The Suzuki cross-coupling reaction for the synthesis of porphyrazine possessing bulky 2,5-(biphenyl-4-yl)pyrrol-1-yl substituents in the periphery

Article abstract of DOI:10.1016/j.poly.2015.09.068

The macrocyclization reactions led to higher-symmetry and lower-symmetry porphyrazines bearing peripheral 2,5-di(4′-chlorophenyl)pyrrol-1-yl and dimethylamino substituents, which were characterized using NMR and X-ray crystallography. The reactions were performed in the conditions of Linstead macrocyclization with magnesium n-butanolate in n-butanol with an addition of a malonitrile derivative in solid form or after dissolving it in DMF. It is interesting to note that the addition of DMF increases the total yield of the reaction from low to moderate, and forces the synthesis of the higher-symmetry over the lower-symmetry porphyrazine. The non-alternate order of peripheral substituents in lower-symmetry porphyrazine resulted in the non-equivalence of dimethylamino groups in ¹H and ¹³C NMR spectra. The X-ray crystal structures of both porphyrazines revealed an almost perpendicular orientation of the bulky, 2,5-di(4′-chlorophenyl)pyrrol-1-yl substituents to the cores. Higher-symmetry porphyrazine was used in the Suzuki-Miyaura reaction with phenylboronic acid. This led with a high yield to the derivative possessing peripheral 2,5-di(biphenyl-4-yl)pyrrol-1-yl and dimethylamino substituents.

Full text of DOI:10.1016/j.poly.2015.09.068

Accepted Manuscript
The Suzuki cross-coupling reaction for the synthesis of porphyrazine possessing
bulky 2,5-(biphenyl-4-yl)pyrrol-1-yl substituents in the periphery
Wojciech Szczolko, Anna Wzgarda, Tomasz Koczorowski, Barbara Wicher,
Lukasz Sobotta, Zofia Gdaniec, Maria Gdaniec, Jadwiga Mielcarek, Ewa
Tykarska, Tomasz Goslinski
PII:
S0277-5387(15)00583-5
DOI:
http://dx.doi.org/10.1016/j.poly.2015.09.068
POLY 11587
Reference:
Polyhedron
To appear in:
Received Date:
Accepted Date:
11 August 2015
15 September 2015
Please cite this article as: W. Szczolko, A. Wzgarda, T. Koczorowski, B. Wicher, L. Sobotta, Z. Gdaniec, M. Gdaniec,
J. Mielcarek, E. Tykarska, T. Goslinski, The Suzuki cross-coupling reaction for the synthesis of porphyrazine
possessing bulky 2,5-(biphenyl-4-yl)pyrrol-1-yl substituents in the periphery, Polyhedron (2015), doi: http://
dx.doi.org/10.1016/j.poly.2015.09.068
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The Suzuki cross-coupling reaction for the synthesis of porphyrazine possessing bulky 2,5-
(biphenyl-4-yl)pyrrol-1-yl substituents in the periphery
Wojciech Szczolkoa, Anna Wzgardaa, Tomasz Koczorowskia, Barbara Wichera, Lukasz Sobottab,
Zofia Gdaniecc, Maria Gdaniecd, Jadwiga Mielcarekb, Ewa Tykarskaa, Tomasz Goslinskia,*
a Department of Chemical Technology of Drugs, Poznan University of Medical Sciences,
Grunwaldzka 6, 60-780 Poznan, Poland
b Department of Inorganic and Analytical Chemistry, Poznan University of Medical Sciences,
Grunwaldzka 6, 60-780 Poznan, Poland
c Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704
Poznan, Poland
d Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan
ABSTRACT:
The macrocyclization reactions led to higher-symmetry and lower-symmetry porphyrazines bearing
peripheral 2,5-di(4’-chlorophenyl)pyrrol-1-yl and dimethylamino substituents, which were
characterized using NMR and X-ray crystallography. The reactions were performed in the
conditions of Linstead macrocyclization with magnesium n-butanolate in n-butanol, catalytic
amount of iodine in n-butanol with an addition of a malonitrile derivative in solid form or after
dissolving it in DMF. It is interesting to note that the addition of DMF increases the total yield of
the reaction from low to moderate, and forces the synthesis of the higher-symmetry over the lower-
symmetry porphyrazine. The non-alternate order of peripheral substituents in lower-symmetry
porphyrazine resulted in the non-equivalence of dimethylamino groups in 1H and 13C NMR spectra.
The X-ray crystal structures of both porphyrazines revealed an almost perpendicular orientation of
the bulky, 2,5-di(4’-chlorophenyl)pyrrol-1-yl substituents to the cores. Higher-symmetry
1

porphyrazine was used in the Suzuki-Miyaura reaction with phenylboronic acid. This led with a
high yield to the derivative possessing peripheral 2,5-di(biphenyl-4-yl)pyrrol-1-yl and
dimethylamino substituents.
KEYWORDS: cross-coupling reaction, Suzuki-Miyaura reaction, Linstead macrocyclization,
porphyrazines, crystal structure
*Correspondence to: T. Goslinski, Department of Chemical Technology of Drugs, University of
Medical Sciences, Grunwaldzka 6, 60-780, Poznan, Poland. Tel.: +48 61 8546631, fax: +48
618546639. E-mail: tomasz.goslinski@ump.edu.pl
2

