Role of steric hindrance in the Newman-Kwart rearrangement and in the synthesis and photophysical properties of arylsulfanyl tetrapyrazinoporphyrazines

Article abstract of DOI:10.1021/jo402791c

Conditions for the Newman-Kwart rearrangement of phenols into thiophenols were investigated in relation to the bulkiness of substituents at the 2 and 6 positions of the starting phenol derivative with an emphasis on eliminating side reactions. Thiophenols with different 2,6-disubstitution patterns (including hydrogen, methyl, isopropyl or tert-butyl groups) were used for the synthesis of 5,6-bis(arylsulfanyl)pyrazine-2,3-dicarbonitriles that underwent cyclotetramerization leading to the corresponding zinc tetrapyrazinoporphyrazines (TPyzPz), aza-analogues of phthalocyanines. Several methods for the cyclotetramerization were attempted to eliminate problematic side reactions. Magnesium butoxide was found as the most suitable cyclotetramerization agent and afforded TPyzPzs in reasonable yields of approximately 30% under mild conditions. The varying arrangements of the peripheral substitutions resulting from the different bulkiness of the substituents were demonstrated by the X-ray structures of the pyrazine-2,3-dicarbonitriles. The prepared zinc arylsulfanyl TPyzPzs showed an absorption maximum at a Q-band over 650 nm, fluorescence quantum yields between 0.078 and 0.20, and singlet oxygen quantum yields ranging 0.58-0.69. TPyzPzs with isopropyl groups were found to be the best derivatives in this series as they combined facile cyclotetramerization, no aggregation, and good photophysical properties, which makes them potentially suitable for photodynamic therapy.

Full text of DOI:10.1021/jo402791c

Article
pubs.acs.org/joc
Role of Steric Hindrance in the Newman-Kwart Rearrangement and
in the Synthesis and Photophysical Properties of Arylsulfanyl
Tetrapyrazinoporphyrazines
Veronika Novakova,*,† Miroslav Miletin,‡ Tereza Filandrova,‡ Juraj Lenco,⊥,§ Ales Ruzicka,∥
́
̌
̌
̊
̌ ̌
and Petr Zimcik*,‡
†Department of Biophysics and Physical Chemistry, ‡Department of Pharmaceutical Chemistry and Drug Control, and ⊥Department
of Biochemical Sciences, Faculty of Pharmacy, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho
1203, 500 05, Hradec Kralove, Czech Republic
§Institute of Molecular Pathology, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec
́ ́
Kralove, Czech Republic
∥Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska
Pardubice, Czech Republic
́
573, 532 10,
S
* Supporting Information
ABSTRACT: Conditions for the Newman-Kwart rearrange-
ment of phenols into thiophenols were investigated in relation
to the bulkiness of substituents at the 2 and 6 positions of the
starting phenol derivative with an emphasis on eliminating side
reactions. Thiophenols with different 2,6-disubstitution
patterns (including hydrogen, methyl, isopropyl or tert-butyl
groups) were used for the synthesis of 5,6-bis(arylsulfanyl)-
pyrazine-2,3-dicarbonitriles that underwent cyclotetrameriza-
tion leading to the corresponding zinc tetrapyrazinoporphyrazines (TPyzPz), aza-analogues of phthalocyanines. Several methods
for the cyclotetramerization were attempted to eliminate problematic side reactions. Magnesium butoxide was found as the most
suitable cyclotetramerization agent and afforded TPyzPzs in reasonable yields of approximately 30% under mild conditions. The
varying arrangements of the peripheral substitutions resulting from the different bulkiness of the substituents were demonstrated
by the X-ray structures of the pyrazine-2,3-dicarbonitriles. The prepared zinc arylsulfanyl TPyzPzs showed an absorption
maximum at a Q-band over 650 nm, fluorescence quantum yields between 0.078 and 0.20, and singlet oxygen quantum yields
ranging 0.58−0.69. TPyzPzs with isopropyl groups were found to be the best derivatives in this series as they combined facile
cyclotetramerization, no aggregation, and good photophysical properties, which makes them potentially suitable for
photodynamic therapy.
fact that (hetero)arylsulfanyl Pcs are routinely synthesized18,19
INTRODUCTION
■
and widely studied because of their electrochemical proper-
ties,20,21 their efficient binding to various nanoparticles,22,23 and
their potential as photosensitizers in photodynamic therapy
(PDT)24 or models in catalysis.25,26 The reason for the lack of
these derivatives in TPyzPzs may be the instability of the
thioether linkage during the harsh conditions of the cyclo-
tetramerization reaction to form the TPyzPz macrocycles.
Thus, the synthesis of arylsulfanyl TPyzPzs has represented a
challenge for chemists since the first unsuccessful synthetic
attempt of Mørkved in 1996.27
Peripheral substitution in TPyzPzs significantly influences
their aggregation, solubility, and photophysical properties,
including fluorescence emission, singlet oxygen production,
and to some extent the position and shape of the absorption
maximum. The nonaggregating character of TPyzPzs is
Phthalocyanines (Pcs) have attracted steady attention since
their synthesis was first described in a publication in 1907.1 In
the next hundred years, synthesis of Pcs became an interesting
subject of research2,3 that has also resulted in their wide
application potential.4 Their aza-analogs, azaphthalocyanines, in
particular, tetrapyrazinoporphyrazines (TPyzPz), are charac-
terized by similar properties. However, the presence of
additional nitrogen atoms in the macrocyclic core renders the
azaphthalocyanines significantly electron-deficient,5 which
enables the use of TPyzPzs in new applications that are not
available for Pcs.6,7 Thus, the syntheses of a number of alkyl-,8
alkenyl-,9 alkinyl-,10 aryl-,11 heteroaryl-,11,12 alkylsulfanyl-,13
alkyl/arylamino-,13−15 and alkyl/aryloxy-8,13,16 substituted
TPyzPzs have been published. Notably, TPyzPz molecules
bearing bulky phenoxy substituents16,17 were found to maintain
a monomeric form, improving their solubilities and photo-
physical properties. TPyzPzs bearing arylsulfanyl groups on
their periphery are absent from the TPyzPz family despite the
Received: December 17, 2013
Published: February 18, 2014
© 2014 American Chemical Society
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Scheme 1. Synthesis of Thiophenols 4c−f (4a and 4b Are Commercially Available Compounds) By the Newman-Kwart
a
Rearrangement
a
Method A: melting the reactant in a preheated metal block at 260 °C; Method B: microwave irradiation in a closed vessel (300 W, 280 °C) in N,N-
dimethylacetamide.
a
believed to be the key factor responsible for their high solubility
and desirable photophysical parameters. The bulkiness of the
peripheral substituents maintains TPyzPzs in their monomeric
form.28 Considering the central metal in this study, zinc
TPyzPz complexes were chosen to investigate the potential of
prepared compounds in the field of PDT. Coordination of a
closed-shell metal with a high atomic number into the center of
a macrocycle prolongs the lifetimes of the triplet states and
enhances relaxation of the excited state through the intersystem
crossing followed by production of singlet oxygen. This is
known as the heavy atom effect16,29 and is used favorably in
PDT.
The aim of this work is to synthesize the previously
unreported arylsulfanyl TPyzPzs and describe the detailed
investigation of their synthesis and photophysical behavior with
respect to the bulkiness of their peripheral substituents. A
reliable synthetic pathway based on a Newman-Kwart
rearrangement30 leading to suitable thiophenols will be
discussed in the first part of this paper along with a discussion
of the role of the bulkiness of the ortho substituent.
Table 1. Synthesis of Thiophenols 4c−f
starting
material
reaction conditions
yield
1c
NaH, NMP, DMTCC, 1 h, 2c (45%), Y-c (traces), Z-c
80 °C (traces)
NaH, NMP, DMTCC, 12 h, 2d (22%), Y-d (38%); Z-d (2%)
80 °C
1d
1e
1f
NaH, NMP, DMTCC, 2 h, 2e (81%), Y-c (traces), Z-c
80 °C
(traces)
NaH, NMP, DMTCC, 4 h, 2f (19%), Y-d (41%); Z-d (6%)
80 °C
2c
2d
2d
Method A (260 °C, 1 h)
Method A (260 °C, 1 h)
3c (89%)
b
n.w.
Method B (mw, DMA, 280 3d (70%)
°C, 4 h)
2e
2f
2f
Method A (260 °C, 1 h)
Method A (260 °C, 1 h)
3e (85%)
b
n.w.
Method B (mw, DMA, 280 3f (57%)
°C, 3 h)
3c
3d
3e
3f
DME, LiAlH4, argon, rt, 4 h 4c (79%), 5c (9%), or only 4c
c
(88%)
DME, LiAlH4, argon, rt, 4 h 4d (∼82%), 5d (traces) or only
c
4d (82%)
RESULTS AND DISCUSSION
DME, LiAlH4, argon, rt, 4 h 4e (75%), 5e (10%), or only 4e
■
c
(84%)
Synthesis. A brief retrosynthetic analysis revealed that
arylsulfanyl TPyzPzs can be prepared by the cyclotetrameriza-
tion of 5,6-bis(arylsulfanyl)pyrazine-2,3-dicarbonitriles. These
precursors result from the nucleophilic substitution of 5,6-
dichloropyrazine-2,3-dicarbonitrile with the appropriate thio-
phenols. Both thiophenol (4a) and 2,6-dimethylthiophenol
(4b) are commercially available. Thus, the synthesis of
thiophenols starting from phenols with bulky substituents in
the 2 and 6 positions remained a key goal of the project. The
exchange of an oxygen atom for a sulfur atom in a molecule can
be achieved through the use of thionation agents such as P2S5,31
thiourea,32 or Lawesson’s reagent.33 However, such approaches,
which have often been reported for aliphatic alcohols, amides,
carbonyls, or esters, failed with 2,6-diisopropylphenol or 2,6-
di(tert-butyl)phenol. The Newman-Kwart rearrangement30 was
found to be the only suitable approach (Scheme 1 and Table
1). Concisely, the phenolic OH group of 1 was deprotonated
with NaH and reacted with thiocarbamoyl chloride to form O-
aryl thiocarbamates 2. Heating 2 to temperatures exceeding 250
°C initiated its rearrangement and provided the more stable S-
DME, LiAlH4, argon, rt, 4 h 4f (∼52%), 5d (traces), or only
c
4f (52%)
a
DMTCC = dimethylthiocarbamoyl chloride, NMP = N-methyl-2-
pyrrolidinone, mw = microwave irradiation, DME = 1,2-dimethoxy-
ethane, DMA = N,N-dimethylacetamide. n.w. = not working, starting
compound was recovered. After treatment of reaction mixture with
b
c
dithiothreitol.
aryl thiocarbamates 3. Subsequent cleavage of the S-aryl
thiocarbamates with LiAlH4 afforded the required thiophenols
4.
