A Pseudotetrahedral Terminal Oxoiron(IV) Complex: Mechanistic Promiscuity in C?H Bond Oxidation Reactions

Article abstract of DOI:10.1002/anie.202015896

S=2 oxoiron(IV) species act as reactive intermediates in the catalytic cycle of nonheme iron oxygenases. The few available synthetic S=2 Fe^IV=O complexes known to date are often limited to trigonal bipyramidal and very rarely to octahedral geom

Full text of DOI:10.1002/anie.202015896

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Accepted Article
Title: A Pseudotetrahedral Terminal Oxoiron(IV) Complex: Mechanistic
Promiscuity in C-H bond Oxidation Reactions
Authors: Kallol Ray, Katrin Warm, Alice Paskin, Uwe Kuhlmann,
Eckhard Bill, Marcel Swart, Michael Haumann, Holger Dau,
and Peter Hildebrandt
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10.1002/anie.202015896
Angewandte Chemie International Edition
RESEARCH ARTICLE
A Pseudotetrahedral Terminal Oxoiron(IV) Complex: Mechanistic
Promiscuity in C-H bond Oxidation Reactions
Katrin Warm,[a] Alice Paskin,[a] Uwe Kuhlmann,[b] Eckhard Bill,[c] Marcel Swart,[d] Michael Haumann,[e]
Holger Dau, [e] Peter Hildebrandt, [b] Kallol Ray*[a]
Dedicated to Prof. Dr. Wolfgang Kaim on the occasion of his 70th Birthday
[a]
[b]
M. Sc. K. Warm, M. Sc. A. Paskin, Prof. Dr. K. Ray
Institut für Chemie
Humboldt-Universität zu BerlinBrook-Taylor-Str. 2, 12489 Berlin
E-mail: kallol.ray@hu-berlin.de
Dr. U. Kuhlmann, Prof. Dr. P. Hildebrandt
Institut für Chemie
Technische Universität Berlin
Fakultät II
Straße des 17. Juni 135, 10623 Berlin
Dr. E. Bill
Max-Planck-Institut für Chemische Energiekonversion (CEC)
Stiftstraße 34-36, 45470 Mülheim
Prof. Dr. M. Swart
[c]
[d]
Institut de Química Computacional i Catàlisi
Universitat de Girona, Campus Montilivi (Ciències)
Maria Aurèlia Capmany i Farnés, 69, 17003 Girona
ICREA
Pg. Lluís Companys 23, 08010 Barcelona
Dr. M. Haumann, Prof. Dr. H. Dau
Institut für Physik
[e]
Freie Universität Berlin
Arnimallee 14, 14195 Berlin
Supporting information for this article is given via a link at the end of the document.
High-valent oxoiron(IV) intermediates act as the active oxidants
in the catalytic cycles of a variety of mononuclear non-heme iron
oxygenases.[1] These high-valent species have been
characterized by rapid freeze quench methods in few cases[1] and
were unambiguously shown by UV-Vis, Mössbauer, and X-ray
absorption spectroscopic methods to contain high-spin (S=2)
iron(IV) centres. However, the available experimental data could
not reveal other important structural features, such as the number,
identity, and disposition of ligands in the Fe(IV) coordination
sphere. Density functional theoretical (DFT) studies[2] on the
taurine:αKG dioxygenase (TauD) system have shown that the
spectroscopic properties of the hydrogen-abstracting oxoiron(IV)
key intermediate (TauD-J) are consistent with both suggested
structural models (Scheme 1), i.e. with trigonal bipyramidal (TBP)
as well as distorted octahedral (Oh) coordination. Significant
synthetic efforts in the past decade have led to the generation of
oxoiron(IV) cores in both TBP and Oh geometries (Scheme 1).
