Mononuclear Nonheme High-Spin (S=2) versus Intermediate-Spin (S=1) Iron(IV)–Oxo Complexes in Oxidation Reactions

Article abstract of DOI:10.1002/anie.201603978

Mononuclear nonheme high-spin (S=2) iron(IV)–oxo species have been identified as the key intermediates responsible for the C?H bond activation of organic substrates in nonheme iron enzymatic reactions. Herein we report that the C?H bond activation of hydrocarbons by a synthetic mononuclear nonheme high-spin (S=2) iron(IV)–oxo complex occurs through an oxygen non-rebound mechanism, as previously demonstrated in the C?H bond activation by nonheme intermediate (S=1) iron(IV)–oxo complexes. We also report that C?H bond activation is preferred over C=C epoxidation in the oxidation of cyclohexene by the nonheme high-spin (HS) and intermediate-spin (IS) iron(IV)–oxo complexes, whereas the C=C double bond epoxidation becomes a preferred pathway in the oxidation of deuterated cyclohexene by the nonheme HS and IS iron(IV)–oxo complexes. In the epoxidation of styrene derivatives, the HS and IS iron(IV) oxo complexes are found to have similar electrophilic characters.

Full text of DOI:10.1002/anie.201603978

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International Edition: DOI: 10.1002/anie.201603978
German Edition: DOI: 10.1002/ange.201603978
Bioinorganic Chemistry
Mononuclear Nonheme High-Spin (S = 2) versus Intermediate-Spin
(S = 1) Iron(IV)–Oxo Complexes in Oxidation Reactions
Seong Hee Bae+, Mi Sook Seo+, Yong-Min Lee, Kyung-Bin Cho, Won-Suk Kim, and
Wonwoo Nam*
Abstract: Mononuclear nonheme high-spin (S = 2) iron(IV)–
oxo species have been identified as the key intermediates
reactivity and mechanistic studies were conducted using the
intermediate-spin (IS) iron(IV)–oxo complexes in nonheme
iron models. In contrast, the reactivities of the high-spin (HS)
iron(IV)–oxo complexes in oxidation reactions are poorly
understood. In addition, although it has been proposed in
density functional theory (DFT) calculations that the HS
À
responsible for the C H bond activation of organic substrates
in nonheme iron enzymatic reactions. Herein we report that the
À
C H bond activation of hydrocarbons by a synthetic mono-
nuclear nonheme high-spin (S = 2) iron(IV)–oxo complex
occurs through an oxygen non-rebound mechanism, as
FeIVO complexes are more reactive than the corresponding IS
IV
À
À
previously demonstrated in the C H bond activation by
Fe O complexes in C H bond activation reactions (that is,
nonheme intermediate (S = 1) iron(IV)–oxo complexes. We
exchange-enhanced reactivity),[6] the reactivity differences
between the mononuclear nonheme IS and HS FeIVO
complexes have yet to be demonstrated clearly in experi-
ments. Furthermore, the reaction mechanisms and reactivity
patterns of the IS and HS FeIVO complexes in oxidation
reactions have been rarely compared.[7] Thus, to understand
why mononuclear nonheme iron enzymes utilize HS FeIVO
intermediates in their enzymatic reactions, a mechanistic
comparison of the nonheme IS and HS FeIVO complexes in
À
=
also report that C H bond activation is preferred over C C
epoxidation in the oxidation of cyclohexene by the nonheme
high-spin (HS) and intermediate-spin (IS) iron(IV)–oxo com-
=
plexes, whereas the C C double bond epoxidation becomes
a preferred pathway in the oxidation of deuterated cyclohexene
by the nonheme HS and IS iron(IV)–oxo complexes. In the
epoxidation of styrene derivatives, the HS and IS iron(IV) oxo
complexes are found to have similar electrophilic characters.
À
oxidation reactions is necessary, considering especially the C
H bond activation reactions which are the primary oxidation
reactions executed by nonheme iron enzymes.