The role of the bulkiness of the substituents at the ortho
positions of the phenol/thiophenol groups was obvious in all
steps of the synthetic pathway. The reaction with thiocarba-
moyl chloride proceeded well with 2,6-diisopropylphenol (1c)
and 3-bromo-2,6-diisopropylphenol (1e) with yields of 45%
and 81% for 2c and 2e, respectively. However, both 2,6-di(tert-
butyl)phenol (1d) and its 3-bromo derivative (1f) underwent a
side reaction under basic conditions that lowered the yields of
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2d and 2f to 22% and 19%, respectively. Side products Y-d and
Z-d were also isolated in yields of 38% and 2%, respectively,
starting from compound 1d and in yields of 41% and 6%,
respectively, starting from compound 1f. A possible explanation
for this side reaction is that the steric hindrance of bulky tert-
butyl groups protected the phenol OH from attacking the
thiocarbamoyl chloride. As a consequence, the competitive and
well-known formation of a C−C bond between two molecules
of 1d or 1f predominated.34 Notably, this side reaction was
negligible for 2c and 2e, and only traces of corresponding Y-c
and Z-c were observed on the TLC (not isolated). In the next
step, the rearrangement was accomplished using two different
methods based on the principle of heating the reactant to a high
temperature. Method A involved melting the reactant in a
preheated metal block at 260 °C, and method B utilized
microwave irradiation in a closed vessel (300 W, 280 °C) with
N,N-dimethylacetamide as the solvent. The rearrangement of
2c−f to form 3c−f was easily detected by the change in the Rf
value from approximately 0.5 to 0.2 (the mobile phase was
chloroform/toluene 1:1) or in the shifts of the carbon CO
(187−190 ppm) and CS (166−168 ppm) signals in the 13C
NMR spectrum. Method A showed several advantages with
compounds bearing isopropyl moieties (3c, 3e), including
solvent-free conditions, an easier purification procedure, and
lack of a microwave reactor. However, this method was not
effective for 3d and 3f, which possessed bulkier tert-butyl
groups. No products were formed at all, and the starting
compounds 2d and 2f were completely recovered from the
reaction mixture, even at temperatures over 260 °C. On the
other hand, 3d and 3f were obtained via method B in
reasonable yields of 70% and 57%, respectively. Differing
reactivities were also observed in the last step involving the
cleavage of the S-aryl thiocarbamates to thiophenols. Disulfides
5c and 5e were always obtained in noticeable yields (9% and
10%, respectively) as side products in addition to the desired
products, thiophenols 4c and 4e. This side reaction was
significantly suppressed for 4d and 4f, with bulky tert-butyl
groups attached at positions 2 and 6, due to the steric
constraint (the side products appeared as traces on TLC only
and were not isolated). The treatment of the reaction mixtures
with a reducing agent at the end of the synthesis (dithiothreitol
or a large excess of 2-mercaptoethanol) in a one-pot reaction
ensured the cleavage of the disulfides and gave thiophenols 4c−
f in yields over 52%.
Scheme 2. General Synthesis of 5,6-Disubstituted Pyrazine-
2,3-Dicarbonitriles
moieties influencing the solubility, photophysical properties, or
targeting ability can be introduced onto the TPyzPz periphery
via these precursors. Modification of precursor 6a via coupling
reactions will be included in a follow-up project studying
application potential of arysulfanyl TPyzPz in detail.
In general, TPyzPzs are prepared through two different
approaches: the template method or the successive con-
struction of the macrocycle using alkoxide to initiate the
reaction. The latter method usually gives higher yields but may
suffer from the nucleophilic substitution of labile peripheral
groups with the alkoxy groups of the initiator. This side
reaction was described in detail in several published papers
concerning alkyloxy- and aryloxy-TPyzPzs.36,37 This is also the
reason that the first and only attempt to synthesize arylsulfanyl
TPyzPz by Mørkved failed.27 The cyclotetramerization of
precursors 6a−d with magnesium butoxide (method C,
Scheme 3) was tested first. It gave, in all cases, magnesium
TPyzPzs as green products that were demetalated under acidic
conditions and transformed to zinc complexes. Interesting
relationships were observed in the 6a−d series using mass
spectrometry (MS) when considering the extent of the
undesirable exchange reaction38 (see Table 2 or the mass
a
Scheme 3. Synthesis of TPyzPzs 7a−d by Method C
Thiophenols 4a−f were further used in reactions with 5,6-
dichloropyrazine-2,3-dicarbonitrile (see Scheme 2). The
electron deficient carbons at positions 5 and 6 of the latter
are highly activated for nucleophilic aromatic substitution.
Different solvents (DMF and THF) and bases (NaOH, K2CO3,
and NaH) and direct reaction with sodium thiophenolate were
tested, but only traces of products 6a−f were detected by TLC.
The best results were only achieved using acetone as the
solvent and pyridine as the base to afford the desired products
6a−f in reasonable yields of 67−94%. Thiophenols 4a−c and
4e reacted immediately at room temperature, irrespective of the
bulkiness of the substituent at the ortho position (i.e., hydrogen,
methyl, or isopropyl). On the other hand, thiophenols 4d and
4f, bearing bulky tert-butyl substituent groups, required heating
at reflux and prolonged reaction times of up to 14 h to react.
Precursors 6e and 6f substituted with bromine were added to
the series because they can serve as building blocks for further
modification of the TPyzPz peripheral groups. Arylbromides
are known to undergo coupling reactions.35 Thus, several
a
(i) Mg(OBu)2, BuOH, reflux, 5 h; (ii) p-TSA, THF, rt, 1 h; and (iii)
Zn(CH3COO)2, pyridine, reflux, 1 h; (other possible synthetic
pathways discussed in text are described in the Experimental Section).
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Table 2. Summary of the Different Cyclotetramerization Methods
a
relative intensities of the signal in the mass spectra, %
yield of
isolated zn
complex
cyclotetramerization
agent
8 × SAr 7 × SAr 6 × SAr 5 × SAr 4 × SAr 3 × SAr 2 × SAr 1 × SAr 0 × SAr
0 × OBu 1 × OBu 2 × OBu 3 × OBu 4 × OBu 5 × OBu 6 × OBu 7 × OBu 8 × OBu
cpd.
method
b
c
7aZn
7aZn
C
D
Mg(OBu)2
29%
100
100
66
-
37
-
16
-
3
-
-
-
-
-
-
-
-
-
Zn(CH3COO)2,
2%
d
DMF
e
7aZn
7bZn
7cZn
7cZn
E
Zn(quinoline)2Cl2
15%
100
100
100
100
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
b
f
C
C
D
Mg(OBu)2
27%
2
-
b
f
Mg(OBu)2
35%
Zn(CH3COO)2,
23%
-
d
DMF
e
7cZn
7cZn
7cZn
7cZn
7dZn
E
Zn(quinoline)2Cl2
23%
100
-
-
-
-
-
-
-
-
-
g
c
F
LiOBu
60%
-
-
-
-
10
10
-
38
-
30
-
100
h
c
G(1)
DBU (1)
54%
45
52
100
89
86
-
100
100
-
63
51
-
25
9
-
-
-
-
i
c
G(10) DBU (10)
17%
-
-
b
f
C
Mg(OBu)2
23%
-
-
-
a
Analyzed directly from the crude reaction mixture before purification (for the appropriate MS spectra see Figures S1−S10 in the Supporting
b
c
Information). Mg(OBu)2, BuOH, reflux, 5 h; p-TSA, THF, rt, 1 h; Zn(OAc)2, pyridine, reflux, 1 h. Yield of the TPyzPzs mixture (after a column
d
e
f
chromatography). Zn(CH3COO)2, DMF, reflux, 3−10 h, argon atmosphere. Zn(quinoline)2Cl2, 250 °C, 5 min. Yield of pure TPyzPzs (with 8 ×
SAr) from three step reaction. LiOBu, BuOH, reflux, 2.5 h. Zn(CH3COO)2, DBU (1 equiv), BuOH, reflux, 6 h. Zn(CH3COO)2, DBU (10
equiv), BuOH, reflux, 6 h.
g
h
i
spectra in the Supporting Information). The tert-butyl and
isopropyl substituents on the phenyl were bulky enough to
protect the reactive electron-deficient carbons in the pyrazine
ring from attack by magnesium butoxide. No side products due
to the exchange of peripheral substituents were detected by MS
in the 7c and 7d series. Traces of TPyzPzs with some
arylsulfanyl groups exchanged for butoxy groups were observed
in the crude reaction mixture of 7bZn, but the pure
octaarylsulfanyl complexes 7b were easily obtained by column
chromatography. The susceptibility to this side reaction was
most pronounced in the 7a series, in which the butoxide anion
can easily reach the reactive center, and a mixture of inseparable
TPyzPzs with butoxy and phenylsulfanyl substituents was
obtained. The results for the 7a series were in good agreement
with those published by Mørkved, who noticed the exchange of
peripheral substituents during the cyclotetramerization of 5,6-
bis(p-tolylsulfanyl)pyrazine-2,3-dicarbonitrile with magnesium
propoxide.27 Thus, method C is not suitable for the synthesis of
7a complexes and unhindered arylsulfanyls in general. The
mass spectrum of compound 7dZn showed not only the correct
mass ([M]+ = 2345.8) and the sodium and potassium adducts,
but also a mass of 2287.7 and the corresponding potassium
adduct. However, 7dZn appeared as the only spot on the TLC
(see Figure S11 in the Supporting Information) and also
provided satisfactory elemental analysis results. The NMR
spectra did not provide any answers regarding this second
observed mass peak, and only signals corresponding to the
expected hydrogen or carbon atoms were observed (see Figure
S12 in the Supporting Information). Unfortunately, the origin
of the unexplained mass peak has not yet been explained.
The cyclotetramerization conditions were then studied
further. Precursor 6c, bearing isopropyl groups, was chosen as
a model precursor for this purpose. First, several reactions for
the alkoxide approaches, which differed in the manner in which
the alkoxide was formed (i.e., methods C, F, and G), were
performed. Surprisingly, the reactivity of 6c differed signifi-
cantly when magnesium, lithium, or 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) was used to form the butoxide. No
exchange of the peripheral substituents was detected with the
use of magnesium butoxide; however, the side reaction partially
proceeded in the case of DBU (with 1 or 10 equiv of DBU to
6c). Only a mixture of products containing mostly butoxy
substituents was obtained when lithium butoxide was used (see
Table 2 or Figures S1−S10 in the Supporting Information).
This approach showed that the strength of the butoxide attack
increases in the following order: magnesium ≪ DBU < lithium.
From this perspective, magnesium butoxide can be considered a
mild cyclotetramerization agent. The reaction conditions for
the cyclotetramerization using template methods were also
studied. Template cyclotetramerization is usually performed in
high boiling solvents with a metal salt. Cyclotetramerization
proceeds in different manner than the previous method. The
metal serves as a template that allows four precursor molecules
to approach each other and form a TPyzPz macrocycle after
heating. Thus, heating 6c with anhydrous zinc acetate in DMF
(method D) or performing the cyclotetramerization in a melt
with Zn(quinoline)2Cl2 (method E) gave pure 7cZn in 23%
yield in both cases. These yields, however, were lower than
those for the magnesium butoxide method (35% for the three
step reaction, calc. from 6c). As mentioned above, the alkoxide
approach cannot be used for the cyclotetramerization of 6a, and
the template methods with zinc acetate in DMF (method D) or
melting with Zn(quinoline)2Cl2 (method E) must be used. In
this case they provided pure 7aZn in yields of 2% and 15%,
respectively. In addition to the lower efficiencies of the
template methods, the very low yields can partially be explained
by the difficult purification that results from the low solubility
of 7aZn, caused by aggregation.
UV−vis Spectra. Prepared TPyzPzs had absorption spectra
profiles typical for this group of compounds with a high energy
B-band at 380 nm and a low energy Q-band at 660 nm and
extinction coefficients up to 133 000 and 237 000 M−1 cm−1,
respectively (see Figure 1a and Figure S13 in the Supporting
Information). The shapes of the Q-bands of most of the
complexes suggested that they were in the monomeric form in
THF even at high concentrations (up to 10−5 M). However,
7aMg and 7aH tended to aggregate, which was indicated by a
broadening of the absorption spectra, a decrease in the
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The position of the Q-band is primarily influenced by the
conjugated bond system of the TPyzPz core, while the
peripheral groups usually play a minor role. Nevertheless, Q-
bands of the prepared arylsulfanyl TPyzPzs were shifted by 10
nm compared to the alkylsulfanyl TPyzPzs13 (as an example,
see TPyzPz 8Zn in Table 3) most likely due to the enlargement
Table 3. Absorption and Photophysical Data of the TPyzPzs
Involved in the Study Determined in THF at Room
Temperature
compound peripheral substituent λabs/nm λem/nm
ΦF
ΦΔ
7aZn
7bZn
7cZn
7dZn
PhS
656
658
661
659
649
624
662
668
677
665
656
630
0.18
0.18
0.12
0.078
0.35
0.41
0.61
0.64
0.69
2,6-diMe-PhS
2,6-bis(iPr)PhS
2,6-bis(tBu)PhS
tBuS
a
a
0.58
0.55
0.50
b
8Zn
b
9Zn
2,6-bis(iPr)PhO
a
b
Ambiguous composition (see discussion). Data from literature.13
of the conjugated system with the attached arylsulfanyl
moieties. This indicates that some level of electronic
communication between the peripheral phenyl groups and
the TPyzPz core persists despite the almost perpendicular
orientation of these two moieties (see the X-ray analysis data
and discussion of 6a−d in Supporting Information). Consid-
ering the role of the connecting heteroatom, sulfur is
advantageous compared to isosteric oxygen due to the
significant bathochromic shift of almost 40 nm (Table 3,
compare 7cZn with the isosteric TPyzPz 9Zn). These
observations are in accord with the literature13 where Q-
bands of alkyloxy TPyzPzs are hypsochromically shifted from
the alkylsulfanyl TPyzPzs by 30 nm. Absorption at a longer
wavelength is advantageous for any biological application (e.g.,
for PDT) because red light is less scattered and is not absorbed
by endogenous chromophores, thus resulting in the ability of
the light to penetrate deeper into biological material.
