Hydroxylation versus Halogenation of Aliphatic C?H Bonds by a Dioxygen-Derived Iron–Oxygen Oxidant: Functional Mimicking of Iron Halogenases

Article abstract of DOI:10.1002/anie.201509914

An iron–oxygen intermediate species generated in situ in the reductive activation of dioxygen by an iron(II)–benzilate complex of a monoanionic facial N₃ligand, promoted the halogenation of aliphatic C?H bonds in the presence of a protic acid and a halide anion. An electrophilic iron(IV)–oxo oxidant with a coordinated halide is proposed as the active oxidant. The halogenation reaction with dioxygen and the iron complex mimics the activity of non-heme iron halogenases.

Full text of DOI:10.1002/anie.201509914

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Communications
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International Edition: DOI: 10.1002/anie.201509914
German Edition: DOI: 10.1002/ange.201509914
Biomimetic Oxidation
À
Hydroxylation versus Halogenation of Aliphatic C H Bonds by
a Dioxygen-Derived Iron–Oxygen Oxidant: Functional Mimicking of
Iron Halogenases
Sayanti Chatterjee and Tapan Kanti Paine*
Abstract: An iron–oxygen intermediate species generated in
situ in the reductive activation of dioxygen by an iron(II)–
benzilate complex of a monoanionic facial N ligand, pro-
3
moted the halogenation of aliphatic CÀH bonds in the presence
of a protic acid and a halide anion. An electrophilic iron(IV)–
oxo oxidant with a coordinated halide is proposed as the active
oxidant. The halogenation reaction with dioxygen and the iron
complex mimics the activity of non-heme iron halogenases.
D
ioxygen-activating non-heme iron enzymes exhibit versa-
tile reactivity, such as halogenation, hydroxylation, desatura-
Scheme 1. Reaction catalyzed by non-heme iron(II)/a-ketoglutarate-
dependent halogenases.
tion, cyclization, ring-expansion, epoxidation, cis-dihydroxy-
lation, and oxo-transfer activity.
[1–3]
These reactions are
essential in the synthesis of important biomolecules and in
bioremediation processes. In many of these biological oxida-
tions, high-valent iron–oxo species have been invoked as key
halide ligand results in a halogenated product through
[
5]
a stepwise radical pathway (Scheme 1).
Although a number of synthetic models
[
4,5]
[19,20]
intermediates. For the four-electron reduction of dioxygen,
reducing equivalents required are supplied by organic and/or
metal cofactors. The reductants (cofactors) in the non-heme
of the cis-
iron(IV)–oxo–halide species observed in non-heme halogen-
ases have been reported, their use in CÀH bond halogenation
[2]
enzyme family include a-ketoglutarate, tetrahydrobiop-
reactions remains unexplored. The involvement of iron(IV)–
oxo complexes in electron-transfer reactions with halides has
[
6]
[7]
terin, and ascorbic acid. In a-ketoglutarate-dependent
oxygenases, the iron-coordinated a-ketoglutarate cofactor
provides two electrons for dioxygen reduction at the iron
center, thus resulting in the generation of an active iron(IV)–
[
21]
also been documented.
However, examples of struc-
[22,23]
tural
are rare.
and functional mimics of non-heme halogenases
[24–26]
Although high-valent iron–oxo species have
[1,2,8,9]
[27]
oxo oxidant, carbon dioxide, and succinate.
The iron–
been proposed to participate in the halogenation of alkanes
by biomimetic iron complexes with hydrogen peroxide or
alkyl hydroperoxides, there has been no study reported on the
use of non-heme iron complexes to mimic the function of iron
halogenases with dioxygen as the oxidant.
oxo oxidant then hydroxylates the CÀH bond of substrates.
Direct evidence of high-valent iron–oxo intermediates have
been found in the enzymatic reactions of several a-keto-acid-
[5,10,11]
dependent oxygenases.
The non-heme iron(II)/a-keto-acid-dependent halogen-
ases SyrB2 and CytC3 catalyze the chlorination of threonine
in syringomycin E biosynthesis and multiple chlorination of
the terminal methyl group in l-aminobutyrate, respec-
Dioxygen activation by non-heme iron(II) complexes in
the presence of electron and proton sources has been
reported to lead to the formation of different iron–oxygen
[28–33]
intermediates.