1. Introduction
Porphyrazine (Pz) macrocycles belong to porphyrinoids, which are represented mainly by
porphyrins, chlorins, corroles and phthalocyanines. Pzs have unique spectroscopic and
electrochemical properties resulting from their structure.1 Therefore Pzs have been actively studied
as chemical sensors able to detect various analytes2 and precursors to optical, magnetic, conductive
materials for nanotechnology and electronic devices.3 High expectations are connected with the
potential use of Pzs in medicine. This is especially the case in photodynamic therapy of cancer
(PDT), non-oncological diseases (psoriasis, actinic keratosis, age-related macular degeneration),
and photodynamic antimicrobial chemotherapy against viral, fungal and bacterial infections.4-6 Pz
macrocycles can be modified in two ways: (i) by metal ion insertion to a core and/or (ii) by
peripheral functionalization in the β-positions with alkyl, aryl, sulfur, oxygen and nitrogen residues
or rings bound to both β,β-positions. It is noteworthy that these modifications result in significant
modulations of Pzs electrochemical and spectroscopic properties.1
There is a continuous interest in the development of practical synthetic methods for
macrocyclic chemistry. Striving for the desired substitution pattern of porphyrinoids influenced the
search for applications of cross-coupling reactions. Many examples of Suzuki cross-coupling for the
synthesis of β-aryl- and meso-substituted porphyrins have been demonstrated so far.7-9 Cross-
coupling reactions have been applied in the synthesis of A2B2 aryl-substituted porphyrins,10 aryl and
arylethenyl N-confused porphyrins,11 and the construction of large porphyrin-based assemblies.12
Moreover, Pd-catalyzed cross coupling reactions were found to be a convenient method in the
synthesis of phthalocyanine-phthalocyanine dimers and triads,13 phthalocyanine oligomers,14
various phthalocyanine-porphyrin hetero-dyads, and -triads.15 There is no significant amount of data
which comes from the synthetic studies towards Pzs involving the Suzuki cross-coupling reaction in
the synthetic pathway. An easy route has been found in van Lier research group for the synthesis of
pyrazine-2,3-dicarbonitrile derivatives by Suzuki cross coupling reactions. This has given access to
symmetrical and non-symmetrical pyrazinoporphyrazines.16 Despite the lack of the results, the first
3

Suzuki cross-coupling arylation of Pzs giving access to highly non-symmetrical aryl-substituted
thioalkyl-porphyrazines has been performed by Belviso, Lelj and their co-workers.17,18
In our research, we focused on the synthesis of Pzs with different 5-membered ring
heteroaromatic groups. Although this type of Pzs periphery has been reported previously by Luo et
al. (trimethyl-3-thienyl groups),19 the other studies concerning pyrrolyl substituents have come from
our group. We have already reported the synthesis, physico-chemical characterization and spectral
properties of Pzs with the following peripheral substituents: (i) 2,5-dimethylpyrrol-1-yl and
methyl(3-pyridylmethyl)amino,20 (ii) 2,5-dithienylpyrrol-1-yl and dimetylamino groups,21 (iii) 2,5-
dimethylpyrrol-1-yl and dimethylamino,22,23 (iv) 2,5-diphenylpyrrol-1-yl and dimethylamino,24 and
(v) 2-(1-adamantyl)-5-phenylpyrrol-1-yl and dimethylamino groups.25 These Pzs revealed
interesting optical and electrochemical properties. In our research we extended our study to the
synthesis of Pz with bulky, peripheral 2,5-di(biphenyl-4-yl)pyrrol-1-yl and dimethylamino groups.
The application of the Suzuki-Miyaura cross-coupling reaction will be demonstrated in the final
step of the synthesis starting from the Pz derivative with peripheral 2,5-di(4’-chlorophenyl)pyrrol-
1-yl and dimethylamino substituents.
2. Results and Discussion
2.1. Synthesis
Following the Ceylan et al. procedure,26 2-bromo-4'-chloroacetophenone 1 was used in the
Würtz-like reaction with zinc (powder) and catalytic amount of iodine in THF to give 2. The Paal-
Knorr reaction of 2 with diaminomaleonitrile following the Begland et al.27 approach using
trifluoroacetic acid in methanol led to maleonitrile derivative 3. Next, 3 was methylated to give
derivative 4 in the conditions (NaH, (CH3)2SO4 in THF) proposed by Baum et al. (Scheme 1).28
4

Cl
Cl
Cl
NH
N
N
N
2
N
Cl
N
O
(iii)
(ii)
(i)
O
N
O
N
Br
1
2
3
4
Cl
Cl
Cl
Cl
N
N
N
R
1
N
N
R
N
1
R
R
1
1
N
N
N
Mg
N
N
N
N
Mg
N
(iv)
N
N
+
N
N
R =
1
N
R
R
1
1
N
N
N
N
N
N
R
R
Cl
1
1
5
6
(v)
N
R
2
N
N
R
2
R
=
2
N
N
N
Mg
N
N
N
N
R
2
N
N
N
R
2
7
Scheme 1. Reagents and conditions: (i) Zn, I2, THF, reflux, 24 h;26 (ii) diaminomaleonitrile,
methanol, TFA, reflux, 24 h; (iii) NaH (60% suspension in mineral oil), (CH3O)2SO2, THF, -15 °C
to rt, 20 h; (iv) Mg(n-BuO)2, n-BuOH, reflux, 20 h; (v) tris(dibenzylideneacetone)dipalladium(0),
cesium carbonate, tricyclohexylphospine, phenylboronic acid, 1,4-dioxane, reflux, 20 h; TFA -
trifluoroacetic acid.
Compound 4 was used in the Linstead macrocyclization reaction with magnesium n-
butanolate, in the presence of a catalytic amount of iodine in n-butanol.29 Noteworthy is that we
used two different methods of adding the maleonitrile derivative 4 to the reaction mixture. Firstly
we used a solid compound and secondly as a solution in DMF. In both instances, the reaction led to
a separable mixture of two porphyrazines: 5 with an alternate system of peripheral substituents
(higher-symmetry isomer) and 6 with a non-alternate system of peripheral substituents (lower-
symmetry isomer). Interestingly, in the first approach an excess of 6 over 5 was found with the
yields 7% and 4% respectively. However, in the second approach an excess of 5 over 6 was found
with the yields 29% and 10% respectively. Moreover, the total yield for the synthesis of both Pzs
5

