Kinetic Studies on the Oxoiron(IV) Complex with Tetradentate Aminopyridine Ligand PDP: Restoration of Catalytic Activity by Reduction with H2O2

Article abstract of DOI:10.1021/acs.inorgchem.9b02269

Oxoiron(IV) is a common catalytic byproduct observed in the oxidation of alkenes by the combination of H₂O₂ and nonheme iron catalysts including complex 1, Fe^IIPDP? (where PDP? = bis(3,5-dimethyl-4-methoxypyridyl-2-methyl)-(R,R)-2,2′-bipyrrolidine). The oxoiron(IV) species have been proposed to arise by O-O homolysis of the peroxyiron(III) or acylperoxyiron(III) intermediates formed during the presumed Fe^III-Fe^V catalytic cycle and have generally been regarded as off-pathway. We generated complex 1^IV=O (λ_max = 730 nm, ? = 350 M^-1 cm^-1) directly from 1 and an oxygen atom donor IBX^i-Pr (isopropyl 2-iodoxybenzoate) in acetonitrile in the temperature range from-35 to +25 °C under stopped-flow conditions. Species 1^IV=O is metastable (half-life of 2.0 min at +25 °C), and its decay is accelerated in the presence of organic substrates such as thioanisole, alkenes, benzene, and cyclohexane. The reaction with cyclohexane-d₁₂ is significantly slower (KIE = 4.9 ± 0.4), suggesting that a hydrogen atom transfer to 1^IV=O is the rate limiting step. With benzene-d₆, no significant isotope effect is observed (KIE = 1.0 ± 0.2), but UV-vis spectra show the concomitant formation of an intense 580 nm band likely due to the Fe(III)-phenolate chromophore, suggesting an electrophilic attack of 1^IV=O on the aromatic system of benzene. Treatment of 1^IV=O with H₂O₂ resulted in rapid decay of its 730 nm visible band (k = 102.6 ± 4.6 M^-1 s^-1 at-20 °C), most likely occurring by a hydrogen atom transfer from H₂O₂. In the presence of excess H₂O₂, the oxoiron(IV) is transformed into peroxyiron(III), as seen from the formation of a characteristic 550 nm visible band and g_eff = 2.22, 2.16, and 1.96 electron paramagnetic resonance (EPR) spectroscopy signals. Reductively formed 1^III-OOH was able to re-enter the catalytic cycle of alkene epoxidation by H₂O₂, albeit with lower yields versus those of oxidatively formed (i.e., 1 + H₂O₂) peroxyiron(III) owing to a loss of ca. 40% active iron. As such, the oxoiron(IV) species can be reintroduced to the catalytic cycle with extra H₂O₂, acting as an iron reservoir. Alternatively, peroxycarboxylic acids, which have a stronger O-H bond dissociation energy, do not reduce 1^IV=O, ensuring that more oxidant is productively employed in substrate oxidation. While this reaction with H₂O₂ may occur for other nonheme oxoiron(IV) complexes, the only previously reported examples are 3^IV=O and 4^IV=O, which are reduced by hydrogen peroxide 130- A nd 2900-fold more slowy, respectively (as in Angew. Chemie-Int. Ed. 2012, 51 (22), 5376-5380, DOI: 10.1002/anie.201200901).

Full text of DOI:10.1021/acs.inorgchem.9b02269

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Kinetic Studies on the Oxoiron(IV) Complex with Tetradentate
Aminopyridine Ligand PDP*: Restoration of Catalytic Activity by
Reduction with H2O2
Marc C. Piquette,* Sergiy V. Kryatov,* and Elena V. Rybak-Akimova†
Department of Chemistry, Tufts University, 62 Talbot Avenue, Medford, Massachusetts 02155, United States
S
* Supporting Information
ABSTRACT: Oxoiron(IV) is a common catalytic byproduct
observed in the oxidation of alkenes by the combination of H2O2
and nonheme iron catalysts including complex 1, FeIIPDP* (where
PDP* = bis(3,5-dimethyl-4-methoxypyridyl-2-methyl)-(R,R)-2,2′-bi-
pyrrolidine). The oxoiron(IV) species have been proposed to arise by
O−O homolysis of the peroxyiron(III) or acylperoxyiron(III)
intermediates formed during the presumed FeIII−FeV catalytic cycle
and have generally been regarded as off-pathway. We generated
complex 1IVO (λmax = 730 nm, ε = 350 M−1 cm−1) directly from 1
and an oxygen atom donor IBXi‑Pr (isopropyl 2-iodoxybenzoate) in
acetonitrile in the temperature range from −35 to +25 °C under
stopped-flow conditions. Species 1IVO is metastable (half-life of 2.0
min at +25 °C), and its decay is accelerated in the presence of organic substrates such as thioanisole, alkenes, benzene, and
cyclohexane. The reaction with cyclohexane-d12 is significantly slower (KIE = 4.9 0.4), suggesting that a hydrogen atom
transfer to 1IVO is the rate limiting step. With benzene-d6, no significant isotope effect is observed (KIE = 1.0 0.2), but
UV−vis spectra show the concomitant formation of an intense 580 nm band likely due to the Fe(III)-phenolate chromophore,
suggesting an electrophilic attack of 1IVO on the aromatic system of benzene. Treatment of 1IVO with H2O2 resulted in
rapid decay of its 730 nm visible band (k = 102.6 4.6 M−1 s−1 at −20 °C), most likely occurring by a hydrogen atom transfer
from H2O2. In the presence of excess H2O2, the oxoiron(IV) is transformed into peroxyiron(III), as seen from the formation of
a characteristic 550 nm visible band and geff = 2.22, 2.16, and 1.96 electron paramagnetic resonance (EPR) spectroscopy signals.
Reductively formed 1III−OOH was able to re-enter the catalytic cycle of alkene epoxidation by H2O2, albeit with lower yields
versus those of oxidatively formed (i.e., 1 + H2O2) peroxyiron(III) owing to a loss of ca. 40% active iron. As such, the
oxoiron(IV) species can be reintroduced to the catalytic cycle with extra H2O2, acting as an iron reservoir. Alternatively,
peroxycarboxylic acids, which have a stronger O−H bond dissociation energy, do not reduce 1IVO, ensuring that more
oxidant is productively employed in substrate oxidation. While this reaction with H2O2 may occur for other nonheme
oxoiron(IV) complexes, the only previously reported examples are 3IVO and 4IVO, which are reduced by hydrogen
peroxide 130- and 2900-fold more slowy, respectively (as in Angew. Chemie - Int. Ed. 2012, 51 (22), 5376−5380, DOI: 10.1002/
anie.201200901).
activate H2O2 (with or without a carboxylic acid cocatalyst) for
aromatic hydroxylations,9,10 regiospecific aliphatic hydroxyla-
tions,11−13 and alkene epoxidations.14−16 Scheme 1 shows the
current mechanistic consensus for the reaction of an iron(II)
starting catalytic material with H2O2, where it forms
peroxyiron(III) or acylperoxyiron(III) intermediates (in the
presence of a carboxylic acid), which are sluggish oxidants by
themselves. Heterolytic O−O cleavage of 1III−OOH or 1III−
OOAc affords the putative active species, formally oxoiron(V),
which rapidly oxidizes organic substrates, returning to an
iron(III) state.17−20 Oxoiron(IV) species were also observed
under catalytically relevant conditions (presumably due to the
INTRODUCTION
■
The selective oxidation of unactivated C−H bonds and
prochiral alkenes is of the utmost importance for organic
synthesis, potentially allowing for the transformation of cheap
hydrocarbon feedstocks into commodity chemicals.1,2 In
nature, iron-containing enzymes, including TauD, TyrH, and
cytochrome P450, afford selective C−H and CC bond
oxidation and typically exhibit a formally oxoiron(IV) or
oxoiron(V) active oxidant.3−6 Researchers have developed
small-molecule catalysts based on the active sites of these
metalloenzymes for the two-fold purpose of harnessing nature’s
ability to perform challenging oxidations under green
conditions and to further understand the mechanisms of
these enzymes.7,8
Iron complexes with tetradentate aminopyridine ligands like
1 and 2 (Figure 1) are among the best known catalysts to
Received: July 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.inorgchem.9b02269
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Inorganic Chemistry
Article
Figure 1. Structure of complex 1 used in this work and complexes 2−4 referenced for comparison. Sol refers to a weakly coordinating solvent
molecule, usually CH3CN.