The reactivity of iron–oxygen oxidants
[
12–15]
tively.
Enzymatic studies have revealed that the a-
generated in the reductive activation of dioxygen by
Ph2
II
ketoglutarate-dependent hydroxylases and halogenases
involve hydrogen-abstracting iron(IV)–oxo oxidants in the
an iron(II)–benzilate complex, [(Tp )Fe (benzilate)]
Ph2
(1; Tp = hydrotris(3,5-diphenyl-pyrazol-1-yl)borate), has
[16,17]
[34–36]
reaction pathway (Scheme 1).
However, substrate posi-
been investigated by us (Scheme 2).
A nucleophilic
tioning directs the reaction toward halogenation or hydrox-
ylation. Abstraction of a hydrogen atom by a non-heme cis-
iron(IV)–oxo–halide intermediate followed by rebound of the
iron(II)–hydroperoxo species was proposed to form in the
oxidative decarboxylation of the iron(II)–benzilate complex.
In the presence of a Lewis acid, the complex generates an
[
18]
electrophilic
iron(IV)–oxo–hydroxo
oxidant,
which
exchanges its oxygen atoms with water. The electrophilic
oxidant performs a range of selective oxidation reactions,
such as oxo-atom transfer to sulfides, the cis-dihydroxylation
[
*] S. Chatterjee, Dr. T. K. Paine
Department of Inorganic Chemistry
Indian Association for the Cultivation of Science
[36]
of alkenes, and the oxygenation of aliphatic CÀH bonds.
Computational analyses have previously indicated that the
2
A & 2B Raja S. C. Mullick Road, Jadavpur, Kolkata-700032 (India)
proton-mediated heterolytic OÀO bond cleavage of iron(II)–
E-mail: ictkp@iacs.res.in
hydroperoxo species has a lower energy barrier than that of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509914.
[37,38]
iron(III)–hydroperoxide intermediates.
In analogy to the
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that observed in the reaction of 1 with O in the presence or
2
[35,36]
absence of Lewis acids.
To probe the nature of the iron–oxygen intermediate
formed in the presence of a proton source, we carried out
interception experiments with various external substrates.
The reaction of complex 1 with thioanisole (1 equiv) and
pyridinium perchlorate (2 equiv) afforded thioanisole oxide
(36%) as the sole product (see Figure S1 in the Supporting
Information), whereby 55% intraligand hydroxylation oc-
curred. However, the amount of pyridinium perchlorate
controlled the selectivity for the formation of the sulfoxide
versus the sulfone. In the oxidation of thioanisole, about
2
equivalents of pyridinium perchlorate were needed to fully
Scheme 2. Proposed iron–oxygen oxidants formed in the reaction
between complex 1 and O2.
inhibit the formation of sulfones (see Figure S2). In the
presence of 10 equivalents of thioanisole, no intraligand
hydroxylation was observed, and the yield of thioanisole
oxide was found to be 90% (Table 1; see also Scheme S1 in
reactivity of the iron(II)–benzilate complex in the presence of
a Lewis acid, it was expected that the nucleophilic oxidant
derived from 1 would undergo heterolytic OÀO bond
1
6
the Supporting Information). A labeling experiment with O
2
18
and H2 O revealed 24% incorporation of the labeled oxygen
atom into thioanisole oxide (Table 1). Hammett analysis with
various para-substituted thioanisoles showed a 1 value of
À1.71, thus supporting the electrophilic nature of the oxidant
(Figure 2). Thus, similar to that formed in the presence of
cleavage in the presence of a protic acid to generate an
electrophilic oxidant. Therefore, the main objective of the
present study was to explore the reactivity of complex 1 in the
presence of a protic acid and its implications for the
halogenation of aliphatic CÀH bonds with suitable external
[36]
a Lewis acid, the iron–oxygen oxidant formed from 1 in the
presence of a protic acid has electrophilic character.
halide sources.
