[Fe2(μ-SR)2(NO)4]0 complexes with R being phenolyl with different substituents in the meta-position: Synthesis, structure, and NO release

Article abstract of DOI:10.1016/j.ica.2018.05.015

Single crystals of new binuclear tetranitrosyl iron complexes ([Fe₂(SR)₂(NO)₄]) have been synthesized, with R being m-aminophenyl (1) and m-hydroxyphenyl (2). The structure, physical–chemical properties, and NO release of

Full text of DOI:10.1016/j.ica.2018.05.015

Accepted Manuscript
Research paper
[Fe2(µ-SR)2(NO)4]0 complexes with R being phenolyl with different substituents
in the meta-position: synthesis, structure, and NO release
Galina I. Kozub, Nataliya A. Sanina, Nina S. Emel'yanova, Andrey N.
Utenishev, Tat'yana A. Kondrat'eva, Vladimir N. Khrustalev, Nikolay S.
Ovanesyan, Nadezhda E. Kupchinskaya, Sergey M. Aldoshin
PII:
S0020-1693(17)31870-4
https://doi.org/10.1016/j.ica.2018.05.015
ICA 18266
DOI:
Reference:
Inorganica Chimica Acta
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 December 2017
12 April 2018
14 May 2018
Please cite this article as: G.I. Kozub, N.A. Sanina, N.S. Emel'yanova, A.N. Utenishev, T.A. Kondrat'eva, V.N.
Khrustalev, N.S. Ovanesyan, N.E. Kupchinskaya, S.M. Aldoshin, [Fe2(µ-SR)2(NO)4]0 complexes with R being
phenolyl with different substituents in the meta-position: synthesis, structure, and NO release, Inorganica Chimica
Acta (2018), doi: https://doi.org/10.1016/j.ica.2018.05.015
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[Fe2(µ-SR)2(NO)4]0 complexes with R being
phenolyl with different substituents in the meta-
position: synthesis, structure, and NO release
Galina I. Kozuba, Nataliya A. Saninaa, Nina S. Emel’yanova *a, Andrey N. Utenisheva, Tat’yana
A. Kondrat’evaa, Vladimir N. Khrustalevb, Nikolay S. Ovanesyana, Nadezhda E. Kupchinskayac,
Sergey M. Aldoshina
aInstitute of Problems of Chemical Physics, Russian Academy of Sciences,1, Acad. Semenov
Av., Chernogolovka, Russia, 142432
b
National Research Center “Kurchatov Institute”, Acad. Kurchatov Sq.1, Moscow,
Russia,123182
c M.V. Lomonosov Moscow State University, 1, Leninskie gory, Moscow, Russia, 119991
Abstract
Single crystals of new binuclear tetranitrosyl iron complexes ([Fe2(SR)2(NO)4]) have been
synthesized, with R being m-aminophenyl (1) and m-hydroxyphenyl (2). The structure, physical-
chemical properties, and NO release of new complexes in comparison with the formerly studied
isostructural analog, the complex with R being m-nitrophenyl ligand, were studied by
experimental (X-ray, IR, Mössbauer spectroscopy and amperometry) and theoretical (quantum
chemical modeling (DFT)) methods.
1

Key words: NO donors, nitrosyl iron complexes, X-ray diffractometry, Mössbauer spectroscopy,
DFT, аmperometry.
1. Introduction
Over the last decade, binuclear nitrosyl complexes of tetrahedral iron with functional sulfur-
containing ligands ([Fe2(SR)2(NO)4]), which are mimetics of the active sites of nitrosyl non-
heme [2Fe-2S] proteins [1], attracted the attention of researchers as the base for innovative
medicines [2-9 ]. For example, for the first time the antitumor activity in vitro and in vivo has
been shown for binuclear tetranitrosyl iron complex with thiophenol [10, 11]. The ligands in
complexes of this family are reversible inhibitors of the cellular DNA synthesis, and they
suppress the growth of tumors of various genesis, while the NO group, the second component of
the hybrid structure, is a key signal molecule, which participates in carcinogenesis. We have
shown that the use of a sulfur containing ligand with the amino group in the ortho- [12] or para-
[13] position of the phenyl ligand yields nitrosyl iron complexes with a more prolonged NO
generation in aqueous solutions and with a wider spectrum of cytotoxic activity, as compared to
the nitrosyl iron complex with thiophenol. The complexes were shown to cause accumulation of
p50-containing factor NF-kB in the cell nuclei, and death of tumor cells through the apoptosis
mechanism [14], thus reducing the expression of anti-apoptotic genes of BIRC family and
inducing PARP protein degradation.
The present work is aimed at the synthesis of novel complexes of this structural type, viz.
neutral binuclear tetranitrosyl iron complexes of [Fe2(µ-SR)2(NO)4] composition with R being 3-
amino (1) and m-hydroxyphenyl (2), and investigation of their structure and kinetic regularities
2

