Dioxygen-Derived Nonheme Mononuclear FeIII(OH) Complex and Its Reactivity with Carbon Radicals

Article abstract of DOI:10.1021/jacs.9b03329

A new tetradentate, monoanionic, mixed N/O donor ligand (BNPA^Ph2O^-) with second coordination sphere H-bonding groups has been synthesized for stabilization of a terminal Fe^III(OH) complex. The complex Fe^II(BNPA^Ph2O)(OTf) (1) reacts with O₂ to give a mononuclear terminal Fe^III(OH) complex, Fe^III(OH)(BNPA^Ph2O)(OTf) (2), both of which were characterized by X-ray diffraction, electrospray ionization mass spectrometry, UV-vis, ¹H and ¹⁹F nuclear magnetic resonance, ⁵⁷Fe M?ssbauer, and electron paramagnetic resonance spectroscopies. Treatment of 2 with carbon radicals (Ar₃C·) gives Ar₃COH and the Fe^II complex 1, in direct analogy with the elusive radical "rebound" process proposed for nonheme iron enzymes.

Full text of DOI:10.1021/jacs.9b03329

Communication
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III
Dioxygen-Derived Nonheme Mononuclear Fe (OH) Complex and Its
Reactivity with Carbon Radicals
Vishal Yadav, Jesse B. Gordon, Maxime A. Siegler, and David P. Goldberg*
Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218, United States
*
S Supporting Information
Scheme 1. Selective Rebound Step in Different Nonheme
Iron Enzymes
ABSTRACT: A new tetradentate, monoanionic, mixed
N/O donor ligand (BNPAPh2O ) with second coordina-
tion sphere H-bonding groups has been synthesized for
−
III
stabilization of a terminal Fe (OH) complex. The
II
Ph2
complex Fe (BNPA O)(OTf) (1) reacts with O to
2
III
give a mononuclear terminal Fe (OH) complex,
Fe (OH)(BNPA O)(OTf) (2), both of which were
characterized by X-ray diffraction, electrospray ionization
III
Ph2
1
19
mass spectrometry, UV−vis, H and F nuclear magnetic
5
7
resonance, Fe Mossbauer, and electron paramagnetic
̈
resonance spectroscopies. Treatment of 2 with carbon
II
radicals (Ar C·) gives Ar COH and the Fe complex 1, in
3
3
direct analogy with the elusive radical “rebound” process
proposed for nonheme iron enzymes.
ioxygen activation at nonheme iron centers is of
D
fundamental importance for a range of enzymatic and
1
−3
synthetic catalysts.
An archetypal example is seen in the
alpha-ketoglutarate (α-KG) dependent nonheme iron enzyme
the control of sulfur versus OH rebound in IPNS, as well as
more generally, the factors that influence Fe (OH) reactivity
in hydroxylases and halogenases. We recently described the
taurine dioxygenase (TauD). The mechanism of TauD
III
II
involves the binding of O to Fe , followed by electron
2
II
transfer from the Fe /α-KG unit to cleave the O−O bond and
observation of C−O bond formation with a porphyrinoid,
IV
IV
IV
27
III
give a ferryl (Fe (O)) intermediate. The Fe (O) species then
formally Fe (OH) complex, and a nonheme Fe (OMe)
III
28
cleaves the substrate C−H bond to give an Fe (OH) complex
and substrate radical, which recombines via an “oxygen
rebound” mechanism to give the final hydroxylated product
complex, in reactions with carbon radicals. However,
reactivity between an isolated nonheme Fe (OH) complex
III
and a carbon radical, in direct analogy with the enzymatic
processes described in Scheme 1, has not been achieved in any
II
4−8
and the reduced Fe active site (Scheme 1).
A related class
29
of nonheme Fe enzymes are the α-KG-dependent halogenases,
which exhibit an interesting mechanistic divergence at the
ferric hydroxide stage, in which a coordinated halide, or other
synthetic system to date. Such studies are hampered by the
inherent difficulty of synthesizing well-defined, mononuclear
III
Fe (OH) complexes, which arises in part from their tendency
−
−
−
−
9−13
30,31
pseudohalide X (e.g., X = Cl , Br , N , NO ),
can
to convert to O(H)-bridged, diferric species.
Only a
3
2
preferentially recombine with the substrate radical in lieu of the
relatively small number of mononuclear, nonheme, terminal
III
hydroxide group. Recent efforts to model the latter processes
Fe (OH) complexes have been structurally character-
1
4−18
32−40
have been described.
