Direct hydroxylation of benzene and aromatics with H2O2 catalyzed by a self-assembled iron complex: Evidence for a metal-based mechanism

Article abstract of DOI:10.1039/c7cy01895a

An iminopyridine Fe(ii) complex, easily prepared in situ by self-assembly of cheap and commercially available starting materials (2-picolylaldehyde, 2-picolylamine, and Fe(OTf)₂ in a 2 : 2 : 1 ratio), is shown to be an effective catalyst for the direct hydroxylation of aromatic rings with H₂O₂ under mild conditions. This catalyst shows a marked preference for aromatic ring hydroxylation over lateral chain oxidation, both in intramolecular and intermolecular competitions, as long as the arene is not too electron poor. The selectivity pattern of the reaction closely matches that of electrophilic aromatic substitutions, with phenol yields and positions dictated by the nature of the ring substituent (electron-donating or electron-withdrawing, ortho-para or meta-orienting). The oxidation mechanism has been investigated in detail, and the sum of the accumulated pieces of evidence, ranging from KIE to the use of radical scavengers, from substituent effects on intermolecular and intramolecular selectivity to rearrangement experiments, points to the predominance of a metal-based S_EAr pathway, without a significant involvement of free diffusing radical pathways.

Full text of DOI:10.1039/c7cy01895a

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Qingzhu Zhang et al.
Catalytic mechanism of C–F bond cleavage: insights from QM/MM
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Catalysis, Science & Technology
ARTICLE
Direct Hydroxylation of Benzene and Aromatics with H O
2
2
Catalyzed by a Self-Assembled Iron Complex: Evidence for a
Metal-based Mechanism
¥
Received 00th January 20xx,
Accepted 00th January 20xx
a,
a,b,
a
a
DOI: 10.1039/x0xx00000x
Giorgio Capocasa, † Giorgio Olivo, † Alessia Barbieri, Osvaldo Lanzalunga and
a,
www.rsc.org/
Stefano Di Stefano *
An iminopyridine Fe(II) complex, easily prepared in situ by self-assembly of cheap and commercially available starting
2
materials (2-picolylaldehyde, 2-picolylamine, and Fe(OTf) ) in a 2:2:1 ratio), is shown to be an effective catalyst for the
direct hydroxylation of aromatic rings with H under mild conditions. This catalyst shows a marked preference for
2
O
2
aromatic ring hydroxylation over lateral chain oxidation, both in intramolecular and intermolecular competitions, as long
as the arene is not too electron poor. The selectivity pattern of the reaction closely matches that of electrophilic aromatic
substitutions, with phenol yields and positions dictated by the nature of the ring substituent (electron-donating or
electron-withdrawing, ortho-para or meta-orienting). The oxidation mechanism has been investigated in detail, and the
sum of the accumulated pieces of evidence, ranging from KIE to use of radical scavengers, from substituent effects on
intermolecular and intramolecular selectivity to rearrangement experiments, points to the predominance of a metal –
based
S
E
Ar pathway, without
a
significant involvement of free diffusing radical pathways.
challenging, since the oxidation can also take place on the side
chain, where benzylic C-H bonds are particularly weak and
Introduction
•
activated. Oxygen-centered radicals (such as HO or HOO ) can
•
Phenols are ubiquitous motifs in both pharmaceutical products
1
and fine chemicals.
1
1
,2
effectively hydroxylate aromatic rings, but they generally
suffer the common drawbacks of poor selectivity and side
However, in spite of their great
multistep
relevance, their synthesis usually requires
a
5
reactivity associated with free radical chemistry. Moreover,
protocol, with the installation of an intermediate moiety which
is subsequently converted into the hydroxyl function. An
archetypical example is the industrial phenol synthesis, which
they often oxidize the benzylic positions (whenever present)
5
,11
more effectively than the aromatic rings
Combination of
metal complexes and peroxide oxidants to generate high
12-
is still produced in
a three-step process via cumyl
9
valent metal-oxo species is also possible, with several Ni, Cu
3
hydroperoxide with a rather low overall efficiency (5% yield).
No doubt an attractive preparation of phenols would be the
direct hydroxylation of aromatic compounds. Yet, only a
handful of synthetic aromatic hydroxylation protocols have
1
6
17-22
and Fe
complexes tested as catalysts with H
2
O
2
oxidant.
However, most of these systems were found to trigger the
•
17,18,23
formation of reactive HO
•14,24
HOO
or slightly more stable
4
-10
through Fenton-type processes, which are ultimately
been developed so far.
The high stability towards oxidation
responsible for the aromatic hydroxylation with the same
5
problems faced by radical-type chemistry. A remarkable
imparted by aromaticity coupled with the great strength of the
C-H bonds demands a highly reactive oxidant, which is usually
unable to limit the oxidation at the desired phenol stage, since
the latter is more reactive than the parent substrate,
2 2
exception to this mechanistic scenario is the Ni-TPEA/H O
9
system described by Itoh, which works through a genuine
metal-based mechanism. Ionic reactions forging aromatic
C-OH bonds via C-H metalation can avoid the overoxidation
issue as well as the problems of free radical chemistry, but
(chemoselectivity issue) or to discriminate among different
oxidation sites (regioselectivity issue). When alkyl benzenes
are used as substrates, these selectivity issues are even more
2
5
have seldom been successful, and only few methodologies
8
,26-28
with Pd have been recently disclosed.
Over the last years, reaction of H O and bioinspired iron
a.
Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza” and Istituto
CNR di Metodologie Chimiche (IMC-CNR), Sezione Meccanismi di Reazione, c/o
Dipartimento di Chimica, Università degli Studi di Roma “La Sapienza”, P.le A.
Moro 5, I-00185 Rome, Italy. E-mail: stefano.distefano@uniroma1.it.
Current address: Institut de Química Computacional i Catàlisi (IQCC) and
Departament de Química, Universitat de Girona, Campus de Montilivi, 17071
Girona, Spain.
2 2
complexes which are minimalistic models of natural
oxygenases were found to catalytically generate a powerful yet
selective oxidant, competent for selective aliphatic C-H
b.
2
9-35
hydroxylation.
This approach is attractive also from the
¥
green chemistry point of view, since it relies on abundant and
† These authors contributed equally to this work. This work is dedicated to Prof.