of NO generation in aqueous solutions as compared to the tetranitrosyl iron complexes with NO2
group in the meta-position of the thiophenyl ligand (3) [15].
2. Experimental Section.
2.1. Materials and physical measurements
All solvents and chemicals were purchased from commercial sources and used without further
purification. Elemental analyses were performed on an elemental analyzer “VarioMicrocube”.
Infrared spectra (cm-1) have been recorded on a Perkin-Elmer Spectrum 100 at room
temperature. Mössbauer 57Fe absorption spectra of 1-3 were recorded at a WissEl apparatus
performing in the mode of permanent acceleration. 57Co in Rh matrix was used as a source.
Measurements of the spectra at low temperatures were performed at a CF-506 flow helium
cryostat with controlled temperature (Oxford Instruments). The Mössbauer spectra were
processed using the least squares method in assumption of the Lorentz form of the individual
spectral components.
2.2 Amperometric study of NO generation
The sensor electrode “amiNO-700” of an “inNO Nitric Oxide Measuring System” (Innovative
Insruments, Inc., Tampa, FL, USA) was used for determination of the NO amount generated by
complexes 1-3 in solution. The amperometric microsensor senses NO directly. It consists of a
porphyrin polymer attached to the tip of the carbon fiber and, together with a chlorine-silver
reference electrode, is isolated from the environment by a selective membrane. Such an electrode
is immersed directly in the sample. NO oxidizes on the working surface of the electrode. The
oxidation current of NO is proportional to the concentration of nitric oxide at the electrode [16].
The concentration of NO was recorded during ~500 seconds (with pace 0.2 s) in 1% dimethyl
3

sulfoxide (DMSO) aqueous solution with the NO donor concentration 0.1 µM. DMSO was
purified according to procedure [17]. The electrochemical sensor was calibrated using the
standard NaNO2 aqueous solution (100 mkmol), which was added to the mixture of 0.12 M of KI
and 2 ml of 1 M H2SO4 in 18 ml of water. All experiments were performed in aerobic solutions
at 250С and pH 6.5 (pH of solutions was measured by a membrane pH-meter “HI 8314”
(HANNA instruments, Germany). All experiments were carried out in thermostatically
controlled electrochemical cell in the absence of the light and reducing agents in the investigated
solutions. The commercial donor NO- diethylenetriamine/nitric oxide adduct (Sigma) was used
for comparison in this work.
2.3. Synthesis and spectral properties
2.3.1. Synthesis of complex [Fe2(SC6H4NH2)2(NO)4] (1)
Complex 1 was synthesized as follows: 0.36 g (0.66 mM) of complex 3 dissolved in 10 ml of
methylene chloride was placed in the reaction flask, and 0.3 g (6 mM) of hydrazine hydrate in 3
ml of methylene chloride was added dropwise at room temperature. In 2 hours, the reaction
mixture was placed in the freezer at -180. In a day, the black crystals were filtered and dried in
air.
Elemental analysis C12H12N6O4S2Fe2. Found: % С – 30.21, Н – 2.63, N – 17.23, S – 13.61, Fe –
23.1. Calculated: % С – 30.02, Н – 2.51, N – 17.50, S – 13.35, Fe – 23.26.
IR spectrum of 1: 3474.1 (w.), 3387.7(w.), 3199.7(v.w.), 3065.6(v.w.), 2361.9(v.w.), 1816.8(w.),
1766.3(w.), 1733.4(w.), 1615.4(m.), 1588.5(m.), 1524.8(w.), 1481.9(m.), 1434.2(w.),
4