Although the majority of the synthetic complexes exhibit S=1
ground states in Oh geometry,[3] DFT-studies predicted
stabilization of the more reactive[4] S=2 oxoiron(IV) units[5] either
by enforcing a TBP geometry at the iron(IV) centre[5a-5d] or by
weakening the equatorial donation in Oh geometry.[5e]
Abstract: S=2 oxoiron(IV) species act as reactive intermediates in the
catalytic cycle of nonheme iron oxygenases. The few available
synthetic S=2 FeIV═O complexes known to date are often limited to
trigonal bipyramidal and very rarely to octahedral geometries. Herein
we describe the generation and characterization of an S=2
pseudotetrahedral FeIV═O complex 2 supported by the sterically
demanding 1,4,7-tri-tert-butyl-1,4,7-triazacyclononane ligand. 2 is a
very potent oxidant in hydrogen atom abstraction (HAA) reactions with
large non-classical deuterium kinetic isotope effects, suggesting
hydrogen tunneling contributions. For sterically encumbered
substrates, direct HAA is impeded and an alternative oxidative
asynchronous proton-coupled electron transfer mechanism prevails,
which is unique within the nonheme oxoiron community. The high
reactivity and the similar spectroscopic parameters make 2 one of the
best electronic and functional models for a biological oxoiron(IV)
intermediate of taurine dioxygenase (TauD-J).
1
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10.1002/anie.202015896
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RESEARCH ARTICLE
Scheme 1. Left: Proposed structures of S=2 TauD-J based on DFT studies;[2] middle: selected examples of S=1 and S=2 oxoiron(IV) cores in TBP and Oh
geometries; right: A pseudotetrahedral S=2 oxoiron(IV) complex 2 reported in this work; in the inset is shown the DFT calculated structure of 2 in the S=2 state.
In the context of the existing ambiguity related to the coordination
number of iron in biological oxoiron(IV) intermediates,[2] and the
limitation of the synthetic S=2 oxoiron(IV) cores to mainly TBP
and in rare cases to Oh geometries, we have now sought to
identify a tripodal ligand that allows for trapping an FeIV=O core in
a geometry different from the known TBP or Oh geometries.
Herein we report the synthesis and characterization of the S=2
three Fe-N distances of 2.105(2)-2.124(2) Å. The zero-field
Mössbauer spectrum of 1 (Figure S2) revealed a single doublet
with an isomer shift (δ) of 0.97 mm s-1 and a large quadrupole
Table 1. Comparison of the spectroscopic properties of TauD-J and 2.
t
pseudotetrahedral [FeIV(O)(tBu3tacn)]2+ (2, Bu3tacn[6] = 1,4,7-tri-
tert-butyl-1,4,7-triazacyclononane) complex, which exhibits
spectroscopic and reactivity properties distinct from the
oxoiron(IV) cores in TBP or Oh geometries. In particular, in direct
contrast to the vast majority of previous oxoiron(IV) cores, [3a-g, 5a-
TauD-J[1a, 1b, 2, 10]
2
λmax [nm]
318
356
e]
where the reactivity with substrates containing C-H bonds is
R (Fe-O) [Å]
1.62
821
1.66
802
controlled by the C-H bond dissociation energies (BDEC–H),
complex 2 demonstrates a mechanistic promiscuity in its C-H
oxidation reactions. Sterically less hindered C-H bonds are
oxidized via a conventional direct hydrogen atom abstraction
(HAA; Scheme 2) mechanism that is characterized by large
deuterium kinetic isotope effects (KIEs), which are greater than
the semi-classical limit of 7, implying a significant contribution of
hydrogen tunnelling.[7] In contrast, for sterically encumbered
substrates, where the direct access to the FeIV=O core is blocked,
the C-H oxidation reaction proceeds with a significantly lower KIE
and presumably involves a proton-coupled electron transfer
(PCET) mechanism along a spectrum of “asynchronicity”[8] in
which the transition state for the net H-atom transfer contains
more electron transfer character (Scheme 2; Oxidative
asynchronous PCET).