Luigi Mandolini on the occasion of his 75 birthday.
th
Electronic Supplementary Information (ESI) available: Other experimental details,
selected GC and GC-MS chromatograms and characterization of the products of
some oxidation reactions. See DOI: 10.1039/x0xx00000x
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low toxic iron as the metal source coupled with sustainable
oxidant under mild reaction conditions.
2 2
H O
Table 1. Optimization of reaction conditions for the oxidation of benzene with H
O
2 2
a
catalyzed by complex 1 in CH
3
CN at 25 °C.
recov.
sub.
mol%)
Cat
H
2
O
2
Time
PhOH
Quinone
(mol%)
2
2
N
entry
N
(
mol%)
(mol%)
(min)
(mol%)
b
(
O
N
Fe(OTf) (CH CN)
2
+
N
Fe N
2
3
H N CH3CN, rt
N
1
2
1
0
100
90
90
90
90
90
90
“
15
0
3
0
0
7
7
5
4
10
8
0
5
8
7
2
5
9
8
6
0
0
2
5
65
2
N
(OTf)2
N
“
100
90
c
3
0
“
4
1
-
4
1
“
150
21
24
20
20
18
16
12
17
20
17
15
23
20
21
16
11
18
14
17
71
OTf = CF SO
3
3
5
250
68
Scheme 1. Self-assembly of complex 1 from commercial precursors.
6
“
350
250
“
72
3
6-40
Such catalysts are known to hydroxylate aromatic rings,
III
but irreversible phenol binding to Fe center prevents catalytic
7
0.5
3
77
1
7,40,41
turnover.
In fact, the presence of an aromatic ring tends
8
“
44
4
1
not to be tolerated in these reactions, likely due to this
4
phenol inhibition. Nonetheless, some pioneering reports
0
9
5
“
“
33
indicated that certain modifications of the N amino-pyridine
4
3
1,35
19
10
1
“
30
60
180
360
61
ligand architecture
pentadentate complexes
(a bis-carbene ligand
0,21
or some
2
besides more extensively studied
42
1
1
1
1
2
3
“
“
53
2
porphyrin or phtalocyanines ) may avoid inhibition and
0
1
9,20
“
“
59
enable catalytic turnovers in very few cases.
However,
even in these cases, the reaction tends not to stop at the
phenol stage but affords doubly oxidized quinones as the main
“
“
28
2
1,43
d
products.
Recently, we found that complex
catalyze aliphatic C-H bond oxidation with H O through the
14
0.5
1
“
90
68
1
(Scheme 1) efficiently
d
1
1
5
6
“
“
55
2
2
4
4.45
probable intermediacy of a pentadentate oxidizing species.
d
3
“
“
45
Complex
1 could be easily obtained exploiting the imine
6-48
(Scheme 1) by spontaneous self-assembly of
4
d
chemistry
17
5
“
“
45
commercially available starting materials in acetonitrile
4
e
d
4.45
18
1
“
“
77
solution.
Remarkably, such oxidation occurs through a
f
d
g
genuine metal-based mechanism, with little involvement (if
any) of free radical species.
1
9
“
“
“
d
2
0
“
“
10
81
84
53
When we applied such catalyst to the oxidation of benzylic
alcohols, we were surprised to observe some byproducts
d
2
1
“
“
30
4
9
derived from oxidation of the aromatic C-H bonds. This
observation, together with the possibility that pentadentate
d
22
“
“
60
1
7,40,50
oxidizing species may prevent phenol inhibition,
prompted us to investigate the oxidation of aromatic
a
All data are reported in percentage with respect to the initial amount of
substrate whose concentation is 0.36 M. If no otherwise stated H was
2
O
2
substrates with complex
results of this study.
1 and H O , and we herein report the
2 2
slowly added by means of a syringe pump within 30 min from start. Products
were identified by comparison of GC retention times of commercially available
samples and quantified with an internal standard. The reported results are the
average of at least two runs (error within 5%).Workup as described in the
b
Results and discussion
experimental section. To account for benzene evaporation and loss, mass
balances were referred to a blank experiment which furnished 95% recovery of
c
the substrate after 90 minutes and filtration over SiO
the sole presence of Fe(OTf)
without use of syringe pump: H
2
. Reaction carried out in
d
2
, with no ligand added. Reaction carried out
e
2
O
2
added in one shot at time 0. Reaction
f
g
carried out at 40 °C. Reaction carried out at 0 °C. Residual benzene was not
quantified.
Scheme 2
.
2
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We began our investigation by focusing on the simplest yet that the latter derives from phenol overoxidation. All these
challenging aromatic substrate, i.e. benzene. We checked if experiments outlined the following optimized conditions: 1
complex
benzene hydroxylation (Scheme 2) under mild conditions (1 oxidant added in one shot at the beginning (conditions of entry
mol% of catalyst, 1.0 molar equivalents of H oxidant slowly 15 of Table 1).
2 2 2 2 3
1 in combination with H O oxidant can mediate mol % catalyst 1, 250 mol % H O , CH CN, 25 °C, 90 minutes,
2
O
2
added over 30 minutes by syringe pump, acetonitrile solution, It has to be stressed out that benzene oxidation could be easily
room temperature, no exclusion of air and moisture), similar scaled up without losses in efficiency. The reaction was
to those adopted for aliphatic oxidation. We were pleased to performed on 0.5 g scale affording phenol in 26% yield,
observe that the reaction occurs smoothly (entry 1 of Table 1), highlighting the attractiveness of this approach.
furnishing phenol as the main product in an encouraging 15% Next, we extended our study to other aromatic substrates
yield along with a low amount of para-benzoquinone (3%). adopting the optimized conditions described above. At first,
Remarkably, no products deriving from radical coupling, such we considered monosubstituted benzenes (Table 2). In each
as biphenyl, have been detected, suggesting that the reaction case, phenol products are formed along with low amounts of
does not occur through a radical-based mechanism. Control para-benzoquinone overoxidation products. Consistently, 1,4-
experiments show that no oxidation occurs in the absence of benzoquinone is the only detected product in the oxidation of
catalyst
are obtained in the absence of the ligand (i.e. with 1% we studied next, poses
Fe(CF SO (CH CN) as catalyst, entry 3 of Table 1). challenge, since the lateral chain competes with the aromatic
1
(entry 2 of Table 1), while low amounts of products phenol (entry 2 of Table 2). Oxidation of alkylbenzenes, which
a
substantial chemoselectivity
3
3
)
2
3
2
The reaction conditions were subsequently screened in order ring for the oxidation. The amount of lateral chain oxidation
to optimize the phenol yield, and the results are shown in generally correlates with the strength of its aliphatic C-H
Table 1.
