Functional Mononitrosyl Diiron(II) Complex Mediates the Reduction of NO to N2O with Relevance for Flavodiiron NO Reductases

Article abstract of DOI:10.1021/jacs.7b08855

Reaction of [Fe₂(N-Et-HPTB)(CH₃COS)](BF₄)₂ (1) with (NO)(BF₄) produces a nonheme mononitrosyl diiron(II) complex, [Fe₂(N-Et-HPTB)(NO)(DMF)₃](BF₄)₃ (2). Complex 2 is the first example of a [Fe^II{Fe(NO)}⁷] species and is also the first example of a mononitrosyl diiron(II) complex that mediates the reduction of NO to N₂O. This work describes the selective synthesis, detailed characterization and NO reduction activity of 2 and thus provides new insights regarding the mechanism of flavodiiron nitric oxide reductases.

Full text of DOI:10.1021/jacs.7b08855

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Communication
A Functional Mononitrosyl Diiron(II) Complex Mediates the Reduction
2
of NO to NO with Relevance for Flavodiiron NO Reductases
Manish Jana, Nabhendu Pal, Corey White, Claudia Kupper, Franc Meyer, Nicolai Lehnert, and Amit Majumdar
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08855 • Publication Date (Web): 27 Sep 2017
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A Functional Mononitrosyl Diiron(II) Complex Mediates the
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Reduction of NO to N O with Relevance for Flavodiiron NO
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Reductases
†
†
‡
&
&
‡
Manish Jana, Nabhendu Pal, Corey White, Claudia Kupper, Franc Meyer, Nicolai Lehnert * and
†
Amit Majumdar *
†
Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road,
Jadavpur, Kolkata 700032, West Bengal, India
‡
Department of Chemistry, The University of Michigan, 930 N. University, Ann Arbor, MI 48109, USA
&
Institut für Anorganische Chemie, Georg-August-Universität Göttingen, Tammannstraße 4, 37077 Göttingen, Germany
Supporting Information Placeholder
ABSTRACT: Reaction of [Fe
(1) with (NO)(BF ) produces a nonheme mononitrosyl diiron(II)
complex, [Fe (N-Et-HPTB)(NO)(DMF) ](BF ) (2). Complex 2 is
the first example of a [Fe {Fe(NO)} ] species and is also the first
example of a mononitrosyl diiron(II) complex that mediates the
2
(N-Et-HPTB)(CH
3
COS)](BF
4
)
2
Scheme 1. Schematic presentation for the synthesis of 2. Poss-
ible reactive species (not isolated) that may allow the selective
synthesis of 2 are shown within brackets.
4
2
3
4 3
II
7
2
reduction of NO to N O. This work describes the selective synthe-
sis, detailed characterization and NO reduction activity of 2 and
thus provides new insights regarding the mechanism of flavodii-
ron nitric oxide reductases.
Apart from its major role in nerve signal transduction and blood
1-3
pressure control in mammals, nitric oxide (NO) is also a key
component in the defense mechanism against various invading
2-5
pathogens. While up to micromolar concentration of NO can be
6,7
produced in the activated macrophages, many microbes such as
8
9
10
D. gigas, M. thermoacetica , and T. maritima reduce NO to
nitrous oxide (N O) by expressing the enzymes flavodiiron nitric
2
11-13
oxide reductases (FNORs).
The active site of FNOR from D.
8
Nevertheless, investigations into the reactivity of diiron sites with
NO remain of general interest in the context of NORs.
gigas consists of two non-heme iron centers (Fe–Fe = 3.2-3.6 Å).
One iron center is coordinated by two histidines and a glutamate
while the second one is coordinated by a histidine, an aspartate,
and a water-based ligand. A bridging aspartate and a water-based
ligand complete the coordination spheres. In the active sites of M.
Reactivity of NO with non-heme diiron(II) complexes is quite
11,13,19
well-known.
A
dinitrosyl complex, [Fe
(N-Et-HPTB)-
2
20
(PhCOO)(NO) ](BF ) (3), where N-Et-HPTB is the anion of
2 4 2
9
10
thermoacetica and T. maritima (PDB: 1VME) enzymes, the
non-bridging water derived ligand is replaced by an additional
histidine and thus provides an identical, four His coordination
environment around the two iron centers. Mono- and di-nitrosyl
diiron intermediates have been invoked in two different proposed
N,N,N′,N′-tetrakis(2-(l-ethylbenzimidazolyI))-2-hydroxy-1,3-
diaminopropane, has been shown to mediate the photoproduction
of N
of a mononitrosyl species has been invoked in the mechanism.