M
ononuclear nonheme iron enzymes activate dioxygen
(O2) to carry out metabolically important oxidative trans-
formations by generating high-spin (S = 2) iron(IV)–oxo
intermediates that have been trapped, characterized, and
shown to be competent oxidants in enzymatic reactions.[1] In
2003, the first nonheme iron(IV)–oxo intermediate was
characterized spectroscopically in the reaction of taurine
dioxygenase (TauD) and the first X-ray crystal structure of
a synthetic nonheme iron(IV)–oxo complex, [(TMC)FeIV-
(O)]2+ (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclo-
tetradecane), was reported as a model compound of nonheme
iron enzyme intermediates.[2] Since then, a large number of
mononuclear nonheme iron(IV)–oxo complexes have been
synthesized and investigated intensively to elucidate their
structural and spectroscopic properties as well as to study the
reactivities of the novel iron(IV)–oxo intermediates in
enzymatic reactions.[3] However, more than 90% of the
synthetic nonheme iron(IV)–oxo complexes reported so far
possess an intermediate (S = 1) ground spin state, whereas
only a small number of nonheme high-spin (S = 2) iron(IV)–
oxo complexes have been prepared.[4,5] Moreover, most of the
In 2011, we reported a highly reactive nonheme iron(IV)–
oxo complex with a ground S = 1 spin state [(Me3NTB)FeIV-
(O)]2+ (1; Me3NTB = tris((1-methyl-1H-benzo[d]imidazol-2-
yl)methyl)amine; see Figure 1A,C).[8] This iron(IV)–oxo
complex is the most powerful oxidant among the intermedi-
ate-spin (S = 1) iron(IV)–oxo complexes reported so far.[8]
More recently, Bominaar, Mꢀnck, Que, and co-workers
reported the synthesis of a highly reactive high-spin (S = 2)
iron(IV)–oxo complex by substituting the 1-methyl-1H-
benzo[d]imidazol-2-yl moiety in the Me3NTB ligand with
a quinolin-2-yl group, forming [(TQA)FeIV(O)]2+ (2; TQA =
tris(quinolin-2-ylmethyl)amine; see Figure 1B,D).[5] This
high-spin (S = 2) iron(IV)–oxo complex is the most reactive
nonheme iron(IV)–oxo oxidant reported to date in nonheme
IS and HS iron(IV)–oxo complexes.[5] We therefore used
these nonheme IS and HS FeIVO complexes in reactivity
studies to compare their reaction mechanisms and reactivity
À
patterns in the C H bond activation of alkanes (oxygen
rebound versus oxygen non-rebound), the oxidation of cyclo-
À
=
hexene (C H bond activation versus C C double bond
epoxidation), and the epoxidation of olefins.[9–12] We now
report that the reaction mechanisms and reactivity patterns of
the nonheme IS and HS FeIVO complexes are virtually the
same in those reactions. Mechanistic details for the alkane
hydroxylation, cyclohexene oxidation, and olefin epoxidation
reactions by the IS FeIVO complex [(Me3NTB)FeIV(O)]2+ (1)
and the HS FeIVO complex [(TQA)FeIV(O)]2+ (2) are
discussed in the present study.
[*] S. H. Bae,[+] Dr. M. S. Seo,[+] Dr. Y.-M. Lee, Dr. K.-B. Cho,
Prof. Dr. W.-S. Kim, Prof. Dr. W. Nam
Department of Chemistry and Nano Science
Ewha Womans University
Seoul 03760 (Korea)
E-mail: wwnam@ewha.ac.kr
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603978.
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Figure 1. Structures of Me3NTB (A) and TQA (B) ligands and DFT-
optimized structures of [(Me3NTB)FeIV(O)]2+ (C) and [(TQA)FeIV-
(O)]2+ (D). The coordinates for [(Me3NTB)FeIV(O)]2+ and [(TQA)FeIV-
(O)]2+ were taken from References [8] and [5], respectively. Atom
colors: Fe=gray, O=red, N=blue, C=black.
À
We first considered the C H bond activation of alkanes in
terms of the oxygen rebound versus oxygen non-rebound
À
À
Scheme 1. Proposed mechanisms for A) the C H bond activation of
alkanes, B) the oxidation of cyclohexene and [D10]cyclohexene, and
C) the epoxidation of para-X-substituted styrenes by nonheme IS and
HS FeIVO complexes 1 and 2.
mechanisms. It has been shown that the C H bond activation
of alkanes by nonheme IS FeIVO and other nonheme metal-
(IV)–oxo (M = Cr, Mn, and Ru) complexes occurs by means
of an oxygen non-rebound mechanism,[9,10] not through an
oxygen rebound mechanism as shown in heme iron–oxo
intermediates.[13] We therefore compared the C H bond
a major product (see Table S1) and the oxygens in the
cyclohexanol and cyclohexanone products were found to be
derived from 18O2 (Figure S2). In addition, when we carried
out the hydroxylation of cyclohexane by 1 and 2 in the
presence of CCl3Br under an Ar atmosphere, we detected the
formation of bromocyclohexane (about 55% yield) as the
sole product (Scheme 1A; pathway e). Based on the results of
the 18O2 and CCl3Br experiments, we conclude that after the
FeIVO intermediates abstracted a H atom from cyclohexane
(Scheme 1A; pathway a), a cyclohexanyl radical escaped
from the cage (pathway c) and then was trapped either by 18O2
(pathway d) or by CCl3Br (pathway e).