bonds, as found for instance in previous iron-catalyzed
5
,9,19,29,40,50,52-54
Increase of the oxidant amount (up to 3.5 equivalents with alkylbenzene oxidations:
the weaker the C-H
mainly oxidizes
entries 4-6), but also leads to an increase of the toluene to cresols (20% yield, ortho + meta + para, o:m:p, in a
respect to the substrate) enhances the phenol yield up to 24% bond, the more prone to oxidation. Catalyst
1
(
benzoquinone yield, strongly suggesting that the latter 4:3:1 ratio, entry 3 of Table 2) in a total yield comparable to
compound derives from phenol overoxidation. The best the one obtained in benzene oxidation (entry 1, as entry 15 of
oxidant amount is therefore adjusted to 2.5 equivalents. A Table 1, reported for the sake of comparison). Remarkably,
second set of runs indicated that the optimal catalyst loading is only low amounts of products deriving from aliphatic hydrogen
1
mol% (entries 7 - 9). Both decrease of the loading to 0.5 atom abstraction (benzaldehyde 2%, traces of bibenzyl <1%)
mol% and increase to 3 or 5 mol% causes a significant loss in were detected, indicating that complex is highly selective for
yield and selectivity, similarly to what previously found in aromatic over aliphatic oxidation (92% selectivity). When
1
4
4
aliphatic C-H oxidations. At higher loadings, oxidative secondary aliphatic C-H bonds are considered, namely the
degradation of likely takes place, wasting catalytic activity ones of ethylbenzene (Table 2, entry 4), the selectivity for
1
and/or triggering side reactions. The reaction time was aromatic oxidation is maintained (92% selectivity, with 15%
subsequently optimized to 90 minutes (entries 10 – 13). While yield of ethylphenols in a 3:2:1 o:m:p ratio and 1% of
§
increase from 30 to 90 minutes is productive (compare entries acetophenone byproduct). The preference (80%) is retained
10, 11 and 5), any additional increase (180 or 360 minutes) even in cumene oxidation, which bears a much weaker tertiary
erodes the yield and the mass balance (entries 5, 12 and 13). benzylic C-H bond (isopropylbenzene, entry 5 of Table 2). In
The benzoquinone yield increases with reaction time, and this this case, isopropylphenols are produced with 21% yield to be
is again consistent with phenol overoxidation.
Generally, in nonheme iron complexes mediated oxidations, 1,4-benzoquinone is again collected within the products with
is slowly added to the reaction mixture in order to keep 3% yield. Oxidation of tert-butylbenzene by complex and
concentration low and avoid unproductive gives the best results in the series with a 28% yield of
disproportionation, which becomes dominant at high peroxide phenols along with 3% of tert-butyl-1,4-benzoquinone as the
compared with 6% yield of 2-phenyl-2-propanol. 2-isopropyl-
H
2
O
2
1
its
2 2
H O
2
9,51
concentrations.
However, when we added the oxidant all only byproduct. In all these cases, hydroxylation on the ortho
at once at the beginning of the reaction, only a very slight and para positions of the alkylbenzenes is favored, showing a
decrease of phenol yield was unexpectedly observed, from selectivity pattern resembling that of electrophilic aromatic
24% to 23% (compare entry 5 with entry 15) accompanied by a substitutions.
pleasant decrease of benzoquinone production (from 7 to 5%). The distribution of phenol products among the vicinal (ortho)
This result prompted us to select the one-shot oxidant addition and the distal (meta and para) positions is also sensitive to the
protocol, which is also experimentally more convenient. steric hindrance of the lateral chain, with the ratio (m+p)/o
Additional runs aimed at reassessing the best oxidation steadily increasing going from methyl (toluene), ethyl
conditions were carried out with variation of: i) catalyst (ethylbenzene),
isopropyl
(cumene),
t-butyl
(tert-
loading (entries 14-17), ii) temperature (entries 18-19), iii) butylbenzene) (1.0, 1.1, 2.0 and 4.6 respectively).
reaction time (compare entry 15 with entries 20, 21 and 22). Other functional groups are also tolerated in this aromatic
Remarkably, at short reaction times (10 minutes, entry 20), hydroxylation protocol. Fluoro, chloro and bromobenzenes
only traces of benzoquinone were detected, again suggesting (Table 2, entries 7-9) are smoothly oxidized to the
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49
41
corresponding phenols, along with some 1,4-benzoquinone us and others in iron-catalyzed oxidation of benzylic C-H
byproducts. Halogens are ortho-para directing substituents in bonds or alcohols. On the other hand, electron-releasing
classical aromatic substitution reactions, and consistently only groups enhance the electron-density of the aromatic ring and
ortho and para halophenols are detected in these oxidations. thus favor its oxidation, as in the hydroxylation of anisole
Moreover, electron-withdrawing groups (such as a cyano or a (Table 2, entry 12). Such a preference for the oxidation of
trifluoromethyl group, entry 10 and 11, respectively), which electron-rich arenes allows selective hydroxylation of
deactivate the aromatic rings towards electrophiles, almost substrates bearing two different arene rings, such as phenyl
completely switch off the oxidation, as previously found by benzoate.
a
2 2 3
Table 2. Oxidation of 0.36 M aromatic compounds by H O in CH CN at room temperature catalyzed by complex 1.
entry
substrate
unreacted
substrate
product 1
(o phenol)
product 2
(p+m phenols)
product 3
(chain Ox.)
product 4
(chain Ox.)