Another functional model complex of FNOR,
[Fe (BPMP)(OPr)(NO) ](BPh (4) , where BPMP is the anion
of 2,6-bis[(bis(2-pyridylmethyl)amino)methyl]-4-methylphenol,
could mediate the reduction of NO to N O upon chemical or
electrochemical reduction. Very recently, a dinitrosyl diiron(II)
complex, [L{Fe(NO)} (μ-OAc)](ClO (5, L is a dinucleating
2
O in high yield (at low temperature only) and the formation
2
1
11-17
22
mechanisms for the catalytic reduction of NO to N O.
Some
2
2
4 2
)
2
recent results substantiate the formation of a mononitrosyl species
9
,10,18
as an intermediate in the catalytic cycle.
These results
2
include the formation of a stable mononitrosyl adduct, formed by
the addition of 1 equiv of NO per diiron(II) site of both FMN-
)
4 2
2
1
8
9
23
containing and FMN-free flavin diiron proteins. However, a
more recent study on the mechanism of FNORs has shown that
although the NO reductase reaction proceeds through the
successive formation of mononitrosyl and dinitrosyl species, the
mononitrosyl complex is not the catalytically active species for
pyrazolate/triazacyclononane hybrid ligand) has been reported
7
which displays an anti orientation of the {Fe(NO)} units in
2
0
22
contrast with the syn orientation in 3 and 4 and was unable to
produce N O upon reduction. However, synthesis and reactivity
2
of a pure mononitrosyl diiron(II) complex, especially with a
symmetric ligand platform like in FNORs, remained elusive to
date. While the complex, [Fe (N-Et- HPTB)(NO)0.6(DMF)3.4]-
2
1
5
N–N bond formation. Rather, it is the diferrous-dinitrosyl
species that is converted to a diferric species and N O.
2
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2
4
viously been reported for 6. The Fe–NO and N–O distances in 2
are 1.775 and 1.066 Å respectively while the Fe–N–O angle is
160.5°. These bond distances and angle observed in 2 are
comparable with the previously reported bond distances (Fe–NOav
for 3, 1.750 Å; Fe–NO for 4, 1.773 and 1.779 Å; N–Oav for 3,
1
2
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1
.154 Å; N–O for 4, 1.172 and 1.156 Å) and Fe–N–O angles
20,22
(
166.6, 168.3° for 3; 155.5, 144.7° for 4).
The νNO in 2 was
−1
found to be 1768 cm (as KBr pellet; νNO in MeCN solution =
1
values reported for 3 (1785 cm ) and 4 (1760 cm ) and
−1
791 cm , figure S4) which is intermediate between the ν
NO
−1 20 −1 22
conforms to the typical NO stretching frequencies for high-spin
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nonheme {Fe(NO)} complexes. The amide-like vibrations
2
1
from metal coordinated DMF and free DMF in MeCN are
−1
observed at 1655 and 1677 cm , respectively (figure S4). The
electronic absorption spectrum of 2 consists of at least five
distinct transitions in the absorption spectrum (figure S5) and is in
agreement with the absorption spectroscopic features associated
with non-heme {Fe(NO)} complexes.
centered at 610 nm (ε = 160 ± 2 M cm ) may be attributed to
the spin-forbidden d–d transition. Complex 2 exhibits a second
7
13,20
The broad feature
−
1
−1
Figure 1. Molecular structure of 2 with 50% probability thermal
ellipsoids and partial atom labeling scheme. Hydrogen atoms are
omitted for clarity.
−
1
−1
band at 510 nm (ε = 220 ± 5 M cm ), an additional shoulder at
28 nm (ε = 640 ± 50 M cm ) and the underlying tail from the
−1
−1
4
2
4
−1
−1
-
(BF
4
)
3
may be considered as the closest approach so far, the
UV bands at 340 nm (ε = 2407 ± 175 M cm ) and 310 nm (ε =
−1
−1
aforementioned complex was essentially described as a mixture of
2
820 ± 145 M cm ). The bands ranging from 310–510 nm are
II
7
II
24
−
*
III
∼
60% [Fe {Fe(NO)} ] species and ∼40% Fe
species and no
2
attributed to NO (π ) to Fe charge transfer transitions in non-
7
13
account for the reactivity of the complex has been reported. A
heme {Fe(NO)}
complexes.
Mössbauer spectroscopic
2
4
related complex, [Fe (N-Et-HPTB)(NO)(OH)(DMF) ](BF ) (6)
2
2
4 3
characterization of the thioacetate bridged diiron(II) compound, 1,
III
7
featured a [Fe (OH){Fe(NO)} ] formulation and was reported to
displays a two-site spectrum in a 1:1 ratio (figure S6) with nearly
2
0
−1
be inactive toward photoproduction of N O.