a
Scheme 1. Proposed Mechanism of Catalysis for Complexes 1 and 2
a
X = solvent or OAc, depending on the pathway. Following the formation of an iron(III)-peroxo intermediate, it can proceed via a heterolytic
pathway forming active 1VO or a homolytic pathway forming 1IVO, previously believed to be a catalytic dead end.19 In this work, we
demonstrate additional pathways shown in red, in which 1IVO directly oxidizes organic substrates (slow reactions) or is reduced (quickly) by
H2O2, thus returning to the main FeIII−FeV catalytic cycle.
O−O bond homolysis, Scheme 1) but generally are considered
off-pathway iron sinks.21,22
AcOH without added organic substrate, and it was
independently generated by the reaction of 1 with an oxygen
atom donor IBXi‑Pr (isopropyl 2-iodoxybenzoate).17
Complex 2, [Fe(BPMEN)(CH3CN)2]2+, was one of the first
reported nonheme iron catalysts for the hydroxylation of
alkanes and the epoxidation and dihydroxylation of alkenes
with H2O2,23−26 and it was later found to also effect aromatic
hydroxylation reactions.10,27 However, complex 2 is incon-
venient for kinetic mechanistic studies, since all of its catalytic
intermediates are very short-lived (such as 2III−OOH and
2IVO) or have never been reliably observed (such as
putative 2VO).10,17,20,28 Therefore, we shifted our attention
to complex 1 with ligand PDP*, which has a rigid backbone
and additional electron-donating groups (Figure 1), thus
affording more stable catalytic intermediates.14,15,17,29 Inter-
mediate 1IVO was cursorily communicated by our group in
2014 from a reaction of iron(II) complex 1 with H2O2 and
Specifically, we decided to focus on the reaction of the
oxoiron(IV) species with hydrogen peroxide, since such a
process may play an important role in catalytic systems like 1/
H2O2/substrate but has been largely ignored in previous
studies. To the extent of our knowledge, there is only one
report of the reaction of monomeric nonheme oxoiron(IV)
species (derived from complexes 3 and 4, Figure 1) with
hydrogen peroxide by Lim, Rohde, and co-workers published
in 2012.18 They generated complexes 3IVO and 4IVO
from the iron(II) precursors and PhIO and found both
oxoiron(IV) species to oxidize H2O2. For complex 3IVO, the
reaction proceeded by a clean 2:1 stoichiometry yielding 3III−
OH and O2 gas; with an excess of H2O2, 3III−OOH was
B
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Article
before injecting into the instrument. Signals included m/z = 609.2 and
610.3 corresponding to ions [1IVO(ClO4)]+ and [1III(OH)-
(ClO4)]+, respectively, with matching isotopic satellites (Figure S7).
Gas Chromatography. GC-MS experiments were run using a
SHIMADZU GC-17A gas chromatograph and GCMS-QP5050 gas
chromatograph−mass spectrometer equipped with Thermo Scientific
TraceGOLD TG-5MS GC column (30 m × 0.25 mm × 0.25 μm).
Data were collected and analyzed with the GCMSsolution version
1.20 software. Some experiments had outputs that were below the
GC-MS limit of detection of the above instrument and were instead
run with on an Agilent 7890B GC system with FID detector and
Agilent Technologies HP-5 column (30 m × 0.320 mm × 0.25 μm)
and analyzed with the OpenLAB CDS software, otherwise following
the matching sample preparation protocols.
GC Quantification. Alkene epoxidation products were quantified
using the following procedure. Stock solutions (1 M each) of
chlorobenzene, alkene, and its corresponding epoxide were prepared.
Calibration standards were made by taking the following volumes of
the stock solutions and diluting to 1 mL total volume with
acetonitrile: 80 μL of 1 M chlorobenzene and a variable volume of
1 M alkene or epoxide (40, 80, 120, 160, or 200 μL). Then, a 10 μL
portion of each standard was diluted into 1 mL of acetonitrile and
analyzed by GC-MS in triplicate. Integrated areas (subjected to
Grubbs test at 95% interval) were used to establish a calibration curve
of concentration ratio (analyte/chlorobenzene) versus peak area ratio
(analyte/chlorobenzene).
generated. We hypothesized that if such mechanistic scheme is
also applicable in the case of complex 1 then it may provide a
pathway to return the relatively inactive FeIV intermediate to
the FeIII/V active cycle that apparently dominates in the
catalytic epoxidation and hydroxylation reactions (Scheme 1).
In the present work, we report a stopped-flow kinetic study
of the reaction between iron(II) complex 1 (Figure 1) and
oxygen donor IBXi‑Pr that quickly generates metastable
species 1IVO. This oxoiron(IV) intermediate is reduced by
H2O2 in a reaction that is 2−3 orders of magnitude faster than
analogous processes with 3IVO and 4IVO.18 The reaction
of 1IVO with H2O2 results in the formation of 1III−OH,
which is converted to 1III−OOH in the presence of excess
H2O2. When organic substrates are injected into the resulting
solution, fast aromatic hydroxylation (with benzoic acid and
benzene) and epoxidation (with cyclohexene and cyclooctene)
are observed, thus demonstrating a restoration of catalytic
activity (Scheme 1). Complex 1IVO is also found to quickly
oxidize thioanisole (an active oxygen atom acceptor), but its
direct reactions with benzene, alkenes, and cyclohexane are
found to be relatively slow (compared to the reaction with
H2O2).
EXPERIMENTAL SECTION
■
Materials. All reagents were obtained from commercial vendors
and used without additional purification unless otherwise specified.
All experiments were run in HPLC-grade acetonitrile additionally
purified via an Innovative Technology PS-MD-7 solvent purification
system. Alkene substrates (cyclohexene and cyclooctene) were filtered
through an alumina plug before use. Hydrogen peroxide was taken
from a 50 wt % stock solution (Aldrich) and diluted into acetonitrile
before use. Peracetic acid was taken from stock solution (ca. 39% in
acetic acid (Aldrich)) and diluted into acetonitrile before use; it had a
reported ∼6% H2O2 impurity. mCPBA was purified according to ref
30. Ligand PDP* and its iron(II) complex 1 (as a perchlorate salt)
were synthesized as previously reported.17 Isopropyl 2-iodoxyben-
zoate (IBXi‑Pr) was synthesized according to ref 31. Mentions of
“reductively formed” 1III−OOH refer to its formation from 1IVO
and H2O2, while “oxidatively formed” 1III−OOH was made from
iron(II) complex 1 and H2O2 (all at low temperatures in acetonitrile
solutions).
Catalysis experiments with oxidatively formed 1III−OOH were
performed by mixing 0.25 mL each of acetonitrile, 4 mM 1, H2O2 (20,
40, 60, 80, 120, or 200 mM), and 0.4 M alkene with a 0.16 M
chlorobenzene reference. Reaction mixtures were stirred for 30 min.
Afterward, 20 μL of the reaction mixture was diluted into 1 mL of
acetonitrile and subjected to GC-MS analysis in triplicate. With
reductively formed 1III−OOH, an altered procedure was used.