product 5
(quinone)
selectivity for
aromatic
oxidation
OH
O
-
-
1
2
55
52
47
-
-
-
-
O
2
3
5
O
OH
-
-
-
-
O
1
3
OH
Me
O
b
3
92%
Me
Et
CHO
Me
O
1
0
10 (p:m 3:1)
8 (p:m 2:1)
2
3
3
OH
Et
O
O
4
47
65
92%
80%
O
Et
Me
7
<1
1
OH
O
OH
Me
Me
O
c
5
iPr
iPr
iPr
O
Me
7
14 (p>>m)
3
6
traces
OH
HO
O
6
48
73
76
65
tBu
tBu
tBu
100%
tBu
O
O
O
O
5
3
7
23
3
2
3
4
OH
F
HO
O
F
d
7
-
-
-
-
-
-
-
-
-
F
F
6
OH
Cl
HO
O
Cl
O
Br
8
9
Cl
Cl
10
OH
Br
HO
Br
Br
1
9
10
1
0
99
99
-
-
-
-
-
-
HO
HO
CN
CN
traces
<1%
e
1
1
-
OH
O
1
2
58
-
-
-
OMe
OMe
O
OMe
1
0
8
3
a
2 2 3
All data are reported in percentage with respect to the initial amount of substrate. Reaction conditions: 250 mol % H O , 1 mol % catalyst 1, CH CN at 25 °C,
reaction time 90 minutes, oxidant added in one shot at time 0. The reported results are the average of at least two runs (relative error within 5%, within 10% for
b
c
d
e
yields < 5%). Traces of bibenzyl detected. Traces of cumyl hydroperoxide detected. Traces of 1,4 benzoquinone detected. Traces of o and p phenols detected.
4
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ARTICLE
In line with the selectivity observed so far, catalyst
1
preferentially hydroxylates the most electron rich phenolic
moiety over the benzoylic ring, generating mainly ortho and
para phenols (see Scheme 3, top). The most electron-releasing
group dictates also the selectivity in the oxidation of
disubstituted benzene derivatives. 5-Bromo-2-methoxyphenol
is indeed the only phenol product observed when para-
bromoanisole is used as a substrate (see Scheme 3, bottom).
Furthermore, we studied in more detail the preference for
aromatic over aliphatic oxidation exhibited by
intermolecular competitive oxidation. A 1:1 mixture of
cyclohexane and a substituted benzene was oxidized with H
and (see Scheme 4 and Table 3). Competition of benzene and
cyclohexane oxidation (Table 3, entry 4) highlights the
preference for aromatic hydroxylation of
1 by means of
2 2
O
1
1.
Scheme 3. Oxidation selectivity in the presence of substituents with different
Phenol production is clearly favored over alkane oxidation, in
line with the results obtained in intramolecular competitions.
Such a clear preference for arene hydroxylation is inconsistent
electronic properties.
•
5,55-57
with the involvement of HO radicals
than what generally reported for iron catalysts,
approaching the most selective catalytic systems reported in
and much higher
1
8,19,50,52,58-61
9
,10
the literature.
arene could have a considerable impact over this preference.
Strongly electron-withdrawing groups (NO , CF ) completely
However, electronic modification of the
2
3
suppress the arene reactivity (entries 1 and 2 of Table 3),
allowing selective alkane oxidation. When a moderate EWG
substituent is present (COCH
distributed between the two substrates. Conversely, electron-
donating groups (CH and OCH ) favor aromatic hydroxylation
3
, entry 3), the oxidation is
3
3
Scheme 4. Competitive oxidation of cyclohexane and a substituted benzene.
even more effectively (entries 5 and 6). Therefore, it is possible
to tune the reaction chemoselectivity (i.e. aromatic or aliphatic
hydroxylation) just by modifying the electron richness of the
aromatic ring.
a
Table 3. Competitive oxidation experiments.
Combined
yield of ArX
oxidation
Combined
yield of CyH
oxidation
Ratio
ArX:CyH)
Entry
X
(
Mechanistic outlook. At this point, our efforts were devoted
to the elucidation of the mechanism of action of catalyst 1 in
aromatic hydroxylation. In principle, several possible
mechanistic pathways are feasible (Fig. 1). The oxidation could
be mediated by oxygen-centered radicals formed through
Fenton-type reactions of the iron complex with H O (path a).
1
2
3
4
5
NO
2
traces
traces
5.5%
10%
9%
7%
<0.01
<0.01
2.8
CF
3
COCH
3
2%
2
2
Alternatively, the oxidation can be mediated by a high-valent
iron species formed after controlled H activation at the iron
H
2%
5
2 2
O
CH
3
10%
1%
9.3
centre (metal-based mechanism, paths b, c, d, e). This species
can in turn generate the phenol by hydrogen atom abstraction
from the aromatic substrate and subsequent rebound (path b),
electrophilic aromatic substitution (path c), radical aromatic
substitution (path d) or arene epoxidation and subsequent
rearrangement (path e).
6
OCH
3
11%
<1%
12.5
a
)
3
Conditions: cat 1:ArX:CyH:H2O2 1:50:50:100, CH CN, rt, 90 min. Products
analysed by GC with biphenyl as internal standard. Every experiment has
been replicated twice. Error ±5% of the value.
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Free radical benzene oxidations (path a) are well-known in the substituent, and afford comparable yields of lateral chain
5
6,63
literature and usually display relatively low efficiency and a oxidation.
poor selectivity, as could be expected with a highly reactive Additional pieces of evidence in favor of a metal-based
•
55-57,63,64
species such as HO radical.
Moreover, significant mechanism were collected as follows and reported in Table 4.
are poorly
such as biphenyl), rearrangements (whenever possible) or sensitive to the presence/absence of atmospheric oxygen (see
amounts of byproducts generated by radical-radical coupling Oxidation of benzene and cumene catalyzed by
1
(
2
lateral chain oxidation (in alkylaromatic substrates) are usually Table 4), while the presence of O is known to strongly affect
5
5-57,62,63
56,62,63
observed.
oxygen exerts a significant influence on the reaction,
radical traps generally inhibit the oxidation. Exclusive of O
The presence (or absence) of atmospheric the efficiency and the selectivity of Fenton-type systems,
5
7,62,63
and with biphenyl favored over phenol production in the absence
5
.