An interesting relationship of the Q-band position was
observed in the prepared TPyzPz series, as the Q-band maxima
in THF were located at 656, 658, and 661 nm for 7aZn, 7bZn,
and 7cZn, respectively (see Figure 1a). This can most likely be
explained by the slight distortion of the macrocyclic core as a
result of the increased bulkiness of the peripheral substituents.
A similar distortion effect was described by Chambrier for
nonperipherally substituted Pc.39 The absorption maxima of
7dMg, 7dH, and 7dZn were an exception because the Q-band
position was shifted to slightly shorter wavelengths and an
additional broad band in the absorption spectrum was observed
at 720 nm. This fact could be connected with the complex
composition of the sample described above.
Photophysical Properties. Fluorescence emission and
singlet oxygen production, the two main excited state relaxation
pathways of the prepared TPyzPzs 7a−dZn, were investigated
in THF. Singlet oxygen is the main cytotoxic species in PDT,
and strong red fluorescence can be used for visualization in
PDT or for detection purposes. The fluorescence emission
spectra showed the typical shapes for Pcs and related
compounds and mirrored the absorption spectra (Figure 1b).
Only the small Stokes shifts documented in Table 3 were
observed, and they did not exceed 10 nm, which is also typical
for this group of compounds. The fluorescence excitation
spectra for the compounds in the monomeric forms matched
the absorption spectra (Figure 1b). This fact further confirmed
Figure 1. Spectral properties of TPyzPzs in THF: (a) Q-band area of
the normalized absorption spectra of 7a−cZn (7aZn blue, 7bZn
green, and 7cZn red); (b) normalized absorption (black), emission
(red), and excitation (blue) spectra of 7cZn.
extinction coefficient, and their lower solubility. It must be
noted that samples 7aMg and 7aH were mixtures containing
some exchanged butoxy substituents, which may also contribute
to the aggregation. 7aZn was a pure compound prepared by the
template method and did not show aggregation. Similarly, the
metal-free derivative 7bH from the 7b series exhibited
aggregation in THF, while the corresponding zinc and
magnesium complexes were highly soluble and monomeric at
all of the tested concentrations (up to 10−5 M). Compounds
from the 7c series remained in their monomeric forms
throughout all of the measurements and were highly soluble
in common organic solvents (chloroform, dichloromethane,
THF, DMF, and pyridine), indicating that the bulkiness of the
isopropyl substituents completely prevented aggregation. The
aggregation phenomenon also correlates well with the rotation
of the phenyl out of the plane of the pyrazine ring, as discussed
in the paragraph dedicated to the X-ray analysis of precursors
6a−d in Supporting Information. From this perspective,
derivatives from the 7d series bearing tert-butyl groups should
behave similarly to those from the 7c series. However, the Q-
band of 7dZn and 7dMg contained a shoulder at approximately
720 nm (see Figure S13d in the Supporting Information). The
presence of residual metal free impurity in 7dZn and 7dMg
stocks comes as one of the plausible explanations. This
assumption can be, however, excluded due to only one clear
spot of 7dMg and 7dZn on TLC with quite different retention
factors from 7dH (see TLC in Figure S11b in the Supporting
Information; Rf(7dH) = 0.86, Rf(7dMg) = 0.16, Rf(7dZn) = 0.32 in
toluene/THF 40:1 as a mobile phase). No presence of 7dH
mass (m/z 2225.83) in mass spectra of 7dMg and 7dZn
supports this interpretation. The band at 720 nm cannot be
attributed even to aggregation, due to the extreme bulkiness of
the substituents, but indicates that the composition of this
sample is more complex, as already suggested by the mass
spectra. The absorption spectrum of metal-free 7dH was fully
distorted in the Q-band, thus supporting these suggestions.
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4-Bromo-2,6-diisopropylphenol (1e). Compound 1e was prepared
using a previously published method.40 Bromine was added dropwise
to a solution of 2,6-diisopropylphenol (3 g, 16.8 mmol) in acetic acid
(50 mL) until discoloration of the solution stopped. After stirring at rt
for the next 1 h, the solution was poured into water (100 mL) and
extracted three times with ethyl acetate. The organic layers were
collected, dried over anhydrous Na2SO4, and purified by column
chromatography on silica with hexane/toluene 2:1 as the eluent. Yield:
4.06 g of yellowish oil (94%); 1H NMR (300 MHz, CDCl3): δ = 1.25
(d, J = 6.9 Hz, 12H), 3.12 (hept, J = 6.8 Hz, 2H), 4.75 (s, 1H), and
7.15 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): δ = 22.5, 27.2, 113.3,
126.4, 136.0, 149.0 ppm; IR (ATR): ν = 2961, 1910, 2869, 1457, 1442,
1385, 1362, 1338, 1294, 1241, 1196, 1148, 1108, 1072, and 935 cm−1.
General Procedure for the Synthesis of O-Substituted
Dimethylcarbamothioates (2). The appropriate phenol (1 equiv)
was dissolved in N-methyl-2-pyrrolidone under an argon atmosphere
and cooled in an ice/water bath. NaH (60% dispersion in mineral oil;
1.1 equiv.) was slowly added in several portions. The cooling bath was
removed and the reaction mixture was stirred at rt for 30 min.
Dimethylcarbamoyl chloride (1.3 equiv) dissolved in N-methyl-2-
pyrrolidone was added dropwise, and the reaction was heated to 80 °C
for 1−12 h (specified for each compound below). The reaction
mixture was diluted with water and extracted with ethyl acetate (3×).
The organic layer was collected, dried over anhydrous Na2SO4, and
concentrated under high vacuum. The crude product was purified two
times by column chromatography on silica. The exact amounts of the
reactants as well as the mobile phases are specified for each compound
below.
O-(2,6-Diisopropylphenyl)dimethylcarbamothioate (2c). 2,6-Dii-
sopropylphenol (1.78 g, 10 mmol), NaH (440 mg 60% dispersion in
mineral oil, 11 mmol), dimethylthiocarbamoyl chloride (1.66 g, 13
mmol); reaction time of 1 h; purification by recrystallization from
EtOH; Yield: 1.19 g of yellow needles (45%); melting point 144.7−
146.5 °C (EtOH; lit. 152.5−154.0 °C13); 1H NMR (300 MHz,
CDCl3): δ = 1.18 (d, J = 6.9 Hz, 6H), 1.27 (d, J = 6.9 Hz, 6H), 2.93
(hept, J = 6.9 Hz, 2H), 3.40 (s, 3H), 3.50 (s, 3H), and 7.15−7.23 ppm
(m, 3H); 13C NMR (75 MHz, CDCl3): δ = 22.2, 24.4, 27.4, 38.4, 43.3,
123.8, 126.5, 140.9, 148.5, and 187.8 ppm; IR (ATR): ν = 2964, 2875,
1531, 1462, 1440, 1393, 1360, 1333, 1287, 1254, 1178, 1139, 1095,
1060, 937, 833, 799, and 768 cm−1; Elemental analysis calcd. (%) for
C15H23NOS: C 67.88, H 8.73, N 5.28; found 67.98, H 8.09, N 5.49.
O-[2,6-Di(tert-butyl)phenyl]dimethylcarbamothioate (2d). 2,6-
Di(tert-butyl)phenol (3.6 g, 17.5 mmol), NaH (772 mg 60%
dispersion in mineral oil, 19.3 mmol), dimethylthiocarbamoyl chloride
(2.81 g, 22.8 mmol); reaction time of 12 h; toluene as the eluent (Rf =
0.4); recrystallization from MeOH; Yield: 1.13 g of white needles
(22%); melting point 115.0−115.8 °C (MeOH); 1H NMR (300 MHz,
CDCl3): δ = 1.37 (s, 18H), 3.45 (s, 3H), 3.47 (s, 3H), 7.21−7.14 (m,
1H), and 7.30−7.34 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): δ =
32.0, 35.9, 38.7, 43.2, 125.4, 126.6, 142.6, 150.8, and 189.7 ppm; IR
(ATR): ν = 3004, 2967, 2875, 1521, 1479, 1419, 1396, 1386, 1362,
1283, 1223, 1187, 1161, 1140, 1116, 1049, 887, 843, 800, and 766
cm−1; Elemental analysis calcd. (%) for C17H27NOS: C 69.58; H 9.27;
N 4.77; found C 69.38, H 9.54, N 4.74.
that aggregation of the studied compounds 7a−dZn did not
occur. The fluorescence quantum yields (ΦF) as well as the
singlet oxygen quantum yields (ΦΔ) were determined by
comparative methods using zinc phthalocyanine as a reference.
The data are summarized in Table 3. The ΦF and ΦΔ values of
7a−cZn did not differ much within the series and reached
values of 0.12−0.18 and 0.61−0.69, respectively. The photo-
physical data of the alkylsulfanyl TPyzPz 8Zn and the aryloxy
TPyzPz 9Zn are provided in Table 3 for comparison. It is
obvious that the photophysical properties of the arylsulfanyl
TPyzPzs differed from the related alkylsulfanyl derivative 8Zn.
Arylsulfanyl TPyzPzs 7a−cZn preferred relaxation of their
excited states through singlet oxygen production, and
fluorescence emission was significantly suppressed. Comparison
of 7cZn with the isosteric 9Zn confirmed that the oxygen
linkage in the peripheral substitution led to higher ΦF and
lower ΦΔ values compared with the sulfur linkage. Similar
relationships have been described for alkyloxy and alkylsulfanyl
TPyzPzs.13 The photophysical data of 7dZn were also studied.
Excitation spectrum corresponded well with the absorption
spectrum (see Figure S16 in Supporting Information), but the
ΦF and ΦΔ did not fully correlate with the others of the series
reaching only 0.078 and 0.58, respectively. We believe that the
decrease cannot be attributed to the cofacial aggregation
(typically H-dimers) due to extreme bulkiness of peripheral
substitution, but probably to the ambiguous composition of the
sample (see above).
CONCLUSIONS
■
The Newman-Kwart rearrangement was demonstrated to be
useful for the synthesis of thiophenols bearing bulky aliphatic
substituents in positions ortho to SH groups; however, suitable
reaction conditions must be selected to avoid side products in
the reactions. Furthermore, 5,6-bis(arylsulfanyl)pyrazine-2,3-
dicarbonitriles were synthesized and used for the preparation of
TPyzPzs. Different cyclotetramerization methods were tested,
leading to the conclusion that magnesium butoxide is the best
reagent to ensure the initiation of cyclotetramerization under
mild conditions with reasonable product yields. Bulkiness of the
peripheral substituents played an important role not only
during the synthesis but also in the properties of the TPyzPzs.
The isopropyl group was found to be bulky enough to
completely prevent undesirable side reactions during cyclo-
tetramerization and maintain the TPyzPzs in their monomeric
form in solution. Tert-butylsulfanyl TPyzPz showed unexpected
and unclarified behavior. All of these data indicate that
arylsulfanyl TPyzPzs bearing isopropyl substituents in the
ortho positions seem to be most appropriate compounds for
further development in this group of compounds. Fluorescence
quantum yields up to 0.20 and in particular high singlet oxygen
quantum yields (up to 0.69) significantly exceeding both
aryloxy isosters and alkylsulfanyl analogues in addition to
absorption maximum over 650 nm show the potential of
arylsulfanyl TPyzPzs in the field of photodynamic therapy.