1347.9(m.), 1302.1(w.), 1269.4(w.), 1165.4(w.), 1105.1(w.), 990.5(m.), 874.9(w.), 858.9(w.),
802.0(w.), 773.9(m.), 730.9(w.), 683.6(m.).N-O 1766 cm-1, 1733 cm-1; N-H 1615 cm-1.
2.3.2. Synthesis of complex [Fe2(SC6H4OH)2(NO)4] (2)
1 g of 3,3’- m-hydroxyphenyl disulfide (4 mM) was dissolved in 20 ml of ethanol, and 2 g
(50mM) of hydrazine hydrate was added dropwise. The reaction mixture was heated at 450 for 3
hours. Then ethanol was removed in vacuum, and the residue was dissolved in slightly alkaline
solution (20 ml of H2O + 0. 3 g of NаОН). This solution was added dropwise in a three-necked
flask containing solutions of TNIC (0.8 g or 1.48 mM) and Na2S2O3 (0.75 g or 3.02 мМ) in 25 ml
of water (the flask was purged with argon for 0.5 hours). The black deposit was filtered in three
hours, washed with ether, and dissolved in methylene chloride. The solution was then evaporated
to the minimum, and left in the freezer at -180 for a day. The resulting crystals were filtered and
dried in air for a day. 0.43 g of the complex was obtained. Yield 66%.
Elemental analysis for C12H10O6N4S2Fe2. Found: % С – 29.97; Н – 2.21; N – 11.38; S – 13.24.
Calc. %: С – 29.90; Н – 2.23; N – 11.63; S – 13.28.
IR spectrum of 2: 3506 (v.w.), 3382(v.w.), 2769 (v.w.), 2556 (v.w.), 1779 (m.), 1737 (s.), 1597
(w.), 1581 (m.), 1472 (m.), 1444 (w.), 1306 (m.), 1210 (m.), 1168 (v.w.),1093 (v.w.), 1071 (w.),
996 (w.), 970 (w.), 877 (m.), 851(w.), 777 (m.).N-O 1779 cm-1, 1737 cm-1
2.3.3. Synthesis of complex [Fe2(SC6H4NO2)2(NO)4] (3)
Complex 3 was synthesized according to procedure [15].
Solid complexes 1, 2, 3 are stable for a long time (up to 2 years) if stored at 4-80С, this being
confirmed by Mössbauer and IR spectra recorded after long storing. Complexes 1 and 2 are
5

insoluble in water, moderately soluble in alcohols and easily soluble in dichloromethane,
chloroform, acetonitrile, acetone, tetrahydrofuran, and dimethylsulfoxide. However, in organic
solvents the complexes are unstable and decompose within a few hours at room temperature.
2.4. X-Ray Crystallography for 1 and 2
X-ray study of single crystals of 1 and 2 was carried out on the ‘Belok’ beamline of the National
Research Center “Kurchatov Institute” (Moscow, Russia) using a Rayonix SX165 detector at λ =
0.96990 Å. The data were indexed and integrated using the iMOSFLM utility in the CCP4
program [18], and then scaled with the absorption compensation using the Scala Program [19].
The crystallographic data and main parameters are shown in Table S1 (see Supplementary Data).
The structures were solved by the direct method [20]. Positions and temperature parameters of
non-hydrogen atoms were refined in anisotropic approximation by the full-matrix least-squares
method [20]. Positions of all hydrogen atoms were calculated geometrically and then refined in
the riding model with restrictions [20]. All calculations were carried out with the
SHELXTL program package [20].
2.5. Computational Methods.
Quantum-chemical calculations were performed using the Gaussian 09 program, version D [21]
by means of meta-hybrid functional TpssH [22] and 6-311++G**//6-31G* basis set). TpssH
meta-hybrid functional was chosen because of good convergence and calculation speed it
provided for the systems under consideration, as compared to other methods, and good
description of the experimental data [23, 24]. Geometry optimization for all initial compounds
and the reaction products was performed taking into account solvation in DMSO solution in the
frame of Polarized Continuum Model (PCM). The computations have shown the absence of
6

imaginary frequencies, this being the evidence of the fact that all optimized geometries
correspond to the minima.
3. Results and discussion
3.1. Syntheses and spectral characterization
Complex 1 was synthesized from complex 3 (see scheme 1) through the reduction of the
nitrogroups located in meta-positions of the phenyl ligands by hydrazine hydrate in
dichloromethane.
Scheme 1.
O2N
H2N
N2H4.H2O;CH2Cl2
NO
S
ON
ON
NO
NO
S
ON
ON
Fe
Fe
Fe
Fe
NO
S
S
NO2
NH2
3
1
Complex 2 was synthesized by substitution of the thiosulfate ligands of
Na2[Fe2(S2O3)2(NO)4]4Н2O complex (synthesized according to [25]) by 3- hydroxyphenyl
ones, using 3- hydroxyphenyl disulfide as the initial chemical (see scheme 2).
Scheme 2.
7

