz, DMSO-d6) δ,
reaction mixture was sonicated and Celite filtered, which was ppm: 159.6, 155.4, 155.0, 154.0, 152.3, 146.5, 145.7, 138.5,
rinsed with CH2Cl2. Filtrates were evaporated to dryness with 138.0, 131.4, 131.3, 131.3, 129.8, 129.5, 129.2, 122.5, 122.4,
addition of toluene, giving dark-green solid residue.
Magnesium(II) 2,3,9,10,16,17,23,24-octakis(4-
113.7, 113.6, 55.1, 55.0. UV/Vis (DMSO): λmax nm (log ε) 368
nm (4.66), 603 (4.22), 667 (4.95). HRMS (MALDI) Found [M]+
750.2125; molecular formula C44H26MgN10O2 requires [M]+
750.2091.
methoxyphenyl)-1,4,8,11,15,18,22,25-
(octaaza)phthalocyanine (6)
Magnesium(II) 2,3-bis[4-[3,5-
The obtained product was precipitated from CH2Cl2/n-hexane
mixture. Solid precipitate was filtered on blotting paper,
washed with n-hexane, CH3OH and acetone, then rinsed down
bis(benzyloxy)benzyloxy]phenyl]-1,4-(diaza)phthalocyanine
(9)
with CH2Cl2. Evaporation of the solvent gave 6 as a green Obtained product was purified by means of column
powder (13%): 1H NMR (800 MHz, DMSO-d6): δ, ppm: 7.41 (m, chromatography using silica gel and eluents: CH2Cl2, n-
16H), 6.95 (bs, 16H), 3.78 (s, 24H). 13C NMR (201 MHz, DMSO- hexane/AcOEt (7:2), CH2Cl2/CH3OH (200:1) to give a deep
1
d6) δ, ppm: 159.7, 131.3, 113.9, 55.3. UV/Vis (DMSO) λmax nm green film (48% yield). Rf (CH2Cl2/CH3OH 50:1) 0.61. H NMR
(log ε) 384 nm (4.91), 597 (4.28), 658 (5.08). HRMS (MALDI) (800 MHz, DMSO-d6) δ, ppm: 9.13-8.59 (m, 6H), 8.09-7.93 (m,
Found: [M]+ 1393.4336; molecular formula C80H56MgN16O8 6H), 7.89 (m, 4H), 7.47 (m, 8H), 7.41 (m, 8H), 7.35 (m, 4H), 7.22
requires [M]+ 1393.4345.
Magnesium(II) 2,3,9,10,16,17,23,24-octakis[4-[3,5-
(m, 4H), 6.81 (m, 4H), 6.69 (m, 2H), 5.18 (s, 4H), 5.13 (s, 8H).
13C NMR (201 MHz, DMSO-d6) δ, ppm: 159.6, 158.7, 154.7,
154.4, 153.8, 153.5, 152.4, 152.2, 152.0, 145.8, 145.7, 139.3,
138.5, 138.1, 138.0, 136.9, 132.5, 131.9, 129.4, 129.2, 128.4,
128.4, 128.3, 127.9, 127.7, 127.7, 122.5, 114.6, 106.6, 101.3,
69.4, 69.3. UV/Vis (DMSO): λmax, nm (log ε) 363 nm (4.37), 604
(4.36), 626 (4.38), 676 (5.07). HRMS (MALDI) Found [M+H]+
1327.4710; molecular formula C84H58MgN10O6+H+ requires
[M+H]+ 1327.4469. HPLC purity (see Supplementary data).
X-ray crystallography
bis(benzyloxy)benzyloxy]phenyl]-1,4,8,11,15,18,22,25-
(octaaza)phthalocyanine (7)
Obtained green oil was purified on silica-gel using CH2Cl2 with
1% triethylamine. Collected samples were vaporized and
precipitated from CH2Cl2/CH3OH. Formed green solid was
subsequently washed with methanol, hexane and acetone to
give 32% yield of pure product as green powder. Rf (CH2Cl2+1%
triethylamine) 0.22. 1H NMR (800 MHz, DMSO-d6) δ, ppm: 7.79
(bs, 16H), 7.40 (d, J = 7.5 Hz, 32H), 7.34 (t, J = 7.5 Hz, 32H), 7.28
(t, J = 7.5 Hz, 16H), 7.04 (bs, 16H), 6.77 (s, 16H), 6.65 (s, 8H),
5.10 (s, 16H), 5.06 (s, 32H). 13C NMR (201 MHz, DMSO-d6) δ,
ppm: 159.43, 158.68, 152.98, 149.67, 138.91, 136.65, 131.46,
127.89, 127.82, 127.28, 127.06, 127.00, 114.25, 106.50,
101.42, 69.31, 69.20. UV/Vis (DMSO): λmax nm (log ε) 388 nm
(5.06), 597 (4.48), 658 (5.32). HRMS (MALDI) Found [M]+
3700.4450; molecular formula C240H184MgN16O24 requires [M]+
3700.4267. HPLC purity (see Supplementary data).
Reflection intensities for 5b and 5c were measured at 130 K
with an Oxford Diffraction Xcalibur E diffractometer using
MoKα radiation and with an Oxford Diffraction SuperNova
diffractometer using hi-flux micro-focus Nova CuKα radiation,
respectively. Data were processed with CrysAlis PRO
software.39 The structures were solved by direct methods
using SIR201440 and refined by full matrix least-squares based
on F2 (SHELXL-2014).41 C-bound hydrogen atoms were placed
at idealized positions. All hydrogen atoms were refined as
riding on their carriers with Uiso(H)=1.2Ueq (CH, CH2).