Solutions of 1 and IBXi‑Pr (0.25 mL of 4 mM each in acetonitrile)
were mixed for ∼3 s, and 0.25 mL of H2O2 (20, 40, 60, 80, 120, or
200 mM) and 0.25 mL of 0.4 M olefin with 0.16 M chlorobenzene
were added.
To explore the possibility of asymmetric induction in the oxidation
of cis-β-methylstyrene and thioanisole by 1IVO, equal volumes of 4
mM 1, 4 or 40 mM IBXi‑Pr, 200 mM substrate, and acetonitrile were
mixed at room temperature for 30 min and then analyzed by GC-MS
using a Chiraldex beta cyclodextrin dimethyl column (30 m × 0.25
mm).
Electron Paramagnetic Resonance Spectroscopy. X-band
electron paramagnetic resonance (EPR) spectra were acquired on a
Bruker EMX EPR instrument at 120 K, with BVT-3000 temperature
controller, ER 081 magnet, and ER 041 X G microwave bridge using
the WIN-EPR Acquisition Program version 3.01. Integration and
quadratic baseline correction were done with the WIN-EPR 2.11
software. Due to the fleeting nature of catalytic intermediates, they
were typically generated in cold baths, either ethylene glycol and dry
ice (−17 °C) or acetonitrile and dry ice (−41 °C). Quantification of
1III−OOH was done using 1.6 mL of 0.125 mM CuII(ClO4)2 in
acetonitrile as an external reference. Subsequently, oxidatively formed
1III−OOH was prepared (−17 °C, 0.4 mL each of 4 mM 1 and 40
mM H2O2, 0.8 mL of acetonitrile) in the same EPR tube, to the same
total volume, placed into microwave cavity to the same depth, and run
under the same parameters to minimize differences. See Figures S1−
S6 for all parameters and spectra. Reductively formed 1III−OOH was
generated by mixing 0.4 mL each of 4 mM acetonitrile solutions of
IBXi‑Pr and 1 (for 5 s at −41 °C) to generate 1IVO followed by the
addition of 0.4 mL of 40 mM H2O2 in acetonitrile and 0.4 mL of
dichloromethane. Adding CH2Cl2 allowed for better signal resolution
compared to that using pure MeCN solvent, although was not
necessary for the formation of 1III−OOH.
The oxidation of cyclohexane by 1IVO was studied by mixing
0.25 mL each of acetonitrile, 4 mM 1, 4 mM IBXi‑Pr, and 400 mM
cyclohexane at +25 °C for 60 min, and an alcohol/ketone ratio was
determined by the ratio of peak areas in GC-FID.
Stopped-Flow Spectroscopy and Data Analysis. Stopped-
flow UV−vis−near-IR spectroscopy was carried out using a Hi-Tech
Scientific SF-43 cryogenic double-mixing stopped-flow system.
Multiwavelength measurements were collected with a TIDAS I
diode-array detector. Low temperatures were maintained using a
stirred liquid-nitrogen-cooled ethanol bath equipped with a cryostat.
All solutions were prepared and handled with air-free techniques.
Reactant solutions were prepared in a glovebox under argon and
transferred to the stopped-flow instrument in Hamilton Gastight
Syringes. The instrument was controlled using TgK Scientific Kinetic
Studio version 1.08 software package with J&M TIDAS-DAQ version
2.20 software to collect multiwavelength data. For each experiment,
1000 scans were taken at 2.5−3.0 ms intervals and 60−1000 averages,
depending on experiment length. Kinetic traces were fit using the
Kinetic Studio KS-1 version 4.0.8 software, by applying appropriate
kinetic equations (single or double exponential). An example kinetic
fit is provided in Figure S8. Experiments were typically run in
triplicate or quadruplicate, with outliers (Grubbs test, 95% interval)
removed prior to data averaging. All concentrations reported in
stopped-flow experiments refer to the “after mixing” conditions.
Electrospray Ionization-Mass Spectrometry. Electrospray
ionization-mass spectrometry (ESI-MS) was carried out using a
Finnigan LTQ apparatus. Complex 1IVO was generated by mixing
1 mM acetonitrile solutions of 1 and IBXi‑Pr at 0 °C immediately
C
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IV
RESULTS AND DISCUSSION
d[1 O]
■
= k1[1] + k2[1][IBX]
Formation of 1IVO. Mixing acetonitrile solutions of
iron(II) complex 1 and oxygen atom donor IBXi‑Pr (isopropyl
2-iodoxybenzoate)10,31 at −35 °C under stopped-flow
conditions resulted in the rapid growth of a 730 nm absorption
band characteristic of low-spin oxoiron(IV) complex with
aminopyridine ligands (Figure 2).17,28,32 The identity of the
(1)
dt
At−35 °C, the values of the rate constants are k1 = 1.12 0.05
−1 and k2 = 38 2 M−1 s−1 (Figure S9). Such kinetic behavior
s
may suggest two pathways for the reaction of coordinatively
saturated complex 1, [FeII(PDP*)(CH3CN)2]2+, with the
oxygen donor IBXi‑Pr: a dissociative monomolecular pathway
controlled by the loss of a solvent molecule and an associative
bimolecular pathway that depends on the concentration of
both reactants.33 At higher temperatures, the monomolecular
pathway becomes dominant; on the basis of the dependence of
rate constant k1 on temperature in the range from −35 to +22
°C (Figure S10), the activation parameters were determined as
ΔH⧧ = +49.0 0.6 kJ·mol−1 and ΔS⧧ = −34.4 2.3 J·mol−1
K−1. The relatively small value of ΔH⧧ and the negative sign of
ΔS⧧ do not agree well with the dissociative nature of the rate-
limiting step in this pathway, suggesting that the actual
mechanistic picture may be more complicated than described
above. Other experimental evidence confirms the mechanistic
complexity of the reaction between 1 and IBXi‑Pr; thus, the
reported kinetic parameters should be taken as a first
approximation and only serve for rough comparisons in
relation to the reactivity of the thus generated 1IVO. The
maximum absorbance at 730 nm (attributed to 1IVO) is not
reached with the use of 1 equiv of IBXi‑Pr; instead, it gradually
increases with the use of 1−3 equiv and plateaus at 4−10 equiv
of the oxidant. Moreover, the very fast formation of the 730
nm chromophore is immediately followed by its relatively fast
partial decay, where about 15% of the 730 nm optical
absorbance is lost (Figure S8). The rate of this partial decay is
not influenced significantly by the amount of IBXi‑Pr used
(Figure S12). At−35 °C, the partial decay has a half-life of 9 s,
and after its completion the 730 nm chromophore is stable for
at least 30 min. As temperature is increased, both phases in the
decay of this chromophore accelerate, and its overall half-life is
reduced to just 2 min at +25 °C (Figure S13). The complex
kinetic behavior of this system may be caused by the following
factors: (1) IBXi‑Pr (ortho-i-PrOOC-C6H4−IO2) has an iodoxy
group with two oxygen atoms that can be used for oxidation.
(2) Both IBXi‑Pr and the product of its monodeoxygenation
(ortho-i-PrOOC-C6H4−IO) can coordinate to iron. (3)
Complex 1IVO, [FeIV(O)(PDP*)(CH3CN)]2+, can ex-
change the solvent molecule for other ligands present in the
system.31,34 Notwithstanding these possible complications, we
Figure 2. Formation of 1IVO from 1 mM 1 and equimolar IBXi‑Pr
in acetonitrile at −35 °C followed by stopped-flow spectropho-
tometry. Inset: 730 nm kinetic trace.
730 nm chromophore as 1IVO was confirmed by ESI-MS.