6
2
Furthermore, benzene oxidation catalyzed by
1 is
•
formation of the more stable HOO radical can increase the hardly affected by the addition of a well-behaved radical trap
1
,14
selectivity of the reaction,
reactivity. On the other hand, a higher (and more predictable) and thus cannot alter the mechanism in other ways)
selectivity is observed in metal-based reactions which Conversely, Fenton-type benzene oxidation (i.e. with simple
generally do not form side products, and are not affected by Fe(OTf) (CH CN) salt as the catalyst) carried out in the
presence of CBrCl forms significant amounts of
The selectivity observed in the oxidation of substituted bromobenzene byproduct, likely derived from Br atom
benzene derivatives catalyzed by as well as the high abstraction by an intermediate carbon-centered radical.
sensitivity to the electronic properties of the substituent are Remarkably, no traces of bromobenzene were detected when
generally not consistent with a free radical reaction, but point the reaction was carried out with catalyst (see Table 4 and
3
but does not shut down side such as CBrCl (which does not coordinate to the metal centre
5
1,64
.
2
3
2
2
0
the presence/absence of O
2
or other radical traps.
3
1
1
to a metal-based oxidation mechanism mediated by an Electronic Supplementary Information, ESI), indicating that it
electrophilic species. In particular, oxidation of electron-rich, must occur through a different pathway. Eventually, we
ortho-para directing anisole yields only para and ortho
studied the oxidation of cyclopropyl benzene, whose strained
three-membered ring is known to rapidly rearrange if radical
intermediates are formed. Almost all of the oxidation
mediated by
1 is directed towards the formation of ortho and
para-phenols, while the main product in the reaction mediated
by simple iron salt (in the absence of the ligand) is the benzylic
alcohol derived from cyclopropyl rearrangement, along with
traces of phenol byproducts (see Table 4). All these pieces of
evidence consistently point to an aromatic hydroxylation fully
devoid of free radical intermediates, allowing us to confidently
discard the radical path a and to consider rather unlikely path
d (radical aromatic substitution), which generates also radical
intermediates.
At this point, we measured the KIE in a competitive oxidation
of benzene and perdeuterated benzene (measured as the ratio
5
between phenol and pentadeuterophenol d PhOH in the
crude; the result was validated by replication). KIE indeed
represents a powerful tool to discriminate among different
aromatic oxidation mechanisms, since almost each pathway
is reported to have a different and diagnostic KIE value (see
Fig. 1). A KIE of 0.98 ± 0.02 was obtained with catalyst 1. This
Fig. 1. Possible mechanisms operating in the aromatic oxidation catalyzed by complex
KIE value rules out both a direct HAT process (path b, which
typically furnishes much higher values) and, again, radical
reactions (a KIE of 1.7 is reported for Fenton-type systems,
path a, while normal KIE values in the range 1.1-1.7 have been
1
.
phenols, with no detectable traces of the meta isomer. The
yield regularly decreases at the increase of the electron-
withdrawing properties of the substituent (in the series Br, Cl,
F, CN yields are 29, 17, 9, <1% respectively), and the reaction is
almost shut down when highly electron-withdrawing groups
•
IV
reported for caged HO /Fe =O mediated aromatic
17
hydroxylations, in which the first step is probably the
•
addition of the caged HO radical to the aromatic ring).
3
(CN or CF ) are present. Oxidation regioselectivity is dictated
exclusively by the more electron-rich substituent (see para-
bromoanisole oxidation), and aromatic hydroxylation is
preferred over aliphatic oxidation. Conversely, Fenton-type
oxidations are much less sensitive to the electronic effects of
6
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substitution mechanism. In the latter case, product II could
derive from a methyl rearrangement within the σ-complex
intermediate.
a
Table 4. Clues in favor of a metal-based oxidation mechanism.
Cat
Additive
Substrate
Product
Product
OH
O
O
1
1
under air
“
“
23%
26%
5%
4%
under argon
b
1
1
under air
“
“
21%
6%
7%
c
under argon
27%
OH
Br
d
e)
1
BrCCl
3
“
“
20%
3%
n.d.
1%
-
2
+ f
Fe
2
BrCCl
-
3
+ f
Fe
4%
g
h
1
“
“
37%
1%
< 0.5%
4%
2
+ f,i
Fe
a
b
c
d
Conditions as in Table 2. +3% p-quinone. +4% p-quinone. Added as 0.1
e
f
molar equivalent with respect to the substrate. +3% p-quinone. Added as
g
h
i
2 3 2
Fe(OTf) (CH CN) salt. Conversion 42%. o/m/p 46/5/49. Conversion 20%.
2
Conversely, such a value is consistent with a sp → sp change
3
6
5
in the configuration of aromatic carbon atom directly
involved in the reaction (paths c and d). It has to be stressed
Scheme 5. Methyl rearrangements that can follow the direct oxygen transfer from the
out that aliphatic hydroxylation mediated by
by a HAT mechanism gives a much higher KIE value of 3.3 .
The KIE value of benzene hydroxylation mediated by is
1 and occurring iron based active species to the aromatic moieties.
4
5
1
Regarding the oxidizing species, we have not yet been
successful in detecting the intermediate formed upon addition
6
6,67
comparable with that observed in natural iron oxygenases
in line with the one measured in almost single-turnover
2 2
of H O to 1. Nonheme iron complexes are known to react with
1
9,40
III
oxidation experiments mediated by other nonheme
or
the latter reagent to afford Fe -OOH intermediates which
subsequently undergo O-O bond cleavage either to unmask a
4
2
phtalocyanine iron catalysts.
V
Two pathways are finally left for the oxidation mechanism:
electrophilic aromatic substitution (path c) or arene
epoxidation (path e). We did not collect any clear-cut evidence
in favor of one of these two paths, but a hint in favor of the
latter comes from the observation of a rearranged byproduct
highly reactive Fe =O complex, invoked as the oxidizing
IV
•
species, or to form a Fe =O intermediate (and HO ), which is
generally regarded as not competent for challenging oxidation
3
1,35
reactions.
reported that neither Fe -OOH
are competent for arene hydroxylation, but the intermediacy of
Several experimental and theoretical evidences
III
17,38,40
IV
38,40
nor Fe =O
species
(2,2 dimethyl cyclohexadienone II, Scheme 5ii) deriving from
V
IV
methyl migration in the 1 catalyzed oxidation of ortho-xylene.
