{Fe(NO)2}9 dinitrosyl iron complex acting as a vehicle for the NO radical

Article abstract of DOI:10.1021/jacs.6b11454

To carry and deliver nitric oxide with a controlled redox state and rate is crucial for its pharmaceutical/medicinal applications. In this study, the capability of cationic {Fe(NO)₂}⁹ dinitrosyl iron complexes (DNICs) [(^RDDB)Fe(NO)₂]⁺ (R = Me, Et, Iso; ^RDDB = N,N'-bis(2,6-dialkylphenyl)-1,4-diaza-2,3-dimethyl-1,3-butadiene) carrying nearly unperturbed nitric oxide radical to form [(^RDDB)Fe(NO)₂(?NO)]⁺ was demonstrated and characterized by IR UV-vis, EPR, NMR, and single-crystal X-ray diffractions. The unique triplet ground state of [(^RDDB)Fe(NO)₂(?NO)]⁺ results from the ferromagnetic coupling between two strictly orthogonal orbitals, one from Fe d₂² and the other a π^?_op orbital of a unique bent axial NO ligand, which is responsible for the growth of a half-field transition (ΔM_S = 2) from 70 to 4 K in variable-temperature EPR measurements. Consistent with the NO radical character of coordinated axial NO ligand in complex [(^MeDDB)Fe(NO)₂(?NO)]⁺, the simple addition of MeCN/H20 into CH₂Cl₂ solution of complexes [(^RDDB)Fe(NO)₂(?NO)]⁺ at 25 °C released NO as a neutral radical, as demonstrated by the formation of [S₅Fe(NO)₂]-from [S₅Fe(μ-S)₂FeS₅]^2-.

Full text of DOI:10.1021/jacs.6b11454

Communication
pubs.acs.org/JACS
{Fe(NO)2}9 Dinitrosyl Iron Complex Acting as a Vehicle for the NO
Radical
Chun-Hung Ke,† Chien-Hong Chen,*,‡ Ming-Li Tsai,*,§ Hsuan-Chi Wang,† Fu-Te Tsai,†
Yun-Wei Chiang,† Wei-Chih Shih,† D. Scott Bohle,# and Wen-Feng Liaw*,†
†Department of Chemistry and Frontier Research Center of Fundamental and Applied Science of Matters, National Tsing Hua
University, Hsinchu 30013, Taiwan
‡Department of Medical Applied Chemistry, Chung Shan Medical University, and Department of Medical Education, Chung Shan
Medical University Hospital, Taichung 40201, Taiwan
§Department of Chemistry, National Sun Yat-sen University, Kaohsiung 80424, Taiwan
#Department of Chemistry, McGill University 801 Sherbrooke Street West, Montreal, Quebec H3A2K6, Canada
S
* Supporting Information
carriers, researchers have tested an extensive series of NO-
ABSTRACT: To carry and deliver nitric oxide with a
controlled redox state and rate is crucial for its
pharmaceutical/medicinal applications. In this study, the
capability of cationic {Fe(NO)2}9 dinitrosyl iron com-
plexes (DNICs) [(RDDB)Fe(NO)2]+ (R = Me, Et, Iso;
RDDB = N,N′-bis(2,6-dialkylphenyl)-1,4-diaza-2,3-dimeth-
yl-1,3-butadiene) carrying nearly unperturbed nitric oxide
radical to form [(RDDB)Fe(NO)2(•NO)]+ was demon-
strated and characterized by IR, UV−vis, EPR, NMR, and
single-crystal X-ray diffractions. The unique triplet ground
state of [(RDDB)Fe(NO)2(•NO)]+ results from the
ferromagnetic coupling between two strictly orthogonal
release compounds in preclinical studies/trials in order to
modulate the relative stability as well as the releasing rates (e.g.,
SNP, GTN, PABA/NO, Spermine-NONOate, SNAP, DETA/
NONOate, GSNO) (Table S1).6,7 Interestingly, DNICs
present exceedingly diverse reactivities resulting from the
non-innocent character of Fe-NO bonding interactions, such as
S-nitrosylation, N-nitrosylation, nitrite/nitrate activation, H2S
storage, and the cellular permeation of DNICs/Roussin’s red
esters (RREs) for subsequent protein S-nitrosylation,8,9 also
serving as pro-drugs capable of controlled delivery of NO to
biological targets.10 Despite the diverse reactivities of DNICs
which have been demonstrated,11 the possibility/capability of
{Fe(NO)2} core serving as a vehicle to carry and deliver
unperturbed NO radical is still unknown.12 In this work, we
synthesize and characterize NO-radical vehicle {Fe(NO)2}9
DNICs [(RDDB)Fe(NO)2(•NO)][BF4] (R = Me, Et, Iso;
RDDB = N,N′-bis(2,6-dialkylphenyl)-1,4-diaza-2,3 dimethyl-
1,3-butadiene) and control its release triggered by solvents
(MeCN/H2O).