HO SS OH
N2H4.H2O
C2H5OH
HO
2-
O3S
Fe
H5N2S OH
NO
NO
NO
NO
S
S
ON
ON
ON
ON
Fe
Fe
Fe
Na2S2O3
S
S
SO3
OH
2
3.2. Description of crystal structures of 1-3
Figure 1 shows the molecular structure of complexes 1-3.
2.
3.
1.
Fig. 1. Molecular structures of complexes 1-3
8

In contrast to 2, 1 and 3 have centrosymmetrical binuclear structure. Molecular structure of
complexes 1-3 is similar to that of earlier studied anionic [26-28] and neutral [Fe2(-SL)2(NO)4]
(L = Me, Et, n-C5H11, CMe3 [29,30], and Py [31]) nitrosyl iron complexes. In all complexes, the
phenyl ligands have a trans position with respect to the central Fe2S2 fragment, with the rotation
angles with respect to this fragment being different. In complex 1, the angle between the m-
aminophenyl substituents and the central moiety is 90.7(1), in 3 such angle between m-
nitrophenyl substituents and the central fragment is 63.0(1), while in 2 m-hydroxophenyl
substituents are oriented with respect to the central part in different ways: m-ОНPh(С(1)-С(6))
forms the angle of 61.5(2), similar to that in complex 3, and m-ОНPh(С(7)-С(12)) forms the angle
of 91.4(2), similar to that in 1. Figure 2 shows complexes 1-3 superposed along the plane of the
central Fe2S2 fragment.
Fig. 2. Molecules of complex 1 (solid line) and 2, 3 (dotted lines) superposed over the plane of
the central Fe2S2 fragment
Interatomic Fe(1)-Fe(1A) distance in 3, 2,731(1) Å, is the longest; similar distances in 1 and 2
are 2.695(1) and 2.707(2) Å, respectively. Apparently, this is due to the influence of the
9

substituent of the phenyl fragment: for the most electron donating NH2 substituent, the Fe(1)-
Fe(1A) distance is the shortest, while for the most electron accepting NO2 substituent it is the
longest. The Fe-S bond lengths and the SFeS valence angle change inconsiderably: 2.272(1),
2.273(1) Å, 107.25(5)  in 1; 2.267(3), 2.283(3), 2.269(3), 2.260(3) Å, 106.4(1), 107.1(1) in 2
and 2.270(1), 2.279(1) Å, 106.22(2)  in 3, respectively The carbon-sulfur bond length in the SR-
ligands is 1.802(4) Å (1), 1.786(11), 1.779(11) Å (2) and 1.793(3) Å (3), this being close to the
similar bond lengths in -S binuclear complexes [32], and much longer than the S=C bond
length (1.684 Å) [33]. This may be due to the participation of the thiolate form (in complexes)
with a single C-S bond. The amino-group in 1 lies in the plane of the phenyl ring, while the
nitro-group in 3 deviates from the plane of the phenyl ring by 12.3. The nitrosyl groups do not
almost differ from formerly studied ones [27, 28, 29]. The N-O, Fe-N bond lengths and the
values of FeNO valence angles are presented in Table 1. However, the difference in the N-O
bond lengths between the complexes under study has been observed. While in 1 and 3 the N-O
bond lengths and values of the Fe-N-O valence angles are essentially similar (see Table 1), in 2
there is a considerable difference of the N-O bond lengths: one of the two N-O bonds at each
iron atom is elongated as compared to the other: N(1)-O(1) = 1.213(12) and N(2)-O(2) =
1.165(12) Å, N(3)-O(3) = 1.195(12) and N(4)-O(4) = 1.168(11) Å, respectively. Later we will
present the reason of this elongation. The Fe-N bond lengths and the values of FeNO valence
angles differ inconsiderably (Table 1).
Table 1. Bond lengths and valence angles in complexes 1-3
Bond length /Å
2
Angle /°
2
Bond
Angle
1
3
1
3
10