Fe=O [cm-1]
δ [mm-1 s-1]
0.31
0.88
0.11
0.96
ΔEQ [mm-1 s-1]
Axx, Ayy, Azz [T]
S = 2:
‒18.4, ‒17.6, ‒31
S = 2:
‒10.1, ‒3.3, ‒36.1
Eo [eV]
7123.8
7123.2
Figure 1. A) UV-Vis spectra 1 (dashed line) and 2 (solid line) in CH2Cl2 at
90 °C; inset shows the rRaman spectra of 16O- (solid line) and 18O-labelled
(dashed line) 2 (4mM solution) in CH2Cl2 upon 406 nm irradiation at 90 °C;
solvent signals are indicated by an asterisk; B) Zero-field Mössbauer spectrum
(grey) of a frozen sample of 2 in PrCN/CH2Cl2 (10:1) and simulation with δ =
0.11 mm s1 and ΔEQ = 0.96 mm s1 for the main species (solid line, 87%). The
minor species (dashed line) with δ = 0.97 mm s1 and ΔEQ = 1.98 mm s1
corresponds to unreacted 1.
Scheme 2. Mechanisms of net hydrogen atom transfer.
splitting (ΔEQ=1.98 mmꢀs−1), consistent with an S=2 spin state,
which is also supported by DFT[11] (Table S3). Reaction of 1 in
pure CH2Cl2 or butyronitrile (PrCN) at 90 oC with 2-(tert-
Combination of equimolar amounts of the previously reported
tBu3tacn ligand[6,9] and FeII(OTf)2(CH3CN)2 in CH2Cl2 afforded
[FeII(tBu3tacn)(OTf)](OTf) (1), whose crystal structure (Figure S1;
Tables S1-S2) exhibited a distorted tetrahedral geometry (N-Fe-
N angles of 86.5-88.3°) with an Fe-O distance of 1.935(2) Å and
butylsulfonyl)-iodosobenzene (sPhIO,)[12] yielded
a
transient
species 2 (Figure 1A; half-life at 70 °C = 20 min) with electronic
2
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10.1002/anie.202015896
Angewandte Chemie International Edition
RESEARCH ARTICLE
δ-value (0.06 mm s–1), on the ground S=2 state are in satisfactory
agreement with experiments (Table S3). Notably, the calculated
data for the S=1 and S=0 states deviate significantly from the
experiments, such that we take the calculations as a further
support for the S=2 ground state in 2.
absorption features centered at λmax = 356 nm (ε = 7500 M1 cm1)
and 780 nm (ε = 150 M1 cm1). Notably, the presence of a well-
defined strong absorption band in the near-UV region is typical of
S=2 oxoiron(IV) cores (Table S4)[5a-d]; in 2 this band at λmax = 356
nm is slightly red-shifted (Table 1) relative to that of TauD-J (λmax
= 318 nm).[1a] The S=2 spin state of 2 was additionally
corroborated by the Evans[13] NMR method (Figure S3) at 90 °C
which yielded the magnetic moment µeff = 4.50 µB (theoretical
value for S=2: 4.90 µB). An electron spray ionization mass
spectrum (Figure S4) of 2 exhibited a signal at m/z = 518.7,
consistent with its formulation as [FeIV(O)(tBu3tacn)(OTf)]+ (m/z
calc = 518.2). However, the 19F-NMR spectrum (Figure S5) of 2
displayed a single resonance at −77.0 ppm, which confirmed that
the triflate (OTf) anion is not bound to the Fe-centre in 2. This
observation together with the same UV-vis spectrum (Figure S6)
of 2 in both coordinating (PrCN) and non-coordinating (CH2Cl2)
solvents corroborates the absence of any exogeneous ligands
binding to the iron centre. Thus, the 4-coordinate geometry found
in 1 is retained in 2, leading us to formulate the latter as
[FeIV(O)(tBu3tacn)]2+.