We also analyzed the decayed iron products of 1 and 2
with electron paramagnetic resonance (EPR) spectroscopy
and cold-spray ionization mass spectrometry (CSI-MS). EPR
spectra of the reaction solutions exhibited signals at g = 7.3,
4.3, and 2.00 for 1 and g = 7.2, 4.3, and 2.00 for 2 (Figure S3),
characteristic of high-spin FeIII species (S = 5/2), demonstrat-
ing that iron(III) species were formed as the major products
in the hydroxylation of cyclohexane by 1 and 2. Furthermore,
upon addition of decamethylferrocene (Me10Fc) to the
resulting solutions (Scheme 1A; pathway f), the EPR spectra
became silent (see insets in Figure S3), indicating that the FeIII
species were reduced to FeII species by the one-electron
reductant. In the CSI-MS experiments, we detected ion peaks
at mass-to-charge ratios m/z = 671.1 and 261.1 in the reaction
À
activation mechanism(s) of nonheme IS and HS FeIVO
complexes by carrying out the hydroxylation of cyclohexane
by 1 and 2 under various reaction conditions, such as under an
Ar atmosphere, under an 18O-labeled dioxygen (18O2) atmos-
phere, and in the presence of an alkyl radical scavenger
(CCl3Br; Scheme 1A).
The nonheme iron(IV)–oxo complexes 1 and 2 were
prepared using the reported procedures.[5,8] Upon addition of
cyclohexane to the solutions of 1 and 2 at À408C, intermedi-
ates 1 and 2 disappeared with the first-order kinetic profile
(see Figure S1 in the Supporting Information). The product
analysis of the reaction solutions revealed the formation of
cyclohexanol (24 Æ 3%), cyclohexanone (3 Æ 2%), and cyclo-
hexene (15 Æ 2%) in the reaction of 1, whereas in the reaction
of 2, cyclohexanol (27 Æ 4%), cyclohexanone (5 Æ 3%), and
cyclohexene (17 Æ 3%) were formed (Table S1). It is of
interest to note that in addition to the hydroxylated products,
a significant amount of a desaturated product (that is,
cyclohexene) was formed in these reactions (it has been
reported that heme and nonheme iron–oxo intermediates
produce desaturated products in the hydroxylation of alka-
nes).[9,14] Interestingly, when the hydroxylation of cyclohexane
by 1 and 2 was carried out in the presence of 18O2
(Scheme 1A; pathway d), the product distribution was
changed. Specifically, cyclohexanone was obtained as
2
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of 1 and cyclohexane (Figure S4a). These ion peaks corre-
spond to [FeIII(OH)(Me3NTB)(CF3SO3)]+ (calculated m/z =
671.1) and [FeIII(OH)(Me3NTB)]2+ (calculated m/z = 261.1),
respectively. In the reaction of 2 and cyclohexane, we detected
one ion peak at m/z = 662.1 (Figure S4b), which corresponds
to [FeIII(OH)(TQA)(CF3SO3)]+ (calculated m/z = 662.1).
Based on the spectroscopic analyses of iron products using
EPR and CSI-MS, we conclude that FeIII species, not FeII
species, were formed as the decayed products of 1 and 2
(Scheme 1A, pathways a,c).
À
For the C H bond activation of alkanes, the experimental
evidence supports an oxygen non-rebound mechanism by
nonheme IS and HS FeIVO complexes (Scheme 1A, path-
ways a and c) rather than the oxygen rebound mechanism
(Scheme 1A, pathways a and b), corresponding to previous
work by us and others on the hydroxylation of alkanes by
nonheme metal(IV)–oxo and metal(V)–oxo complex-
es.[7a,9,10,12,15]
Figure 2. Plots of pseudo-first-order rate constants (kobs) against
concentrations of cyclohexene (black line for 1 and blue line for 2) and
[D10]cyclohexene (red line for 1 and green line for 2). The plots are
used to determine second-order rate constants (k2) in the oxidation of
cyclohexene and [D10]cyclohexene by 1 and 2 in CH3CN at À408C.