O-(4-Bromo-2,6-diisopropylphenyl)dimethylcarbamothioate
(2e). 4-Bromo-2,6-diisopropylphenol (3.5 g, 13.6 mmol), NaH (599
mg 60% dispersion in mineral oil, 15.0 mmol), dimethylthiocarbamoyl
chloride (2.19 g, 17.7 mmol); reaction time of 2 h; hexane/toluene 2:1
as the eluent (Rf = 0.22); Yield: 3.8 g of white needles (81%); melting
point 114.0−115.1 °C; 1H NMR (300 MHz, CDCl3): δ = 1.15 (d, J =
6.9 Hz, 6H), 1.25 (d, J = 6.9 Hz, 6H), 2.88 (hept, J = 6.9 Hz, 2H), 3.38
(s, 3H), 3.48 (s, 3H), and 7.26 ppm (s, 2H); 13C NMR (75 MHz,
CDCl3): δ = 22.0, 24.2, 27.5, 38.5, 43.4, 120.0, 127.1, 143.4, 147.6, and
187.2 ppm; IR (ATR): ν = 2967, 2925, 2863, 1572, 1537, 1464, 1449,
1410, 1392, 1363, 1330, 1287, 1236, 1179, 1126, 1097, 1071, 1059,
945, 878, 861, 843, 779, and 758 cm−1; Elemental analysis calcd. (%)
for C15H22BrNOS: C 52.33, H 6.44, N 4.07; found C 52.53, H 6.50, N
4.16.
EXPERIMENTAL SECTION
■
Syntheses. General. Unsubstituted zinc phthalocyanine as a
reference compound was purchased from Sigma-Aldrich. A CEM
Discover and Explorer 24 Automated Microwave Synthesis Work-
station with a 24-position reaction deck (CEM Corporation,
Matthews, North Carolina, USA) was used for the reactions under
microwave irradiation. Reaction temperatures during microwave
heating were controlled by external infrared sensor.
O-[4-Bromo-2,6-di(tert-butyl)phenyl]dimethylcarbamothioate
(2f). 4-Bromo-2,6-di(tert-butyl)phenol (5 g, 17.5 mmol), NaH (772
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mg 60% dispersion in mineral oil, 19.3 mmol), dimethylthiocarbamoyl
chloride (2.82 g, 22.8 mmol); reaction time of 4 h; hexane/toluene 1:1
as the eluent; Yield: 1.21 g of yellowish solid (19%); melting point
analysis calcd. (%) for C15H22BrNOS: C 52.33, H 6.44, N 4.07; found
C 52.50, H 6.62, N 3.83.
S-[4-Bromo-2,6-di(tert-butyl)phenyl]dimethylcarbamothioate
(3f). Method A. Did not work.
1
133.9−134.7 °C; H NMR (300 MHz, CDCl3): δ = 1.34 (s, 18H),
3.43 (s, 3H), 3.46 (s, 3H), and 7.40 ppm (s, 2H). 13C NMR (75 MHz,
CDCl3): δ = 32.1, 36.5, 39.1, 43.6, 119.5, 130.0, 145.2, 150.3, and
189.5 ppm; IR (ATR): ν = 2959, 1563, 1529, 1482, 1418, 1387, 1365,
1285, 1253, 1198, 1141, 1113, 1053, 948, 887, 869, 776, and 735 cm−1;
Elemental analysis calcd. (%) for C17H26BrNOS: C 54.83, H 7.04, N
3.76; found C 55.09, H 7.17, N 3.82; MS (ESI): m/z: 371.87 [M+H]+.
Side Product Y-d: 3,3′,5,5′-Tetra(tert-butyl)-(1,1′-biphenyl)-4,4′-
diol. Isolated from column chromatography of 2f. Yield: 2.95 g of
Method B. 2f (225 mg, 0.60 mmol); 3 h; chloroform/toluene 1:1.
Yield: 129 mg of yellow oil (57%); 1H NMR (300 MHz, CDCl3): δ =
1.47 (s, 18H), 2.99 (s, 3H), 3.13 (s, 3H), and 7.54 ppm (s, 2H); 13C
NMR (75 MHz, CDCl3): δ = 29.5, 31.8, 37.0, 37.9, 126.9, 127.3,
129.0, 158.0, and 167.6 ppm; IR (ATR): ν = 2959, 2874, 1562, 1529,
1396, 1285, 1255, 1198, 1141, 1113, 1052, and 869 cm−1; HRMS
(ESI-Q-TOF) m/z: [M + H]+ Calcd for C17H27BrNOS 372.0997;
Found 372.1015.
General Procedure for the Synthesis of the Thiols (4).
Compound 3c−f (1 equiv) in 1,2-dimethoxyethane was added
dropwise to a suspension of LiAlH4 (1.5 equiv) in 1,2-dimethoxy-
ethane under an argon atmosphere while being cooled in an ice/water
bath. Then, the cooling bath was removed, and the reaction was heated
at reflux for 4 h under argon. Excess LiAlH4 was quenched with several
drops of MeOH until gas evolution stopped. Then, the reaction
mixture was diluted with water, acidified with diluted sulfuric acid (5%
v/v), and extracted three times with diethylether. The organic layer
was dried over anhydrous Na2SO4. The crude product was dissolved in
chloroform and an excess of 2-mercaptoethanol (20−50 equiv) was
added and stirred at rt for 8 h to cleave the disulfide bond of side
product 5 (observed on TLC with a slightly higher Rf than the
product). The excess 2-mercaptoethanol was removed under reduced
pressure, and the crude product was purified by column chromatog-
raphy on silica (the mobile phases are specified for each compound
below).
2,6-Diisopropylbenzenethiol (4c). 3c (420 mg, 1.58 mmol);
LiAlH4 (90 mg, 2.37 mmol); hexane/toluene 3:1 as an eluent. Yield:
271 mg of yellowish oil (88%); 1H NMR (300 MHz, CDCl3): δ = 1.28
(d, J = 6.8 Hz, 12H), 3.23 (s, 1H), 3.48 (hept, J = 6.7 Hz, 2H), 7.11−
7.24 ppm (m, 3H). 13C NMR (75 MHz,CDCl3): δ = 23.1, 31.7, 123.1,
126.4, 127.7, and 147.8 ppm.
2,6-Di(tert-butyl)benzenethiol (4d). 3d (480 mg, 1.64 mmol);
LiAlH4 (186 mg, 4.91 mmol); hexane as an eluent (Rf = 0.42); Yield:
297 mg of colorless oil (82%); 1H NMR (300 MHz, CDCl3): δ = 1.60
(s, 18H), 3.72 (s, 1H), 7.15−7.06 (m, 1H), and 7.37 ppm (d, J = 8.0
Hz, 2H); 13C NMR (75 MHz, CDCl3): δ = 31.3, 37.2, 125.3, 125.7,
129.6, and 150.8 ppm; IR (ATR): ν = 2959, 2917, 2872, 2360, 2343,
1572, 1482, 1460, 1393, 1384, 1363, 1252, 1243, 1215, 1188, 1151,
1105, 1044, 925, 792, and 728 cm−1.
4-Bromo-2,6-diisopropylbenzenethiol (4e). 3e (5.0 g, 14.5 mmol);
LiAlH4 (789 mg, 20.8 mmol); hexane/toluene 1:1 as an eluent. Yield:
3.35 g of yellowish oil (84%); 1H NMR (300 MHz, CDCl3): δ = 1.25
(d, J = 6.8 Hz, 12H), 3.16 (s, 1H), 3.43 (hept, J = 6.8 Hz, 2H), and
7.24 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): δ = 22.9, 31.8,
121.03, 126.4, 150.0, and 155.7 ppm; IR (ATR): ν = 2963, 2928, 2871,
1716, 1675, 1563, 1460, 1412, 1384, 1363, 1323, 1234, 1153, 1106,
1060, 1046, 889, 864, and 805 cm−1.
4-Bromo-2,6-di-tert-butylbenzenethiol (4f). 3f (300 mg, 0.81
mmol); LiAlH4 (48 mg, 1.26 mmol); hexane as an eluent; Yield:
126 mg of yellowish oil that solidifies to yellowish solid (52%); melting
point 60.0−61.8 °C; 1H NMR (300 MHz, CDCl3): δ = 1.56 (s, 18H),
3.66 (s, 1H), and 7.46 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): δ =
31.0, 32.2, 37.3, 120.8, 128.4, 128.7, and 152.9 ppm; IR (ATR): ν =
3105, 2955, 2919, 2872, 1730, 1558, 1485, 1398, 1382, 1363, 1243,
1198, 1161, 1101, 1043, 918, 871, 843, and 769 cm−1; Elemental
analysis calcd. (%) for C14H21BrS: C 55.81, H 7.03; found C 56.66, H
7.05; HRMS (ESI-Q-TOF) m/z: [M - H]− Calcd for C14H20BrS
299.0469; Found 299.0476.
1
yellow solid (41%); melting point 181.2−182.8 °C; H NMR (300
MHz, CDCl3): δ = 1.51 (s, 36H), 5.20 (s, 2H), and 7.32 ppm (s, 4H);
13C NMR (75 MHz, CDCl3): δ = 30.3, 34.4, 124.1, 133.9, 135.9, and
152.8 ppm; IR (ATR): ν = 3630, 2915, 2957, 2846, 1466, 1424, 1389,
1359, 1318, 1303, 1247, 1227, 1202, 1139, 1105, 1022, 933, 885, and
871 cm−1.
Side Product Z-d: 3,3′,5,5′-Tetra(tert-butyl)-[1,1′-bi-
(cyclohexylidene)]-2,2′,5,5′-tetraene-4,4′-dione. Isolated from col-
1
umn chromatography of 2f. Yield: 430 mg of yellow solid (6%); H
NMR (300 MHz, CDCl3): δ = 1.36 (s, 36H) and 7.70 ppm (s, 4H);
13C NMR (75 MHz, CDCl3): δ = 29.6, 36.0, 126.0, 136.1, 150.4, and
186.5 ppm; IR (ATR): ν = 2959, 2921, 2866, 1640, 1603, 1567, 1541,
1482, 1458, 1389, 1363, 1339, 1290, 1262, 1092, 1043, 997, 934, and
899 cm−1.
General Procedures for the Synthesis of the S-Substituted
Dimethylcarbamothioates (3). Method A. O-substituted dimethyl-
carbamothioate (2) was placed into a metal block preheated to 260 °C
which was maintained at this temperature for 1 h. The crude product
was purified by column chromatography on silica (the mobile phases
are specified for each compound below).
Method B. O-substituted dimethylcarbamothioate (2) was dissolved
in N,N-dimethylacetamide and heated under microwave irradiation
(300 W, 280 °C) for 3−4 h. The crude product was purified by
column chromatography on silica (the mobile phases are specified for
each compound below).
S-(2,6-Diisopropylphenyl)dimethylcarbamothioate (3c). Method
A. 2c (330 mg, mmol); chloroform/toluene 1:1 as the eluent; Yield:
294 mg of colorless oil that solidifies to yellow solid (89%); melting
point 105.4−105.8 °C; 1H NMR (300 MHz, CDCl3): δ = 1.22 (d, J =
7.1 Hz, 12H), 2.94−3.25 (m, 6H), 3.61 (hept, J = 6.9 Hz, 2H), 7.18−
7.25 (m, 2H), and 7.35−7.42 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3): δ = 20.1, 27.9, 33.1, 119.6, 121.9, 126.3, 149.6, and 162.7
ppm; IR (ATR): ν = 2960, 2927, 2869, 1726, 1664, 1575, 1459, 1407,
1381, 1326, 1312, 1264, 1180, 1100, 1053, 934, and 824 cm−1. HRMS
(ESI-Q-TOF) m/z: [M + H]+ Calcd for C15H24NOS 266.1579; Found
266.1606.