2
identical isomer shifts (δ = 1.02 and 1.05 mm s ) but distinctly
−1
Here we report the selective synthesis of a nonheme mononitrosyl
diiron(II) complex [Fe (N-Et-HPTB)(NO)(DMF) ](BF ) (2) from
Q
different quadrupole splitting values (ΔE = 2.97, 3.33 mm s ) as
2
3
4 3
[
Fe
precedented redox controlled synthetic strategy (Scheme 1).
Complex 2 generates N O in a near-quantitative yield (~89%)
upon either electrochemical or chemical reduction and is the first
2 3 4 2
(N-Et-HPTB)(CH COS)](BF ) (1) using a unique and un-
2
II
7
example, to the best of our knowledge, of a [Fe {Fe(NO)} ]
species that mediates the reduction of NO to N O. Complex 1
2
3
(figure S1) was synthesized by addition of CH COSH into a
2
5,26
solution of H–N–Et–HPTB,
Et N and Fe(BF ) ·6H O in
3
4 2
2
MeCN. Reaction of 1 with one equivalent of (NO)(BF
4
) yielded 2.
+
Upon treatment of 1 with NO , the bridged thioacetate in 1 may
2
7,28
form CH
3
COSNO,
which, in turn, may undergo homolytic
•
cleavage to generate NO and CH COS (Scheme 1). Unlike the
weak bridging capacity of RSNO and RS , both CH COSNO and
3
CH COS may still remain bound to one of the two Fe(II) centers
3
•
•
3
via the oxygen atom and hence two different coordination
environments for the two Fe(II) centers may be maintained even
during the reaction course (Scheme 1). This asymmetry in the
coordination sphere of the Fe(II) centers along with the inherently
controlled release of NO in the reaction solution, may then favor
the selective formation of 2 (figure 1) along with (CH
3 2
COS)
(
figure S2). Structural characterization of 1 revealed two different
coordination environments for the two five-coordinate Fe(II)
centers with Fe2–O2 = 2.045 Å and Fe1–S1 = 2.431 Å while the
C=O and C–S distances of the bridged thioacetate are 1.219 Å and
1.687 Å respectively. Structural characterization of 2 revealed a
unprecedented mononitrosyl diiron(II) unit where one iron center
is coordinated by one NO and one DMF molecule, while the other
iron center is coordinated by two DMF molecules. Hexa-
coordination for both the Fe(II) centers is satisfied by four
1−
coordination sites from the deprotonated ligand, N-Et-HPTB , to
enforce pseudo-octahedral geometries around both the Fe(II)
centers in 2. Structural characterization of 2 was performed with
four different batches of single crystals (figure S3, table S1)
which showed different Fe-NO, N-O distances and Fe-N-O angles
of which only one set of metric parameters are discussed here
5
7
Figure 2. (a) Fe Mössbauer spectra of polycrystalline samples
of 2 at 80K. (b) EPR spectra of 2 in MeCN. Conditions: [2] =~2
mM, 9.302 GHz microwave frequency, 20.46 mW microwave
power, 5 G modulation amplitude, and 10.24 ms time constant.
(
figure 1, mononitrosyl4 in table S2). Such a situation has pre-
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spectroelectrochemistry experiments (figure 4), which show N
2
O
1
2
3
4
5
6
7
8
9
formation without any detectable intermediates. The band at
-1
~1655 cm (bound DMF) decreases while the band at ~ 1675
-1
cm (free DMF) increases during N
implying release of coordinated DMF upon reduction of NO to
O. Rapid production of N O was also confirmed by IR
2
O formation (figure S9), thus
N
2
2
spectroscopic analysis of the reaction headspace upon reduction
of 2 by 1 equivalent of cobaltocene (figure S10). Integration of
the N O N-N stretching band against a calibration curve generated
2
2 2
from known N O gas standards revealed ~ 89% yield of N O
(based on the conc. of 2) within ~5 min in the presence of
cobaltocene as the reductant (figure S10).
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While generation of N
unprecedented,
2
O by dinitrosyl diiron(II) complexes is not
a similar reaction mediated by a hitherto
unknown mononitrosyl diiron(II) complex, 2, is surely
noteworthy. The generation of by the mononitrosyl
2
0,22
Figure 3. Cyclic voltammetric traces for 2 (two consecutive scans
for each of three different scan rates) in DMF.