Prominent ESI-MS peaks from a freshly prepared mixture of 1
and IBXi‑Pr in MeCN at 0 °C and analyzed at +40 °C can be
attributed to [(1IVO)(ClO4)]+ and [1III(OH)(ClO4)]+
based on the m/z values and isotopic satellite pattern (Figure
S7). The observation of the peak attributable to [1III(OH)-
(ClO4)]+ suggests that the most likely fate of the high-valent
intermediate is the abstraction of a hydrogen atom from
solvent or other organic molecules present in the system,
which is supported by other data (vide infra).
The growth of the 730 nm band at different ratios of
reagents (1 vs IBXi‑Pr), including a 1:1 ratio, could be fit well to
a single-exponential function (Figures 2 and S8). The plot of
observed pseudo-first-order rate constants versus [IBXi‑Pr] is a
straight line with a significant intercept (Figure S9) indicating
the following rate law.
Table 1. Second-Order Rate Constants (M−1 s−1) for the Oxidation of Selected Organic Substrates by Oxoiron(IV)
a
Complexes
complex
thioanisole
cyclohexane
1,4-cyclohexadiene
683 98
ref
8.7 1.1 (−15 °C)
1IVO
0.099 0.011
this work
274
4
3IVO
0.87 0.04 (0 °C)
9 × 10−4
3.3 0.09 × 10−2 (−40 °C)
3.1 0.11 × 10−1 (−40 °C)
1.03 0.03 (−10 °C)
7.4 (−10 °C)
6.7 × 10−5
no reaction
0.3 0.02
2.9 0.1
6.73 × 10−4
0.029
10.69
0.12
36, 39, 40
37, 41
40
4IVO
(N3PyB)FeIVO
(N2Py2B)FeIVO
(N4PyMe2)FeIVO
(N2Py2Q)FeIVO
(Me2EBC)FeIVO
(Me3NTB)FeIVO
(TQA)FeIVO
40
39
42
37
38
43
0.78
0.41 (0 °C)
2.1 × 104 (−40 °C)
7.4 (0 °C)
9.4 × 102 (−40 °C)
0.25 (−40 °C)
0.37 (−40 °C)
a
The temperature is +25 °C unless specified otherwise.
D
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have sufficient evidence that complex 1IVO forms very
quickly from 1 and IBXi‑Pr, as suggested by UV−vis
spectroscopy and ESI-MS data, and that 1IVO is sufficiently
stable in solution to study its reactivity with substrates by the
double-mixing stopped-flow technique.
reported one such complex, (PyMAC)FeIVO (where
PyMAC is a tetradentate pyridine containing macrocycle),
which epoxidized cyclooctene with a rate constant of 0.45 M−1
s−1 at 0 °C.34 The most reactive oxoiron(IV) complex reported
to date, (TQA)FeIVO (where TQA = tris(2-
quinolylmethyl)amine), reacts with cyclooctene with a rate
constant of 3.3 M−1 s−1 at −40 °C yielding 80% epoxide.43
Complex 2IVO was claimed to be competent for alkene
epoxidation when promoted by ScIII ions,49 as was 3IVO
with triflic acid,50 as well as a derivative of 3IVO.51
Reactions of 1IVO with Thioanisole and Hydro-
carbons. The reactivity of 1IVO was studied by
pregenerating the intermediate from an equimolar solution of
1 and IBXi‑Pr in acetonitrile under stopped-flow conditions
until the concentration of 1IVO reached maximum, then
adding the substrates in a second mix. First, we examined
thioanisole (PhSMe), which had commonly been employed in
an oxoiron(IV) reactivity studies.28,35 Mixing 1IVO with 10−
100 equiv of PhSMe afforded rapid bleaching of the 730 nm
chromophore with a second-order rate constant of 8.7 1.1
The relatively slow rate of olefin epoxidation compared to
the putative oxoiron(V) pathway (Scheme 1), combined with
the preference for allylic oxidation in cyclohexene, makes 1IV
O a poor choice for catalytic epoxidation. Still, a slower rate
may afford a more enantioselective oxidant, so we briefly
investigated its potential for the asymmetric epoxidation of cis-
M
−1 s−1 at −15 °C or 274 4 M−1 s−1 at +25 °C (Figure S14).
These rate constants are considerably faster than those
β-methylstyrene. First, 0.25 mL each of 4 mM 1, 4 mM IBXi‑Pr
,
reported for complexes 3IVO (0.87
0.04 M−1 s−1 at 0
and 200 mM cis-β-methylstyrene in acetonitrile were mixed at
room temperature for 30 min before GC-MS analysis. On the
basis of the peak area, both enantiomers of the epoxide were
present in nearly equal abundances, indicating no significant
asymmetric induction by 1IVO. By comparison, putative
1VO intermediate generated from 1 and H2O2 with S-
ibuprofen acid cocatalyst in the epoxidation of cis-β-
methylstyrene gave 86% ee, making the oxoiron(V) pathway
preferable for asymmetric epoxidation.14 We also carried out
the sulfoxidation of thioanisole under analogous conditions,
but again, both enantiomers of thioanisole sulfoxide were
present in nearly equal amounts showing a lack of
enantioselectivity. This is in contrast to successful ee induction
in the sulfoxidation of para-methoxythioanisole by complex
[FeIV(O)(asN4Py)]2+ (a chiral homologue of complex 3IV
O) reported recently by Kaizer and co-workers.52
°C) and 4IVO (9 × 10−4 M−1 s−1 at +25 °C).36,37 In
contrast, Nam reported a trigonal bipyramidal oxoiron(IV)
species that oxidized PhSMe with a second-order rate constant
as high as 2.1 × 104 M−1 s−1 at −40 °C.38 A comparison of
these and some other rate constants is provided in Table
1.36−43
Mixing of 1IVO with cyclohexene, cyclooctene, or
cyclohexane at −15 °C yielded no reaction on the stopped-
flow time scale (up to 10 min). However, when the
temperature was increased to +25 °C, oxidation of these and
some other hydrocarbons was observed. In stopped-flow
experiment, mixing of 1IVO with cyclohexene in acetonitrile
solution at +25 °C afforded fast bleaching of the 730 nm
chromophore (k = 5.4 0.4 M−1 s−1, Figure S15), far faster
than the self-decay of 1IVO at this temperature. For product
analysis, a benchtop room-temperature experiment was carried
out, in which a 1 mM acetonitrile solution of 1, equimolar
IBXi‑Pr, and 50 equiv of cyclohexene were mixed for 30 min,
then analyzed by GC-MS. The major oxidation products as
analyzed by GC-MS were cyclohexene-3-ol (29.1%), cyclo-
hexene-3-one (49.7%), and epoxycyclohexane (21.2%) (Figure
S16).44 A hydroperoxide product is also possible from this
reaction, and it may decompose to the enone in the GC
injector.45 To account for this, a control experiment was
conducted where excess PPh3 was added to the reaction
mixture prior to the GC injection (potentially converting
hydroperoxide to alcohol),46 but the product distribution
remained unchanged, thus excluding the formation of
cyclohexene hydroperoxide. A similar reactivity of cyclohexene,
with a marked preference for allylic oxidation over epoxidation
by oxoiron(IV) species, has been reported by Talsi et al. for
2IVO, by Paine et al. for a derivative of 3IVO, and by Que
et al. for the oxoiron(IV) complex of TPA (tris(2-
pyridylmethyl)-amine).39,44,47
With the oxidation of thioanisole and olefins by 1IVO
established, we turned our attention to the oxidation of C−H
bonds, particularly in comparison to the reported reactivity of
3IVO and 4IVO. A fast reaction was observed from a
combination of 1IVO and 1,4-cyclohexadiene, which has
activated allylic C−H bonds (BDE = 78 kJ·mol−1).41 In a
stopped-flow experiment, 1 mM 1 and IBXi‑Pr each were mixed
at +25 °C for 0.6 s, and then 1,4-cyclohexadiene (10−60
equiv) was added in a second mix. The second-order rate
constant for the oxidation of 1,4-cyclohexadiene by 1IVO
was determined to be 683
98 M−1 s−1 (Figure S18),
compared to the reported values of 10.69 M−1 s−1 for 3IVO
and 0.12 M−1 s−1 for 4IVO at +25 °C.39,41
Cyclohexane, which has unactivated C−H bonds (BDE =
99.3 kJ·mol−1),53 also accelerated the bleaching of 1IVO. In
an analogous stopped-flow experiment with 25−300 equiv of
cyclohexane, a second-order rate constant for the reaction of
1IVO with cyclohexane was determined as 0.099
0.011
M−1 s−1 (Figure S19), 4 orders of magnitude faster than that
for 3IVO (5.5 × 10−5 M−1 s−1).40 GC analysis of the product
mixture confirmed the oxidation of cyclohexane by 1IVO,
but showed little selectivity with an alcohol/ketone ratio of ca.