was seen significantly higher in the second rather than the first approach (39% and 11%,
respectively). The solvent composition consisting of protic solvent - n–butanol and aprotic solvent -
DMF seems to affect the reorganization of solvent molecules around the maleonitrile derivative 4,
and influences the reaction rate. Moreover, the presence of DMF in the reaction mixture raises the
yield of the higher-symmetry isomer.
Porphyrazine 5 was used in the Suzuki-Miyaura reaction with phenylboronic acid.30 Four
different reaction conditions were tested, differing in the polarity of solvent, type of base, phosphine
ligand and palladium catalyst. The following adapted from the literature31-34 were used: (i)
palladium acetate, tripotassium phosphate in morpholine, (ii) palladium acetate, cesium carbonate,
1,3-bis(diphenylphosphino)propane in morpholine and (iii) palladium acetate, cesium carbonate and
tetrakis(triphenylphosphine)palladium(0) in toluene. All were found to be unsuccessful. The desired
Pz 7 was obtained in the presence of cesium carbonate as a base, catalytic amount of
tricyclohexylphosphine, tris(dibenzylideneacetone)dipalladium(0) as a catalyst, and 1,4-dioxane as
a solvent following the Littke and Fu procedure (Scheme 1).35 There is a continued interest in Pzs
containing bulky peripheral substituents. Pzs with 4-biphenyl groups have been studied in terms of
spectral properties and aggregation.36 The obtained methodology can lead to novel photosensitizers,
which can be equipped with oligo(p-phenylene) groups. Moreover, the oligo(p-phenylene) linkers
can be used in the construction of an array of potential applications in the studies of artificial
photosynthesis. The case has already been presented for oligo(p-phenylene)-linked dyads
containing porphyrins in terms of their application in artificial photosynthesis.37
3.2. NMR study
6

Fig. 1. Expansion of 1H NMR spectra of 5-7 showing the aromatic protons (6.50-8.00 ppm) and the
1
dimethylamino groups (3.00-3.50 ppm). Insets present corresponding H-13C HSQC experiments
for dimethylamino group regions. The identity of the peaks A-G (1H, 13C) in ppm: A (3.34, 42.1), B
(3.36, 41.4), C (3.34, 41.4), D (3.24, 41.2), E (3.09, 41.0), F (3.36, 41.7; 3.39, 41.7), G (3.13, 42.4;
3.14, 42.5).
The structural features of macrocycles 5-7 were initially inferred from 1H and 13C NMR data (1H-1H
1
1
1
COSY, H-13C HMBC, H-13C HSQC) (see Supplementary data). Analysis of H and 13C NMR
spectra of compounds 5 and 6 reveals that Pz 5 and Pz 6 represent two different isomers (Fig. 1). In
1H NMR and 13C NMR spectra of Pz 5 recorded in pyridine-d5, the resonances attributed to
dimethylamino groups appear at 3.34 ppm and at 42.1 ppm respectively. The presence of only one
resonance corresponding to the dimethylamino groups indicates the symmetrical nature of
1
compound Pz 5. On the other hand, the appearance of four signals in H NMR spectrum of
compound 6 (DMSO-d6, 3.09, 3.24, 3.34, 3.36 ppm, the last two overlapped by water signal) and
four signals in 13C NMR spectrum (2 × 41.7, 42.4, 42.5 ppm) reflects the chemical inequivalence of
7

dimethylamino groups. This inequivalence results from the asymmetry imposed by the non-
alternate order of both peripheral substituents.
1
Interestingly, four signals characteristic of dimethylamino groups have been identified in H and
13C NMR spectra of Pz 7 (DMSO-d6) (see Supplementary data). Also found during our studies was
that steric crowding of dimethylamino and 2,5-disubstituted pyrrolyl groups caused steric
repulsions, which resulted in a differentiation of the signals of each dimethylamino group.
Additionally, phenyl rings of biphenyl substituents have reduced conformational freedom and, as a
consequence, the aromatic proton signals between 6.70-7.30 ppm appear as broad signals. All of
this is a result of steric effects present in the structure of Pz 7.
3.3. X-ray structural analyses
Single crystals suitable for X-ray analysis were obtained for maleonitrile derivatives 3 and 4
and for Pzs 5 and 6. The crystalline sample of maleonitrile 4 consisted of plate-like crystals which
were identified as cis isomer of 4 (4-cis) and block-shaped crystals of trans isomer (4-trans). Each
of the three studied maleonitriles, 3, 4-cis and 4-trans, comprise a planar maleonitrile fragment, a
twisted amino group (dihedral angles 4.32(1)°, 10.39(5)° and 29.4(5)°, respectively), and a nearly
perpendicular-oriented pyrrole ring (dihedral angles 89.05(6)°, 84.57(6)° and 86.1(1)°, respectively)
with its 4-chlorophenyl substituents protruding from both sides of the maleonitrile plane. In the
crystal, the molecule of the trans isomer is disordered over two sites related by a twofold symmetry
axis (Fig. S1).
The crystals of 5 and 6 consist of neutral Pz magnesium(II) complex molecules with a
solvent molecule located in an apical position. In 5 this position is solely occupied by a water
molecule (Fig. 2a). However, in 6 one of the symmetry independent complex molecules has just the
DMSO molecule attached to the Mg2+ ion (Fig. 2b), whereas in the other molecule this coordination
site is partially occupied by DMSO (37%), methanol (34%) and water (29%) molecules (Fig. 2c).
8