The factors that may bias an
ized.
III
−
−
Fe (OH)(X) center toward rebound of X versus OH are
still not well understood. A similar conundrum arises in the
proposed mechanism for isopenicillin N synthase (IPNS), in
which a nascent carbon radical recombines with a ligated sulfur
Herein we describe a new tetradentate ligand that was
designed to fulfill three criteria: (1) stabilization of an
III
II
Fe (OH) unit, (2) O activation at an Fe center, and (3)
2
inclusion of an open site cis to the OH group. This ligand led
19−21
III
−
to the isolation of an Fe (OH) complex that was obtained via
center instead of the OH ligand.
activation of O . We can react this complex with exogenous
Our research group has made significant efforts toward
2
carbon radicals to give the hydroxylated product and the
reduced ferrous form, providing a direct analog of the radical
constructing inorganic analogs of sulfur-ligated thiol dioxyge-
2
2−26
nases,
a subclass of nonheme Fe dioxygenases. Part of
“
rebound” step in nonheme iron oxygenases.
these efforts has involved discerning the general structural
II
requirements for synthesizing mononuclear Fe complexes that
facilitate O activation. In the course of this work, we have also
Received: April 2, 2019
2
become interested in examining the factors that contribute to
©
XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b03329
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Ph2
II
−1
1
The new tetradentate ligand BNPA OH, and Fe complex
cm ). The H nuclear magnetic resonance (NMR) spectrum
II
Ph2
Fe (BNPA O)(OTf) (1), were prepared as shown in
Scheme 2. The neopentylamine substituents were included
of 1 in CD CN reveals paramagnetic peaks from +100 to −20
ppm (Figure 2), indicative of a high-spin (hs) Fe complex.
3
II
Scheme 2. Synthesis of BNPAPh2OH and Complex 1
1
Figure 2. H NMR spectra (CD CN) of 1 (top), 2 (middle), and
3
reaction of 2 with excess (Ph C) (bottom) after removal of THF and
3
2
4
1
as potential stabilizing H-bond donors, a strategy that has
been used by others to stabilize metal/oxygen spe-
dissolution in CD CN.
3
3
3,34,36,42−45
cies.
In addition, an anionic alkoxide donor was
installed to facilitate O activation. Metalation with Fe
followed by crystallization gave yellow-green crystals of 1
suitable for X-ray diffraction (XRD). The structure of 1
Figure 1) reveals a 5-coordinate (τ = 0.67) mononuclear
1
9
II
The F NMR spectrum in CD CN shows a sharp peak at −78
3
2
ppm, whereas a broad peak at −74 ppm is observed in
tetrahydrofuran (THF)-d (Figure S29), indicative of free and
8
bound triflate ligand, respectively. These data suggest the
46
(
−
CD CN displaces the OTf ligand and the H-bonded site is
3
iron(II) complex, with a triflate ligand occupying the fifth site.
The neopentyl amine groups are oriented toward the triflate,
forming two hydrogen bonds with N1(H)−O2 = 3.026(2) Å
and N5(H)−O2 3.116(2) Å.
relatively labile, which would allow for O binding. Mo
̈
ssbauer
2
spectroscopy on solid 1 at 80 K shows a sharp quadrupole
−
1
doublet with δ = 1.03 and |ΔE | = 2.42 mm s , also typical of
Q
II
a hs-Fe center (Figure S16).
Complex 1 is pale yellow in CH CN, with UV−vis maxima
Complex 1 was reacted with excess, dry O gas in CH CN at
3
2
3
at 323 nm (ε = 9550 M− cm ) and 420 nm (ε = 990 M
1
−1
−1
23 °C, causing an immediate color change from pale yellow to
dark orange, with new UV−vis features appearing at 315 nm (ε
−
1
−1
−1
−1
=
(
9000 M cm ), 365 nm (ε = 2400 M cm ), and 440 nm
−
1
−1
ε = 950 M cm ). The new dark orange species is air-stable,
and the CH CN can be removed in vacuo to give an orange
3
solid, which was dissolved in toluene/THF and layered with
pentane to afford orange crystals in 24 h that were suitable for
XRD.