1:1.4. In a complementary reaction with cyclohexane-d12, the
oxidation was markedly slower, with a H/D kinetic isotope
effect of 4.9 0.4 (Figure S19). This compares well to the H/
D KIE of 4.5 with 3IVO in the oxidation of cyclohexane
reported by van den Berg et al., and it supports a metal-based
oxidant with a HAT rate-determining step.54
By comparison, oxidation of cyclooctene by 1IVO at +25
°C had a second-order rate constant of 1.36 0.07 M−1 s−1
(Figure S17), about 4 times slower than that observed for
cyclohexene. A benchtop oxidation of cyclooctene by a mixture
of 1 and IBXi‑Pr showed exclusive formation of the epoxide and
no appreciable amounts of allylic oxidation products as
observed in GC-MS. Therefore, the lower rate constant
observed with cyclooctene likely reflects its lessened reactivity
for allylic oxidation compared to cyclohexene. It should be
noted that oxoiron(IV) complexes capable of alkene
epoxidation have been rarely reported.20,34,43,48 Our group
Benzene was also oxidized by 1IVO, but at the slowest rate
among studied hydrocarbons. In stopped-flow, 50−300 equiv
E
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of benzene was added to pregenerated 1IVO in acetonitrile
solution at +25 °C, which resulted in the decay of the 730 nm
oxoiron(IV) band that proceeded faster than that with no
substrate and accelerated in proportion to the amount of
added benzene with the second-order rate constant of 0.046
0.007 M−1 s−1 (Figure S20). As the 730 nm chromophore
decayed, subsequent growth of a 580 nm band was observed,
suggesting the formation of an Fe(III)-phenolate complex after
the hydroxylation of C6H6.10 Benzene-d6 reacted with 1IVO
with nearly the same rate constant (0.043 0.007 M−1 s−1 at
+25 °C, Figure S20), showing a negligible H/D kinetic isotope
complex (Me2EBC)FeIVO (where Me2EBC is 4,11-
dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) resulted
in enforced cis-coordination and higher reactivity (Table
1),37 yet complex (Me2EBC)FeIVO had a rather long half-
life of about 5 h at 0 °C and was not able to oxidize
unactivated hydrocarbons.
Complex 3IVO that features a pentadentate ligand N4Py
(N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine, Fig-
ure 1) is less stable than 4IVO and also more reactive, able to
hydroxylate cyclohexane with a rate constant of 6.7 × 10−5
M−1 s−1 at +25 °C.39 Structural modifications of N4Py aimed
at increasing steric bulk resulted in lower ligand field, affording
less stable oxoiron(IV) complexes with higher reactivity.
Nordlander showed that in replacing one pyridine on 3IV
O with 1-methylbenzimidazole in (N3PyB)FeIVO, the +25
°C cyclohexane oxidation rate constant of 0.30 0.02 M−1 s−1
was 4 orders of magnitude higher than that of the unmodified
complex and increased further by replacing a second pyridine
with 1-methylbenzimidazole in (N2Py2B)FeIVO (Table
effect of 1.0
0.2 and suggesting an electrophilic aromatic
substitution mechanism.9,10
To the extent of our knowledge, this is the first experimental
observation of a direct reaction between a synthetic low-
molecular oxoiron(IV) complex and benzene, although the
hydroxylation of aromatic substrates is commonly attributed to
the FeIVO intermediates in native nonheme iron oxygenases
(such as TyrH).4 Goldberg and co-workers reported an
intramolecular hydroxylation of a pendant phenyl group that
was part of a polydentate ligand (a derivative of complex 3)
that likely proceeded via an oxoiron(IV) intermediate.
Interestingly, when a 2,6-difluorophenyl group was appended
instead, the FeIVO intermediate was trapped at low
temperature, but it effected the hydroxylation of a C−F
bond at room temperature.55,56 Nam and co-workers observed
the hydroxylation of anthracene by complexes 3IVO and
(Bn−tpen)FeIVO that proceeded smoothly at +25 °C in
acetonitrile/dichloromethane (1:1) solutions with rate con-
stants of 0.24 and 0.68(5) M−1 s−1, respectively; their
computational studies suggested the possibility of benzene
hydroxylation by these complexes as well, but no experimental
confirmation was reported.53,54 Banse and co-workers observed
hydroxylation of aromatic substrates (including benzene) with
1).40 The results were less dramatic and mixed for Paine, who
-
replaced two pyridines with 6-methylpyridines in (N4PyMe2
)
FeIVO: The rate constant for the oxidation of cyclohexane
was 1 order of magnitude faster than that of unmodified 3IV
O, but 1 order of magnitude slower for the oxidation of 1,4-
cyclohexadiene (Table 1).39 Que reported a variant with two
pyridines replaced by quinolines, (N2Py2Q)FeIVO, which
oxidized cyclohexane with an intermediate rate constant of
0.029 M−1 s−1 at +25 °C (Table 1).42 Overall, lower ligand
field strength (and longer average Fe−N bond distances)
correlated well with log k values for substrate oxidation for
complex 3IVO and its derivatives.42 Such a trend in reactivity
of the oxoiron(IV) species was justified by lowering the energy
gap from the unreactive S = 1 ground state to the reactive S = 2
state as suggested by computational analysis.42,59−61
2
2
the help of a (L5 )FeIII−OOH complex, where L5 is a
pentadentate analog of ligand 2 with an additional amino-
pyridine arm; their proposed mechanism included homolysis
of the Fe(III)-OOH intermediate to generate a caged
A decrease of ligand denticity from N5 to N4 appears to
increase the reactivity of oxoiron(IV) complexes, which may be
justified by either a decrease in ligand field stabilization or the
appearance of a labile site near the oxo ligand in the LFeIVO
unit (for the cis N4 ligand topology). The most reactive
examples of such complexes known to date, (Me3NTB)FeIV
O and (TQA)FeIVO, feature bulky tripod N4 ligands and
oxidize cyclohexane at −40 °C with rate constants of 0.23 and
0.37 M−1 s−1, respectively.38,43
•
oxoiron(IV) + OH pair, which worked together to afford
hydroxylation of regular and deuterated benzenes with small
KIE’s of 1.05−1.53 in different experiments.57
Our group previously reported preliminary experiments
showing that the relatively fast self-decomposition of complex
2IVO in acetonitrile solution at +20 °C was not accelerated
by added benzene or toluene.10 However, when we tried to
replicate those experiments more recently, we did observe
some acceleration of the bleaching of 2IVO in the presence
of added benzene.58 Complex 1IVO differs from 2IVO by
the presence of electron-donating groups in the ligand
(Scheme 1). Thus, it is expected that complex 2IVO should
be more electrophilic than 1IVO. It should be mentioned
that complex 2IVO has been only cursorily studied,10 and
more experimental work is necessary to determine its actual
reactivity with benzene and other substrates.