The crystals of 5 and 6 are solvated with one water and six DMF molecules in the
asymmetric unit in 5. In case of 6 the solvent molecules occupy 19.3% of the crystal volume38 but
due to severe crystal disorder, they were not identified and omitted from the structural model.
Fig. 2. X-ray structures of (a) porphyrazine 5 and (b, c) two independent molecules of porphyrazine
6. Displacement ellipsoids are shown at the 30% probability level. For clarity H atoms and non-
coordinating solvent molecules were omitted. Only magnesium, oxygen and chlorine atoms are
labeled.
In all molecules, the coordination geometry of Mg2+ is square-pyramidal with the Mg-O distances
in the range of 1.974(5) - 2.002 (3) Å and Mg-N(pyrrolyl) distances in the range of 2.026(3) – 2.056(4)
Å (Tab. S3). The Mg2+ ions are significantly displaced from the plane defined by the four
coordinating porphyrazine N atoms [0.730(3) - 0.777(3) Å].
Similarly to the previously reported porphyrazines20,21 with tertiary amino groups and
pyrrole rings at β,β-positions, the outer pyrrolyl substituents in 5 are almost perpendicular to the
central part of the porphyrazine molecule, while the amino groups are nearly in the plane of the
9

porphyrazine core (Tab. S3). An interesting feature of this structure is that five DMF solvent
molecules are enclosed within one complex molecule between p-chlorophenyl substituents - four on
the porphyrazine side with the coordinated water molecule, and one on the unoccupied side (Fig.
S2, Tab. S2). This leads to some variations in the orientation of p-chlorophenyl substituents relative
to the pyrrole ring that can be best characterized by differences in Cl···Cl distances on each side of
the molecule (Tab. S6). The remaining solvent molecules (DMF, water) are accommodated in a
centrosymmetric void formed by six porphyrazine molecules (Fig. S3).
In compound 6 (Fig. 2), in which the asymmetric unit contains two complex molecules,
some of the amino groups are not only twisted relative to the porphyrazine core (Tab. S4) but also
the configuration of bonds around the N atom is pyramidal. (Fig. 2, Tab. S7). The porphyrazine
core forms with the pyrrole rings dihedral angels in the range of 71.9° - 83.2° (Tab. S4). Like in 5,
the orientation of 4-chlorophenyl groups relative to the pyrrolyl rings allows to enclose solvent
molecules within the complex molecule. However, these molecules were not identified due to
extensive disorder, as indicated in the experimental part.
4.4. UV-Vis spectroscopy
10

11

Fig. 3. UV-Vis spectra of porphyrazines 5-7 in dichloromethane. Absorption spectra of 5-7 (a);
emission spectra of porphyrazine 7 after irradiation at λmax = 317 nm (b) and at λmax = 633 nm (c).
The absorption spectrum of porphyrazine 5 shows two intense sharp bands: the Soret band at
λmax = 311 nm, and the Q band π→π* transitions at λmax = 737 nm (Fig. 3). The Q-band transition of
Pz 6 is broad and complex as a result of the reduced symmetry of the macrocycle, in accordance
with Gouterman's four-orbital model,1 with the intense Soret band at λmax = 308 nm, and the Q band
π→π* transitions at λmax = 725 nm. Additionally, for Pz 6, n→π* transitions at λmax = 654 nm, and a
less intense Soret band at λmax = 452 nm next to the Soret peak, were observed. Similar data was
previously obtained for lower-symmetry Pzs with non-alternate order of peripheral 2,5-di(2-
thienyl)pyrrol-1-yl groups.21 The Soret and Q-band transitions of 7 at λ = 326 and λ = 725 nm
respectively, are again sharp, which is typical of the higher-symmetry isomer. It is worth noting that
the intense absorption of the Soret band of Pz 7 is reinforced by π → π * transition in the biphenyl
substituents. In addition to the spectral studies, the emission spectra of Pz 7 were recorded in
dichloromethane.
Figs 3b and 3c present the emission spectra recorded at different excitation wavelengths (λexc = 317
nm and 633 nm). For the excitation wavelength of 317 nm, two emission bands in the emission
spectra appeared: namely a short-wavelength broad emission band which resulted in the S2→S0
radiative transition with a maximum at 389 nm, and a relatively narrow long-wavelength emission
band which is correlated to the S1→S0 radiative transition. When the excitation wavelength of 633
nm was used, only one long-wavelength emission band with the same maximum at 749 nm was
observed. The Stokes shifts at the irradiation with 317 nm were 5838.8 cm-1 and 442.0 cm-1 for the
Soret and Q-band respectively. For the irradiation with 633 nm, the Stokes shift was also 442.0 cm-
1
.
3. Conclusion
12