The 4-coordinate geometry of 2 was also supported by Extended
X-ray Absorption Fine Structure (EXAFS) analysis (Figure S7A,
Table S5), which yielded a good fit with an oxygen ligand at 1.66
Å, assigned to the Fe=O bond, and a further shell of three nitrogen
ligands at 2.06 Å, corresponding to the N donors of tBu3tacn. The
Fe K-edge X-ray absorption spectrum (Figure S7B) of 2 reveals
an edge energy of 7123.2 eV (vs. 7119.7 eV for 1), which is within
the range of values found for synthetic FeIV=O complexes.[3b, 5a-c]
Furthermore, in contrast to the pre-edge features of existing S=1
complexes that can be modelled with a single Gaussian,[13] in the
pre-edge region of 2 two spectral features at ~7115 and ~7117
eV are tentatively discernible (Figure S7A,C), which may be
rationalized in terms of a splitting of the α and β dz2 orbitals by
spin polarization in the S=2 oxoiron(IV) cores.[5a, 5b]
Figure 2. A) Plot of the logarithm of the second order rate constants k2’
(normalized to the number of equivalent H atoms) of the reactions of 2 with
different substrates vs the BDEC-H of the respective substrates; the inset shows
the substrates that deviate from a linear correlation; B) Plot of the logarithm of
the second order rate constants k2 of the reactions of 2 with different polycyclic
substrates vs the ionization energy of the respective substrates; C) plot of the
first-order rate constants kobs vs the concentration of ethylbenzene (black) and
d10-ethylbenzene (grey) for determination of the second-order rate constants k2
and the deuterium KIE; D) plot of the first-order rate constants kobs vs the
concentration of DHA (black) and d4-DHA (grey) for determination of the
second-order rate constant k2 and the deuterium KIE.
Resonance Raman spectroscopy revealed a (Fe=O) stretching
mode at 802 cm−1 in 2 (Figure 1A, inset) that shifted to 767 cm−1
upon 18O-labelling. The observed (Fe=O) mode has one of the
lowest energies reported to date for oxoiron(IV) cores. This may
be attributed to the high spin (S=2) ground state of 2 as this would
(in a simplified pseudotetrahedral ligand field) require a d(x2-
y2)1d(xy)1d(xz,yz)2d(z2)0 electronic configuration with an Fe-O
bond order (BO) of 2.0.[15] Notably, the high-spin ground state of
2 is unique for a pseudotetrahedral geometry; previously reported
pseudotetrahedral M-X (X=O2, NR2, or N3) complexes,[16]
including the recent CoIII≡O complex,[8, 17] all possess a low-spin
ground state with a M-X BO of 3. The zero field Mössbauer
spectrum of 2 exhibits a doublet (87% yield) with a quadrupole
splitting, ΔEQ = 0.96 mm/s, and an isomer shift, δ = 0.11 mm/s
(Figure 1B). Although, the ΔEQ value is very close to the value
reported for TauD-J (Table 1),[1b] the δ-value is significantly lower,
which may reflect the nitrogen-rich character in 2 in contrast to the
harder oxygen-containing ligand sphere in TauD-J. In applied
magnetic fields, the spectra of 2 exhibit paramagnetic hyperfine
structure, which were analysed by assuming an S=2 center
yielding a non-axial A-tensor with Axx/gnβn = −10.1 T, Ayy/gnβn =
−3.3 T and Azz/gnβn = −36.1 T (Figure S8). The structure of 2 as
obtained by DFT calculations (Scheme 1, inset) reveals an off-
axis tilt of the oxo ligand resulting in a deviation from the C3
symmetry, which may account for the non-axial A-tensor
determined from magnetic Mössbauer studies. The quintet state
was calculated to be more stable than the triplet and the singlet
states by 0.8 and 6.6 kcalꢀmol−1, respectively (Table S3).