The rate of the reaction between complex 1IVO and
cyclohexane (0.099 0.011 M−1 s−1 at +25 °C) reported in
this work is roughly in the middle of the range observed for
oxoiron(IV) species, and the same can be stated about most
other studied substrates taking into account different temper-
atures used (Table 1). Thus, the reactivity of 1IVO with
thioanisole, 1,4-cyclohexadiene, alkenes, and cyclohexane is
reasonable for a low-spin FeIVO complex with a cis-α-
coordinated tetradentate aminopyridine ligand. However, the
observed hydroxylation of benzene by 1IVO is unusual and
may deserve a more detailed study, which is beyond the scope
of this article.
The oxidations of cyclohexane, 1,4-cyclohexadiene, and
thioanisole by different oxoiron(IV) complexes have been
studied extensively, and some kinetic data are summarized in
Table 1. Generally, more stable complexes have been found to
be less reactive. The most stable oxoiron(IV) complex, 4IVO
or trans-[FeIVO(TMC)(MeCN)]2+ (where TMC is 1,4,8,11-
tetramethyl-1,4,8,11-tetraazacyclotetradecane, Figure 1), is also
the least reactive and is not able to hydroxylate unactivated C−
H bonds.28 The change of the macrocyclic ligand topology in
Reaction of 1IVO with H2O2. As mentioned in the
Introduction, we were particularly interested in the reactivity of
1IVO with H2O2, as it had been frequently employed as the
oxidant in catalytic experiments with 1. The O−H bond
dissociation energy of 86 kJ·mol−1 for hydrogen peroxide falls
between the BDE values of cyclohexane and 1,4-cyclo-
hexadiene described above.62 As such, 1IVO was expected
to be capable of H-atom abstraction from H2O2. At −35 °C, 1
F
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mM 1 and 1 mM IBXi‑Pr in acetonitrile were premixed for 1 s,
after which 1−15 equiv of of H2O2 was added in a second
mixing. Decay of the 730 nm oxoiron(IV) chromophore was
rapid (Figures 3 and S21), with a second-order rate constant of
Figure 5. Overlay of the 120 K EPR spectra of 1III−OOH formed by
reductive and oxidative pathways, from 1IVO and 1, respectively.
Orange: reductive, 2.5 equiv of H2O2. Red: reductive, 5 equiv of
H2O2. Blue: reductive, 10 equiv of H2O2. Purple: oxidative, 10 equiv
of H2O2. While possessing the same primary features, the intensity of
the oxidatively formed (purple) spectrum is noticeably greater than
that of the reductively formed (blue) spectrum, corresponding to
∼50% and ∼30% iron, respectively. The feature below 2000 G
belongs to the unidentified Fe(III) byproduct with geff = 4.3.
Figure 3. Decay of 1IVO in the presence of 1 equiv of hydrogen
peroxide. 1IVO was pregenerated from 1 mM 1 and IBXi‑Pr for 1 s at
−35 °C, and then 1 mM H2O2 was added, causing the 730 nm band
of 1IVO to rapidly decay. Inset: Kinetic trace at 730 nm.
44.5 0.8 M−1 s−1 (Figure S22). With only 1 equiv of H2O2,
the 730 nm band was bleached completely, with no features
forming in the visible region following decay of 1IVO
(Figure S23). At higher loadings of H2O2, the growth of an
intense 550 nm band occurred isosbestically as the 730 nm
oxoiron(IV) chromophore decayed (Figure 4). The 550 nm
chromophore has previously been connected to peroxyiron-
(III) species 1III−OOH, a sluggish oxidant but en route to a
highly potent oxoiron(V).10
spin peroxyiron(III) complexes.10,17,21 These signals compare
well to a sample of 1III−OOH generated by the “oxidative”
pathway from mixing 0.4 mL each of 4 mM iron(II) complex 1
and 40 mM H2O2, diluted with 0.8 mL of acetonitrile for 5 s at
−17 °C (Figures 5 and S3). In both the reductively and
oxidatively formed samples of 1III−OOH, an intense broad
signal at geff = 4.3 was also observed, belonging to an
unidentified, unreactive high-spin iron(III) byproduct com-
monly observed in similar systems.63−65 At low H2O2 loadings,
one more signal was observed with geff = 2.42, likely belonging
to iron(III)-hydroxy species 1III−OH.18,66
In quantifying the peroxyiron(III) formed via the two
pathways (“reductive” from 1IVO and “oxidative” from
iron(II) complex 1, with 10 equiv of H2O2 each), we saw a
considerable difference in the amount of EPR-active iron
present in the system. In reference to an acetonitrile solution of
0.125 mM CuII(ClO4)2,67 about 50% of the iron formed from
the reaction of 1 with 10 equiv of H2O2 at −15 °C existed as
1III−OOH, while in the reaction of 1IVO with 10 equiv of
H2O2 at −40 °C, this amount was only ca. 30%, indicating a
substantial loss of EPR-active iron by the “reductive” pathway.
In both cases, the quantity of the geff = 4.3 species is roughly
equivalent at 30 and 27%, respectively, so the loss of EPR-
active iron in the 1IVO-mediated pathway was due to the
formation of some unidentified EPR-silent species, which were
also catalytically inactive (vide infra).
Figure 4. Decay of 1IVO at −15 °C after addition of 10 equiv of
H2O2 in a second mixing. Nearly isosbestic conversion of the 730 nm
band to the 550 nm band resembling 1III−OOH was observed. Inset:
550 nm trace (red) and 730 nm trace (blue).
A similar reactivity of oxoiron(IV) species with H2O2 was
reported previously by Lim and Rohde based on complexes 3
and 4 (Figure 1).18 They started by oxidizing the iron(II)
precursors with PhIO to make acetonitrile solutions of 3IVO
and 4IVO, respectively. Subsequent addition of 0.5 equiv of
The identity of this 550 nm chromophore as 1III−OOH was
confirmed by EPR spectroscopy: First, 0.4 mL each of 4 mM 1
and 4 mM IBXi‑Pr in acetonitrile were mixed at −41 °C in a dry
ice/acetonitrile bath to generate 1IVO; after ca. 2 s, 2.5, 5, or
10 equiv of H2O2 in 0.4 mL of acetonitrile and 0.4 mL of
dichloromethane were added and mixed for ca. 3 s before
freezing in liquid nitrogen (Figures 5, S5, S22, and S23). The
resulting samples were EPR-active and showed a prominent set
of rhombic signals of geff = 2.22, 2.16, and 1.96 consistent with
past reports of analogous 2III−OOH and other known low-
H2O2 to 3IVO yielded a hydroxyiron(III) species with geff
=
2.40, 2.14, 1.94, further supporting the identification of our
observed geff = 2.42 shoulder peak as 1III−OH (vide supra).
With 50 equiv of H2O2, a rhombic EPR signature of g = 2.20,
2.14, and 1.97 with a visible band of λmax = 536 nm was
observed, attributed to 3III−OOH.18 Their proposed mecha-
G
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Table 2. Kinetic Parameters for the Reactions of Oxoiron(IV) Species with H2O2
oxoiron(IV)
second-order rate constant of HAT with H2O2, −20 °C
activation enthalpy
activation entropy
ref
1IVO
3IVO
4IVO
102.6 4.6 M−1 s−1
0.80 0.02 M−1 s−1
0.035 M−1 s−1
22.6 1.3 kJ·mol−1
30.8 0.7 kJ·mol−1
not reported
−151 5 J·mol−1 k−1
−158 2 J·mol−1 k−1
not reported
this work
18
18
nism involved a 2:1 stoichiometric reaction of FeIV with H2O2,
in which one oxoiron(IV) unit abstracted hydrogen from H2O2
yielding hydroxyiron(III) and a superoxy radical HO2 , from
which another oxoiron(IV) unit quickly abstracted the
remaining H atom, ultimately yielding two hydroxyiron(III)
units and a molecule of O2.18 At higher peroxide loadings,
3III−OH was readily transformed into 3III−OOH by labile
ligand substitution (Scheme 1).