Novel higher- and lower-symmetry Pzs bearing peripheral 2,5-di(4’-chlorophenyl)pyrrol-1-
yl and dimethylamino substituents were synthesized and characterized. The reactions were
performed in the conditions of Linstead macrocyclization with magnesium n-butanolate in n-
butanol, catalytic amount of iodine in n-butanol with an addition of a malonitrile derivative in solid
form or after dissolving it in DMF. It is interesting to note that the addition of DMF increases the
total yield of the reaction from low to moderate, and forces the synthesis of the higher-symmetry
over the lower-symmetry Pz. The lower-symmetry Pz shows an alternate order of substituents for
three out of four fragments only. The asymmetry imposed by the non-alternate order of peripheral
substituents resulted in the inequivalence of dimethylamino groups in 1H and 13C NMR spectra. The
X-ray structures of both Pzs revealed an almost perpendicular orientation of the bulky, 2,5-di(4’-
chlorophenyl)pyrrol-1-yl substituents to the core of the macrocycles.
Higher-symmetry Pz was used in the Suzuki-Miyaura reaction with phenylboronic acid. The
desired Pz with 2,5-di(biphenyl-4-yl)pyrrol-1-yl and dimethylamino substituents was obtained with
a high yield in the presence of cesium carbonate as a base, catalytic amount of
tricyclohexylphosphine, tris(dibenzylideneacetone)dipalladium(0) as a catalyst, and 1,4-dioxane as
a solvent.
4. Experimental section
4.1. General experimental methods
All reactions were conducted in oven dried glassware under argon. All solvents were rotary
evaporated at or below 50 °C. Reaction temperatures reported refer to external bath temperatures.
All solvents and reagents were obtained from commercial suppliers and used without further
purification. Melting points (mp) were obtained on a “Stuart” Bibby apparatus and are uncorrected.
Dry flash column chromatography was carried out on Merck silica gel 60, particle size 40-63 µm.
Thin layer chromatography (TLC) was performed on silica gel Merck Kieselgel 60 F254 plates and
visualized with UV (λmax 254 or 365 nm). UV-Vis spectra were recorded on a Hitachi UV-Vis U-
13

1900 spectrometer; λmax (logε), nm. Elemental analyses and mass spectra (ES, MALDI TOF) were
carried out by the Advanced Chemical Equipment and Instrumentation Facility at the Faculty of
Chemistry, Adam Mickiewicz University in Poznan. NMR spectra were recorded using a Bruker
AVANCE 400 and 600 spectrometers. Chemical shifts (d) 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, pq, d, h, t, and m refer to singlet, pseudoquartet, doublet, hidden, triplet, and
1
1
1
multiplet, respectively. H-1H COSY, H-13C HSQC and H-13C HMBC experiments were used to
1
assign H and 13C NMR spectra. Analytical HPLC was carried out on an Agilent 1200 instrument
equipped with an UV-DAD detector (see Supplementary data).
4.2. Synthesis and characterization of new compounds
Known compound: 1,4-di(4’-chlorophenyl)butane-1,4-dion 2 was synthesized starting from 1 by
adapting the literature procedure.26
2-Amino-3-[2,5-di(4’-chlorophenyl)-1H-pyrrol-1-yl]-(2Z)-butene-1,4-dinitrile (3)
1,4-Di(4’-chlorophenyl)butane-1,4-dion 2 (190 mg, 1.80 mmol), diaminomaleonitrile (550 mg, 1.80
mmol) and trifluoroacetic acid (100 µL) were refluxed in methanol (50 mL) for 24 h. Then solvent
was evaporated and a residual solid was chromatographed (n-hexane – ethyl acetate, 7:3 ) to give
yellow crystals 3 (460 mg, 68% yield). Mp 198 oC (dec). Rf (n-hexane:ethyl acetate 7:3) 0.32. UV-
1
Vis (CH2Cl2): λmax, nm (logε) 295 (5.4). H NMR (400 MHz, DMSO-d6): δH, ppm 8.29 (s, 2H,
3
3
NH2), 7.65 (d, J = 8.5 Hz, 4H, C6H4), 7.52 (d, J = 8.5 Hz, 4H, C6H4), 6.69 (s, 2H, 3’,4’-
pyrrolyl).13C NMR (100 MHz, DMSO-d6): δC, ppm 135.4, 132.5, 132.0, 130.5, 129.1, 128.8, 117.0,
112.7, 112.1, 88.6. MS (ES+): m/z 379 [M+H]+, 401 [M+Na]+. MS (ES-): m/z 377 [M-H]-. Anal.
Calc. for C22H12Cl2N4: C 63.34, H 3.19, N 14.77. Found: C 63.26, H 3.07, N 14.70.
2-[2,5-Di(4’-chlorophenyl)-1H-pyrrol-1-yl]-3-dimethylamino-(2Z)-butene-1,4-dinitrile (4)
14