Fe(1)-N(1)
Fe(1)-N(2)
N(1)-O(1)
N(2)-O(2)
N(3)-O(3)
N(4)-O(4)
Fe(1A)-N(3)
Fe(1A)-N(4)
1.673(4)
1.673(10)
1.681(9)
1.213(12)
1.165(12)
1.195(12)
1.168(11)
1.685(10)
1.687(9)
-
1.675(3)
Fe(1)N(1)O(1)
Fe(1)N(2)O(2)
N(1)Fe(1)S(1)
N(2)Fe(1)S(1)
N(3)Fe(1A)S(1A)
N(4)Fe(1A)S(1A)
O(3)N(3)C(3)
O(4)N(3)C(3)
C(2)C(3)O(5)
C(4)C(3)O(5)
C(8)C(9)O(6)
C(10)C(9)O(6)
Fe(2)N(3)O(3)
Fe(2)N(4)O(4)
171.5(3)
170.5(8)
170.1(1)
113.4(3)
104.1(3)
107.8(3)
109.7(3)
-
168.7(3)
1.690(4)
1.658(3)
171.1(4)
169.1(3)
1.188(5)
1.169(3)
108.1(1)
111.86(9)
1.174(5)
1.169(4)
106.7(1)
106.2(1)
-
-
-
-
-
-
-
1.240(4)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
117.8(3)
-
-
118.9(3)
N(3)-O(4)
O(5)-C(3)
O(6)-C(9)
1.230(4)
116.2(9)
121.3(9)
116.7(9)
121.6(9)
167.3(8)
172.3(1)
-
-
-
-
-
-
1.413(14)
1.385(11)
-
-
In the crystalline structure of 1, the shortest contacts between the О(1)…О(2’) {x, 1 + y,
z}, О(2)…О(2’) {-x, -y, 1 - z} oxygen atoms of the nitrosyl groups are 3.133 (3) and 3.031(3) Å,
respectively (Figures 3a and 3b).
Fig. 3a. Intermolecular contact O(1)…O(2’)N(2’) {x, 1 + y, z} in the crystalline structure of
complex 1 (without hydrogen atoms)
11

Fig. 3b. Intermolecular contact O(2)…O(2’)N(2’) {-x, -y, 1 - z} in the crystalline structure of
complex 1 (without hydrogen atoms)
The values of the О(1)О(2’)N(2’) and О(2)О(2’)N(2’) angles are 131.3(3) and 110.7(2),
respectively, The nitrosyl oxygen atom O(2) forms interatomic contacts with the O(1’)N(1’)
nitrosyl group{x, -1+y, z}: О(2)…N(1’) 3.040(3) Å, O(2)N(1’)O(1’) angle 83.3(2) and
О(2)…O(1’) 3.299(3) Å, O(2)О(1’)N(1’) angle 74.5(2) (Figure 3с).
Fig. 3с. Intermolecular contact О(2)…О(1’)N(1’) {x, -1+y, z} in the crystalline structure of
complex 1 (without hydrogen atoms)
In 2, the nitrosyl oxygen atoms O(1) and O(3) participate in the formation of interatomic
contacts with the oxygen atoms of the hydroxyl groups: О(1)…O(5’) {1-x, -1/2+y, 3/2-z}
12

2.963(3) Å, N(1)O(1)O(5’) angle 153.6(2), and О(3)…O(6”) {-x, 1/2+y, 1/2-z} 2.959(3) Å,
N(3)O(3)O(6”) angle 125.0(2) (Figure 4).
Fig. 4. Intermolecular contacts in complex 2: О(1)…O(5’) {1-x, -1/2+y, 3/2-z},
О(3)…O(6”) {-x, 1/2+y, 1/2-z} (without hydrogen atoms)
Apparently, participation of the nitrosyl oxygen atoms О(1) and О(3) in these interatomic
contacts results in the elongation of the corresponding NO bonds, as indicated above. In the
crystal of 2, interatomic hydrogen bonds of O-H…O type form. As far as the hydroxyl hydrogen
atoms are geometrically determined, we do not present the corresponding bond lengths and
angles values. Values of the O(5)…O(6A) {1/2 - x, 1 - y, 1/2 + z} and O(6)…O(5А) {1/2 - x, 1 -
y, -1/2 + z} contacts are 2.878(4) Å (Figure 5).
13