2
orbitals, one from Fe dz and the other a π*op orbital of a
unique bent axial NO ligand, which is responsible for the
growth of a half-field transition (ΔMS = 2) from 70 to 4 K
in variable-temperature EPR measurements. Consistent
with the NO radical character of coordinated axial NO
ligand in complex [(MeDDB)Fe(NO)2(•NO)]+, the simple
addition of MeCN/H2O into CH2Cl2 solution of
complexes [(RDDB)Fe(NO)2(•NO)]+ at 25 °C released
NO as a neutral radical, as demonstrated by the formation
of [S5Fe(NO)2]− from [S5Fe(μ-S)2FeS5]2−.
Addition of 1 equiv of [Fe(CO)2(NO)2] to the THF
R
solution of DDB (R = Me, Et, Iso) led to the formation of
four-coordinate {Fe(NO)2}10 DNICs [(MeDDB)Fe(NO)2] (1-
Me) ([(EtDDB)Fe(NO)2] (1-Et) and [(IsoDDB)Fe(NO)2] (1-
Iso)) characterized by single-crystal X-ray diffractions (Figure
S1).13 As shown in Scheme 1a and Figure S2, oxidation of
{Fe(NO)2}10 1-Me by [Cp2Fe][BF4] in CH2Cl2 afforded the
nonclassical five-coordinate {Fe(NO)2}9 [(MeDDB)Fe(NO)2]-
[BF4] (2-Me) with the F atom of [BF4]− anion weakly
coordinated to Fe metal (Fe---F = 2.28 Å), characterized by IR
(νNO 1834 s, 1769 s cm−1 (CH2Cl2)) and single-crystal X-ray
diffraction (Figure S3). In a similar fashion, oxidation of
{Fe(NO)2}10 DNIC 1-Me by [Cp2Fe][BF4] in CH3CN
afforded the five-coordinate {Fe(NO)2}9 [(MeDDB)Fe-
(NO)2(CH3CN)][BF4] (4) with CH3CN coordinated to
{Fe(NO)2}9 core, characterized by IR (νNO 1801 s, 1724 s
cm−1 (CH3CN)) and an EPR g-value (gav = 2.019 at 77 K)
(Scheme 1c),14 compared to the previous reports of Fe-based
riven by the versatile pharmaceutical/clinical applications
Dof nitric oxide (NO) related to vasodilation, smooth
muscle relaxation, inhibition of platelet aggregation, memory
formation/learning processes in neurons, and cellular pro-
liferation/differentiation/apoptosis,1,2 the fundamental inves-
tigations for storage and transport of highly reactive NO (with a
physiological half-life <5 s) have attracted widespread interest
in the past decades.2 One of the key challenges of delivering
NO for exerting physiological functions is to preserve the
functionality of NO in complex biological environments before
reaching the designated proteins/molecules.3 Although NOS
isoforms are widely distributed, nature has evolved to utilize
prevalent amino acid residues and abundant transition metal
iron for storage and transport of NO in the forms of S-
nitrosothiols (RSNOs) and dinitrosyl iron complexes (DNICs),
respectively.4,5 Inspired by the diverse range of natural NO
Received: November 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b11454