We next considered chemoselectivity in the oxidation of
cyclohexene, focusing on whether the reaction occurs through
Table 1: Products obtained in the oxidation of cyclohexene and
[D10]cyclohexene by 1 and 2.[a]
À
=
C H bond activation or C C double bond epoxidation. We
Substrate
Product Yield [%]
À
have previously shown that C H bond activation is preferred
=
over C C double bond epoxidation in the oxidation of
cyclohexene by nonheme IS FeIVO and other MIVO com-
=
plexes (Scheme 1B, pathway a), whereas the C C double
bond epoxidation is the preferred pathway in the oxidation of
deuterated cyclohexene ([D10]cyclohexene; Scheme 1B, path-
way b).[10] In the present study, we compared the chemo-
selectivity in the oxidation of cyclohexene and
[D10]cyclohexene by nonheme IS and HS FeIVO complexes
1 and 2 (Scheme 1B). Upon addition of cyclohexene to
a solution of 1, the absorption band at l = 770 nm attributable
to 1 disappeared with the first-order kinetic profile (Fig-
ure S5a). Pseudo-first-order rate constants, determined by
the first-order fitting of the kinetic data for the decay of 1 (see
Figure S5a, inset), increased linearly with the increase of the
cyclohexene concentration (Figure 2, black line), giving
a second-order rate constant of 17(2) mÀ1 sÀ1 at À408C.
When 1 was reacted with [D10]cyclohexene, 1 decayed much
1
2
cyclohexene
[D10]cyclohexene
cyclohexene
N.D.
34(3)
N.D.
30(4)
27(3)
25(3)
23(3)
17(4)
11(3)
4(2)
14(3)
8(2)
[D10]cyclohexene
[a] Reactions were run with intermediates 1 or 2 (1.0 mm) and substrates
cyclohexene or [D10]cyclohexene (100 mm) under an Ar atmosphere in
CH3CN at À408C. Values in parentheses indicate the estimated standard
deviations. N.D.=not detected.
[D10]cyclohexene by 1 and 2 led primarily to the formation of
the epoxide. These results imply that the cyclohexene
oxidation by 1 and 2 occurs mainly through the C H bond
activation pathway (Scheme 1B, pathway a), whereas the
À
more slowly, giving
a
second-order rate constant of
2.1(2) MÀ1 sÀ1 at À408C (Figure 2, red line). Thus, the reaction
of 1 with cyclohexene was 8.1(6) times faster than that of
1 with [D10]cyclohexene.
[D10]cyclohexene oxidation by 1 and 2 preferentially occurs
=
À
through C C double bond epoxidation with concurrent C H
bond activation (Scheme 1B, pathway b). We previously
proposed that this change of mechanisms in the oxidation of
cyclohexene and [D10]cyclohexene by nonheme MIVO com-
plexes is due to the different C H(D) bond strengths of the
allylic C H and C D bonds in the substrates.
We also analyzed the iron products obtained in the
oxidation of cyclohexene and [D10]cyclohexene by 1 and 2.
First, in the oxidation of cyclohexene by 1 and 2, EPR spectra
of the reaction solutions exhibited signals at g = 7.4, 4.3, and
2.00 for 1 and g = 9.2, 4.3, and 2.00 for 2 (Figure S6, black
lines), characteristic of high-spin FeIII species (S = 5/2). In
CSI-MS experiments, we detected ion peaks at mass-to-
charge ratios m/z = 671.1 and 261.1 in the reaction of 1 and
cyclohexene (Figure S7a). These ion peaks correspond to
[FeIII(OH)(Me3NTB)(CF3SO3)]+ (calculated m/z = 671.1)
and [FeIII(OH)(Me3NTB)]2+ (calculated m/z = 261.1), respec-
A similar reactivity pattern was detected in the oxidation
of cyclohexene and [D10]cyclohexene by a HS FeIVO complex
2. Upon addition of cyclohexene and [D10]cyclohexene to
a solution of 2 at À408C, the absorption band at l = 650 nm
corresponding to 2 disappeared (Figure S5b). The pseudo-
first-order rate constants increased linearly with the increase
of the substrate concentrations to give second-order rate
constants of 1.2(1) ꢁ 102 and 5.1(4) mÀ1 sÀ1 in the reactions of
cyclohexene and [D10]cyclohexene, respectively (Figure 2,
blue and green lines). Thus, 2 reacted with cyclohexene
24(2) times faster than with [D10]cyclohexene.