S-[2,6-Di(tert-butyl)phenyl]dimethylcarbamothioate (3d). Meth-
od A. Did not work.
Method B. 2d (100 mg, 0.34 mmol); 4 h; chloroform/toluene 1:2.
Yield: 70 mg of colorless needles (70%); melting point 110.2−111.5
1
°C; H NMR (300 MHz, CDCl3): δ = 1.49 (s, 18H), 3.06 (s, 6H),
7.28 (t, J = 7.6 Hz, 1H), and 7.44 ppm (d, J = 7.6 Hz, 2H); 13C NMR
(75 MHz, CDCl3): δ = 32.0, 36.9, 37.7, 125.6, 128.0, 129.4, 156.1, and
168.2 ppm; IR (ATR): ν = 3000, 2954, 2920, 1664, 1507, 1458, 1406,
1387, 1363, 1253, 1216, 1099, 1042, 909, 873, 799, and 746 cm−1;
Elemental analysis calcd. (%) for C17H27NOS: C 69.58; H 9.27; N
4.77; found C 69.78, H 9.46, N 4.72.
S-(4-Bromo-2,6-diisopropylphenyl)dimethylcarbamothioate (3e).
Method A. 2e (6.3 g, 18.3 mmol); toluene as an eluent (Rf = 0.15)
changed to chloroform/toluene 1:1 during column chromatography;
Yield: 5.13 g of colorless oil that solidifies to white solid (85%);
melting point 104.2−106.4 °C; 1H NMR (300 MHz, CDCl3): δ = 1.19
(d, J = 6.8 Hz, 12H), 3.02 (s, 3H), 3.16 (s, 3H), 3.56 (hept, J = 6.8 Hz,
2H), and 7.32 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): δ = 23.8,
31.9, 37.1, 125.0, 125.5, 127.0, 155.7, and 165.9 ppm; IR (ATR): ν =
2961, 2928, 2873, 1716, 1655, 1561, 1458, 1419, 1368, 1315, 1260,
1235, 1098, 1060, 1045, 910, 891, 867, and 805 cm−1. Elemental
1,2-Bis(2,6-diisopropylphenyl)disulfane (5c). In one instance, the
disulfide side product 5c was isolated from the reaction mixture before
cleavage with 2-mercaptoethanol to confirm its identity. Reaction
mixture was dissolved in 20% NaOH; undissolved precipitate was
collected and purified by column chromatography on silica with
1
hexane/toluene 3:1 as an eluent. Melting point 127.0−127.9 °C; H
NMR (300 MHz, CDCl3): δ = 1.03 (d, J = 6.9 Hz, 24H), 3.56 (hept, J
= 6.9 Hz, 4H), 7.06−7.11 (m, 4H), and 7.22−7.29 ppm (m, 2H); 13C
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NMR (75 MHz,CDCl3): δ = 23.8, 31.4, 123.6, 130.0, 132.3, and 153.5
ppm; IR (ATR): ν = 3057, 2961, 2866, 1573, 1463, 1421, 1381, 1360,
1337, 1309, 1248, 1179, 1104, 1056, 928, and 797 cm−1; Elemental
analysis calcd. (%) for C24H34S2: C 74.55, H 8.86; found C 74.88, H
9.01; Pure 5c was subsequently reduced affording 4c as follows: 5c (50
mg, 0.13 mmol) and dithiothreitol (60 mg, 0.40 mmol) were dissolved
in chloroform. Triethylamine (0.054 mL, 0.04 mmol) was then added
and mixture was stirred at rt for 5 h. Product was extracted three times
with water; organic layer was dried over anhydrous Na2SO4, and
purified by column chromatography on silica with hexane/toluene 3:1
as an eluent. Yield: 42 mg (76%) of yellow oil. The analytical data
corresponded well with those for 4c.
General Procedure for the Synthesis of 5,6-Disubstituted
Pyrazine-2,3-Dicarbonitriles (6). Compound 4a−f (2.2 equiv) was
added to 5,6-dichloropyrazine-2,3-dicarbonitrile (1 equiv) in acetone.
Then, pyridine (5 equiv) was added at rt. The reactions proceeded
immediately with 4a−c and 4e. Heating at reflux and a reaction time of
14 h was necessary for thiophenols 4d and 4f which had bulky tert-
butyl substituents. The crude product was purified by column
chromatography on silica and recrystallized from EtOH or MeOH.
The exact amounts of reactants and the mobile phases are specified for
each compound below.
changed to chloroform/toluene 1:2 after impurities eluted from
column; Yield: 1.33 g of white solid (90%); melting point 261.9−263.3
1
°C (EtOH); H NMR (500 MHz, CDCl3): δ = 1.18 (br, 24H), 3.35
(hept, J = 6.8 Hz, 4H), and 7.43 ppm (s, 4H); 13C NMR (75 MHz,
CDCl3): δ = 24.3, 32.6, 113.0, 121.7, 127.3, 127.5, 128.1, 155.5, and
159.2 ppm; IR (ATR): ν = 2967, 2925, 2856, 2243, 1481, 1362, 1284,
1181, 1152, 1055, and 977 cm−1; Elemental analysis calcd. (%) for
C30H32Br2N4S2: C 53.58, H 4.80, N 8.33; found C 53.35, H 4.70, N
8.38.
5,6-Bis{[4-bromo-2,6-di(tert-butyl)phenyl]sulfanyl}pyrazine-2,3-
dicarbonitrile (6f). 5,6-Dichloropyrazine-2,3-dicarbonitrile (45 mg,
0.27 mmol), 4d (150 mg, 0.50 mmol), pyridine (91 μL, 1.13 mmol),
14 h reflux, toluene/hexane 1:1 as an eluent; Yield: 110 mg of
1
yellowish solid (67%); melting point 287.4−288.1 °C (EtOH); H
NMR (300 MHz, CDCl3): δ = 1.40 (s, 36H) and 7.64 ppm (s, 4H);
13C NMR (75 MHz, CDCl3): δ = 31.8, 37.9, 113.3, 122.2, 126.7,
126.8, 130.2, 158.2, and 160.6 ppm; IR (ATR): ν = 3000, 2970, 2870,
2234, 1556, 1481, 1397, 1386, 1365, 1301, 1279, 1246, 1198, 1148,
1134, 1035, and 974 cm−1; Elemental analysis calcd. (%) for
C30H32Br2N4S2: C 53.58, H 4.80, N 8.33; found C 53.30, H 4.84, N
7.96.
General Procedures for the Cyclotetramerization to Zinc
TPyzPz (7a-dZn). The reaction mixtures that were used to assess the
level of transetherification by MS were analyzed as crude mixtures
without purification by column chromatography (the MS data are
summarized in Table 2). The yields and analytical data mentioned
below are for the purified compounds after column chromatography
(including the MS data for purified compounds).
5,6-Bis(phenylsulfanyl)pyrazine-2,3-dicarbonitrile (6a). 5,6-Di-
chloropyrazine-2,3-dicarbonitrile (1.0 g, 5.0 mmol), 4a (1.22 g, 11.1
mmol), pyridine (2.01 mL, 25.0 mmol), 30 min rt, chloroform/toluene
1:1 as an eluent; Yield: 1.23 g of yellow solid (71%); melting point
1
202.0−203.4 °C (MeOH); H NMR (300 MHz, CDCl3): δ = 7.46−
7.61 ppm (m, 10H); 13C NMR (75 MHz, CDCl3): δ = 113.3, 124.8,
127.5, 129.9, 130.9, 135.4, and 159.2 ppm; IR (ATR): ν = 2238 (CN),
1574, 1481, 1439, 1365, 1284, 1136, 1069, 1023, 976, 846, 750, and
703 cm−1; Elemental analysis calcd. (%) for C18H10N4S2: C 62.41, H
2.91, N 16.17; found 62.54, 3.27, N 16.17.
Method C − with Mg(OBu)2 in BuOH. This method included the
synthesis of magnesium complexes, and their demetalation and
subsequent complexation with zinc. The magnesium and metal-free
derivatives were also isolated and fully characterized.
5,6-Bis(2,6-dimethylphenylsulfanyl)pyrazine-2,3-dicarbonitrile
(6b). 5,6-Dichloropyrazine-2,3-dicarbonitrile (320 mg, 1.64 mmol),
4b(510 mg, 3.62 mmol), pyridine (0.66 mL, 8.22 mmol), 30 min rt,
chloroform/acetone 1:1 as an eluent; Yield: 600 mg of yellowish solid
(94%); melting point 261.8−263.9 °C (MeOH); 1H NMR (300 MHz,
CDCl3): δ = 2.42 (s, 12H), 7.22−7.28 (m, 4H), and 7.32−7.39 ppm
(m, 2H); 13C NMR (75 MHz, CDCl3): δ = 21.6, 113.4, 124.7, 127.2,
128.9, 130.9, 143.5, and 159.0 ppm; IR (ATR): ν = 2969, 2234 (CN),
1584, 1478, 1463, 1376, 1360, 1301, 1280, 1146, 1134, 1113, 1048,
973, 780, and 732 cm−1; Elemental analysis calcd. (%) for C22H18N4S2:
C 65.64, H 4.51, N 13.92; found 65.14, H 4.57, N 13.91.
5,6-Bis(2,6-diisopropylphenylsulfanyl)pyrazine-2,3-dicarbonitrile
(6c). 5,6-Dichloropyrazine-2,3-dicarbonitrile (470 mg, 2.34 mmol), 4c
(1.0 g, 5.16 mmol), pyridine (1.0 mL, 11.7 mmol), 30 min rt,
chloroform/toluene 1:1 as an eluent; Yield: 1.02 g of yellow solid
(85%); melting point 217.6−218.4 °C (MeOH); 1H NMR (300 MHz,
CDCl3): δ = 1.21 (br, 24H), 3.42 (hept, J = 6.7 Hz, 4H), 7.30−7.35
(m, 4H), and 7.49−7.56 ppm (m, 2H); 13C NMR (75 MHz, CDCl3):
δ = 24.0, 32.5, 113.2, 122.8, 124.6, 127.2, 131.8, 153.4, and 160.0 ppm;
IR (ATR): ν = 2966, 2925, 2869, 2239 (CN), 1581, 1482, 1382, 1360,
1343, 1283, 1181, 1152, 1137, 1054, 977, 930, 802, 794, and 746 cm−1;
Elemental analysis calcd. (%) for C30H34N4S2: C 70.00, H 6.66, N
10.88; found 69.91, H 6.44, N 11.01.
5,6-Bis[(2,6-di(tert-butyl)phenylsulfanyl]pyrazine-2,3-dicarboni-
trile (6d). 5,6-Dichloropyrazine-2,3-dicarbonitrile (134 mg, 0.67
mmol), 4d (330 mg, 1.48 mmol), pyridine (277 μL, 3.44 mmol), 14
h reflux, toluene as an eluent; Yield: 315 mg of yellowish solid (82%);
melting point 283.4−284.6 °C (EtOH); 1H NMR (300 MHz,
CDCl3): δ = 1.42 (s, 36H), 7.40 (m, 2H) and 7.56−7.48 ppm (m,
4H); 13C NMR (75 MHz, CDCl3): δ = 32.0, 37.7, 113.5, 123.1, 126.4,
126.7, 130.9, 156.3, and 161.3 ppm; IR (ATR): ν = 2963, 2872, 2235,
1575, 1474, 1396, 1387, 1365, 1358, 1300, 1280, 1252, 1215, 1151,
1107, 1032, and 973 cm−1; Elemental analysis calcd. (%) for
C34H42N4S2: C 71.54, H 7.42, N 9.81; found C 71.30, H 7.44, N 9.98.