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Journal of the American Chemical Society
Communication
(NO)2}9 core hindering NO radical binding. Interestingly,
upon CH2Cl2 solution of complex 3-Me under vacuum at room
temperature for 1 min, the IR νNO stretching frequencies shift
from (1846 s, 1771 vs, 1753 sh cm−1) to (1834 s, 1771 s cm−1)
via (1846 s, 1834 s, 1771 vs, 1753 sh cm−1) indicating the
transformation of 3-Me to 2-Me under vacuum via the mixture
of 3-Me and 2-Me, as shown in Figure S5 (a → b→c). The
subsequent addition of NO gas into the CH2Cl2 solution of 2-
Me reformed complex 3-Me (Figure S5 (c→ d)). These results
suggest the IR νNO stretching frequency 1753 cm−1 (CH2Cl2) is
mainly due to the “arrested” NO radical which is weakly bound
and severely bent in the {Fe(NO)2}9 core. Isotopic experiments
(15NO) led to the complete scrambling of the label. To further
elucidate the NO-releasing ability of complexes 3-Me and 3-Et,
addition of MeCN/H2O to the complexes 3-Me (or 3-Et) was
conducted, respectively. Addition of 1 equiv of MeCN to
CH2Cl2 solution of complex 3-Me (5 mM) at 25 °C yielded
complex 4 (IR νNO stretching frequencies shifting from (1846 s,
1771 vs, 1753 sh) to (1801 s, 1724 s) cm−1 (CH2Cl2))
accompanied by the release of NO, probed by [S5Fe(μ-
S)2FeS5]2− producing the known [S5Fe(NO)2]−.17 The half-life
(32 min) of NO release was measured by UV−vis (based on
absorption band 620 nm (ε = 202 M−1 cm−1)) upon 1 equiv
(or 2/4/10 equiv (SI Experimental Section)) of MeCN added
Scheme 1
oxidation of {Fe(NO)2}10 [(sparteine)Fe(NO)2], yielding the
unstable four-coordinate {Fe(NO)2}9 [(sparteine)Fe(NO)2]-
[BF4] with ΔνNO shift 125 cm−1 and EPR gav = 2.032.15,16
Inspired by the formation of complex 4 with {Fe(NO)2}9
core coordinated by α-diimine and CH3CN, we injected dry
NO (1.5-fold excess) into the CH2Cl2 solution of complex 2-
Me (complex 2-Et) with a gastight syringe, as shown in Scheme
1b. The reaction solution was stirred under N2 atmosphere at
ambient temperature for 5 min. The color of the reaction
solution changed from brown to dark green. The IR νNO
stretching frequencies shifting from (1834 s, 1769 s) to (1846 s,
1771 vs, 1753 sh) cm−1 indicate the formation of [(MeDDB)-
Fe(NO)2(•NO)][BF4] (3-Me) ([(EtDDB)Fe(NO)2(•NO)]-
[BF4] (3-Et)), characterized by IR, UV−vis, EPR, NMR, and
single-crystal X-ray diffraction (Figure 1).
into CH2Cl2 solution (5 mM) of complex 3-Me at 25 °C (t1/2
=
42 min for addition of 1 equiv of H2O into CH2Cl2 solution (5
mM) of complex 3-Me at 25 °C).
