Bioinspired Oxidation of Methane in the Confined Spaces of Molecular Cages

Article abstract of DOI:10.1021/acs.inorgchem.9b00199

Non-heme iron, vanadium, and copper complexes bearing hemicryptophane cavities were evaluated in the oxidation of methane in water by hydrogen peroxide. According to ¹H nuclear magnetic resonance studies, a hydrophobic hemicryptophane cage accommodates a methane molecule in the proximity of the oxidizing site, leading to an improvement in the efficiency and selectivity for CH₃OH and CH₃OOH compared to those of the analogous complexes devoid of a hemicryptophane cage. While copper complexes showed low catalytic efficiency, their vanadium and iron counterparts exhibited higher turnover numbers, ≤13.2 and ≤9.2, respectively, providing target primary oxidation products (CH₃OH and CH₃OOH) as well as over-oxidation products (HCHO and HCOOH). In the case of caged vanadium complexes, the confinement effect was found to improve either the selectivity for CH₃OH and CH₃OOH (≤15%) or the catalytic efficiency. The confined space of the hydrophobic pocket of iron-based supramolecular complexes plays a significant role in the improvement of both the selectivity (≤27% for CH₃OH and CH₃OOH) and the turnover number of methane oxidation. These results indicate that the supramolecular approach is a promising strategy for the development of efficient and selective bioinspired catalysts for the mild oxidation of methane to methanol.

Full text of DOI:10.1021/acs.inorgchem.9b00199

Article
pubs.acs.org/IC
Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
Bioinspired Oxidation of Methane in the Confined Spaces of
Molecular Cages
‡,⊥
Sk Asif Ikbal,†,⊥ Cedric Colomban, Dawei Zhang,§ Magalie Delecluse,‡ Thierry Brotin,§
́
||
§
Veronique Dufaud, Jean-Pierre Dutasta, Alexander B. Sorokin,*,† and Alexandre Martinez*,‡
†
́
́
Institut de Recherches sur la Catalyse et l’Environnement de Lyon (IRCELYON), UMR 5256, CNRS-Universite Lyon, 69626
Villeurbanne Cedex, France
‡Aix Marseille Univ., Centrale Marseille, CNRS, iSm2 UMR 7313, 13397 Marseille, France
§
́
́
́
Laboratoire de Chimie, Ecole Normale Superieure de Lyon, CNRS, UCBL, 46 allee d’Italie, F-69364 Lyon, France
||
̀
́
́
́
Laboratoire de Chimie, Catalyse, Polymeres, Procedes (C2P2), UMR5265, CNRS, Universite Claude Bernard Lyon 1, CPE Lyon,
43 Bd du 11 novembre 1918, F-69616 Villeurbanne Cedex, France
S
* Supporting Information
ABSTRACT: Non-heme iron, vanadium, and copper com-
plexes bearing hemicryptophane cavities were evaluated in the
oxidation of methane in water by hydrogen peroxide.
According to 1H nuclear magnetic resonance studies, a
hydrophobic hemicryptophane cage accommodates a methane
molecule in the proximity of the oxidizing site, leading to an
improvement in the efficiency and selectivity for CH3OH and
CH3OOH compared to those of the analogous complexes
devoid of a hemicryptophane cage. While copper complexes
showed low catalytic efficiency, their vanadium and iron
counterparts exhibited higher turnover numbers, ≤13.2 and ≤9.2, respectively, providing target primary oxidation products
(CH3OH and CH3OOH) as well as over-oxidation products (HCHO and HCOOH). In the case of caged vanadium
complexes, the confinement effect was found to improve either the selectivity for CH3OH and CH3OOH (≤15%) or the
catalytic efficiency. The confined space of the hydrophobic pocket of iron-based supramolecular complexes plays a significant
role in the improvement of both the selectivity (≤27% for CH3OH and CH3OOH) and the turnover number of methane
oxidation. These results indicate that the supramolecular approach is a promising strategy for the development of efficient and
selective bioinspired catalysts for the mild oxidation of methane to methanol.