III
Analysis by XRD revealed a six-coordinate Fe (OH)
III
Ph2
complex, Fe (BNPA O)(OH)(OTf) (2) (Figure 1). A
terminal hydroxide ligand occupies the hydrogen bonding
site, and the axial triflate ligand of 1 has shifted to an equatorial
−
position cis to the OH ligand in 2. The hydroxide ligand
forms two intramolecular hydrogen bonds with the neopentyl
amine substituents, with N1(H)−O2 = 2.831(3) and N5(H)−
O2 = 2.857(2) Å. There is a third H-bonding interaction
−
−
between the OH and the OTf ligands, with O2(H)−O5 =
2
.832(1) Å. The Fe−O(H) bond length is 1.880(1)Å, in the
range of other H-bonded and non-H-bonded Fe (OH)
III
32−36
complexes.
However, a proper comparison with a non-
H-bonded analog of 2 is currently not available. The Fe−N
py
and Fe−N
distances are shorter by 0.1−0.2 Å when
amine
II
compared to the Fe analog 1, and the Fe−O1 distance is also
contracted by 0.05 Å.
Complex 2 shows paramagnetic peaks in the H NMR
spectrum from 150 to 1 ppm (Figure 2). The F NMR
1
1
9
spectrum for 2 in CD CN shows a sharp peak at −74.6 ppm,
3
−
−
which corresponds to free OTf , and indicates the OTf ligand
is likely displaced by solvent. In contrast, the same spectrum in
the more weakly coordinating THF-d shows no peaks from
8
−
+
200 to −200 ppm, consistent with OTf remaining
coordinated (Figure S30). The EPR spectrum (20 K) reveals
Figure 1. Displacement ellipsoid plots (50% probability level) for 1
and 2 at 110(2) K. Hydrogen atoms (except for N−H and O−H)
have been omitted for clarity.
signals at g = 9.01, 4.23, which is consistent with an S = 5/2
B
DOI: 10.1021/jacs.9b03329
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
ferric ion (Figure S15). Analysis of a crystalline sample of 2 by
temperature. However, at temperatures as low as −90 °C,
only the formation of 2 was observed as seen at 23 °C, and at
lower temperatures (e.g., −105 °C) no reaction occurs.
The similarity of complex 2 to the enzymatic species shown
in Scheme 1 motivated us to examine its reactivity with
Mo
doublet which can be fit with δ = 0.47 mm s and |ΔE | =
̈
ssbauer spectroscopy at 80 K reveals a broad quadrupole
−
1
Q
−
1
0
.97 mm s (Figure S17). The broadened spectrum comes
from 2 likely being in an intermediate spin relaxation
4
7,48
regime.
The Mo
̈
ssbauer spectrum of 2 at 5 K shows a 6
carbon-based radicals. Addition of Ph C· to 2 in THF at 23 °C
3
line hyperfine splitting pattern which is expected for a high-
causes a color change from dark orange to yellow over 4 h. The
III
1
spin Fe species (Figure S18).
H NMR spectrum shows complete loss of 2, and the
Density functional theory (DFT) was employed to obtain
optimized structures for 1 and 2 at the BP86/6-311G*/6-
appearance of peaks for 1 (Figure 2). A new peak at δ 5.50
ppm was also formed, arising from the alcohol (Ph COH) in
3
3
1G* (for C and H atoms) level of theory. These optimized
8
4% (±3) yield (Scheme 4).
structures matched well with the structures from XRD for 1
and 2, and were then used for the calculation of Mossbauer
spectroscopic parameters. The calculations gave δ = 1.05 and
Changing to the more electron-rich (p-OMe-C H ) C· (1
6
4 3
̈
equiv) causes faster conversion (∼45 min) of 2 to 1 as seen by
1
H NMR spectroscopy. Quantification of (p-OMe-
−
1
|
ΔE | = 2.61 mm s for 1, and δ = 0.47 and |ΔE | = 1.42 mm
Q
Q
C H ) COH gives a yield of 87% (±2) (Scheme 4), consistent
−
1
6
4 3
s
for 2. These parameters are in reasonable agreement with
with 1:1 stoichiometry between 2 and the radical.
experiment for the solid-state samples.