Single-crystal X-ray structures of complexes 3-Me and 3-Et
show the isostructural analogues (Figure 1). The average
equatorial Fe−N(NO) bond distance of 1.688(2) Å (Fe(1)−
N(1) 1.701(2) Å, and Fe(1)−N(2) 1.676(2) Å) and the
average N−O bond length of 1.163(2) Å (N(1)−O(1)
1.159(2) Å and N(2)−O(2) 1.168(2) Å) observed in complex
3-Me (1.690(2) Å and 1.156(3) Å observed in complex 3-Et,
respectively) are consistent with those of other {Fe(NO)2}9
DNICs.15,18 We notice the axial N(3)−O(3) bond length of
1.141(2) Å for complex 3-Me and N(3)−O(3) bond length of
1.136(3) Å for complex 3-Et are comparable to that (1.15 Å) of
free NO radical.19 The significantly longer axial Fe(1)−N(3)
bond length of 2.096(2) Å for 3-Me and Fe(1)−N(3) bond
length of 2.062(2) Å for 3-Et, in contrast to the average Fe−
N(NO) bond distance falling in the range of 1.64−1.70 Å for
{Fe(NO2)}9 DNICs,18 implicate the axial N(3)O(3) radical is
“arrested” by the {Fe(NO2)}9 core. It is noted that the
diamagnetic {Fe(NO)3}10 trinitrosyl iron complex (TNIC)
[(IMes)Fe(NO)3][BF4] bound by three nearly equivalent NO
ligands with average N−O bond distance of 1.143(6) Å and
average Fe−N(NO) bond distance of 1.688(5) Å were reported
by Darensbourg and other groups.12 Of importance, in contrast
to the average Fe−N−O bond angle of 173.5° obtained in
TNIC,12 the Fe(1)−N(3)−O(3) bond angle of 120.1° in
complex 3-Me and Fe(1)−N(3)−O(3) bond angle of 123.0° in
complex 3-Et were observed.
Figure 1. ORTEP drawing and labeling scheme of [(RDDB)Fe-
(NO)2(•NO)]+ ((a) R = Me (3-Me), (b) R = Et (3-Et)) with the
thermal ellipsoid drawn at 50% probability. Hydrogen atoms are
omitted for clarity. Selected bond lengths (Å) and angles (deg): (a)
Fe(1)−N(1) 1.701(2), Fe(1)−N(2) 1.676(2), Fe(1)−N(3) 2.096(2),
N(1)−O(1) 1.159(2), N(2)−O(2)1.168(2), N(3)−O(3) 1.141(2),
Fe(1)−N(1)−O(1) 164.3(1), Fe(1)−N(2)−O(2) 169.9(2), Fe(1)−
N(3)−O(3) 120.1(1). (b) Fe(1)−N(1) 1.683(2), Fe(1)−N(2)
1.698(2), Fe(1)−N(3) 2.062(2), N(1)−O(1) 1.155(3), N(2)−O(2)
1.158(3), N(3)−O(3) 1.136(3), Fe(1)−N(1)−O(1) 167.1(2),
Fe(1)−N(2)−O(2) 163.6(2), Fe(1)−N(3)−O(3) 123.0(2).
In contrast to the diamagnetic {Fe(NO)3}10 TNIC,12 EPR
spectrum of complex 3-Me exhibits a rhombic signal gav = 2.019
and a weak half-field signal at g = 3.99 at 77 K (Figure 2). The
formally forbidden transition due to ΔMs = 2 is detected at
approximately 1700 G, consistent with the expected transition.
The intensity of the half-field resonance increases with
decreasing temperature (Figure 2b), in line with the typical
temperature-dependent changes of EPR signal intensity for a
molecule with triplet ground state.20 Presumably, the weak
magnetic coupling (dipolar coupling) between the {Fe-
In the same reaction condition, injection of NO into the
CH2Cl2 solution of the more steric IsoDDB-containing analogue
[(IsoDDB)Fe(NO)2][BF4] (2-Iso) displaying the IR νNO
stretching frequencies at 1847 s, 1773 vs, 1742 sh cm−1
suggested the formation of [(IsoDDB)Fe(NO)2(•NO)][BF4]
(Figure S4). In contrast, addition of NO (1.5-fold excess) to
[(CycDDB)Fe(NO)2][BF4] (CycDDB = N,N′-dicyclohexylethy-
lenediimine) (2-Cyc) did not yield the expected [(CycDDB)-
Fe(NO)2(•NO)][BF4]. Presumably, it is mainly attributed to
CycDDB promoting more electronic donation to the {Fe-
B
DOI: 10.1021/jacs.6b11454
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Journal of the American Chemical Society
Communication
Figure 2. Variable-temperature EPR spectra of complex 3-Me: (a) gav
= 2.019 (g1 = 2.036, g2 = 2.019, g3 = 2.004) from 70 to 4 K and (b) the
half-field signal at g = 3.99 from 70 to 4 K in CH2Cl2.