Furthermore, among all spin states, the calculated spectroscopic
properties of the S=2 state provide the best description of the
experimental data. The calculated Fe═O and Fe-N bond
distances (1.63 and 2.06 Å, respectively), Fe=O stretching mode
frequency (893 cm–1, 18O isotope shift −36 cm–1), and Mössbauer
The oxidative reactivity of 2 (Figures S9-S18; Table S6) has been
investigated with several substrates in oxygen atom transfer
(OAT) and HAA reactions and the second order rate constants
derived from these studies in CH2Cl2 are compared with three of
the most reactive high-valent Fe-oxo intermediates reported to
date (namely the [(TQA)FeIV(O)(CH3CN)]2+ (TQA
=
tris(2-
quinolylmethyl)amine),[5e] [(Me3NTB)FeIV(O)]2+ (Me3NTB = tris((N-
methyl-benzimidazol-2-yl)methyl)amine)[3c]
and
[(TMCO)FeIV(O)(CH3CN)]2+ (TMCO
=
4,8,12-trimethyl-1-oxa-
[3f]
4,8,12-triazacyclotetradecane)
complexes (Table 2). In
reactions with ethylbenzene, 1,4-cyclohexadiene (1,4-CHD), and
toluene, 2 is a stronger oxidant than [(TMCO)FeIV(O)(CH3CN)]2+,
but
comparable
to
[(TQA)FeIV(O)(CH3CN)]2+
and
[(Me3NTB)FeIV(O)]2+. Interestingly, the reactivity trend is reversed
in reactions with 9,10-dihydroanthracene (DHA), where 2 exhibits
the least reactivity. Furthermore, when the logarithms of the
second order rate constants (k2) were plotted vs the BDEC-H
values of the substrates (Figure 2A, Figure S20A), the linear
correlation typically observed for oxoiron(IV) cores[3a-i, 5] is found
to be not valid for 2. While the respective log k2 values associated
with 2 for the oxidation of 1,4-CHD, 1,3-cyclohexadiene (1,3-
CHD), ethylbenzene, cyclohexene and toluene fall on a line
(Figure 2A, black points), xanthene, DHA, indene and fluorene
substrates (Figure 2A, inset) deviate from this pattern and exhibit
significantly lower rates than predicted by the linear relationship.
Particularly interesting is the large rate difference of two orders of
magnitude for DHA and 1,4-CHD, which are known to have small
difference in BDEC-H values.[18] Furthermore, large deuterium KIEs
of 7(Figure S9), 12 (Figure S10), and 53 (Figure 2C, Figure S11)
were recorded for toluene, 1,4-CHD, and ethylbenzene reactions,
respectively, suggesting a HAA mechanism with significant
contribution of hydrogen-tunnelling, as is frequently proposed in
3
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10.1002/anie.202015896
Angewandte Chemie International Edition
RESEARCH ARTICLE
C−H bond activation reactions of FeIV=O species.[7] In contrast,
significantly reduced KIEs of 1.2 (Figure 2D, Figure S12) and 2.1
(Figure S13) were determined for DHA and xanthene,
respectively, thereby pointing to a change of mechanism. Further
mechanistic insights were obtained by plotting the rate constants
against the pKa and the ionization energies (IE) of the substrates.
The log k2 vs IE plot (Figure 2B, Figure S20B) revealed that for
reactions of 2 with xanthene, DHA, indene and fluorene the rate
decreased linearly with increasing IE, whereas the rates for 1,4-
CHD, 1,3-CHD, ethylbenzene, cyclohexene and toluene scatter
irregularly. Furthermore, no linear trend was observed in the log
k2 vs pKa plot (Figure S20C) for all the investigated substrates.
Thus, the tBu3tacn ligand blocks the HAA pathway by presumably
impeding access of the bulkier polycyclic hydrocarbons to the
Fe=O unit in 2. An alternative oxidative asynchronous PCET
mechanism (Scheme 2) prevails in such cases, which are typically
characterized by low KIEs and a linear correlation of the reaction
rates to IEs.