Sodium hydride (60% dispersion in mineral oil, 169 mg, 1.13 mmol) was suspended in THF (20
mL) at (- 17 ºC). Next 3 (768 mg, 2.00 mmol) in THF (5 mL) was added and stirred 30 min at
temperature (-15 ºC). After that (CH3O)2SO2 (504 µL, 4.40 mmol) was added dropwise to the
reaction mixture for 30 min at (-10 ºC) and stirred at room temperature for 20 h. The reaction was
carefully quenched by adding water (2 mL) and the reaction mixture was poured into ice-water
mixture (100 mL). The yellow solid precipitated after that and was filtrated to give 4 (822 mg, 86%
o
yield). Mp 191 C. Rf (n-hexane:ethyl acetate 7:3) 0.24. UV-Vis (CH2Cl2): λmax, nm (log ε) 305
(6.7). 1H NMR (400 MHz, DMSO-d6): δH, ppm 7.55 (pq, 3J = 8.5 Hz, 8H, C6H4), 6.58 (s, 2H, 3’,4’-
pyrrolyl), 2.56 (s, 6H, N(CH3)2). 13C NMR (100 MHz, DMSO-d6): δC, ppm 136.4, 133.0, 132.6,
130.0, 129.4, 128.8, 118.5, 112.2, 111.5, 87.7, 40.9. MS (ES)+: m/z 407 [M+H] +, 429 [M+Na] +,
445 [M+K] +. MS (ES)-: m/z 406 [M]-, 441 [M+Cl]-. Anal. Calc. for C22H16Cl2N4: C 64.88, H 3.96,
N 13.76. Found: C 64.96, H 4.01, N 13.76.
{2,7,12,17-Tetrakis[2,5-di(4’-chlorophenyl)-1H-pyrrol-1-yl]-3,8,13,18-
tetrakis(dimethylamino)porphyrazinato}magnesium(II) (5)
{2,7,12,18-Tetrakis[2,5-di(4’-chlorophenyl)-1H-pyrrolyl]-3,8,13,17-
tetrakis(dimethylamino)porphyrazinato}magnesium(II) (6)
Mg turnings (194 mg, 8.00 mmol), a crystal of I2, and 1-butanol (20 mL) were heated under reflux
for 6 h. After the mixture was cooled to room temperature, maleonitrile derivative 4 (812 mg, 2.00
mmol) was added and the reaction mixture and heated under reflux for 20 h. After cooling to room
temperature, the dark green mixture was filtered through Celite and evaporated. Chromatography
(CH2Cl2:CH3OH, 50:1; n-hexane:EtOAc, 7:3) was performed to give two products:
5 (34 mg, 4% yield) as a dark green solid: mp> 300 ºC. Rf (n-hexane:EtOAc 7:2) 0.65, UV-Vis
(CH2Cl2): λmax, nm (log ε) 311 (8.4), 435 (3.7), 657 (6.4), 737 (7.6). 1H NMR (600 MHz; pyridine-
d5): δH, ppm 7.38 (d 3J = 9.0 Hz, 16H, C6H4), 6.98 (s, 8H, 2’,5’-pyrrolyl), 6.74 (d 3J = 9.0 Hz, 16H,
15

C6H4), 3.32 (s, 24H, N(CH3)2). 13C NMR (100 MHz; DMSO-d6): δC, ppm 154.1, 149.5h, 143.5,
142.2, 138.7, 132.9, 131.9, 129.3, 128.1, 110.5, 42.1. MS (MALDI TOF): m/z 1652.8 [M+H]+.
o
6 (55 mg, 7% yield): mp 295 C. Rf (n-hexane:EtOAc 7:2) 0.4. UV-Vis (CH2Cl2): λmax, nm (log ε)
1
3
308 (8.87), 452 (6.6), 654 (4.7), 725 (5.2). H NMR (400 MHz; DMSO-d6): δH, ppm 7.27 (d, J =
8.0 Hz, 4H, C6H4), 7.20 (d, 3J = 8.0 Hz, 4H, C6H4), 6.99 (d, 3J = 8.0 Hz, 4H, C6H4), 6.93 (d, 3J = 8
3
3
Hz, 4H, C6H4), 6.90 (d, J = 8 Hz, 4H, C6H4), 6.84 (d, J = 8 Hz, 4H, C6H4), 6.79 (s, 2H, 2’,5’-
pyrrolyl), 6.73 (s, 2H, 2’,5’-pyrrolyl), 6.69 (d, 3J = 8 Hz, 4H, C6H4), 6.66-6.63 (m, 8H, C6H4, 2’,5’-
pyrrolyl), 3.36 (sh, 12H, N(CH3)2), 3.24 (s, 6H, N(CH3)2), 3.09 (s, 6H, N(CH3)2). 13C NMR (100
MHz; DMSO-d6): δC, ppm 150.4, 149.2, 146.3, 137.8, 137.6, 137.4, 137.2, 136.7, 132.5, 132.4,
132.2, 130.9, 130.9, 130.6, 129.2, 128.8, 128.6, 128.0, 127.9, 127.6, 127.5, 110.2, 110.1, 110.0,
109.8, 41.8, 41.4, 40.9. MS (MALDI TOF): m/z 1652.8 [M+H]+.
The modification of the reaction conditions by simple addition of the maleonitrile derivative 4 (812
mg, 2.00 mmol) in N,N-dimethylformamide (2 mL) solution led to the increased yields of products
5 (138 mg, 29% yield) and 6 (83 mg, 10% yield).
2,7,12,17–Tetrakis[2,5-di(biphenyl-4-yl)-1H-pyrrol-1-yl]-3,8,13,18-
tetrakis(dimethylamino)porphyrazinato magnesium(II) (7)
Porphyrazine derivative 5 (100 mg; 0.06 mmol), tris(dibenzylideneacetone)dipalladium(0) (67 mg;
0.07 mmol), cesium carbonate (313 mg; 0.96 mmol), tricyclohexylphospine (5 mg; 0.02 mmol),
phenylboronic acid (70 mg; 0.576 mmol) were refluxed in dioxane (20 mL) for 20 h. After being
allowed to cool to room temperature, the dark grey mixture was filtered through Celite and
evaporated. Chromatography (n-hexane:EtOAc, 7:2; n-hexane:EtOAc, 7:3, CH2Cl2) was performed
o
to give product 7 (138 mg; yield 93%). Mp >300 C. Rf (n-hexane:EtOAc, 7:2) 0.34. UV-Vis
(CH2Cl2): λmax, nm (log ε) 326 (8.6), 437 (5.3), 654 (6.1), 734 (7.3). 1H NMR (400 MHz; pyridine -
d5): δH, ppm 7.80-7.83 (m, 6H, Ar), 7.75-7.77 (m, 6H, Ar), 7.66 (d, 3J = 8, 4H, Ar), 7.61 (d, 3J = 8,
16