Fe =O complexes is invoked. However, Fe =O species were
demonstrated to be able to oxidize anthracene to
anthraquinone. The KIE measured with
However, the other expected rearrangement product (2,6-
3
9
dimethylphenol III, Scheme 5ii) was not detected in the
#
reaction mixture. Moreover, no parallel 1,2 alkyl shift was
1 is inconsistent with
IV
•
17
a mechanism involving caged Fe =O/HO systems (KIE > 1),
but is in the range of those reported for high-valent Fe
detected in the oxidation of para-xylene (no trace of 2,4-
¶
dimethylphenol I, Scheme 5i, was observed in the crude).
1
9,20,39,40
species.
the one reported for proposed nonheme Fe =O species.
However, in contrast with previous reports on tetracoordinated
Also the oxidation selectivity is very similar to
V
40
Therefore, the collected pieces of evidence restricted the
mechanistic scenario ruling out a free radical mechanism, and
strongly pointing towards a two electron, electrophilic
aromatic substitution. Other pathways, such as arene
epoxidation, could not be fully excluded, but, at the present
4
0
complexes,
1 is able to mediate catalytic arene oxidation,
while nonheme iron complexes are limited to a handful of
turnovers due to phenolate binding. We speculate that this
could be due to the absence of further labile coordination sites
4
0
#,¶
stage, the most likely hypothesis is an electrophilic aromatic
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available for phenolate binding on the active oxidant formed under vigorous stirring for 90 minutes, during which the color
upon reaction of with H
, which was previously proposed of the reaction changed from purple to orange up to yellowish.
1
2 2
O
to be pentadentate (as the consequence of the detachment of At this point an internal standard was added (nitrobenzene or
one of the pyridine arms to leave a coordination site available bibenzyl, 125 μmol), the reaction mixture was filtered over a
III
45
for H
2
O
2
binding and activation on the Fe
centre).
short pad of SiO with AcOEt, and analyzed by GC. When the
2
Pentadentate complexes can indeed mediate aromatic
succession of colors does not occur as described, some
1
7,52,60
hydroxylation with few turnovers,
efficiency and selectivity than . A parallel increase in
efficiency in the oxidations mediated by compared to general
pentadentate complexes was already observed in aliphatic
albeit with lower
impurity is generally interfering with the reaction.
1
1
0
.5 g-scale benzene oxidation. Fe(CF
2.5 µmol), 2-picolylaldehyde (12 μL, 0.125 mmol) and
-picolylamine (13 µL, 0.125 mmol) were dissolved in 25 mL of
3 3 2 3 2
SO ) (CH CN) (27.3 mg,
6
2
4
5
2 2
oxidations. A different H O activation mechanism was
4
5
indeed proposed to account for this observation, and we
speculate that the same mechanism is responsible also for the
increased efficiency in aromatic oxidations.
acetonitrile in a 50mL round bottom flask placed in a water
bath set at 25°C. Benzene (6.25 mmol, 560 µL) and H (15.6
2 2
O
mmol, 1.76 g of a 30.2% w/w solution) were added to the
reaction mixture and left under stirring for 90 minutes. The
Conclusions
2
mixture was then filtered over a short pad of SiO with AcOEt,
concentrated to roughly half of the initial volume and
extracted with a 1M NaOH solution. The combined aqueous
In this work, we applied the cheap and easily available
complex
1 to the hydroxylation of aromatic compounds with
phases where neutralized with a 2M H
extracted with ethyl acetate. The combined organic layers
were washed with a saturated NaHCO acqueous solution and
Brine, dried over Na SO , and the solvent was removed by
rotatory evaporation. After drying under vacuum, 154 mg of
2 4
SO solution and
2 2
H O
as the terminal oxidant under mild conditions. Gratifying
results in terms of yields and selectivity have been obtained,
particularly when electron-releasing groups are present in the
aromatic ring. Remarkably, the reaction is easily scalable
without loss of efficiency. In the presence of an aliphatic chain,
3
2
4
catalyst
1
is highly selective for aromatic hydroxylation, pure phenol were collected (1.62 mmol, 26% yield).
irrespective of the aliphatic C-H bond strength. However, the
preference for aromatic over aliphatic oxidation can be tuned
by modifying the electron-richness of the aromatic ring, with Conflicts of interest
electron-withdrawing groups that shut down phenol
formation. Moreover, the regioselectivity of the phenol
products is mainly dictated by the electronic effects of the
substituents, with steric factors also playing a role when bulky
groups are present. The selectivity of the reaction, its
insensitivity towards the addition of radical scavengers and the
There are no conflicts to declare.
Acknowledgements
Funding: This work was supported by the Ministero
dell’Istruzione, dell'Università e della Ricerca (MIUR, PRIN
KIE measured strongly point to
E
a metal–based S Ar
2
010CX2TLM). This work was also partially supported by
mechanism, although an arene epoxidation mechanism similar
2
0,66
Università di Roma La Sapienza (Progetti di Ricerca 2014).
Thanks are due to the CIRCC, Interuniversity Consortium of
Chemical Catalysis and Reactivity. The authors also thank Miss
Marika Di Berto Mancini for technical assistance.
to the one of iron and copper oxygenases
cannot be
completely ruled out. However, the involvement of radical
species can be confidently excluded, in line with what found in
aliphatic C-H bond hydroxylation catalyzed by complex
believe that the lack of phenolate inhibition in mediated
oxidations is due to the peculiar H activation mechanism of
catalyst which could generate a probable pentadentate
1. We
1
2 2
O
Notes
1
4
5
§
The higher selectivity for the benzylic side-chain oxidation
found with tetrahydronaphthalene (see ref 44) as compared
to that observed in the oxidation of other alkylaromatic
compounds reflects the operation of stereoelectronic
effects. In tetrahydronaphthalene an optimal overlap
between the benzylic C-H bonds and the aromatic π-system
can be achieved resulting in a weakening of these bonds and
in a more efficient stabilization of the intervening carbon
radical formed following the hydrogen atom abstraction.
oxidizing species retaining a strong oxidative reactivity. Other
studies aimed at identifying the oxidizing intermediate are
currently underway in our laboratory.
Experimental
Typical oxidation procedure. Fe(CF
μmol), 2-picolylaldehyde and 2-picolylamine (5.0 μmol each,
from a 0.1 M CH CN solution) were mixed in a vial at 25°C to
3 3 2 3 2
SO ) (CH CN) (1.09 mg, 2.50
#
Jerina et al (see ref 68) and Wong et al (see ref 69) showed
that formation of 2,2 dimethyl cyclohexadienone II from the
xylene oxide depicted in the brackets of Scheme 5ii, is
accompanied by production of comparable amounts of 2,6-
dimethylphenol III. Evidently, this is not our case.