The formation of the products (p-X-C H ) COH (X = H,
6
4 3
Production of 2 by addition of excess O in acetonitrile
2
OMe) was also confirmed by EI-MS analysis (Figures S23 and
followed by electrospray ionization mass spectrometry (ESI-
1
8
18
2
4). Incorporation of OH into 2 by exchange with H2
was quantitative, and reaction of (p-X-C H ) C· (X = H,
6 4 3
O
MS) reveals the major peak at m/z = 636.89 (positive ion
+
mode), corresponding to [2−OTf] . In comparison, the use of
1
8
1
8
OMe) with O-labeled 2, led to a two unit shift in m/z by EI-
MS analysis (Figures S25 and 26, O incorporation, 99%).
isotopically labeled O leads to the major peak shifted by +2
2
18
18
units to m/z = 638.85. Addition of excess H2 O to 1 in
These results indicate that there is direct transfer of the OH
ligand to the carbon radicals.
The reaction with the p-OMe derivative was monitored by
CH CN, followed by exposure to excess, natural abundance
3
O , does not lead to any shift in the major peak at m/z 636.85.
2
1
8
These O-labeling experiments show that the hydroxide ligand
must originate from dioxygen.
5
7
Mo
̈
ssbauer spectroscopy (Figure 3). The spectrum for Fe-
−
1
labeled complex 1 in 2-MeTHF (80 K) gives δ = 1.14 mm s
A suggested mechanism is given in Scheme S1. Initial
−
1
III
and |ΔE | = 2.24 mm s (Figure 3a). The spectrum for
1
binding of O gives an Fe (superoxo) species that then leads
Q
2
−
complex 2 (Figure 3b) is broad, with δ = 0.47 mm s and
to a peroxo-bridged dimer, followed by homolytic O−O
−
1
IV
|ΔE | = 1.24 mm s (see Figure S19 for fitting details).
cleavage to give an Fe (O) species. The latter species then
Q
Reaction between 2 and (p-OMe-C H ) C· gives a quadrupole
abstracts hydrogen from an exogenous source (e.g., solvent) to
6
4 3
−
1
−1
doublet matching 1 (δ = 1.14 mm s ; |ΔE | = 2.23 mm s )
give 2. Precedent for this mechanism is described for both
Q
34,49−51
(
Figure 3c), which accounts for 90% of the total Fe.
heme and nonheme Fe and Mn complexes.
Carrying
Electrochemical analysis of 2 shows a reversible wave in the
out the reaction of 1 with O in the presence of excess 9,10-
2
cyclic voltammogram with E = −0.69 V (ΔE = 170 mV) vs
dihydroanthracene, a potential H atom donor, leads to
production of anthracene in ∼90% yield (Scheme 3),
1/2
pp
+
Fc /Fc in CH CN. This reduction potential is in line with
other Fe (OH) complexes (Table S8). The redox potentials
3
III
+
for (p-X-C H ) C /(p-X-C H ) C· are −0.11 V (X = H) and
Scheme 3. Activation of Dioxygen by 1
6
4 3
6
4 3
5
2
−
0.58 V (X = OMe), in the same solvent, indicating that
outer-sphere electron-transfer (ET) from (p-X-C H ) C· to 2
should be endergonic by 13.4 kcal mol for X = H, and 2.5
kcal mol for X = OMe. Thus, ET to 2 is thermodynamically
unfavorable for both carbon radicals, suggesting that a
concerted process may be operative (Scheme S2).
6
4 3
−
1
−
1
In conclusion, the incorporation of an anionic donor
combined with H-bond groups in the second coordination
II
sphere of a new tetradentate ligand provided access to an Fe
consistent with H atom abstraction by the putative ferryl
intermediate. Attempts to observe intermediates in the
reaction between 1 and O2 were carried out at lower
complex that activates O and yields a stable, terminal
2
III
Fe (OH) complex. Reaction of the latter complex with trityl
29
radical derivatives led to the first direct observation of a
Scheme 4. Reaction between 2 and Triarylmethyl Radicals
C
DOI: 10.1021/jacs.9b03329
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Journal of the American Chemical Society
Communication
David P. Goldberg: 0000-0003-4645-1045
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The NIH (GM119374 to D.P.G.) is gratefully acknowledged
for financial support. Computer time was provided by the
Maryland Advanced Research Computing Center (MARCC).
We also thank Prof. Guy N. L. Jameson for valuable
discussions.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b03329.
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Corresponding Author
dpg@jhu.edu
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Vishal Yadav: 0000-0002-7016-2991
Jesse B. Gordon: 0000-0002-6331-7940
Maxime A. Siegler: 0000-0003-4165-7810
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