IBXi‑Pr were mixed for 1 s to generate 1IVO, and then 1−20
equiv of mCPBA was added. While with H2O2, decay of the
730 nm oxoiron(IV) band took only seconds, no decay of the
730 nm chromophore was observed with mCPBA over a 5 min
period. An analogous experiment with commercial peracetic
acid solution did result in depletion of the 730 nm band.
However, an important consideration is the presence of
hydrogen peroxide in commercial solutions of peracetic acid.
This peracid exists as an equilibrium mixture with H2O2 and
acetic acid, so the residual H2O2 present may in fact be the
source of 1IVO consumption. In support of this hypothesis,
we noted that in the experiment with 1 equiv of peracetic acid
(∼0.33 equiv of H2O2), the 730 nm band did not decay
completely, whereas at all higher concentrations it did. Earlier,
we established a 2:1 stoichiometry for the reaction of 1IVO
with H2O2 (vide supra), so this observation supports the idea
that the peracid is merely a spectator. This may be owed to the
higher O−H bond dissociation energy of peracetic acid (90.4
kJ·mol−1),71 which renders it less capable or incapable of
reacting with 1IVO. Assuming that only H2O2 present in
commercial peracetic acid solution reacted with 1IVO (while
CH3CO2H and CH3CO3H were merely spectators), we
•
In the reaction of H2O2 and 1IVO, we likewise observed
O2 gas evolution (in benchtop experiments) and a 2:1
stoichiometry (in stopped-flow experiments, Figure S25).
Taken together with the consistency of our EPR and UV−
vis measurements, the mechanism of oxoiron(IV) reduction by
H2O2 proposed by Lim and co-workers is likely to occur with
1IVO as well, but with much greater rate constants compared
to 3IVO and 4IVO (Table 2). We also want to note that
the putative oxoiron(V) active species in catalysis, which is far
more effective for HAT and OAT reactions than 1IVO,
should also be able to quickly abstract hydrogen from H2O2,
leading to unproductive and unaccounted H2O2 consumption.
This may explain why catalysts such as 1 and 2 required very
gradual syringe-pump addition of H2O2 for optimal results.14,26
A common thread in the oxidation of different substrates by
oxoiron(IV) species is that 1IVO affords rate constants 2−3
orders of magnitude greater than those reported for more
stable complexes 3IVO and 4IVO (Tables 1 and 2). At
−20 °C, the rate constant for hydrogen abstraction from H2O2
by 1IVO is 103 5 M−1 s−1, which is 130 times greater than
that reported by Lim and Rohde for 3IVO and 2900 times
greater than that for 4IVO (Table 2).
calculated a second-order rate constant of 53.0
8.7 M−1
s−1 at −35 °C (Figure S27), in reasonable agreement with the
value obtained for the reaction of 1IVO with pure H2O2
(44.5 0.8 M−1 s−1 at −35 °C). In a control experiment, no
reaction between 1IVO and acetic acid (O−H BDE 104.7
0.8 kJ·mol−1)72 was observed under stopped-flow double
mixing conditions at −35 or +25 °C. Likewise, experiments
with mCPBA demonstrated no reaction with 1IVO, showing
that peroxycarboxylic acids are not suitable substrates for 1IV
O. This may lend favor to peracids over H2O2 in catalytic
oxidations of organic substrates, as one avenue of inefficient
oxidant consumption is avoided, allowing more oxidant to
partake in the substrate oxidation.
To study the influence of temperature in the range from −35
to −10 °C, we generated 1IVO under stopped-flow
conditions by premixing 1 mM acetonitrile solutions of 1
and IBXi‑Pr until the maximum formation of oxoiron(IV)
intermediate and then added H2O2 (20 equiv) in a second
mixing. From this, we determined an activation enthalpy of
+22.6 1.3 kJ·mol−1 (Figure S24), somewhat lower than that
As stopped-flow UV−vis and EPR data confirmed, 1IVO
in the presence of excess H2O2 is ultimately converted to 1III−
OOH, which has been previously assigned as a precursor to the
putative active oxidant 1VO in catalysis.19 As such, reacting
1IVO with extra H2O2 (the reductive pathway) should afford
a resurgence of catalytic activity comparable to that obtained
via oxidation of 1 with H2O2 (oxidative pathway). To check
this hypothesis experimentally, we studied the hydroxylation of
benzoic acid. Benzoic acid is known to undergo rapid aromatic
hydroxylation at the ortho position with similar oxidizing
systems, resulting in an intense 570 nm iron(III)-salicylate
absorption band.27 In a stopped-flow experiment at −15 °C, 1
mM each 1 and IBXi‑Pr were premixed for 1 s to generate 1IV
O, and then 3−10 equiv of H2O2 and 2 equiv of benzoic acid
were added in a second mixing. The resulting spectra revealed
the expected consumption of 1IVO on reaction with H2O2,
followed by fast growth of the iron(III)-salicylate product, with
slightly offset kinetic traces indicative of two successive
processes (Figure 6). This behavior is similar to our prior
observations for the reaction of oxidatively formed 2III−
OOH27 and the current observation with oxidatively formed
reported for 3IVO in the same reaction (+30.8
0.7 kJ·
mol−1), which may account for the higher reactivity of 1IVO.
The activation entropies for this reaction by 3IVO and 1IV
O are quite similar at −158 2 and −151 5 J·mol−1K−1,
respectively, indicative of a common, associative rate-
determining step.18 In surveying the literature, we could not
find any other detailed kinetic studies of nonheme oxoiron(IV)
reactivity with H2O2, except in the case of dimeric iron(IV)
species reported previously by our group,68 which is beyond
the scope of the current investigation focused on mononuclear
iron complexes.
As 1IVO was quite capable of hydrogen abstraction from
H2O2, the oxidant commonly used in catalysis with 1, a natural
extension of this work was to look at other oxidants which have
been applied in catalysis−peroxycarboxylic acids. These
species, including mCPBA and peracetic acid, can epoxidize
alkenes by themselves, but the reaction is greatly accelerated
and becomes stereoselective in the presence of catalysts like
1.69,70 In a −15 °C stopped-flow experiment, 1 mM 1 and
H
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pathway (mixing of 1, H2O2, and alkene) than that for the
reductive pathway (generation of 1IVO first, followed by the
addition of H2O2 and alkene), with the discrepancy becoming
more apparent at higher loadings (Figure 7). While the
Figure 6. Oxidation of benzoic acid by the reductively formed FeIII−
OOH. 1IVO was generated by mixing 1 and IBXi‑Pr for 1 s at −15
°C, and then adding 2 equiv of benzoic acid and 5 equiv of H2O2 in a
second mixing. Inset: 730 nm (blue) and 570 nm (red) traces.
1III−OOH (Figure S28). Using the established ε(max) ≈ 2300
M−1 cm−1 for the (BPMEN)FeIII-salicylate complexes,27 we
estimated iron(III)-salicylate yields of 79% for the oxidative
pathway and 57% for the reductive pathway. It should be noted
that less than stoichiometric yields arise from tight binding of
the salicylate to FeIII in the product, preventing multiple
turnovers from occurring,10,73 in addition to some iron being
lost unproductively (e.g., to the g = 4.3 species (vide supra)).