General procedure for synthesis of A3B type porphyrazines (8
and 9)
Crystal data for 5b: C32H22N4O2, M = 494.53 g/mol, monoclinic,
space group P21/n, a = 8.2968(3) Å, b = 11.2161(5) Å, c =
27.6291(10) Å, β = 97.453(3)°, V = 2549.38(17) Å3, Z = 4, T =
130(2) K, μ(MoKα) = 0.082 mm-1, Dcalc = 1.288 g/cm3, 14332
The magnesium butanolate solution was prepared according
to the previously described procedure [13]. Magnesium
turnings (5 equiv) were refluxed in n-butanol (7 mL for each
mmol of substrates) with a catalytical amount of iodine for 3
hours. After cooling down of the slurry, 2,3-dicyanopyrazine
derivative (1 equiv) and 1,2-dicyanobenzene (10 equiv) were
added and the mixture was refluxed for another 20 hours.
After cooling down, reaction mixture was sonicated and
filtered through Celite, which was rinsed with toluene and
CH2Cl2. Filtrates were evaporated to dryness giving dark-green,
solid residue.
reflections measured to θmax = 25.35°, 4651 unique (Rint
=
0.0376, Rsigma = 0.0506). The final R indices for 3332 reflections
with I > 2σ(I) and 343 refined parameters are R1= 0.046, wR2 =
0.086 (R1= 0.0741, wR2 = 0.0969 for all data)
Crystal data for 5c: C60H46N4O6∙2(CH2Cl2), M =1088.86 g/mol,
monoclinic, space group C2/c, a = 23.8249(7) Å, b = 15.5643(4)
Å, c = 16.2565(4) Å, β = 117.473(3)°, V = 5348.4(3) Å3, Z = 4, T =
130(2) K, μ(CuKα) = 2.474 mm-1, Dcalc = 1.352 g/cm3, 12425
reflections measured to θmax = 68.25°, 4913 unique (Rint
=
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ARTICLE
Journal Name
Wierzchowski, J. Mielcarek, E. Tykarska and T. Goslinski,
Tetrahedron Lett., 2012, 53, 2040–2044.
20 M. Kryjewski, E. Tykarska, T. Rebis, J. Dlugaszewska, M.
Ratajczak, A. Teubert, J. Gapiński, A. Patkowski, J. Piskorz, G.
Milczarek, M. Gdaniec, T. Goslinski and J. Mielcarek,
Polyhedron, 2015, 98, 217–223.
21 V. Novakova, M. Lásková, H. Vavřičková and P. Zimcik, Chem.
- Eur. J., 2015, 21, 14382–14392.
22 V. Novakova, M. Miletin, K. Kopecky and P. Zimcik, Chem. –
Eur. J., 2011, 17, 14273–14282.
0.0428, Rsigma = 0.0398). The final R indices for 4091 reflections
with I > 2σ(I) and 344 refined parameters are R1= 0.080, wR2 =
0.234 (R1= 0.0888, wR2 = 0.2337 for all data).
Further details of crystal data collection and structure
refinement are given in Table S7 (Supplementary data).
Crystallographic data for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC no: 1486351 (for 5b) and
1486352 (for 5c). These data can be obtained, free of charge,
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
23 M. Machacek, J. Demuth, P. Cermak, M. Vavreckova, L.
Hruba, A. Jedlickova, P. Kubat, T. Simůnek, V. Novakova and
P. Zimcik, J. Med. Chem., 2016.
24 P. Secondo and F. Fages, Org. Lett., 2006, 8, 1311–1314.
25 J. Zhu, R. Beugelmans, S. Bourdet, J. Chastanet and G. Roussi,
J. Org. Chem., 1995, 60, 6389–6396.
26 K. Thakkar, R. L. Geahlen and M. Cushman, J. Med. Chem.,
1993, 36, 2950–2955.
27 V. Percec, M. Peterca, M. J. Sienkowska, M. A. Ilies, E. Aqad,
Acknowledgements
This study was supported by the Polish National Science
Centre under Grant No. 2012/05/E/NZ7/01204. SJ and LP
acknowledge financial support from the National Centre for
J. Smidrkal and P. A. Heiney, J. Am. Chem. Soc., 2006, 128
3324–3334.
,
Research
and
Development,
contract
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•
Singlet oxygen generation yields and aggregation tendencies were studied for porphyrazines
bearing dendrimeric substituents.