Fig. 5. Intermolecular hydrogen bonds of complex 2 in the crystal
In complex 3, shortened interatomic contacts between the nitrogroups (O(3)…N(3’) {1 -
x, 2 - y, 1 - z} 2.938(4) Å) and weak interatomic hydrogen bonds of C-H…O type
(O(4)…H(4’)–C(4’) and O(3)...H(6’)–C(6’) with parameters: O(4)…H(4’) 2.54 Å, O(4)…C(4’)
3.409(5) Å, O(4)H(4’)C(4’) angle 155 { H(4’)–C(4’) (-x, 2 - y, 1 - z)}, and O(3)...H(6’) 2.54 Å,
O(3)...C(6’) 3.444(5) Å, O(3)H(6’)C(6’) angle 166 { H(6’)–C(6’) (x, y + 1, z)}, respectively,
are present (Figure 6).
Fig. 6. Weak intermolecular hydrogen bonds of NO…HC type in complex 3.
Thus, the nature of substituents in the meta-position of the phenyl ring affects essentially
the molecule packing in the crystal. In 1, the packing is determined by the contacts between the
14

nitrosyl groups; in 2 – by intermolecular hydrogen bonds; in 3 – by weak intermolecular
interactions of the nitrogroups.
Mössbauer spectra of polycrystals of complexes 1-3 are single quadrupole doublets. The
spectra parameters (isomeric shift, quadrupole splitting, and line width) of the complexes at 296
K, as well as average Fe-S and Fe-N(O) bond lengths of the corresponding complexes (X-ray
data, for comparison), are presented in Table 2.
Table 2. Mössbauer parameters of Fe57 and mean interatomic Fe-S, Fe-N(O) distances of
complexes 1- 3 at 296 K.
Г3), mm·s-1
2)
EQ , mm·s-1
1), mm·s-1
0.108(1)
0.089(1)
0.115(1)
Complex Substituent
d(Fe-S), Å d(Fe-NO), Å
-NH2
-OH
1.148(1)
0.237(1)
0.245(1)
0.241(1)
2.272(8)
2.270(3)
2.275(9)
1.682(4)
1.681(10)
1.667(3)
1
2
3
1.050(1)
-NO2
1.171(1)
1)
2)
3)
isomer shift (w.r.t. -Fe);
quadrupole splitting;
line width.
Values of Mössbauer parameters are similar to those for complexes with thiophenolyl [32] and 2-
aminothiophenolyl [12], obtained earlier. In 2, as distinguished from 1 and 3, two iron atoms in
the dimer are structurally nonequivalent. However, two states of the iron are indistinguishable in
the spectrum because of similar values of  and EQ; the nonequivalence, apparently, reveals in a
small increase of the width of the doublet lines with respect to Г values for complexes 1 and 3.
As can be seen in the Table, there is a dependence of the isomer shift value on mean Fe-S
distances in the coordination tetrahedron. Similar to formerly studied mono- and binuclear
nitrosyl iron complexes containing {Fe(NO)2}9 structural unit [33, 34] the increase of the isomer
15

shift and, accordingly, the increase of 4s electron density on the iron atom in 2, 1, 3 are due to
the decrease of mean Fe-S distance (see Table 2). The latter may be due to the increase of
electron-acceptor properties of meta-substituents in the aromatic ring of the ligand in the OH,
NH2, NO2 row. On the other hand, the opposite trend for IS values to the decrease of the less-
covalent Fe-N(O) bond lengths seems to have a minor effect.
3.3. Electrochemical studies
As follows from electrochemical analysis data, hydrolytic decomposition of complexes 1-3 is
accompanied by NO release without additional thermal, photo or other activation similar to
organic NONOates [35]. From direct anaerobic and aerobic measurements with a sensor
electrode, experimental time dependencies of NO amount in 1% DMSO water solutions at
different pH values have been obtained (Figures 7).
16

Fig.7. Kinetic dependences of the NO amount generated by the nitrosyl complexes in 1%
aqueous DMSO solutions (T=250C) on time: A - complex 1; B - complex 2; C- complex 3 in
aerobic and anaerobic (*) conditions at the concentration of complexes of 0.810-5M/L.
Behavior of complexes 1-3 in anaerobic medium is similar to that in aerobic, viz., the presence of
oxygen in the system does not influence the NO generation by the complexes. As follows from
Fig.7, NO release for all complexes is observed immediately after introduction of DMSO
solution of the complex into the aqueous medium. It can be also seen that the nature of the
17