Acknowledgements
This work was funded by the Deutsche Forschungsgemeinschaft
(DFG, German Research Foundation) under
Germany’sExcellence Strategy - EXC 2008 - 390540038 -
UniSysCat to K.R., P.H., and H.D. and the Heisenberg-
Professorship to K.R., and MINECO (CTQ2017-87392-P) and
FEDER (UNGI10-4E-801) to M.S. K.W. also thanks Einstein
Foundation Berlin (ESB) - Einstein Center of Catalysis (EC²) for
its support.
Keywords: Bioinorganic Chemistry • Enzyme Models • High-
Valent Iron • Hydrogen Atom Abstraction • Oxidative Proton
Coupled Electron Transfer Mechanism
Table 2. Comparison of the reaction rate constants k2’ (normalized to the
number of equivalent H atoms) at -40 °C for the C-H activation reaction of 2 and
the highly reactive intermediates (TMCO)FeIV=O, (Me3NTB)FeIV=O and
(TQA)FeIV=O towards a selection of substrates.
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Substrate
(BDEC-H
k2‘ [M-1s-1]
[2]
[3]
,
kcal/mol)
2
(TMCO)
FeIV=O
(Me3NTB)
FeIV=O
(TQA)
FeIV=O
1.0 ∙ 102
1.6 [b]
7.8 ∙ 102
[a]
1,4-CHD (76.0)
DHA (76.3)
nd
nd
nd
Too fast
(90 °C)
0.10 [c]
2.4 ∙ 102
0.75
Ethylbenzene
(85.4)
Toluene (89.7)
3.3 [b]
1.1
0.21
0.43 [b]
0.0044 [c]
0.16
nd = rate not determined; k2’ values at 40 °C were calculated from the values measured at
[b]
[c]
[d]
[a] 90 °C; 70 °C; 60 °C; 50 °C and corrected for the temperature difference by
doubling the rate for every 10 degrees rise in temperature.
Taken together the results presented here unequivocally validate
the formation of
pseudotetrahedral
a
terminal oxoiron(IV) complex
geometry. The computational
2
in
and
a
experimental analyses are consistent with the presence of an S=2
FeIV=O core in 2. Complex 2 represents the only example of a
high-spin complex with metal-ligand multiple bond character in a
pseudotetrahedral geometry; notably,
a
pseudotetrahedral
[4]
[5]
oxoiron(IV) complex has been very recently demonstrated to
possess an S=0 state in the gas-phase.[19] The absorption
spectrum, Mössbauer ΔEQ, Fe K-edge energy, and the (Fe=O)
mode of 2 (Table 1) bear very close resemblance to the
corresponding spectroscopic properties of TauD-J. 2 also exhibits
the distinct high-reactivity features known from the strongly
oxidizing iron-oxo cores in biology and accordingly possesses
one of the most reactive oxoiron(IV) cores that have been
synthesized to date. Furthermore, a large KIE of 53 has been
determined for the reaction of 2 with ethylbenzene, which
compares well with the KIE of 57[1] determined for the oxidation of
taurine by TauD-J. The uniqueness of 2 within the non-heme
oxoiron family is, however, emphasized in its ability to oxidize
sterically hindered C-H bonds by an IE-driven asynchronous
PCET mechanism. Although, limited examples of C-H oxidation
by a basicity controlled PCET mechanism (scheme 2) are
known,[8, 20], evidence of oxidative PCET mechanism has stayed
elusive prior to this study. In conclusion, the high reactivity and
the similar spectroscopic parameters of 2 and TauD-J make 2 one
of the best structural, electronic and functional models for TauD-
J.
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5
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RESEARCH ARTICLE
Entry for the Table of Contents
A highly reactive S=2 pseudotetrahedral oxoiron(IV) complex 2 supported by a sterically demanding 1,4,7-tri-tert-butyl-1,4,7-
triazacyclononane ligand has been synthesized and spectroscopically characterized as one of the best electronic and functional
models for a biological oxoiron(IV) intermediate of taurine dioxygenase (TauD-J).
6
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