3
obtain an intensely colored purple solution. Substrate (250
μmol) and CH CN were then added up to a total volume of 700
3
μL. A 0.7 M CH
3
CN solution of H
2 2
O (diluted from a 35% w/w
2 2
H O solution) was added in one shot and the reaction was left
8
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¶
Jerina et al (see ref 68) showed that the xylene oxide 27 A.K. Cook, M.S. Sanford, J. Am. Chem. Soc., 2015, 137, 3109–
depicted in the brackets of Scheme 5i, generates a mixture 3118.
of 2,4-dimethylphenol and 2,5-dimethylphenol in a pH 28 G. Shan, X. Yang, L. Ma, Y. Rao, Angew. Chemie Int. Ed., 2012,
dependent ratio, with the former exceeding the latter in 51, 13070–13074.
neutral conditions. In contrast in our experimental 29 K. Chen, L. Que Jr., J. Am. Chem. Soc., 2001, 123, 6327–6337.
I
conditions, no trace of 2,4-dimethylphenol
among the reaction products.
I, was found 30 K. Chen, M. Costas, J. Kim, A.K. Tipton, L. Que Jr., J. Am.
Chem. Soc., 2002, 124, 3026–3035.
3
3
1 W.N. Oloo, L. Que Jr., Acc. Chem. Res., 2015, 48, 2612–2621.
2 E.P. Talsi, K.P. Bryliakov, Coord. Chem. Rev., 2012, 256, 1418–
1
434.
3 W. Nam, Acc. Chem. Res., 2007, 40, 522–531.
4 W. Nam, Y.-M. Lee, S. Fukuzumi, Acc. Chem. Res., 2014, 47
3
3
,
,
1
146–1154.
5 G. Olivo, O. Cussò, M. Costas, Chem. - An Asian J., 2016, 11
148–3158.
6 M.P. Jensen, M.P. Mehn, L. Que Jr., Angew. Chemie - Int. Ed.,
003, 42, 4357–4360.
References
3
3
3
3
1
S. Fukuzumi, K. Ohkubo, Asian J. Org. Chem., 2015,
45.
4, 836–
8
2
2
3
J. Genovino, D. Sames, L. G. Hamann, B. B. Tour, Angew.
Chemie - Int. Ed. 2016, 55, 14218–14238.
M. Weber, M. Weber, M. Kleine- Boymann, Ullmann’s
Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim,
7 N.Y. Oh, M.S. Seo, M.H. Lim, M.B. Consugar, M.J. Park, J.-U.
Rohde, J. Han, K.M. Kim, J. Kim, L. Que Jr., et al., Chem.
Commun., 2005,
8 O.V. Makhlynets, P. Das, S. Taktak, M. Flook, R. Mas-Ballesté,
E.V Rybak-Akimova, L. Que Jr., Chem. - A Eur. J., 2009, 15
3171–13180.
9 S.P. de Visser, K. Oh, A.-R. Han, W. Nam, Inorg. Chem., 2007,
, 4632–4641.
0 O.V. Makhlynets, E.V. Rybak-Akimova, Chem. - A Eur. J.,
010, 16, 13995–4006.
1 A.M. Adams, J. Du Bois, H.A. Malik, Org. Lett., 2015, 17
066–6069.
2 E.V. Kudrik, A.B. Sorokin, Chem. – A Eur. J., 2008, 14, 7123–
126.
3 A.C. Lindhorst, J. Schutz, T. Netscher, W. Bonrath, F.E. Kühn,
Catal. Sci. Technol., 2017, , 1902-1911.
4 G. Olivo, G. Arancio, L. Mandolini, O. Lanzalunga, S. Di
Stefano, Catal. Sci. Technol., 2017, , 2900–2904.
5 G. Olivo, M. Nardi, D. Vìdal, A. Barbieri, A. Lapi, L. Gómez, O.
Lanzalunga, M. Costas, S. Di Stefano, Inorg. Chem. 2015, 54
0141–10152.
6 M. Ciaccia, R. Cacciapaglia, P. Mencarelli, L. Mandolini, S. Di
Stefano, Chem. Sci., 2013, , 2253–2261.
3, 5644–5646.
3
Germany, 2000
.
,
4
5
6
7
8
9
1
1
S. Niwa, M. Eswaramoorthy, J. Nair, A. Raj, N. Itoh, H. Shoji,
T. Namba, F. Mizukami, Science 2002, 295, 105–107.
J.P. Hage, A. Llobet, D.T. Sawyer, Bioorganic Med. Chem.,
1
3
4
4
4
4
4
4
4
6
1
995,
S. Enthaler, A. Company, Chem. Soc. Rev., 2011, 40, 4912–
924.
P. T. Tanev, M. Chibwe, T. J. Pinnavaia, Nature 1994, 368
21-323.
3, 1383–1388.
2
4
,
,
6
3
B. Lücke, K.V. Narayana, A. Martin, K. Jähnisch, Adv. Synth.
Catal. 2004, 346, 1407–1424.
Y. Morimoto, S. Bunno, N. Fujieda, H. Sugimoto, S. Itoh, J.
Am. Chem. Soc. 2015, 137, 5867–5870.
0 K. Kamata, T. Yamaura, N. Mizuno, Angew. Chem. Int. Ed.
7
7
4
2
012, 51, 7275–7278.
1 C. Yuan, Y. Liang, T. Hernandez, A. Berriochoa, K. N. Houk, D.
Siegel, Nature 2013, 499, 192–196.
,
1
1
1
2 L. Que Jr., W.B. Tolman, Nature 2008, 455, 333–340.
3 A. Conde, M.M. Dìaz-Requejo, P.J. Pérez, Chem. Commun.
4
4
4
4
5
5
5
4
2
011, 47, 8154–8156.
4 M. Yamada, K.D. Karlin, S. Fukuzumi, Chem. Sci. 2016,
856–2863.
5 K.D. Karlin, J.C. Hayes, Y. Gultneh, R.W. Cruse, J.W. McKown,
J.P. Hutchinson, J. Zubieta, J. Am. Chem. Soc. 1984, 106
121–2128.