1
1
(NO)2}9center (S = /2) and NO radical (S = /2) of complex
3-Me rationalizes the weak ferromagnetic coupling, leading to
triplet ground state also supported by the magnetic moment of
μeff = 2.085 μB obtained from Evans’s method at 183 K.21 At
low temperatures, the zero-field splitting of the resonance is
observed and value of D ≈ 0.0022 cm−1 and gav = 2.019 are
obtained based on a triplet-state low-temperature EPR
theoretical analysis using EasySpin22 (Figure S6). Furthermore,
the J value is determined as (0.58
0.05) cm−1 from
theoretical fitting of intensity variation of EPR signal as a
Figure 3. Bonding and vibrational analysis obtained from DFT
calculations of 3-Me. (a) Spin density distribution of DFT-optimized
3-Me. (b) Representative bonding interactions between {Fe(NO)2}9
core and axial NO of 3-Me. The labels “ip” and “op” of axial NOπ*
orbitals refer to “in-plane” and “out-of-plane”, respectively; the planes
for the notations are defined by axial Fe−N−O. (c) Pictorial
representation of three normal modes associated with axial and
equatorial νNO stretching vibrations derived from DFT calculations.
function of temperatures,20 as shown in Figure S7.
DFT calculations were performed to gain an insight into the
electronic structure and bonding interactions of 3-Me as well as
rationalize the unusual long axial Fe−N(NO) bond distance.11,18
The DFT structure was further verified spectroscopically by the
spin-Hamiltonian parameters derived from the experimental
EPR spectra (as detailed in Figure 2) and IR νNO stretching
frequencies.24 Although the calculated IR νNO stretching
frequencies (1893, 1805, 1793 cm−1) are slightly overestimated
by ∼40 cm−1, the characteristic small separation between first
two νNO stretching frequencies (ΔνNO1(exp) = 18 cm−1,
ΔνNO1(calc) = 13 cm−1) and big separation between the last
two νNO stretching frequencies (ΔνNO2(exp) = 75 cm−1,
ΔνNO2(calc) = 88 cm−1) are successfully reproduced. The spin
density distribution shown in Figure 3a clearly indicates the
antiferromagnetic coupling interactions between Fe center and
two equatorial NO ligands evidenced by positive and negative
spin density on the Fe center and two equatorial NO ligands,
respectively.
contribution from one of the equatorial NO ligands. The 1771
and 1846 cm−1 IR vibrational modes are best described as well-
characterized asymmetric and symmetric vibrational modes of
two equatorial NO ligands of DNICs, respectively, where both
vibrational modes mix with a minor contribution from axial νNO
stretching.
In conclusion, we have successfully demonstrated that
{Fe(NO)2}9 DNICs is capable of acting as a NO radical
vehicle and are easily prepared by reacting NO(g) with
cationic{Fe(NO)2}9 [(RDDB)Fe(NO)2]+. In contrast to the
reported TNICs,12 the [(RDDB)Fe(NO)2(•NO)]+ exhibits an
unusual long Fe−N(NO) (axial) bond distance (∼2.096 Å) as
well as unprecedented triplet ground state resulting from
In addition, the orbital energy diagram and population
analysis of key orbitals associated with Fe and equatorial NO
ligands (Figure S8) also support the description of electronic
structure of (MeDDB)Fe(NO)2 fragment in 3-Me as
{FeIII(NO−)2}9, which is consistent with previous DFT
computational23 and valence-to-core X-ray emission spectro-
scopic studies.24 On the other hand, the axial NO ligand
possess positive spin density (ρNO (axial) ≈ 1.15) and
predominantly localized on π*op orbital. The orthogonality
2
ferromagnetic coupling between two orthogonal orbitals (Fe dz
orbital and π*op orbital of axial NO ligand). The unique
geometry and electronic structure facilitates a fast NO radical
release triggered by simply adding MeCN/H2O to replace the
weakly coordinating axial NO ligand without compromising the
structural integrity of {Fe(NO)2}9 [(RDDB)Fe(NO)2]+ vehicle.