4H, Ar), 7.59-7.54 (m, 4H, Ar), 7.45-7.52 (m, 12H, Ar), 7.35-7.41 (m, 8H, Ar), 7.08-7.28 (m, 24H,
Ar), 6.71-6.87 (m, 8H, Ar, 2’,5’-pyrrolyl), 6.55-6.59 (m, 4H, 2’,5’-pyrrolyl), 3.32 (sh, 12H,
N(CH3)), 3.14, 3.13 (2×s, 12H, N(CH3)).13C NMR (100 MHz; pyridine-d5): δC, ppm 140.2, 139.3,
138.8, 137.9, 136.8, 136.2, 136.1, 130.8, 129.9, 129.0, 128.9, 128.8, 128.6, 127.6, 127.4, 126.9,
126.7, 126.5, 126.1, 111.3, 110.5, 42.5, 42.4. MS (MALDI TOF): m/z 1986.4 [M+H]+.
4.2. X-ray study of 3-6
The X-ray diffraction measurements for 3, 5, 6 at 130 K and 4-trans at 100 K were carried out with
Oxford Diffraction Xcalibur E diffractometer using MoKα radiation. Intensity data for 4-cis were
collected at 298 K with Oxford Diffraction SuperNova diffractometer using hi-flux micro-focus
Nova CuKα radiation. Data were processed with the CrysAlis PRO39 software, the structures were
solved by direct methods (SHELX-S40 or SIR200441) and refined by full matrix least-squares based
on F2 (SHELXL-2013).40 C-bound hydrogen atoms were placed at idealized positions. Positions of
hydrogen atoms for primary amine group of 3 and two water molecules of 5 were located on
electron density difference map. The O-H distances in water molecules were constrained to 0.82 Ǻ.
Hydrogen atom positions of disordered water molecules in 6 were not determined. All hydrogen
atoms were refined as riding on their carriers with Uiso(H)=1.2eq (CH, CH2, OH, NH) and
Uiso(H)=1.5eq(CH3) with the exception of H atoms of the coordinated water molecule O1W in 5 for
which Uiso were freely refined. In 5 and 6, disorder has been observed for some peripheral
porphyrazine substituents and solvent molecules and the atoms from these disordered groups were
refined with isotropic displacement parameters. Additionally, in 6, the disordered solvent molecules
(mostly DMSO) could not be reliably modeled and were thus removed from the model using the
SQUEEZE42 procedure. Crystal data and further details of data collection and structure refinement
are given in Table S1.
Acknowledgements
17

This study was supported by the National Science Centre under Grant No. N N404 069440. ZG
acknowledges financial support from the European Fund for Regional Development No UDA-
POIG.02.01.00-30-182/09.
Supplementary data
Supplementary data related to this article can be found at doi:...........
CCDC 1406126-1406130 contain the supplementary crystallographic data for 3, 4-cis, 4-trans, 5
and 6. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, UK; fax: (+44) 1223-336-033; or e-mail:
deposit@ccdc.cam.ac.uk.
References
1. Michel, S. L. J.; Baum S. M., Barrett, A. G. M.; Hoffman, B. M. In Progress in Inorganic
Chemistry; Karlin, K. D., Ed.; J. Wiley & Sons, New York, 2001; Vol. 50, pp 473–590.
2. Goslinski, T.; Tykarska, E.; Kryjewski, M.; Osmalek, T.; Sobiak, S.; Gdaniec, M.; Dutkiewicz,
Z.; Mielcarek, J. Anal. Sci. 2011, 27, 511–515.
3. Claessens, C. G.; Blau, W. J.; Cook, M.; Hanack, M.; Nolte, R. J. M.; Torres, T.; Wohrle, D.
Monatsh. Chem. 2001, 132, 3–11.
4. Yano, S.; Hirohara, S.; Obata, M.; Hagiya, Y.; Ogura, S.; Ikeda, A.; Kataoka, H.; Tanaka, T.;
Joh, T. J. Photochem. Photobiol. C 2011, 12, 46–67.
5. Wainwright, M. Photochem. Photobiol. Sci. 2004, 3, 406–411.
6. Sobotta, L.; Skupin-Mrugalska, P.; Mielcarek J.; Goslinski, T.; Balzarini, J. Mini Rev. Med.
Chem. 2015, 15, 503–521.
7. Tse, M. K.; Zhou, Z.; Mak, T. C. W.; Chan, K. S. Tetrahedron 2000, 56, 7779–7783.
8. Shi, D. F.; Wheelhouse, R. T. Tetrahedron Lett. 2002, 43, 9341-9342.
18