The reaction between complex 1 and O in the presence of
equivalents of pyridinium perchlorate (or 2 equivalents of
lutidinium perchlorate) yielded benzophenone quantitatively
along with 90% intraligand hydroxylation in 20 min
The nucleophilic iron(II)–hydroperoxide derived from 1,
whose oxygen atoms do not exchange with water, was
previously found to oxidize alkenes to the corresponding cis
2
2
[
35]
diols in high yields.
The electrophilic iron(IV)–oxo–
(
Figure 1). The optical spectrum of the oxidized solution
hydroxo oxidant, formed in the presence of a Lewis acid,
also efficiently participates in the cis-dihydroxylation of
alkenes with partial incorporation of the labeled oxygen
showed a broad absorption band at 640 nm attributable to the
phenolate-to-iron(III) charge-transfer (CT) transition. The
CT band, however, is shifted to lower energy as compared to
18
[36]
atom from H2 O.
Intriguingly, when complex 1 reacted
with alkenes in the presence of a protic acid (2 equiv), the
oxidant thus formed oxidized alkenes to epoxides instead of
cis diols (Table 1; see also Scheme S1). With a low concen-
tration of the protic acid, however, a small amount of the diol
was observed along with the epoxide. Approximately 2 equiv-
alents of the protic acid (pyridinium perchlorate) were
needed for complete inhibition of the cis-dihydroxylation of
alkenes (see Figure S3). With cyclooctene as the substrate
(100 equiv), cyclooctene oxide was formed to an extent of
7
1
0% (Table 1; see also Figure S4). The reaction of complex
with 1-octene (100 equiv) afforded 1,2-epoxyoctane in 67%
yield (Table 1; see also Figure S5). Styrene (100 equiv) was
converted into styrene epoxide in 75% yield along with
benzaldehyde in 20% yield (Table 1; see also Figure S6).
When cyclohexene (100 equiv) was used to intercept the
active oxidant, the corresponding products of allylic oxida-
tion, that is, 2-cyclohexenone (35%) and 2-cyclohexenol
(22%), were formed along with a trace amount of cyclo-
hexene oxide (5%; Table 1; see also Figure S7).
Figure 1. Optical spectra of 1 (0.5 mm in benzene) before the reaction
with O (dotted line with circles) and after the reaction with O in the
2
2
[
36]
18
presence of Sc(OTf) (1 equiv; dashed line), in the presence of
3
A labeling experiment for styrene oxidation with H2 O in
pyridinium perchlorate (PyNHClO , 2 equiv; dotted line with triangles),
4
the presence of pyridinium perchlorate (2 equiv) confirmed
about 35% incorporation of labeled oxygen into the epoxide
product (Table 1; see also Figure S8). In the case of cyclo-
and in the presence of PyNHClO (2 equiv) and tetrabutylammonium
4
chloride (Bu NCl, 2 equiv; solid line). Inset: ESI mass spectrum of the
4
final oxidized solution after the reaction of 1 in the presence of
18
16
Ph2*
hexene, a labeling experiment with H2 O/ O showed the
PyNHClO (2 equiv) and Bu NCl (2 equiv). Tp
is the modified form
2
4
4
Ph2
of Tp in which one ortho position of one of the phenyl rings is
incorporation of 18% labeled oxygen into 2-cyclohexenone,
and around 26% incorporation each into 2-cyclohexenol and
hydroxylated.
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[a]
Table 1: Reactivity of complex 1 toward various substrates under different conditions.