active metal center is confined in the hydrophobic cavity
provided by the enzymatic architecture. This isolated and
constrained hydrophobic environment allows for highly
efficient recognition of methane and prevents back-diffusion
of CH3OH to the active site, thus preventing its further
oxidation.8 This structural organization results in the
remarkable efficiency and selectivity of the oxidation of CH4
to CH3OH. There has been an extensive effort to obtain
synthetic structural models for the MMO;9 however, functional
models capable of oxidizing methane are still rare.10 Among
notable examples of bioinspired catalysts are non-heme
copper11 and heme diiron complexes,12,13 recently described
for the mild oxidation of CH4. For instance, μ-nitrido diiron
phthalocyanine12 and porphyrin13 complexes were found to
efficiently catalyze the oxidation of CH4 by H2O2 in water at
25−60 °C. However, because the primary methane oxidation
products (CH3OH and CH2O) contain more reactive C−H
bonds than CH4, their further oxidation occurred, providing
INTRODUCTION
■
The direct conversion of methane to methanol under mild
conditions is one of the major challenges posed to the scientific
community because of its crucial industrial and ecological
benefits. The selective transformation of CH4 is considered as
a particularly difficult task due to the extreme inertness of the
methane C−H bond (bond dissociation energy of 104.9 kcal
mol−1, high pKa, low polarizability, high ionization potential,
and negligible electron affinity).1 The current industrial
approach to conversion of CH4 to useful products is based
on syngas technology demanding large investments and very
high temperatures (>600 °C). Direct oxidation processes also
require high temperatures, but the conversion and selectivity of
these processes are still low.2 In contrast, in nature, the aerobic
oxidation of CH4 to CH3OH under ambient conditions is
efficiently mediated by the soluble (sMMO) and particulate
(pMMO) methane monooxygenases found in aerobic
methanotrophic bacteria.3−6 The active sites of these two
enzymes are described as non-heme diiron (sMMO) and
copper (pMMO) high-valence metal−oxo species, respectively,
acting as particularly powerful oxidants.7 In these systems, the
Received: January 21, 2019
© XXXX American Chemical Society
A
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Scheme 1. Structures of the Complexes Used in This Study
formic acid with a selectivity of 88−97%. Despite the need to
prevent over-oxidation of CH3OH, the implementation of this
strategy in biomimetic methane partial oxidation systems is still
overlooked.14 Consequently, to increase the selectivity of
methane oxidation for methanol, the structural organization of
the active site should be improved. Several approaches to
circumventing the higher reactivity of the alkane oxidation
products and limiting the over-oxidation reactions have been
proposed. The controlled selective oxidations of aliphatic C−H
bonds have recently been achieved by supramolecular catalysts
either by introducing a recognition group bound to the catalyst
(interactions with the substrate such as hydrogen bonding,15
ligand to metal coordination,16 or hydrophobic effects)17 or by
building a hydrophobic cavity above the catalytic center.18 It is
in this last category that Cu(II)-19 and V(V)-based hemi-
cryptophanes20 have been recently described as being highly
efficient and selective oxidation catalysts compared to the
parent analogues that are devoid of a cavity. Although
improvements in reactivity and selectivity of various reactions
have been achieved using functionalized molecular nano-
reactors,21 to the best of our knowledge, such a strategy has
never been extended to the bioinspired oxidation of methane.
The presence of a hydrophobic cavity in the proximity of the
catalytic site might result in the preferential binding of CH4
with respect to the more polar CH3OH product and favor CH4
oxidation over over-oxidation reactions. Thus, the more
selective oxidation to CH3OH can be achieved. Therefore,
the development of novel artificial models that can
simultaneously bind and oxidize methane is highly desirable
for exploring the benefits of the supramolecular approach. We
present herein a study of the encapsulation and oxidation of
methane mediated by vanadium, copper, and iron supra-
molecular complexes under mild conditions. The interaction
between CH4 and the hydrophobic cavity of hemicryptophane
was confirmed by a H nuclear magnetic resonance (NMR)
1
study. Six supramolecular complexes, including the two novel
tris(2-pyridylmethyl)amine-based hemicryptophane complexes
CuII(Hm-TPA) and FeII(Hm-TPA) (Scheme 1), displaying
various first and second coordination spheres were immobi-
lized onto silica and applied in the heterogeneous oxidation of
CH4 in water by H2O2. We demonstrated that changing the
nature of the second coordination sphere around the VO
site could lead to improved efficiency or selectivity.