9. Shanmugathasan, S.; Edwards, C.; Boyle, R. W. Tetrahedron 2000, 56, 1025–1046.
10. Vaz, B.; Alvarez, R.; Nieto, M.; Paniello A. I.; de Lera, A. R. Tetrahedron Lett. 2001, 42, 7409–
7412.
11. Ishizuka, T.; Yamasaki, H.; Osuka, A.; Furuta, H. Tetrahedron 2007, 63, 5137–5147.
12. Osawa, K.; Aratani, N.; Osuka, A. Tetrahedron Lett. 2009, 50, 3333–3337.
13. Ali, H.; van Lier, J. E. Tetrahedron Lett. 2009, 50, 337–339.
14. Ali, H.; van Lier, J. E. Tetrahedron Lett. 2014, 55, 4163–4167.
15. Ali, H.; van Lier, J. E. Tetrahedron Lett. 2009, 50, 1113–1116.
16. Ali, H.; van Lier, J. E. Tetrahedron Lett. 2012, 53, 4824–4827.
17. Belviso, S.; Amati, M.; Rossano, R.; Crispini, A.; Lelj, F. Dalton Trans. 2015, 44, 2191–2207.
18. Belviso, S.; Amati, M.; De Bonis, M.; Lelj, F. Mol. Cryst. Liq. Cryst. 2008, 481, 56–72.
19. Luo, Q.; Cheng, S.; Tian, H. Tetrahedron Lett. 2004, 45, 7737–7740.
20. Goslinski, T.; Tykarska, E.; Szczolko, W.; Osmalek, T.; Smigielska, A.; Walorczyk, S.; Zong,
H.; Gdaniec, M.; Hoffman, B. M.; Mielcarek, J.; Sobiak, S. J. Porphyr. Phthalocya. 2009, 13, 223–
234.
21. Goslinski, T.; White, A. J. P. Polyhedron. 2009, 28, 2579–2584.
22. Szczolko, W.; Sobotta, L.; Fita, P.; Koczorowski, T.; Mikus, M.; Gdaniec, M.; Orzechowska,
A.; Burda, K.; Sobiak, S.; Wierzchowski, M.; Mielcarek, J.; Tykarska, E.; Goslinski, T.
Tetrahedron Lett. 2012, 53, 2040–2044.
23. Sobotta, L.; Fita, P.; Szczolko, W.; Wrotynski, M.; Wierzchowski, M.; Goslinski, T.; Mielcarek,
J. J. Photochem. Photobiol. A 2013, 269, 9–16.
24. Koczorowski, T.; Szczolko, W.; Burda, K.; Nowak, M.; Dawidowska, M.; Teubert, A.; Sobotta,
L.; Gdaniec, M.; Korecki, J.; Mielcarek, J.; Tykarska, E.; Goslinski, T. Dyes Pigm. 2015, 112, 138–
144.
19

25. Kryjewski, M.; Tykarska, E.; Rebis, T.; Dlugaszewska, J.; Ratajczak, M.; Teubert, A.; Gapiński,
J.; Patkowski, A.; Piskorz, J.; Milczarek, G.; Gdaniec, M.; Goslinski, T.; Mielcarek, J. Polyhedron
2015, 98, 217-223.
26. Ceylan, M.; Gürdere, M. B.; Budak, Y.; Kazaz, C.; Seçen, H. Synthesis 2004, 11, 1750–1754.
27. Begland, R. W.; Hartter, D. R.; Jones, F. N.; Sam, D. J.; Shepperd, W. A.; Webster, O. W.;
Weigert, F. J. J. Org. Chem. 1974, 39, 2341–2350.
28. Baum, S. M.; Trabanco, A. A.; Montalban, A. G.; Micallef, A. S.; Zhong, C.; Meunier, H. G.;
Suhling, K.; Phillips, D.; White, A. J. P.; Williams, D. J.; Barrett, A. G. M.; Hoffman, B. M. J. Org.
Chem. 2003, 68, 1665–1670.
29. Linstead, R. P.; Whalley, M. J. Chem. Soc. 1952, 4839–4846.
30. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
31. Guo, M.; Zhu, Z.; Huang, H.; Zhang, Q. Catal. Commun. 2009, 10, 865–867.
32. Zhang, C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem., 1999, 64, 3804–3805.
33. Shen, W. Tetrahedron Lett. 1997, 38, 5575–5578.
34. Lehmler, H. J.; Robertson, L. W. Chemosphere 2001, 45, 137–143.
35. Littke, A. F.; Fu, G. C. Angew Chem. Int. Ed. 1998, 37, 3387–3388.
36. Gonca, E.; Baklaci, Ü. G.; Dinçer, H. A. Polyhedron 2008, 27, 2431–2435.
37. Taniguchi M.; Lindsey, J. S. Tetrahedron 2010, 66, 5549–5565.
38. Estimation made with Mercury program with probe radius 1.4 Å: Macrae, C. F.; Bruno, I. J.;
Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van
de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466–470.
39. CrysAlis PRO Software; Agilent Technologies: Yarton, Oxfordshire, England, 2012.
40. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122.
41. Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.; Casarano, G. L.; De Caro, L.;
Giacovazzo, C.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 2005, 38 381–388.
42. Spek, A. L. Acta Crystallogr. 2014, C71, 9–18.
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The Linstead macrocyclization reaction has led to higher-symmetry and lower-symmetry
porphyrazines bearing peripheral 2,5-di(4’-chlorophenyl)pyrrol-1-yl and dimethylamino
substituents, which were characterized using NMR and X-ray. The higher-symmetry porphyrazine
was used in the Suzuki-Miyaura reaction with phenylboronic acid. This led, with a high yield, to the
derivative possessing peripheral 2,5-di(biphenyl-4-yl)pyrrol-1-yl and dimethylamino substituents.
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