Substrate
External additive(s)
Product(s)
Yield [%]
Intraligand
hydroxylation
[%]
1
8
(
O incorporation
1
8
[b]
from H2 O [%])
thioanisole
PyNHClO4
thioanisole oxide
thioanisole oxide
cyclooctene oxide
1,2-epoxyoctane
90 (24)
0
0
PyNHClO + Bu NCl
92
70
67
4
4
cyclooctene
PyNHClO4
20
23
0
1
-octene
PyNHClO4
PyNHClO4
styrene
styrene epoxide
benzaldehyde
75 (35)
20 (13)
cyclohexene
PyNHClO4
2-cyclohexenone
35 (18)
22 (26)
5 (26)
26
24
2
-cyclohexenol
cyclohexene oxide
PyNHClO + Bu NCl
2-cyclohexenone
29
15
22
4
4
2
3
-cyclohexenol
-chlorocyclohexene
adamantane
cyclohexane
toluene
PyNHClO4
1-adamantanol
-adamantanol
47 (22)
18 (24)
25
31
38
33
28
32
2
PyNHClO + Bu NCl
1-adamantanol
-chloroadamantane
45
12
4
4
1
PyNHClO4
cyclohexanol
cyclohexanone
45 (20)
8 (18)
PyNHClO + Bu NCl
cyclohexanol
cyclohexanone
51
6
4
4
PyNHClO4
benzaldehyde
benzyl alcohol
37
25
PyNHClO4
benzaldehyde
benzyl alcohol
benzyl chloride
26
13
20
+
Bu NCl
4
1
2
,4-cyclohexadiene
PyNHClO4
benzene
cyclohexa-2,5-dienol
65
20
7
7
PyNHClO + Bu NCl
benzene
cyclohexa-2,5-dienol
38
18
27
4
4
3
-chlorocyclohexa-1,4-diene
,4,6-trimethylbenzoic acid
PyNHClO + Bu NCl
2-(chloromethyl)-4,6-dimethylbenzoic acid
,7-dimethylisobenzo-furan-1(3H)-one
15
12
60
4
4
5
1
8
[
a] Experimental conditions: Complex 1 (0.02 mmol), substrate (10–100 equiv), PyNHClO (2 equiv), Bu NCl (2 equiv). [b] H O (60 equiv with
4 4 2
respect to complex 1) was used for labeling experiments.
cyclohexene oxide (Table 1; see also Figure S9). In intercep-
tion experiments with alkenes, intraligand hydroxylation to
an extent of 20–25% was estimated (Table 1). However, no
ligand hydroxylation took place when styrene was used as
a substrate (Table 1). With a protic acid, therefore, a different
oxidant is generated and carries out olefin epoxidation
instead of cis-dihydroxylation. This switching behavior bears
resemblance to the “chameleonic reactivity” of non-heme
epoxidation reactions have also been reported with high-
valent iron–oxo intermediates generated in situ from model
complexes of a-keto-acid-dependent oxygenases.
[
40]
The electrophilic oxidant generated with pyridinium
perchlorate oxygenated adamantane (50 equiv) to afford 1-
adamantanol (47%) and 2-adamantanol (18%; Table 1; see
also Scheme S1 and Figure S10). In the reaction, ring
Ph2
hydroxylation of the Tp ligand occurred to an extent of
[39]
iron catalysts reported by Que and co-workers. Moreover,
25% (Table 1). Cyclohexane was oxidized to cyclohexanol
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The reactivity toward different alkanes and alkenes of the
oxidant generated in the presence of halide ions was tested.
Interestingly, aliphatic CÀH bond halogenation was observed
as well as CÀH bond hydroxylation (Table 1 and Scheme 3).
For substrates such as adamantane, cyclohexene, and toluene,
around 25–32% intramolecular ligand hydroxylation took
place (Table 1). The reaction of
1
with adamantane
(
(
50 equiv), pyridinium perchlorate (2 equiv), and Bu NCl
2 equiv) gave 1-chloroadamantane (12%; see Figure S13a)
4
and 1-adamantanol (45%). With toluene (50 equiv), benzyl
chloride (20%) was formed (see Figure S13b) along with
benzaldehyde and benzyl alcohol. The reaction of cyclo-
hexene (100 equiv) led to 3-chlorocyclohexene (22%; see
Figure S13c) along with 2-cyclohexenol and 2-cyclohexenone.