substituent affects the NO donor ability of the complexes. The maximum amount of NO (70.10-9
mol NO, that means 0.8810-2 mol NO per1 mol of the complex at pH 7.0) is observed for
complex 2 by the eighth minute of the experiment. Complex 1 has less ability of NO release. NO
donating ability of complex 1 in similar conditions is almost 3.2 times less (22.10-9 mol NO, that
means 0.2810-2 mol NO per 1 mol of the complex at pH 7.0) than of 2, but is higher than that of
isostructural tetranitrosyl iron complexes with ortho-(16.10-9 mol NO, that means 0,210-2 mol
NO per1 mol of the complex at pH 7.0 [8]) and para- (10. 10-9 mol NO, that means 0,1310-2 mol
NO per1 mol of the complex at pH 7.0 [36]) positions of amino- groups in the phenyl ring of the
ligand. For complex 3, a higher initial rate of the NO release and a bell-like shape of the curve of
its generation in aerobic conditions are typical, this being the evidence of the presence of more
active NO donating intermediates in the solution at the initial stage of NO release and its
oxidation.
It can be seen that NO donor ability of the studied complexes upon variation of the medium
acidity also depends on the substituent nature. It decreases with transferring to alkaline medium
(pH 9.0) (the minimum value for 1 is 6.10-9 mol NO, that means 0,07510-2 mol NO per 1 mol of
the complex). In acidic medium (pH 6.5) NO donating activity for complexes 1 and 2 decreases
almost twice, while for 3 it does not change, this apparently being due to the possibility of the
ligands protonation in 1 and 2, and the absence of such possibility in 3. In general, it can be
concluded that under physiological conditions (pH 6.5-7.0), all the complexes under study can be
used as more effective donors of than organic NO donor NONO-ate (13.10-9 mol NO, that means
0,1610-2 mol NO per 1 mol of the NONO-ate).
3.3. Quantum chemical computations
18

Computations of geometrical structure of all studied complexes have been performed using DFT
method. In Table 3, main parameters of optimized geometries are shown in comparison with the
experimental data.
Table 3. Main parameters of optimized geometries as compared to the experimental data
Fe-N
1.687
1.673
1.687
1.673
1.692
1.675
N-O
Fe-S
S-C
Ω, deg.*
88.1
1
2
3
DFT
Exp
1.179
1.174
1.179
1.165
1.177
1.169
2.386
2.272
2.387
2.267
2.398
2.279
1.799
1.802
1.797
1.786
1.791
1.793
90.7
DFT
Exp
89.1
61.5 (91.4)
58.3
DFT
Exp
63.0
*- angle between phenyl substituents and the central fragment Fe2S2
As follows from the Table, the method we have chosen (TPSSh /6-311++G**//6-31G*)
describes the complexes geometry quite satisfactorily. For the Fe-S bond, there are small
deviations from the experiment, however, the general trend is evident, viz., for the two
complexes with electron donor substituents in the phenyl ring of the ligand (1, 2) the bond
lengths are essentially similar, while for complex 3 with the electron acceptor substituent some
discrepancies are observed, in particular, the Fe-S bond in it is the longest. . We can see that the
differences in the phenyl ring orientations in the complexes with electron-donating and
withdrawing substituents on the phenyl rings remains. So it is not the packing effects in the solid
state, because geometry optimization for all initial compounds was performed taking into
account solvation in DMSO solution in the frame of Polarized Continuum Model (PCM). We
can observe the packing effect for complex 2, which, unlike complexes 1 and 3, is not
19

centrosymmetric, according to the experimental data, whereas from the DFT calculations all the
complexes are centrosymmetric
Thus, quantum chemical computations support the experimental data on the effect of the
substituent in the phenyl ring of the ligand on the structure of the complexes.
As follows from the experimental data, complexes 1-3 are insoluble in water, and for studying
their NO donating properties, the complexes are first dissolved in DMSO, and then the obtained
solution is transferred to the aqueous medium (see 2.1. Materials and physical measurements). In
DMSO solution, reactions of the Fe-S bond rupture can occur [37] under the action of the solvent
molecules, to yield mononuclear complexes of various types1.
[Fe2(μ-SR)2(NO)4] + 2DMSO →2[Fe(SR)(DMSO)(NO2)2]
(1)
or
[Fe2(μ-SR)2(NO)4] + 2DMSO →[Fe(DMSO)2(NO2)2]+ [Fe(SR)2(NO2)2]- (2)
Using quantum chemical modeling, energetic features of these reactions and structure of the
forming mononuclear complexes (Fig. 8)
1
From the UV spectrum (see Supplementary Data Fig S1) we see that in 80 minutes the
characteristic bands of the binuclear nitrosyl iron complex disappear and the bands responsible
for the presence of the mononuclear nitrosyl complex appear.
20