5,6-Bis(4-bromo-2,6-diisopropylphenylsulfanyl)pyrazine-2,3-di-
carbonitrile (6e). 5,6-Dichloropyrazine-2,3-dicarbonitrile (439 mg,
2.21 mmol), 4e (3.0 g, 4.85 mmol), pyridine (888 μL, 11.0 mmol), 30
min rt, hexane/toluene 1:1 as an eluent (Rf = 0.38), mobile phase
7a−dMg. Magnesium turnings (7 equiv) and a small crystal of
iodine were refluxed in anhydrous butanol for 3 h. Then, the
appropriate precursor 6a−d (1 equiv) was added and heating at reflux
continued for the next 5 h. The mixture was left to cool, concentrated
under reduced pressure, and diluted with water/MeOH/acetic acid
10:5:1. The precipitate was collected and thoroughly washed with
water and MeOH. The crude product was purified by column
chromatography on silica (the eluents are specified for each compound
below) and washed with MeOH to obtain the magnesium complexes
of 7a−d as green solids.
7a−dH. The magnesium complex 7a−dMg (1 equiv) was dissolved
in THF and stirred at rt for 1 h with p-toluenesulfonic acid (p-TSA, 10
equiv). Then, the reaction mixture was concentrated under reduced
pressure and diluted with water. The crude product was purified by
column chromatography on silica (the eluents are specified for each
compound below) to obtain a green solid.
7a−dZn. Anhydrous zinc acetate (7 equiv) was added to a solution
of appropriate metal-free 7a−dH (1 equiv) in pyridine. The reaction
mixture was heated at reflux for 1 h. Then, the solvent was partially
removed under reduced pressure, and water was added. The
precipitate was collected and thoroughly washed with water and
MeOH. The crude product was purified by column chromatography
on silica (the eluents are specified for each compound below) to
obtain a green solid.
Method D − with Zn(CH3COO)2 in DMF. The appropriate
precursor 6 (1 equiv) and anhydrous zinc acetate (2 equiv) were
dissolved in anhydrous DMF under an argon atmosphere. The
reaction mixture was heated at reflux for 3−10 h. Water was added; a
dark precipitate was collected and washed with water and MeOH. The
crude product was purified by column chromatography on silica (the
eluents are specified for each compound below).
Method E − with Zn(quinoline)2Cl2 in a Melt. The appropriate
precursor 6 (1 equiv) and Zn(quinoline)2Cl2 (1 equiv; prepared
according to the literature41) were thoroughly mixed and heated at 250
°C for 5 min. The green mixture was left to cool. MeOH was added,
the mixture was sonicated for 10 min, and the solid was collected and
thoroughly washed with MeOH. The crude product was purified by
2089
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column chromatography on silica (the eluents are mentioned for each
compound below).
7.97−760 (br, 16H), 7.52−6.99 ppm (br, 24H; overlaps with residual
signal of solvent). Signals of butoxy substituents were also detected at
δ = 3.56, 1.49, 1.32, and 0.60 ppm as small and broad signals; 13C
NMR (CDCl3/pyridin-d5, 75 MHz) no signal was detected in carbon
NMR except one small broad signal at δ 129.5 ppm that corresponds
to aromatic carbons of phenyl; IR (ATR): ν = 3056, 2945, 1736, 1581,
1518, 1476, 1440, 1395, 1304, 1246, 1155, 1087, 1068, 1024, 1001,
967, and 912 cm−1; MS (MALDI-TOF) m/z: no signals were detected
due to weak ionization of sample.
Method D. 6a (50 mg, 0.14 mmol); anhydrous zinc acetate (50 mg,
0,29 mmol); 3 h; chloroform/THF 3:1 as an eluent; Yield: 0.8 mg of
green solid (2%); 1H NMR (CDCl3/pyridin-d5, 300 MHz) δ = 7.23−
7.72 ppm (m, 40 H); IR (ATR): ν = 2924, 2838, 1476, 1440, 1395,
1246, 1155, 1088, 1024, 967, and 778 cm−1; 13C NMR (CDCl3/
pyridin-d5, 75 MHz) δ = 29.8, 129.7, the other signals were not
detected due to low solubility of the sample; MS (MALDI-TOF) m/z:
2934.73 [2M+K]+, 2918.77 [2M+Na]+, 2895.75 [2M]+, 1486.83 [M
+K]+, 1470.87 [M+Na]+, 1447.89 [M]+; UV/vis (THF): λmax:657,
628sh, 599 and 383 nm.
Method F − with LiOBu in BuOH. The compound 6c (1 equiv) was
dissolved in anhydrous BuOH (5 mL) and heated to reflux. Lithium (7
equiv) was added, and refluxing was continued for next 2.5 h. The
reaction mixture was left to cool and water/MeOH/acetic acid 10:5:1
(15 mL) was added. A dark precipitate was collected and washed with
water and MeOH. The crude product (approximately 40 mg) was
dissolved in pyridine (5 mL), anhydrous zinc acetate (approximately
7−10 equiv) was added, and the reaction mixture was refluxed for 1 h.
Then, the reaction mixture was diluted with water; the precipitate was
collected, and washed with water and MeOH. The product was
purified by column chromatography on silica with chloroform as the
eluent.
Method G − with DBU in BuOH. The compound 6c (1 equiv) and
anhydrous zinc acetate (either 0.25 equiv or 0.5 equiv) were dissolved
in anhydrous BuOH (5 mL). 1,8-Diazabicycloundec-7-ene (DBU;
either 1 equiv or 10 equiv) was added and reaction was heated at reflux
for 6 h under an argon atmosphere. Then, water was added; a green
precipitate was collected, and washed thoroughly with water and
MeOH. The crude product was purified by column chromatography
on silica with chloroform as the eluent.
Method E. 6a (150 mg, 0.14 mmol); Zn(quinoline)2Cl2 (165 mg,
0.14 mmol); chloroform/THF 3:1 as an eluent; Yield: 23 mg of green
solid (15%); MS (MALDI-TOF) m/z: 1447.89 [M]+, 1470.89 [M
+Na]+, 1486.85 [M+K]+, 2895.74 [2M]+; The other analytical data
correspond well with those mentioned in Method D.
Reaction Details and Analytical Data of the Prepared
TPyzPzs. 2,3,9,10,16,17,23,24-Octakis(phenylsulfanyl)-
1,4,8,11,15,18,22,25-(octaaza)phthalocyaninato Magnesium(II)
(7aMg). Method C. Magnesium (200 mg, 8.08 mmol); 6a (400 mg,
1.15 mmol); the low solubility of the product did not allow
chromatographic purification. The compound was dissolved in the
mixture of chloroform/pyridine 10:1 and dropped into MeOH. The
precipitate was collected and thoroughly washed with MeOH and
hexane. This purification procedure was repeated three times. The
purity of the product was monitored by TLC with chloroform/THF
3:1 as the eluent. Yield: 238 mg of a green solid (58%). This
compound was obtained as a mixture of TPyzPz with some peripheral
2,3,9,10,16,17,23,24-Octakis(2,6-dimethylphenylsulfanyl)-
1,4,8,11,15,18,22,25-(octaaza)phthalocyaninato magnesium(II)
(7bMg). Method C. Magnesium (170 mg, 7.03 mmol); 6b (400 mg,
1.00 mmol); eluent chloroform/THF 10:1 (Rf = 0.2); Yield: 300 mg
1
of green solid (72%); H NMR (CDCl3/pyridin-d5, 300 MHz) δ =
7.22−7.15 (m, 8H), 7.09 (d, J = 7.4 Hz; 16H), 2.40 ppm (s, 48H); 13C
NMR (CDCl3/pyridin-d5, 75 MHz) δ = 22.6, 129.0, 129.2, 130.0,
143.9, 147.2, and 157.0 ppm; IR (ATR): ν = 3058, 2955, 1514, 1462,
1377, 1239, 1164, 1104, 1050, 966, 849, 775, and 750 cm−1; Elemental
analysis calcd. (%) for C88H72MgN16S8 × 4H2O: C 61.94, H 4.73, N
13.13; found C 61.77, H 4.74, N 12.98; MS (MALDI-TOF) m/z:
3264.35 [2M]+, 1671.12 [M+K]+, 1655.16 [M+Na]+, 1632.16 [M]+;
UV/vis (THF): λmax (ε): 660 (186 300), 631sh (25 700), 600 (26
400), 465sh (17 700), 388 nm (107 200 mol−1 cm−1 L).
1
substituents replaced with butoxy groups. H NMR (CDCl3/pyridin-
d5, 300 MHz) δ = 7.75−7.50 (br, 16H), 7.19−7.03 ppm (br, 24H);
Signals of butoxy substituents were also detected at δ 3.43, 1.75, 1.44,
and 0.60 ppm as small and broad signals; 13C NMR (CDCl3/pyridin-
d5, 75 MHz) no signal was detected in carbon NMR except one small
broad signal at δ 129.5 ppm that corresponds to aromatic carbons of
phenyl; IR (ATR): ν = 3050, 1641, 1582, 1518, 1477, 1440, 1390,
1328, 1244, 1156, 1085, 1024, 1001, 965, 853, 780, and 738 cm−1; MS
(MALDI-TOF) m/z: 1446.90 [M+K]+, 1407.94 [M]+, 1372.01 [M-
SC6H5+OC4H9]+, 1336.07 [M-2 × SC6H5+2 × OC4H9]+; UV/vis
(THF): λmax (ε): 658 (217 100), 628sh, 598 (31 700), 458sh, 388 nm
(123 500 mol−1cm−1 L).
2,3,9,10,16,17,23,24-Octakis(2,6-dimethylphenylsulfanyl)-
1,4,8,11,15,18,22,25-(octaaza)phthalocyanine (7bH). Method C.
Compound 7bMg (190 mg, 0.12 mmol), p-TSA (230 mg, 1.22
mmol); chloroform/toluene/THF 70:30:3 as a mobile phase; Yield:
90 mg of green solid (46%). 1H NMR (CDCl3/pyridin-d5, 300 MHz)
δ = 2.38 (s, 48H), aromatic signals were too weak and overlapped with
residual signal of solvent; 13C NMR (CDCl3/pyridin-d5, 75 MHz) no
signal was detected in carbon NMR; IR (ATR): ν = 3288, 3063, 2963,
1517, 1462, 1438, 1376, 1310, 1226, 1159, 1114, 1080, 1050, 1025,
962, 767, 746, and 718 cm−1; Elemental analysis calcd. (%) for
C88H74N16S8 × 2H2O: C 64.13, H 4.77, N 13.60; found C 63.83, H
4.69, N 13.54; MS (MALDI-TOF) m/z: 1649.18 [M+K]+, 1633.21
[M+Na]+, 1610.22 [M]+, 1546.25 [M-SC8H8+OC4H9]+, 1506.19 [M-
C8H8]+; UV/vis (THF): λmax (ε): 678 (93 900), 653 (75 700), 623
(25 800), 599 (19 800), 472 (38 400), 373 nm (86 100 mol−1 cm−1 L).
2,3,9,10,16,17,23,24-Octakis(2,6-dimethylphenylsulfanyl)-
1,4,8,11,15,18,22,25-(octaaza)phthalocyaninato Zinc(II) (7bZn).
Method C. Compound 7bH (40 mg, 0.025 mmol), Zn(CH3COO)2
(45 mg, 0.25 mmol); chloroform/THF 10:1 as a mobile phase; Yield:
30 mg of green solid (81%). 1H NMR (CDCl3/pyridin-d5, 500 MHz)
δ signal were too weak and broad. The quality of the spectrum did not
allow proper assignation of the signals; 13C NMR (CDCl3/pyridin-d5,
125 MHz) 156.2, 145.7, 143.0, 130.8, 130.4, 129.2, 128.1, 21.6 ppm;
IR (ATR): ν = 3295, 2912, 1623, 1517, 1462, 1376, 1321, 1240, 1163,
1114, 1050, 966, 847, 776, and 745 cm−1; Elemental analysis calcd.
(%) for C88H72N16S8Zn × 4H2O: C 60.48, H 4.61, N 12.82; found C
60.14, H 4.71, N 12.44; MS (MALDI-TOF) m/z: 1711.10 [M+K]+,
1695.12 [M+Na]+, 1672.13 [M]+, 1568.10 [M-C8H8]+; UV/vis
(THF): λmax (ε): 658 (236 500), 630sh, 598 (35 100), 473sh, 431sh
and 381 nm (133 200 mol−1 cm−1 L).