When 1,4-cyclohexadiene (100 equiv) was used as a substrate,
the corresponding unsaturated chlorinated product (see Fig-
ure S13d) was formed along with cyclohexa-2,5-dienol and
benzene. The reaction of cyclohexane, which has strong CÀH
Figure 2. Hammett plots of logkrel versus s for p-X-C H SMe for the
1
6
4
reaction of 1 with PyNHClO (2 equiv; straight line) and with PyNH-
4
ClO (2 equiv) and Bu NCl (2 equiv; dotted line). The k values
4
4
rel
represent the ratio of the concentration of the product from para-
substituted thioanisole and the concentration of the product from
thioanisole.
bonds, afforded a mixture of cyclohexanol (51%) and cyclo-
hexanone (6%) without any halogenated product. 2,4,6-
(
45%) and cyclohexanone (8%; Table 1; see also
Figure S11). The reaction of complex 1 with tolu-
ene (50 equiv) yielded a mixture of benzaldehyde
(
37%) and benzyl alcohol (25%; Table 1; see also
Figure S12). For cyclohexane oxidation, the label-
ing experiment revealed (20 Æ 2)% incorporation
18
of the labeled oxygen atom from H2 O into both
cylohexanol and cyclohexanone (Table 1). In the
reaction with adamantane, about (22 Æ 2)% incor-
poration of the labeled oxygen atom into the
oxygenated products took place (Table 1; see also
Scheme S1). The data from labeling experiments
clearly indicate that the oxidant can exchange its
oxygen atoms with water.
When the reaction of complex 1 was carried out
with O and pyridinium perchlorate (2 equiv) in the
2
presence
2 equiv), benzophenone was formed in quantita-
tive yield. The optical spectrum of the final reaction
of
tetrabutylammonium
chloride
Scheme 3. Halogenation/oxygenation of different substrates with O by complex
2
(
1
(0.02 mmol) in the presence of a proton source (2 equiv) and a suitable external
halide source (2 equiv). Values in the brackets indicate the yields of products when
solution exhibited a charge-transfer chromophore X=Br.
at around 510 nm (Figure 1). The optical spectrum
and the ESI mass spectrum (m/z = 740) of the final
reaction solution support the formation of an iron(III)–
Trimethybenzoic acid, which contains both aliphatic (ben-
Ph2* [35,36]
phenolate complex of the hydroxylated ligand (Tp ).
zylic) and aromatic CÀH bonds, was used as a substrate to
The observed shift of the CT band to higher energy relative to
ensure that the putative iron–oxo–halo oxidant selectively
III
Ph2*
those of the Fe (Tp ) complex formed from 1 in the
absence of chloride suggests the coordination of a chloride
ligand. A Hammett plot for the oxidation of various para-
substituted thioanisoles gave a 1 value of À2.69, which clearly
indicates that the oxidant formed in the presence of protons
and chloride anions is much more electrophilic for the oxo-
transfer reaction to sulfides (Figure 2). The coordination of
a weak donor chloride ligand decreases the electron density at
the iron center of the oxidant, thus resulting in higher
electrophilicity as compared to that of the electrophilic
oxidants formed in the presence of a Lewis acid or protic
acid only.
halogenates the aliphatic CÀH bonds over aromatic CÀH
bonds. In the reaction with 1, 2,4,6-trimethylbenzoic acid
formed only the product of halogenation of one of the
benzylic CÀH bonds (15%; Scheme 3 and Table 1; see also
Figure S14). In that case, no aromatic CÀH bond halogen-
ation was observed. The steric bulk of the substrate prevents
it from coming closer to the oxidant, and thus the oxidant
preferentially participates in intraligand hydroxylation
(Table 1). Notably, in all cases, the yield of halogenated
products was the same if pyridinium chloride was used instead
of a mixture of pyridinium perchlorate and tetrabutylammo-
nium chloride.
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When tetrabutylammonium bromide was used as the
putative iron(IV)–oxo–halo species then participates in the
halide source, the corresponding brominated products were
formed. However, the yields of brominated products are
found to be low as compared to the chlorinated products
halogen-transfer reaction as well as CÀH bond-cleavage
reactions. Complex 1 is capable of carrying out the aliphatic
CÀH bond halogenation of substrates such as adamantane,
(
Scheme 3). Although the overall yields of halogenated
toluene, cyclohexene, 1,4-cyclohexadiene, and 2,4,6-trime-
thylbenzoic acid, but not that of cyclohexane. Enzymatic
halogenation reactions are controlled by positioning the
reactive CÀH bond of the substrate closer to the halogen
products were low (ca. 25–30%), the iron complex reported
herein is the first model system that exhibits halogenase
activity with molecular oxygen. Neither the nucleophilic
oxidant nor the electrophilic oxidant generated from 1 with
a Lewis acid could halogenate aliphatic CÀH bonds.