R= NH2, OH, NO2
-
+
Fig. 8. Optimized geometries of the resulting mononuclear complexes
have been considered (Table 4).
Table 4 Energies of decomposition of the initial complexes in DMSO to yield mononuclear ones
(kcal/mol)
1
2
3
Reaction 1
Reaction 2
-5.6
-1.4
-5.7
-2.5
-10.8
-8.3
21

Reaction (1) is exergonic, the released energy for complexes 1, 2 being almost the same (-5.6
kcal/mol for 1 and -5.7 for 2), while for 3 being almost twice higher (-10.8 kcal/mol).
These data are consistent with the structure of complexes 1, 2, 3. In 3, the Fe-S bond is the
longest, hence, the weakest, as compared to complexes 1 and 2. Reaction (2) is exergonic for
complex 3, but for complexes 1 and 2 they are essentially thermoneutral. We can expect that
DMSO solution of complex 3 contains more mononuclear particles than that of complexes 1 and
2. Thus, the presence of the ligand in the aromatic ring affects the complex decomposition in
DMSO, too.
As follows from the structure of the resulting mononuclear complexes (neutral, cationic, and
anionic), the Fe-NO bond weakens upon the coordination of DMSO molecule. The most serious
elongation of this bond is observed for the cationic complex with two DMSO ligands.
Furthermore, as it was shown earlier [38,39], cationic complexes remove the NO molecule more
easily than anionic ones. Hence, we can assume that just this molecule formed in DMSO is
responsible for NO donation. However, the mononuclear complex is the similar decomposition
product for all three initial complexes, consequently, NO release in 1% aqueous DMSO solutions
occurs essentially similar, this being confirmed by the experiment. However, a higher
concentration of mononuclear particles responsible for NO donation can be the reason of a
higher initial rate of NO release by complex 3.
4. Conclusions
The influence of a substituent in meta-position of the phenyl ring on properties of a series of
neutral binuclear tetranitrosyl iron complexes of [Fe2(µ-SR)2(NO)4] composition has been
22

studied. The ligand nature was shown to affect the rotation angle of the substituted phenyl ring
with respect to the central Fe2S2 fragment. The increase of electron accepting properties of meta-
substituents in the phenyl ring in the OH, NH2, NO2 row causes the growth of the isomeric shift
in Mössbauer spectra, this being due to the increase of 4s electron density on the iron atom.
Using quantum chemical modeling, it was shown for the first time that in DMSO solutions
decomposition of binuclear complexes into mononuclear intermediates can occur, which contain
a weaker Fe-NO bond than initial binuclear complexes.
Acknowledgements
The authors express their gratitude to M.Z. Aldoshina. The work has been performed with
financial support of the Russian Foundation for Basic Research (Grant No.17-03-00837).
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27

Appendix A. Supplementary data
Table S1. Main crystallographic data and parameters of the experiment for compounds 1 and 2 at
100К
Parameter
C12 H12 Fe2 N6 O4 S2 C12 H10 Fe2 N4 O6 S2
Number of the deposit
1539665
480.10
Monoclinic
P2(1)/n
7.0647(14)
6.3514(13)
19.925(4)
90.00
1539665
482.06
Orthorhombic
P2(1)2(1)2(1)
9.829(2)
Mr
Syngony
Space group
a, Å
10.091(2)
17.821(4)
90.0
b, Å
c, Å
, °
99.45(3)
90.00
2
90.0
90.0
, °
, °
Z
4
dc, g/cm3
V, Å3
1.808
881.9(3)
9244
1.804
1767.5(6)
12394
Number of measured
reflections
1468
0.0611
119
3139
0.0673
236
I >2(I)
R
Number of refined
parameters
Scan range, °
3.23 <  < 38.44
4.01 <  < 38.40
GOOF
1.001
1.175
CIF files containing the complete information on the studied structures have been deposited with
CCDC under the numbers indicated in Table S1 and can be received free of charge on the
request via:www.ccdc.cam.ac.uk/data_request/cif.
28

Fig S1 Change in the absorption spectra of a solution of complex [Fe2 (SC6H4OH)2 (NO) 4] in
time. Reaction conditions: 250 C, solvent - DMSO,
29