7 M. Ciaccia, S. Pilati, R. Cacciapaglia, L. Mandolini, S. Di
Stefano, Org. Biomol. Chem., 2014, 12, 3282–3287.
8 M. Ciaccia, S. Di Stefano, Org. Biomol. Chem., 2015, 13, 646–
1
1
7,
2
6
54.
,
9 G. Olivo, S. Giosia, A. Barbieri, O. Lanzalunga, S. Di Stefano,
Org. Biomol. Chem., 2016, 14, 10630–10635.
0 A. Kejriwal, P. Bandyopadhyay, A.N. Biswas, Dalton Trans.,
2
1
6 T. Tsuji, A.A. Zaoputra, Y. Hitomi, K. Mieda, T. Ogura, Y.
Shiota, K. Yoshizawa, H. Sato, M. Kodera, Angew. Chemie Int.
Ed. 2017, 56, 7779–7782.
2
015, 44, 17261–17267.
1 P.A. MacFaul, K.U. Ingold, D.D. M. Wayner, L. Que Jr., J. Am.
Chem. Soc., 1997, 119, 10594–10598.
2 V. Balland, D. Mathieu, N. Pons-Y-Moll, J.F. Bartoli, F. Banse,
P. Battioni, J.J. Girerd, D. Mansuy, J. Mol. Catal. A Chem.,
1
1
1
2
2
2
2
2
7 A. Thibon, V. Jollet, C. Dibal, K. Sénéchal-David, L. Billon, A.B.
Sorokin, F. Banse, Chem. - A Eur. J., 2012, 18, 2715–2724.
8 G.C. Silva, N.M.F. Carvalho, A. Horn Jr., E.R. Lachter, O.A. C.
Antunes, J. Mol. Catal. A Chem., 2017, 426, 564–571.
9 A. Raba, M. Cokoja, W.A. Herrmann, F.E. Kühn, Chem.
Commun., 2014, 50, 11454–11457.
2
004, 215, 81–87.
5
5
5
3 D. Bianchi, M. Bertoli, R. Tassinari, M. Ricci, R. Vignola, J.
Mol. Catal. A Chem., 2003, 200, 111–116.
4 K. Kamata, T. Yamaura, N. Mizuno, Angew. Chemie Int. Ed.,
012, 51, 7275–7278.
5 C. Walling, R.A. Johnson, J. Am. Chem. Soc., 1975, 97, 363–
67.
6 D.I. Metelitsa, Russ. Chem. Rev., 1971, 40, 563–580.
7 A. Kunai, S. Hata, S. Ito, K. Sasaki, J . Am. Chem. Soc., 1986,
108, 6012–6016.
8 R. R. Fernandes, M. V. Kirillova, J. A. L. da Silva, J. J. R. Fraústo
da Silva, A. J. L. Pombeiro, Appl. Catal. A Gen., 2009, 353,
0 A.C. Lindhorst, S. Haslinger, F.E. Kühn, Chem. Commun.,
2
015, 51, 17193–17212.
1 P. Liu, Y. Liu, E.L.-M. Wong, S. Xiang, C.-M. Che, Chem. Sci.
011, , 2187-2195.
2 E.V. Kudrik, A.B. Sorokin, J. Mol. Catal. A Chem., 217, 426
99–505.
3 L. Carneiro, A.R. Silva, Catal. Sci. Technol., 2016,
2
2
2
3
,
5
5
4
6
, 8166–
8176.
4 K. Hirose, K. Ohkubo, S. Fukuzumi, Chem. Eur. J., 2016, 22
5
5
,
1
5 A.N. Vedernikov, Acc. Chem. Res., 2012, 45, 803–813.
6 M.H. Emmert, A.K. Cook, Y.J. Xie, M.S. Sanford, Angew.
Chem. Int. Ed., 2011, 123, 9581–9584.
2904-12909.
107–112.
9 B. Xu, W. Zhong, Z. Wei, H. Wang, J. Liu, L. Wu, Y. Feng, X.
Liu, Dalton Trans., 2014, 43, 15337–15345.
2
2
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6
0 A. Thibon, J. F. Bartoli, R. Guillot, J. Sainton, M. Martinho, D.
Mansuy, F. Banse, J. Mol. Catal. A Chem., 2008, 287, 115–
20.
1
6
6
6
6
6
1 X. Wang, T. Zhang, B. Li, Q. Yang, S. Jiang, Appl. Organomet.
Chem., 2014, 28, 666–672.
2 A. Mitarai, K. Hikino, M. Hirama, K. Sasaki, J. Org. Chem.,
1
992, 57, 6937–6941.
3 T. Kurata, Y. Watanabe, M. Katoh, Y. Sawaki, J. Am. Chem.
Soc., 1988, 110, 7472–7478.
4 G. Olivo, O. Lanzalunga, S. Di Stefano, Adv. Synth. Catal.,
2
016, 358, 843–863.
5 T.H. Lowry, K.S. Richardson, Mechanism and Theory in
Organic Chemistry, III Edition, Harper & Row Publishers, New
York, 1987, p. 628.
6
6
6
6
6 K. H. Mitchell, C. E. Rogge, T. Gierahn, B. G. Fox, Proc. Natl.
Acad. Sci., 2003, 100, 3784–3789.
7 R.P. Hanzlik, K.H.J. Ling, J. Am. Chem. Soc., 1993, 115, 9363–
9
370.
8 N. Kaubisch, J. W. Daly and D. M. Jerina, Biochemistry, 1972,
, 3080-3088.
11
9 C. J. C. Whitehouse, N. H. Rees, S. G. Bell and L.-L. Wong,
Chem. Eur. J., 2011, 17, 6862-6868.
1
0 | J. Name., 2012, 00, 1-3
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Catalysis Science & Technology
Page 11 of 11
Journal Name
View Article Online
DOI: 10.1039/C7CY01895A
ARTICLE
Graphical abstract
An imine-based catalyst easily obtained by self assembly of
cheap and commercially available starting materials,
selectively catalyzes the hydroxylation of aromatic
compounds.
H
N
2
N
Fe2+
+
2
+
2
N
Ar-H + H
O
2 2
O
in situ self-assembly
of the catalyst
selective oxidation of
aromatic C-H bonds
Ar-OH
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