A combination of well-established strategies of the targeted
drug delivery (liposome, micelle, biodegradable polymers/
particles, etc.) and the exceptional ability of {Fe(NO)2}9 motif
for storage and release NO radical could be promising
directions for treating cardiovascular disease and malignant
tumors.
Me
2
between the Fe dz orbital of ( DDB)Fe(NO)2 fragment and
π*op orbital of coordinated axial NO ligand (Figure 3b) derived
from the analysis of bonding molecular orbitals α110 and α115
(Figure S8) provides a plausible pathway for a ferromagnetic
coupling interaction and the orbital rationales for the
observation characteristic EPR half-field transition indicating
triplet ground state of 3-Me. The normal modes of three νNO
stretching frequencies observed in the CH2Cl2 solution of
complex 3-Me are tentatively assigned from the DFT
vibrational calculations (Figure 3c). Consistent with the
preceding assignment, the 1753 cm−1 IR vibrational mode is
composed of major axial NO stretching coupled with a minor
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b11454.
■
S
Experimental details, Tables S1−S3, and Figures S1−S8
(PDF)
C
DOI: 10.1021/jacs.6b11454
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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93.
X-ray crystallographic files for structure determinations
of [(MeDDB)Fe(NO)2(•NO)][BF4], [(EtDDB)Fe-
(NO)2(•NO)][BF4], [(MeDDB)Fe(NO)2][BF4],
[(IsoDDB)Fe(NO)2][BF4], [(MeDDB)Fe(NO)2],
[(EtDDB)Fe(NO)2], and [(IsoDDB)Fe(NO)2](CIF)
AUTHOR INFORMATION
■
Corresponding Authors
*wfliaw@mx.nthu.edu.tw
*mltsai@mail.nsysu.edu.tw
*cchwind@csmu.edu.tw (CHC)
(15) Hung, M.-C.; Tsai, M.-C.; Lee, G.-H.; Liaw, W.-F. Inorg. Chem.
2006, 45, 6041−6047.
ORCID
Yun-Wei Chiang: 0000-0002-2101-8918
Wen-Feng Liaw: 0000-0001-9949-8344
(16) Chen, C.-H.; Ho, Y.-C.; Lee, G.-H. J. Organomet. Chem. 2009,
694, 3395−3400.
(17) Tsai, M.-L.; Chen, C.-C.; Hsu, I.-J.; Ke, S.-C.; Hsieh, C.-H.;
Chiang, K.-A.; Lee, G.-H.; Wang, Y.; Chen, J.-M.; Lee, J.-F.; Liaw, W.-
F. Inorg. Chem. 2004, 43, 5159−5167.
Notes
The authors declare no competing financial interest.
(18) Tsou, C.-C.; Tsai, F.-T.; Chen, H.-Y.; Hsu, I.-J.; Liaw, W.-F.
Inorg. Chem. 2013, 52, 1631−1639.
ACKNOWLEDGMENTS
■
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(20) (a) Abe, M. Chem. Rev. 2013, 113, 7011−7088. (b) Lu, C. C.;
We gratefully acknowledge financial support from the Ministry
of Science & Technology of Taiwan. The authors thank Dr.
Chang-Chih Hsieh, Miss Pei-Lin Chen, and Mr. Ting-Shen
Kuo for single-crystal X-ray structural determinations. We also
thank NCHC for their support on the software applied in this
work.
Bill, E.; Weyhermuller, T.; Bothe, E.; Wieghardt, K. J. Am. Chem. Soc.
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DOI: 10.1021/jacs.6b11454
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