2
N O
diiron(II)complex, 2, may involve an intermolecular reaction
a result of the different coordination environments of the two
Fe(II) sites (figure S1). The Mössbauer spectrum of 2 shows two
quadrupole doublets in ~ 1:1 ratio with isomer shifts δ = 1.21 and
between two molecules of the initially reduced product,
II
8
[Fe {Fe(NO)} ], similar to the behavior reported very recently for
29
a mononuclear cobalt-nitrosyl complex and a mononuclear, high
−1
−1
8
30
0
.63 mm s (ΔE
Q
= 3.05 and 1.35 mm s ) corresponding to a
spin {Fe(NO)} complex. Alternatively, disproportionation of
II 8 II
7
Fe(II) center and a {Fe(NO)} unit, respectively (figure 2a).
Similar isomer shifts have been observed for the {Fe(NO)} units
two molecules of [Fe {Fe(NO)} ] to one unit each of [Fe ]
2
and
may also take place, of which the latter may yield
2
N O (scheme S1). In fact, intermolecular ligand rearrangement
7
8
[{Fe(NO)} ]
2
2
0
24
23
in 3,
6
and in some recently reported dinitrosyl complexes.
23
Complex 2 displays an EPR signal with g ~ 1.97 at 4K (figure 2b)
was previously shown to proceed rapidly after reduction of 5.
The confirmation of the actual mechanism and the possible roles
of protons, protic solvents or adventitious moisture in the whole
process may not be commented upon at this stage.
II
7
and is consistent with a [Fe {Fe(NO)} ] formulation for 2, where
29
an S = 1/2 system results from the antiferromagnetic (AF)
7
coupling of a high-spin Fe(II) ion (S = 2) with a {Fe(NO)} unit
(
S = 3/2). The EPR spectra for 2 at different temperatures are
shown in figure 2b. Together, the single crystal X-ray structure
determination, electronic absorption, IR, Mössbauer and EPR
spectroscopic measurements thus confirm the formulation of 2 as
II
7
a [Fe {Fe(NO)} ] species, which directly models the mononi-
trosyl intermediate in FNORs. In this case, AF coupling between
7
the high-spin Fe(II) and the {Fe(NO)} center is also observed.
Complex 2 shows an irreversible reduction at −1.02 V, which is
7
consistent with the reduction of an {Fe(NO)} unit to an
8
{
Fe(NO)} unit (figure 3). Similar redox events due to the
7
reduction of {Fe(NO)} units were observed at −1.1 V, −1.12 V
and −1.14 V (vs. Cp
+
2
Fe /Cp
2
Fe) for the previously reported
22
23
24
complexes, 4 , 5 and 6 , respectively. This reduction of the
7
8
{Fe(NO)} center to an {Fe(NO)} unit followed by
denitrosylation of 2 to form N O in turn generates a new redox
2
event. Based on the absence of this oxidation event at −0.58 V
when scanning the CV in the potential range of −0.32 to −0.82 V
(
figure S8), the new oxidation event at −0.58 V may be attributed
to the oxidation of the reaction product, presumably a ferrous oxo
II
II
bridged cluster (Fe –O–Fe ) type species. The reduction event at
0.68 V may then be related with the reduction of the now oxi-
−
dized reaction product. Such an assignment is comparable with a
previous report by one of us (Lehnert) where the generation of a
new feature at −0.56 V was assigned to the reaction product
2
2
(
ferrous oxo-bridged cluster) after denitrosylation of 4,
2
consistent with N O formation upon electrochemical reduction of
2
2
8
4
.
The oxidation of the {Fe(NO)} unit in the reverse scan to
7
regenerate the{Fe(NO)} unit is observed at −0.92 V for 2. The
scan-rate dependent return of the −1.02 V reduction peak is due to
the diffusion of 2 to the electrode surface.
Complex 2 as such does not mediate reduction of NO to N
2
O in
Figure 4. Generation of N
Conditions: [2] 5.3 mM; Hold -1.6V vs., Ag Wire; DCM, 0.1M
(Et N)(BF ). The complete IR spectrum is shown in figure S9.
2
O upon electrochemical reduction of 2.
solution, and thus is in agreement with previous observations for
20
22
3
, 4 and the dinitrosyl adducts of methane monooxygenase and
13
4
4
ribonucleotide reductase, which are also inefficient in NO
reduction. Interestingly, 2 was found to produce N O upon
In summary, the first functional analogue (2) of the
mononitrosyl diiron(II) species identified in the catalytic cycle of
FNORs has been synthesized. The long known problems
thwarting the preparation of a mononitrosyl diiron(II) complex
2
electrochemical reduction as well as upon reduction by
cobaltocene at room temperature. The generation of N O upon
2
electrochemical reduction of
2
was confirmed by IR
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housed within a symmetric ligand platform were avoided by using
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(12)
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1
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an innovative synthetic strategy. At present there is no alternative
synthetic route that may yield a pure mononitrosyl diiron(II)
complex. Complex 2 has been extensively characterized by a
combination of single crystal X-ray structure determination,
elemental analysis, and UV-Vis, IR, Mössbauer and EPR
spectroscopic methods. Finally, the mononitrosyl diiron(II)
(
(
(
complex (2) has been shown to generate N
2
O in a near
Kurtz, D. M., Jr. Dalton Trans. 2007, 4115-4121.