2 , 3 , 9 , 1 0 , 1 6 , 1 7 , 2 3 , 2 4 - O c t a k i s ( p h e n y l s u l f a n y l ) -
1,4,8,11,15,18,22,25-(octaaza)phthalocyanine (7aH). Method C.
Compound 7aMg (140 mg, 0.11 mmol), p-TSA (200 mg, 1.1
mmol); chloroform/THF 3:1 as a mobile phase; Yield: 90 mg of green
solid (67%). This compound was obtained as a mixture of TPyzPz
1
with some peripheral substituents exchanged for butoxy. H NMR
(CDCl3/pyridin-d5, 300 MHz) δ = 8.31−7.97 (m, 16H), 7.81−7.06
(m, 24H; overlaps with the residual signal of solvent); signals of
butoxy substituents were also detected at δ 0.40−5.19 ppm as broad
signals; 13C NMR (CDCl3/pyridin-d5, 75 MHz) only some aromatic
signals (phenyl) were detected at δ = 134.2, 129.8, 129.6, 129.3 ppm
together with 14.3, 19.9, 24.2, 25.9, 26.4, 26.8, 30.0, 31.5, 46.5, 46.8,
47.3, 48.1, 49.4 ppm (butoxy groups); IR (ATR): ν = 3048, 1641,
1581, 1514, 1476, 1440, 1401, 1311, 1261, 1170, 1085, 1067, 1026,
and 960 cm−1; MS (MALDI-TOF) m/z: 1446.90 [M+K]+, 1430.93[M
+Na]+, 1407.95 [M]+, 1372.00 [M-SC6H5+OC4H9]+, 1336.07 [M-2 ×
SC6H5+2 × OC4H9]+.
2 , 3 , 9 , 1 0 , 1 6 , 1 7 , 2 3 , 2 4 - O c t a k i s ( p h e n y l s u l f a n y l ) -
1,4,8,11,15,18,22,25-(octaaza)phthalocyaninato Zinc(II) (7aZn).
Method C. Compound 7aH (50 mg, 0.036 mmol), Zn(CH3COO)2
(65 mg, 0.36 mmol); chloroform/toluene/THF 3:3:1 as a mobile
phase; Yield: 40 mg of green solid (74%). This compound was
obtained as a mixture of TPyzPz with some peripheral substituents
2,3,9,10,16,17,23,24-Octakis(2,6-diisopropylphenylsulfanyl)-
1,4,8,11,15,18,22,25-(octaaza)phthalocyaninato magnesium(II)
1
exchanged for butoxy. H NMR (CDCl3/pyridin-d5, 300 MHz) δ =
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(7cMg). Method C. Magnesium (165 mg, 6.80 mmol); 6c (500 mg,
0.971 mmol); eluent chloroform/THF 100:1 (Rf = 0.2); Yield: 399 mg
of green solid (79%); 1H NMR (300 MHz, CDCl3/pyridine-d5 3:1): δ
= 1.32 (s, 48H), 1.34 (s, 48H), 4.00 (hept, J = 6.8 Hz, 16H), 7.44−
7.51 (m, 16H), and 7.61−7.70 ppm (m, 8H); 13C NMR (75 MHz,
CDCl3/pyridine-d5 3:1): δ = 24.3, 32.8, 124.5, 126.6, 130.9, 145.8,
154.0, and 156.8 ppm; IR (ATR): ν = 2962, 2857, 1577, 1506, 1463,
1383, 1362, 1314, 1235, 1159, 1101, 1086, 1054, 1032, 964, 929, 846,
798, 773, 751, and 741 cm−1; Elemental analysis calcd. (%) for
C120H136MgN16S8 × 3H2O: C 67.43, H 6.70, N 10.49; found C 67.70,
H 6.71, N 10.56; MS (MALDI-TOF) m/z: 2119.65 [M+K]+, 2103.67
[M+Na]+, 2080.68 [M]+, 2037.75 [M-iPr]+; UV/vis (THF): λmax (ε):
663 (230 800), 633sh, 605 (38 060), 467sh, 388 nm (154 000 mol−1
cm−1 L).
2,3,9,10,16,17,23,24-Octakis(2,6-diisopropylphenylsulfanyl)-
1,4,8,11,15,18,22,25-(octaaza)phthalocyanine (7cH). Method C.
Compound 7cMg (250 mg, 0.12 mmol), p-TSA (230 mg, 1.1
mmol); chloroform/THF 50:1 as a mobile phase; Yield: 110 mg of
green solid (45%). 1H NMR (300 MHz, CDCl3/pyridine-d5 3:1): δ =
−1.39 (s, 2H), 1.39 (s, 48H), 1.41 (s, 48H), 4.00 (hept, J = 6.8 Hz,
16H), 7.52−7.58 (m, 16H), and 7.72−7.79 ppm (m, 8H); 13C NMR
(75 MHz, CDCl3/pyridine-d5 3:1): δ = 24.4, 33.0, 124.7, 126.0, 131.3,
144.5, 146.9, 154.1, and 158.8 ppm; IR (ATR): ν = 3268, 3049, 2960,
2878, 1576, 1540, 1507, 1463, 1418, 1384, 1361, 1304, 1221, 1190,
1149, 1078, 1054, 1030, 1008, 956, 940, 799, 743, and 712 cm−1;
Elemental analysis calcd. (%) for C120H138N16S8: C 69.93, H 6.75, N
10.87; found C 69.70, H 6.72, N 10.86; MS (MALDI-TOF) m/z:
2097.67 [M+K]+, 2081.70 [M+Na]+, 2058.72 [M]+, 2015.83 [M-iPr]+;
UV/vis (THF): λmax (ε): 680 (135 000), 658 (105 300), 627sh, 603sh,
479 (56 070), 377 nm (128 800 mol−1 cm−1 L).
2,3,9,10,16,17,23,24-Octakis(2,6-diisopropylphenylsulfanyl)-
1,4,8,11,15,18,22,25-(octaaza)phthalocyaninato Zinc(II) (7aZn).
Method C. Compound 7cH (40 mg, 0.019 mmol), Zn(CH3COO)2
(35 mg, 0.19 mmol); chloroform as a mobile phase; Yield: 40 mg of
green solid (99%). 1H NMR (300 MHz, CDCl3/pyridine-d5 3:1): δ =
1.32 (s, 48H), 1.34 (s, 48H), 3.98 (hept, J = 6.8 Hz, 16H), 7.44−7.50
(m, 16H), and 7.61−7.69 ppm (m, 8H); 13C NMR (75 MHz, CDCl3/
pyridine-d5 3:1): δ = 24.3, 32.8, 124.6, 126.4, 131.0, 146.5, 150.3,
154.0, and 157.4 ppm; IR (ATR): ν = 3050, 2963, 2838, 1578, 1507,
1461, 1383, 1362, 1314, 1227, 1158, 1103, 1054, 1032, 965, 929, 843,
798, 775, and 741 cm−1; Elemental analysis calcd. (%) for
C120H136N16S8Zn × 4H2O: C 65.62, H 6.61, N 10.20; found 65.65,
H 6.35, N 10.16; MS (MALDI-TOF) m/z: 2159.54 [M+K]+, 2143.58
[M+Na]+, 2120.57 [M]+, 2077.69 [M-iPr]+; UV/vis (THF): λmax (ε):
661 (190 900), 633sh, 601 (28 500), 477sh, 434sh, and 382 nm (115
200 mol−1 cm−1 L).
Method G(10). 6c (50 mg, 0.097 mmol); anhydrous zinc acetate
(19 mg, 0.04 mmol); DBU (0.14 mL, 0.95 mmol); Yield: 6 mg of
green solid (17%); MS (MALDI-TOF) m/z: 2159.52 [M+K]+,
2143.55 [M+Na]+, 2121.57 [M+H]+, 2077.52 [M-iPr]+, 2039.50 [M-
SC6H5+OC4H9+K]+, 2023.53 [M-SC6H5+OC4H9+Na]+, 2000.55 [M-
SC6H5+OC4H9]+, 1957.50 [M-SC6H5+OC4H9-iPr]+, 1919.48 [M-2 ×
SC6H5+2 × OC4H9+K]+, 1880.52 [M-2 × SC6H5+2 × OC4H9]+,
1837.47 [M-2 × SC6H5+2 × OC4H9-iPr]+, 1761.50 [M-3 × SC6H5+3
× OC4H9]+.
2,3,9,10,16,17,23,24-Octakis(2,6-di-tert-butylpropylphenylsulfan-
yl)-1,4,8,11,15,18,22,25-(octaaza)phthalocyaninato Magnesium(II)
(7dMg). Method C. Magnesium (107 mg, 4.42 mmol); 6d (360 mg,
0.63 mmol); eluent chloroform/THF 20:1 (Rf = 0.41); Yield: 143 mg
of green solid (39%); 1H NMR (300 MHz, CDCl3/pyridine-d5 3:1): δ
= 1.64 (s, 144H), 7.45 (t, J = 8 Hz, 8H), and 7.62 ppm (d, J = 8 Hz,
16H); 13C NMR (75 MHz, CDCl3/pyridine-d5 3:1): δ = 32.8, 38.3,
126.0, 126.8, 130.8, 145.6, 157.5, and 158.4 ppm; IR (ATR): ν = 2963,
2931, 2868, 1573, 1481, 1458, 1393, 1362, 1314, 1248, 1225, 1151,
1103, 1036, and 962 cm−1; Elemental analysis calcd. (%) for
C136H168MgN16S8 × 6H2O: C 67.62, H 7.51, N 9.28; found C
67.75, H 7.58, N 9.17; MS (MALDI-TOF) m/z: 2305.88 [M]+,
2247.80; UV/vis (THF): λmax (ε): 720sh, 661 (238 610), 633 (35
090), 600 (31 780), 466sh, and 382 nm (146 730 mol−1 cm−1 L).
2,3,9,10,16,17,23,24-Octakis(2,6-di-tert-butylpropylphenylsulfan-
yl)-1,4,8,11,15,18,22,25-(octaaza)phthalocyanine (7dH). Method C.
Compound 7dMg (35 mg, 0.015 mmol), p-TSA (20 mg, 0.11 mmol);
toluene/THF 30:1 as a mobile phase; Yield: 29 mg of green solid
1
(84%). H NMR (300 MHz, CDCl3/pyridine-d5 3:1): δ = 1.66 (s,
144H), 7.55 (t, J = 8 Hz, 8H), and 7.70 ppm (d, J = 8 Hz, 16H); 13C
NMR (75 MHz, CDCl3/pyridine-d5 3:1): δ = 32.7, 38.2, 125.6, 126.7,
130.8, and 157.3 ppm; IR (ATR): ν = 3325, 2964, 2917, 2867, 1573,
1508, 1481, 1456, 1393, 1361, 1306, 1240, 1221, 1193, 1139, 1105,
1076, 1034, and 955 cm−1; Elemental analysis calcd. (%) for
C136H170N16S8 × 2H2O: C 70.36, H 7.55, N 9.65; found C 70.55, H
7.70, N 9.57; MS (MALDI-TOF) m/z: 2321.85 [M+K]+, 2305.90 [M
+Na]+, 2282.90 [M]+, 2225.83; UV/vis (THF): λmax (ε): 715 (71
450), 683 (64 650), 654 (41 650), 472sh, and 379 nm (100 180 mol−1
cm−1 L).
2,3,9,10,16,17,23,24-Octakis(2,6-di-tert-butylpropylphenylsulfan-
yl)-1,4,8,11,15,18,22,25-(octaaza)phthalocyaninato Zinc(II) (7dZn).