As a control, we attempted benzoic acid oxidation by 1IVO
in the absence of H2O2 at +25 °C under stopped-flow
conditions, but no accumulation of the 580 nm iron(III)-
salicylate species was observed, indicating the negligible
oxidation of benzoic acid by 1IVO.
Substoichiometric hydroxylation of benzene exposed to
1III−OOH (based on the growth of a 580 nm band attributed
to the iron(III)-phenolate) was observed for both oxidative
and reductive pathways in stopped-flow experiments. For the
oxidative pathway, 1 mM 1, 10 mM H2O2, and 300 mM
benzene were mixed at +25 °C, with the 580 nm chromophore
of Fe(III)-phenolate forming with a pseudo-first-order rate
constant of 0.127 s−1. By the same procedure, but
pregenerating 1IVO with 1 mM IBXi‑Pr for 0.6 s prior to
adding H2O2 and benzene, the iron(III)-phenolate species
appeared with kobs = 0.0543 s−1, about 58% slower. Still, these
reactions proceeded faster than the comparable reaction of
1IVO with benzene in the absence of H2O2 (kobs = 0.0281
s−1 at the same benzene concentration). It should be noted
that 1III−OOH is not expected to directly hydroxylate benzene
in an acetonitrile solution and that the reaction likely proceeds
via the 1VO intermediate.10
Figure 7. Catalytic cyclooctene epoxidation after formation of 1III−
OOH, either oxidatively (from 1II and H2O2) or reductively (from
1IVO and H2O2). Despite the same concentration of H2O2, the
oxidatively formed pathway consistently yielded greater amounts of
epoxide, with the difference becoming most prominent at higher
concentrations. Bottom: Slope of epoxide formation vs H2O2
concentration. Oxidative slope: 0.47 0.025; reductive slope: 0.24
0.01. The slope for the reductive process is smaller by 51%, likely
reflective of the loss of active iron during the reduction of
oxoiron(IV).
restoration of catalytic activity in alkene epoxidation was
observed on reaction of 1IVO with H2O2, the loss of active
iron during reduction makes this pathway less efficient than
oxidative generation of peroxyiron(III) from the iron(II)
catalyst.
While a resurgence of oxidative activity was observed on
reduction of 1IVO with excess H2O2, it was noted during
EPR studies that ca. 40% less active iron was present via the
reductive pathway as compared to the oxidative pathway. As
such, we expected to see a corresponding difference in catalytic
activity between the two pathways. 1IVO reacted with
cyclohexene relatively slowly at +25 °C yielding primarily
allylic oxidation products and only about 20% of epoxide.
When 1IVO (generated from equimolar amounts of 1 and
IBXi‑Pr in a benchtop experiment) was further mixed with
H2O2 (50 equiv of vs Fe) and then with cyclohexene (50
equiv), analysis of the products showed predominant (>80%
yield) formation of epoxide (Figure S29), as expected for the
iron(III)−iron(V) catalytic cycle in Scheme 1.47 Similar
observations were made in experiments with cyclooctene
(100 equiv): The yield of epoxide was greater for the oxidative
CONCLUSIONS
■
In summary, we have demonstrated that nonheme oxoiron(IV)
complex 1IVO is a potent oxidizing agent able to directly
hydroxylate unactivated C−H bonds in substrates such as
cyclohexane and benzene and epoxidize alkenes, but the rates
of these hydrocarbon oxidation reactions are relatively slow.
More relevant to mechanistic studies of the stereoselective
catalytic system 1/H2O2/alkenes (Scheme 1) is the ability of
1IVO to quickly oxidize H2O2, which had previously only
been studied kinetically for 3IVO and 4IVO. Following
reduction with hydrogen peroxide, 1IVO is converted to
1III−OH, which further converts to 1III−OOH with excess
I
DOI: 10.1021/acs.inorgchem.9b02269
Inorg. Chem. XXXX, XXX, XXX−XXX

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considered in future kinetic studies, as well as the possibility
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source of unproductive oxidant consumption.
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Hydroxylation at a Non-Heme Iron Center: Observed Intermediates
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ASSOCIATED CONTENT
■
́
(11) Dantignana, V.; Milan, M.; Cusso, O.; Company, A.; Bietti, M.;
S
* Supporting Information
Costas, M. Chemoselective Aliphatic C-H Bond Oxidation Enabled
by Polarity Reversal. ACS Cent. Sci. 2017, 3 (12), 1350−1358.
(12) White, M. C.; Zhao, J. Aliphatic C-H Oxidations for Late-Stage
Functionalization. J. Am. Chem. Soc. 2018, 140 (43), 13988−14009.
(13) White, M. C. Adding Aliphatic C-H Bond Oxidations to
Synthesis. Science 2012, 335 (6070), 807−809.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b02269.
Additional experimental details, EPR spectra and their
quantification, ESI-MS and GC-MS spectra, additional
stopped-flow UV−vis spectra, kinetic fittings, Eyring
plots, and second-order rate constant calculations (PDF)
́
(14) Cusso, O.; Garcia-Bosch, I.; Ribas, X.; Lloret-fillol, J.; Costas,
M. Asymmetric Epoxidation with H2O2 by Manipulating the
Electronic Properties of Non-Heme Iron Catalysts. J. Am. Chem.
Soc. 2013, 135 (39), 14871−14878.
́
(15) Cusso, O.; Ribas, X.; Costas, M. Biologically Inspired Non-
AUTHOR INFORMATION
■
Heme Iron-Catalysts for Asymmetric Epoxidation. Chem. Commun.
2015, 51, 14285−14298.
Corresponding Authors
*E-mail: marc.piquette@tufts.edu (M.C.P.).
*E-mail: sergiy.kryatov@tufts.edu (S.V.K.).
ORCID
Marc C. Piquette: 0000-0002-8782-5878
Notes
(16) Serrano-Plana, J.; Aguinaco, A.; Belda, R.; García-Espana, E.;
̃
Basallote, M. G.; Company, A.; Costas, M. Exceedingly Fast Oxygen
Atom Transfer to Olefins via a Catalytically Competent Nonheme
Iron Species. Angew. Chem., Int. Ed. 2016, 55 (21), 6310−6314.
(17) Makhlynets, O. V.; Oloo, W. N.; Moroz, Y. S.; Belaya, I. G.;
Palluccio, T. D.; Filatov, A. S.; Muller, P.; Cranswick, M. A.; Que, L.;
̈
The authors declare no competing financial interest.
Rybak-Akimova, E. V. H2O2 Activation with Biomimetic Non-Haem
Iron Complexes and AcOH: Connecting the g = 2.7 EPR Signal with
a Visible Chromophore. Chem. Commun. 2014, 50 (6), 645−648.
(18) Braymer, J. J.; O’Neill, K. P.; Rohde, J.-U.; Lim, M. H. The
Reaction of a High-Valent Nonheme Oxoiron(IV) Intermediates with
Hydrogen Peroxide. Angew. Chem., Int. Ed. 2012, 51 (22), 5376−
5380.
†Elena V. Rybak-Akimova died on March 11, 2018.
ACKNOWLEDGMENTS
■
Financial supports from the NSF (CHE-1412909) and from
Tufts University are gratefully acknowledged. We also
acknowledge the NSF (CHE-0320783) for their contribution
of the ESI-MS instrument used. We thank Daniel Bowen for
contributions towards preliminary experiments that fell outside
of the scope of this paper and Olga Makhlynets for setting up
the EPR instrument. We also thank the anonymous reviewers
for valuable comments and suggestions.
(19) Oloo, W. N.; Fielding, A. J.; Que, L. Rate-Determining Water-
Assisted O−O Bond Cleavage of an FeIII-OOH Intermediate in a Bio-
Inspired Nonheme Iron-Catalyzed Oxidation. J. Am. Chem. Soc. 2013,
135 (17), 6438−6441.
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