Berto, T. C.; Speelman, A. L.; Zheng, S.; Lehnert, N. Coord.
quantitative yield upon electrochemical as well as chemical
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Chem. Rev. 2013, 257, 244-259.
1
5
(14)
Blomberg, L. M.; Blomberg, M. A.; Siegbahn, P. M. J. Biol.
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thesis of a model mononitrosyl diiron(II) complex and its capa-
Inorg. Chem. 2007, 12, 79-89.
0
1
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(15)
Caranto, J. D.; Weitz, A.; Hendrich, M. P.; Kurtz, D. M. J. Am.
2
bility to generate N O are important in the context of bioinorganic
chemistry and may initiate further investigation into detailed syn-
thetic aspects and reactivity of similar complexes in future.
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ASSOCIATED CONTENT
Supporting Information
Hayashi, T.; Caranto, J. D.; Matsumura, H.; Kurtz, D. M., Jr.;
Moënne-Loccoz, P. J. Am. Chem. Soc. 2012, 134, 6878-6884.
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Karlin, K. D. Chem. Rev. 2002, 102, 1201-1234.
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21) Jiang, Y.; Hayashi, T.; Matsumura, H.; Do, L. H.; Majumdar,
(
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedure, X-ray, UV-Vis, IR, Mössbauer, CV,
(
GCMS and N
X-ray crystallographic data for 1 and 2 (4 different batches for 2)
cif)
2
O yield calculation data (PDF)
(
A.; Lippard, S. J.; Moënne-Loccoz, P. J. Am. Chem. Soc. 2014, 136,
12524-12527.
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Speelman, A. L.; Lehnert, N. J. Am. Chem. Soc. 2013, 135, 4902-4905.
23) Kindermann, N.; Schober, A.; Demeshko, S.; Lehnert, N.;
Meyer, F. Inorg. Chem. 2016, 55, 11538-11550.
Zheng, S.; Berto, T. C.; Dahl, E. W.; Hoffman, M. B.;
AUTHOR INFORMATION
Corresponding Author
(
(24)
Majumdar, A.; Lippard, S. J. Inorg. Chem. 2013, 52, 13292-
*
Email: lehnertn@umich.edu; icam@iacs.res.in
13294.
(25)
McKee, V.; Zvagulis, M.; Dagdigian, J. V.; Patch, M. G.;
Author Contributions
Reed, C. A. J. Am. Chem. Soc. 1984, 106, 4765-4772.
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manu-
script.
(26)
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Pal, N.; Majumdar, A. Inorg. Chem. 2016, 55, 3181-3191.
Stamler, J. S.; Singel, D. J.; Loscalzo, J. Science 1992, 258,
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28)
Rhine, M. A.; Sanders, B. C.; Patra, A. K.; Harrop, T. C. Inorg.
Chem. 2015, 54, 9351-9366.
29) Chuang, C.-H.; Liaw, W.-F.; Hung, C.-H. Angew. Chem.
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Notes
(
The authors declare no competing financial interest.
(30)
Confer, A. M.; McQuilken, A. C.; Matsumura, H.; Moënne-
ACKNOWLEDGMENT
Loccoz, P.; Goldberg, D. P. J. Am. Chem. Soc. 2017, 139, 10621-10624.
This work was supported by the grants 01(2804)/14/EMR-II
(CSIR, India) and SB/S1/IC-43/2013 (DST/SERB, India) awarded
to A. M. M.J. and N.P. acknowledge CSIR, India for a JRF and a
SRF respectively. C.K. acknowledges support from the Fonds der
Chemischen Industrie (Kekulé scholarship). N.L. acknowledges
funding from the National Science Foundation (NSF, CHE-
1
608331). X-ray data for 2 (mononitrosyl4) was collected at the
diffractometer funded by DBT (BT/01/CEIB/11/V/13) awarded to
Department of Organic Chemistry, IACS, Kolkata. M.J. & N.P.
acknowledge Ms. Manjistha Mukherjee of Dr. A. Dey group at
IACS for help in the GC experiments with diacetyldisulfide.
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