Method C. Compound 7dH (30 mg, 0.013 mmol), Zn(CH3COO)2
(24 mg, 0.13 mmol); toluene/THF 3:3:1 as a mobile phase; Yield: 22
1
mg of green solid (71%). H NMR (300 MHz, CDCl3/pyridine-d5
3:1): δ = 1.71 (s, 144H), 7.49 (t, J = 8 Hz, 8H), and 7.66 ppm (d, J = 8
Hz, 16H); 13C NMR (75 MHz, CDCl3/pyridine-d5 3:1): δ = 32.8,
38.3, 125.9, 126.8, 130.9, 145.5, 157.5, and 158.7 ppm; IR (ATR): ν =
2964, 2903, 2861, 1575, 1507, 1507, 1481, 1457, 1394, 1362, 1315,
1249, 1227, 1151, 1105, 1037, and 963 cm−1; Elemental analysis calcd.
(%) for C136H168N16S8Zn × 4H2O: C 67.47, H 7.33, N 9.26; found C
67.21, H 7.42, N 9.07; MS (MALDI-TOF) m/z: 2384.76 [M+K]+,
2368.77 [M+Na]+, 2345.80 [M]+, 2325.72, 2287.73; UV/vis (THF):
λmax (ε): 659 (237 870), 631sh, 599 (31 650), 472sh, 434sh, and 382
nm (143 490 mol−1 cm−1 L).
Singlet Oxygen Production and Fluorescence Emission.
Samples for photophysical measurements were taken from Method A
(7bZn, 7cZn, and 7dZn) or from Method C (7aZn) and purified
further by scrapping from TLC plate (mobile phases mentioned for
each compound in synthetic part), extracting to THF, and evaporation
to dryness under the reduced pressure.
Singlet oxygen quantum yields (ΦΔ) were determined in THF
according to a previously described method42 using the decomposition
of 1,3-diphenylisobenzofuran (DPBF) with unsubstituted zinc
phthalocyanine (ZnPc) as the reference (ΦΔ(THF) = 0.53). In detail,
the procedure was as follows: 2.5 mL of a stock solution of DPBF in
THF (5 × 10−5 M) was transferred into a 10 × 10 mm quartz optical
cell and bubbled with oxygen for 1 min. Defined amount of
concentrated stock solution of the tested TPyzPz in THF (usually
20 μL) was added. Absorbance of the final solution in Q-band
maximum was always about 0.1. The solution was stirred and
irradiated for defined times using a xenon lamp (100 W, ozone free XE
Method D. 6c (50 mg, 0.097 mmol); anhydrous zinc acetate (77
mg, 0,097 mmol); chloroform as an eluent; Yield: 12 mg of green solid
(23%); MS (MALDI-TOF) m/z: 2159.55 [M+K]+, 2120.58 [M]+,
2077.65 [M-iPr]+.
Method E. 6c (50 mg, 0.097 mmol); Zn(quinoline)2Cl2 (38 mg,
0.14 mmol); chloroform/THF 3:1 as an eluent; Yield: 12 mg of green
solid (23%); MS (MALDI-TOF) m/z: 2159.56 [M+K]+, 2143.57 [M
+Na]+, 2120.58 [M]+, 2077.37 [M-iPr]+, 1928.51 [M-2,6-diiPrPhS]+.
Method F. 6c (50 mg, 0.097 mmol); lithium (123 mg, 0.68 mmol);
crude product (approximately 40 mg); and anhydrous zinc acetate
(35.5 mg, 0.19 mmol). Yield: 31 mg of green solid (60%); MS
(MALDI-TOF) m/z: 2320.71 [2(M-8 × SC6H5+8 × OC4H9)]+,
1520.45 [M-5 × SC6H5+5 × OC4H9]+, 1400.43 [M-6 × SC6H5+6 ×
OC4H9]+, 1280.40 [M-7 × SC6H5+7 × OC4H9]+, 1160.38 [M-8 ×
SC6H5+8 × OC4H9]+.
Method G(1). 6c (50 mg, 0.097 mmol); anhydrous zinc acetate (9.6
mg, 0.02 mmol); DBU (0.014 mL, 0.095 mmol). Yield 28 mg of a
green solid (54%); MS (MALDI-TOF) m/z: 2159.53 [M+K]+,
2120.63 [M]+, 2077.55 [M-iPr]+, 2039.53 [M-SC6H5+OC4H9+K]+,
2000.56 [M-SC6H5+OC4H9]+, 1957.57 [M-SC6H5+OC4H9-iPr]+,
1919.51 [M-2 × SC6H5+2 × OC4H9+K]+, 1880.52 [M-2 ×
SC6H5+2 × OC4H9]+, 1837.48 [M-2 × SC6H5+2 × OC4H9-iPr]+,
1760.49 [M-3 × SC6H5+3 × OC4H9]+, 1640.48 [M-4 × SC6H5+4 ×
OC4H9]+.
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The Journal of Organic Chemistry
Article
DC short arc lamp, Newport). Incident light was filtered through a
water filter (6 cm) and cutoff filter OG530 to remove heat and light
under 523 nm, respectively. Decrease of DPBF in solution with
irradiation time was monitored at 415 nm. The ΦΔ of the TPyzPz was
calculated using eq 1:
(2) Nemykin, V. N.; Lukyanets, E. A. Arkivoc 2010, 136.
(3) Lukyanets, E. A.; Nemykin, V. N. J. Porphyr. Phthalocyanines
2010, 14, 1.
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Suvorova, O. N. Macroheterocycles 2012, 5, 191.
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Ercolani, C.; Kadish, K. M. Inorg.Chem. 2004, 43, 8626.
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J. 2011, 17, 14273.
kSIaRT
kRIaST
ΦΔS = ΦΔR
(1)
where k is a slope of the plot of the dependence of ln(A0/At) on
irradiation time t, with A0 and At being the absorbances of the DPBF at
415 nm before irradiation and after irradiation time t, respectively. IaT
is a total amount of light absorbed by the TPyzPz. Superscripts R and
S indicate reference and sample, respectively. IaT is calculated as a sum
of intensities of the absorbed light Ia at wavelengths from 523 to 850
nm (step 0.5 nm). Light under 523 nm is completely filtered off by
OG530 filter and light above 850 nm is not absorbed by the studied
TPyzPzs. Ia at given wavelength is calculated using Beer’s law (eq 2):
́
(7) Novakova, V.; Lochman, L.; Zajícova, I.; Kopecky, K.; Miletin,
M.; Lang, K.; Kirakci, K.; Zimcik, P. Chem.Eur. J. 2013, 19, 5025.
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J. Org. Chem. 2010, 2010, 732.
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Phthalocyanines 2010, 14, 793.
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Phthalocyanines 2007, 11, 130.
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Cellai, L.; Monti, S.; Ercolani, C. Inorg. Chem. 2011, 50, 7391.
(13) Zimcik, P.; Novakova, V.; Kopecky, K.; Miletin, M.; Uslu Kobak,
Ia = I0(1 − e−2.3A
)
(2)
where I0 is a transmittance of the filter at the given wavelength and A
absorbance of the TPyzPz at this wavelength. All experiments were
performed three times and data presented in the paper represent a
mean of these three experiments. Estimated error 10%.
Fluorescence quantum yields (ΦF) were determined in THF by a
comparative method with ZnPc as the reference (ΦF(THF) = 0.3213).
The ΦF was calculated using eq 3:
R. Z.; Svandrlikova, E.; Vac
4215.
́ ́
hova, L.; Lang, K. Inorg. Chem. 2012, 51,
(14) Kopecky, K.; Novakova, V.; Miletin, M.; Kucera, R.; Zimcik, P.
Bioconjugate Chem. 2010, 21, 1872.
(15) Kopecky, K.; Novakova, V.; Miletin, M.; Plistilova, L.; Berka, P.;
S
−AR
⎛
⎞
⎠
⎛
⎜
⎞
⎟
Zimcik, P. Macroheterocycles 2011, 4, 171.
F
1 − 10
ΦSF = ΦRF
⎜
⎜
⎟
⎟
(16) Tuhl, A.; Makhseed, S.; Zimcik, P.; Al-Awadi, N.; Novakova, V.;
Samuel, J. J. Porphyr. Phthalocyanines 2012, 16, 817.
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Chem.Eur. J. 2003, 9, 5123.
−AS
⎝ FR ⎠
⎝ 1 − 10
(3)
where F is the integrated area under the emission spectrum, and A is
the absorbance at the excitation wavelength. Superscripts R and S
correspond to the reference and sample, respectively. Absorption in Q-
band was kept below 0.05 in order to eliminate an inner filter effect.
Excitation wavelength was set at 600 nm, emission wavelength
monitored during collecting the excitation spectra was 730 (7aZn,
7bZn, and 7dZn) or 750 nm (7cZn). All experiments were performed
three times and presented data represent the mean of these three
experiments. Estimated error 15%.
(19) Sastre, A.; delRey, B.; Torres, T. J. Org. Chem. 1996, 61, 8591.
(20) Arican, D.; Arici, M.; Ugur, A. L.; Erdogmus, A.; Koca, A.
Electrochim. Acta 2013, 106, 541.
(21) Dolotova, O.; Konarev, A.; Volkov, K.; Negrimovsky, V.; Kaliya,
O. L. J. Porphyr. Phthalocyanines 2012, 16, 946.
(22) Tombe, S.; Antunes, E.; Nyokong, T. New J. Chem. 2013, 37,
679.
(23) Moeno, S.; Antunes, E.; Khene, S.; Litwinski, C.; Nyokong, T.
Dalton Trans. 2010, 39, 3460.
ASSOCIATED CONTENT
* Supporting Information
■
S
(24) Pereira, J. B.; Carvalho, E. F. A.; Faustino, M. A. F.; Fernandes,
R.; Neves, M. G. P. M. S.; Cavaleiro, J. A. S.; Gomes, N. C. M.; Cunha,
A.; Almeida, A.; Tome, J. P. C. Photochem. Photobiol. 2012, 88, 537.
(25) Li, W. M.; Wu, J.; Higgins, D. C.; Choi, J. Y.; Chen, Z. W. ACS
Catal. 2012, 2, 2761.
MS spectra of 7a-dZn, TLC of 7dZn, TLC of 7dMg, 7dH and
7dZn, Absorption spectra of 7a−d (magnesium, metal free and
zinc complexes), Emission spectra 7a−dZn, Comprehensive
discussion on X-ray structures of 6a−d, and H NMR and 13C
1
NMR spectra of all new prepared compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(26) Li, W. M.; Yu, A. P.; Higgins, D. C.; Llanos, B. G.; Chen, Z. W.
J. Am. Chem. Soc. 2010, 132, 17056.
(27) Mørkved, E. H.; Holmaas, L. T.; Kjøsen, H.; Hvistendahl, G.
Acta Chem. Scand. 1996, 50, 1153.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: veronika.novakova@faf.cuni.cz, Fax: +420 495067167;
Tel: +420 495067380.
*E-mail: petr.zimcik@faf.cuni.cz, Fax: +420 495067167; Tel:
+420 495067257.
Notes
■
(28) Kostka, M.; Zimcik, P.; Miletin, M.; Klemera, P.; Kopecky, K.;
Musil, Z. J. Photochem. Photobiol., A 2006, 178, 16.
(29) McClure, D. S. J. Chem. Phys. 1949, 17, 905.
(30) Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980.
(31) Curphey, T. J. J. Org. Chem. 2002, 67, 6461.
(32) Borghi, R.; Cremonini, M. A.; Lunazzi, L.; Placucci, G.;
Macciantelli, D. J. Org. Chem. 1991, 56, 6337.
(33) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061.
(34) Omura, K. J. Org. Chem. 1992, 57, 306.
The authors declare no competing financial interest.
(35) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(36) Novakova, V.; Miletin, M.; Kopecky, K.; Franzova,
Eur. J. Org. Chem. 2011, 5879.
(37) Novakova, V.; Zimcik, P.; Miletin, M.; Vujtech, P.; Franzova, S.
Dyes Pigm. 2010, 87, 173.
ACKNOWLEDGMENTS
■
̌
́
S.; Zimcik, P.
Financial support from Czech Science Foundation (Project No.
13-27761S) is gratefully acknowledged. Authors would like
thank Lucie Novakova for the measurement of HR-MS.
(38) The intensity of the signals in the mass spectra cannot
unequivocally determine the absolute yields of the components in the
mixture. However, it can be considered valuable information due to
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