[
18]
atom of the oxidant.
Although a halogenation reaction
[14]
would be expected to occur preferentially, the CÀH bond of
From the above experimental results, it is evident that the
electrophilic oxidant generated from 1 in the presence of
protons and halide anions is distinctly different from the
electrophilic iron(IV)–oxo–hydroxo intermediate intercepted
in the presence of a Lewis acid. The experimental results in
the present study unambiguously prove that protons can
facilitate heterolytic OÀO bond cleavage to generate an
electrophilic oxidant. To cleave the OÀO bond of iron(II)–
cyclohexane is probably directed away from the halogen atom
of the proposed iron(IV)–oxo–halide oxidant.
In summary, we have investigated the reactivity of
a biomimetic iron(II)–benzilate complex supported by a tris-
(pyrazolyl)borate ligand in the presence of a protic acid.
Mechanistic studies suggest the in situ formation of an
electrophilic iron(IV)–oxo–aquo oxidant from the iron(II)
complex in the presence of a proton source. The electrophilic
oxidant participates in epoxidation reactions instead of the
cis-dihydroxylation of alkenes. It also activates the strong CÀ
hydroperoxo species, 1 equivalent of the proton source should
theoretically be sufficient. However, our experimental results
reveal that 2 equivalents of pyridinium perchlorate are
required to fully inhibit the formation of the sulfone in the
oxidation of thioanisole and to fully inhibit the formation of
the cis diol in the oxidation of alkenes. The additional proton
might be involved in polarizing the protonated hydroperoxide
species through a second-sphere interaction leading to
heterolytic cleavage of the OÀO bond to form an iron(IV)–
H bonds of alkanes. The formation of halogenated organic
products from substrates containing aliphatic CÀH bonds
supports the in situ generation of an iron(IV)–oxo–halo
intermediate in the presence of an external halide source.
Although there is no direct experimental evidence for the
proposed intermediates, indirect evidence for the formation
of such species has been obtained from interception experi-
ments with external substrates. Unlike non-heme iron halo-
genases, which use a a-keto-acid cofactor, the biomimetic
system presented herein utilizes an a-hydroxy acid for
dioxygen reduction and the subsequent generation of
a metal-based oxidant to carry out the halogenation of
aliphatic CÀH bonds. The reactivity of the model complex
oxo–aquo species (Scheme 4). The shift in the absorbance
maxima of the final oxidized solution of 1 in the presence of
a protic acid to 640 nm from 600 nm (Figure 1) is in line with
our proposal. Protonation of the hydroxide-coordinated
III
Ph2*
Fe (Tp ) complex forms the corresponding water-coordi-
nated complex, thus resulting in the observed lower-energy
[
36]
CT band.
The electrophilic iron(IV)–oxo–aquo oxidant
provides new insight into the development of bioinspired
thus formed can exchange its oxygen atoms with water and
performs various oxidation reactions. In the presence of
halides, the iron(IV)–oxo–aquo species is converted into an
iron(IV)–oxo–halide oxidant. However, in contrast to enzy-
catalysts for the oxidative halogenation of aliphatic CÀH
bonds.
matic systems, the halide is proposed to bind after the Acknowledgements
heterolytic OÀO bond cleavage mediated by a proton. The
T.K.P. acknowledges the Council of Scientific and Industrial
Research (CSIR) for financial support (Project File No.
1(2776)/14/EMR-II). S.C. thanks the CSIR for a fellowship.
0
Keywords: dioxygen · electrophilic oxidants · halogenation ·
iron · protic acids
How to cite: Angew. Chem. Int. Ed. 2016, 55, 7717–7722
Angew. Chem. 2016, 128, 7848–7853
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Received: October 23, 2015
Published online: January 28, 2016
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