We then analyzed products formed in the oxidation of
cyclohexene and [D10]cyclohexene by 1 and 2 under an Ar
atmosphere (Table 1). The oxidation of cyclohexene by 1 and
2 afforded allylic oxidation products predominantly (namely
cyclohexenol and cyclohexenone). In contrast, oxidation of
À
[10b,11]
À
À
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tively. In the case of 2, we detected one ion peak at m/z =
662.1 (Figure S7b), which corresponds to [FeIII(OH)(TQA)-
(CF3SO3)]+ (calculated m/z = 662.1). In the oxidation of
[D10]cyclohexene by 1 and 2, intensities of the EPR signals
corresponding to high-spin FeIII species (S = 5/2) were weaker
than those obtained in the cyclohexene oxidation reactions
(Figure S6, red lines). This observation implies that EPR-
silent FeII species were also formed in the [D10]cyclohexene
reactions (see below). In the CSI-MS experiments, in addition
to the ion peaks corresponding to FeIII species, ion peaks
corresponding to FeII species were also present (data not
shown). Thus, based on the spectroscopic analyses of the
reaction solutions, we conclude that FeIII species, not FeII
species, were formed as the products in the oxidation of
cyclohexene by 1 and 2 (Scheme 1B, pathway a). In contrast,
both FeIII and FeII species were formed in the oxidation of
[D10]cyclohexene by 1 and 2 (Scheme 1B, pathway b). These
results should also be considered in terms of the detection of
Figure 3. Plots of logk2 against Eox values for 4-X-styrenes (X=MeO,
Me, H, Cl, and NO2) and 3-Cl-styrene in the oxidation reactions of
styrene derivatives by 1 (solid line) and 2 (dotted line) in CH3CN at
À408C. SCE=standard calomel electrode.
mechanisms and reactivity patterns of the nonheme IS and
IV
FeIII species as the product of C H bond activation (see
HS Fe O complexes are not different in the C H bond
À
À
above) and FeII species as the product of C C double bond
activation of alkanes, the oxidation of cyclohexene, and the
epoxidation of styrene derivatives. However, the question still
remains as to why mononuclear nonheme iron enzymes use
HS FeIVO intermediates in their enzymatic oxidation reac-
tions. This is a key issue that should be addressed in future
biological and biomimetic studies of nonheme iron enzymes.
=
epoxidation (see below for the epoxidation of styrene).
Finally, we considered the role of nonheme IS and HS
FeIVO complexes 1 and 2 in the epoxidation of styrene and
deuterated styrene [D8]styrene. In these reactions, the
reactivity of 1 was greater than that of 2, in contrast to that
À
detected for the C H bond activation of alkanes and the
oxidation of cyclohexene (see above). We also found that for
complexes 1 and 2 the rates of the oxidation of styrene and
[D8]styrene were the same (kinetic isotope effect KIE = 1; see
Figure S8). We also observed this effect in the reaction of
nonheme FeIVO and RuIVO complexes.[10b,11] Product analysis
of the reaction solutions revealed that styrene oxide was the
predominant product (Table S1). The source of the oxygen
atom in the styrene oxide was found to be the FeIVO
complexes, not 18O2, when the styrene epoxidation by 1 and
2 was carried out under an 18O2 atmosphere (Figure S9). In
addition, the decayed iron products of 1 and 2 were FeII
species when the reaction solutions were analyzed by EPR
spectroscopy; EPR spectra of the reaction solutions were
silent (see Figure S6, blue lines). These results demonstrate
that 1 and 2 oxidized styrene to styrene oxide through the
Acknowledgements
The authors acknowledge financial support from the NRF of
Korea through the CRI (NRF-2012R1A3A2048842 to W.N.),
the GRL (NRF-2010-00353 to W.N.), and the MSIP (NRF-
2013R1A1A2062737 to K.-B.C.).
À
Keywords: bioinorganic chemistry · C H activation · iron ·
metalloenzymes · reaction mechanisms
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4
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Received: April 25, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Bioinorganic Chemistry
Biomimetics: The reactivities of synthetic
mononuclear nonheme high-spin (S=2)
and intermediate-spin (S=1) iron(IV)–
oxo complexes were studied. The com-
plexes were found to exhibit similar
S. H. Bae, M. S. Seo, Y.-M. Lee, K.-B. Cho,
W.-S. Kim, W. Nam*
&&&& — &&&&
Mononuclear Nonheme High-Spin (S=
2) versus Intermediate-Spin (S=1)
Iron(IV)–Oxo Complexes in Oxidation
Reactions
reaction mechanisms and reactivity pat-
À
terns in a C H bond activation reaction
of alkanes, the oxidation of cyclohexene,
and the epoxidation of styrene.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!