Importantly, upon incorporation of a hemicryptophane
hydrophobic cavity above a non-heme iron unit, both the
efficiency and the selectivity for primary oxidation products
CH3OH and CH3OOH were simultaneously enhanced. This
work provides a proof of concept for the potential benefits of
developing catalysts bearing a hydrophobic cavity above a
bioinspired active center for the direct and clean trans-
formation of CH4 to methanol.
EXPERIMENTAL SECTION
■
Preparation and Characterization of Metal Hemi-
cryptophane Complexes. To evaluate the importance of the
supramolecular structure to catalytic efficiency, several metal
complexes bearing a hemicryptophane cavity and analogous
complexes devoid of the cage were prepared. Complexes
CuII(Hm-TREN), V(Hm-TKA), V(Hm-BINOL-TKA), and
V(Bz-BINOL-TKA) (Scheme 1) were obtained according to
previously reported procedures.19,20,22 In addition, the new
complex CuII(Hm-TPA)(ClO4)2, based on the Hm-TPA
hemicryptophane bearing a tris(2-pyridylmethyl)amine
(TPA) moiety,23 was prepared (Scheme 1). The air-stable
CuII(Hm-TPA)(ClO4)2 complex was obtained by reacting
Hm-TPA with 1 equiv of copper(II) perchlorate at room
B
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1
temperature in acetone. The metalation occurred immediately,
and the encaged complex was precipitated with diethyl ether,
isolated by filtration, and characterized by ESI-HRMS (Figure
S1), UV−vis (Figure S2), and EPR (Figure S3). In agreement
with the simulated spectrum, the experimental EPR spectrum
of CuII(Hm-TPA)(ClO4)2, in CH2Cl2, reveals the presence of
two Cu(II)-based species in solution, caused by two different
tetragonal distortions. The first one, accounting for 15% of the
S5). The H NMR spectra of the FeII(Hm-TPA)(SO3CF3)2
complex recorded in CD3CN at 298, 270, 260, and 240 K
exhibit downfield resonances when compared to those of the
free ligand, attesting to a low-spin Fe(II) state in agreement
1
with the reported H NMR characterization of the model
complex FeII(TPA)(SO3CF3)2 (Figures S6 and S7).25
Compared to those of the C3 symmetrical Hm-TPA ligand
(Figure S6, top), the signals of FeII(Hm-TPA)(SO3CF3)2
appeared to be broader and splitted, indicating a loss of cage
symmetry due to a metal center in an octahedral geometry
(Figure S6, bottom) [expected for low-spin (LS) Fe(II)
complexes]. This behavior differs from that of the model
complex FeII(TPA)(SO3CF3)2, which displays an effective 3-
fold symmetry in solution due to the fast exchange process that
averages the environment of the three pendant pyridines on
the NMR time scale.25 Clearly, the more rigid supramolecular
structure found in FeII(Hm-TPA)(SO3CF3)2 inhibits these
fast exchange processes.
2
2
global signal, corresponds to an elongated distortion (dx −y ),
which is axial (g = [2.270 2.090 2.090], and a = [150 0 0] ×
10−4 cm−1). The second one, accounting for 85% of the global
2
signal, corresponds to a compressed distortion (dz ), which is
orthorhombic (g = [2.244 2.120 1.987], and a = [0 57 167] ×
10−4 cm−1).24
After replacement of perchlorate anion with triflate, the
complex CuII(Hm-TPA)(SO3CF3)2 afforded single crystals
suitable for X-ray diffraction analysis (Figure 1). The structure
Encapsulation of Methane inside the Hemicrypto-
phane Cavity. Cryptophanes are CTV-based homotopic
capsules, which have been reported as efficient receptors for
CH4.26 On the other hand, a C3 symmetrical covalent
molecular cage based on the TPA ligand has very recently
́
been used by Badjic and co-workers for the trapping of small
hydrophobic molecules, including CH2Cl2 and methane.27 The
hemicryptophane Hm-TPA is a heteroditopic derivative of
cryptophane, built from a CTV unit (northern part) and a TPA
ligand (southern part). We therefore investigated the ability of
Hm-TPA to engage host−guest interaction with small
hydrophobic substrates such as CH2Cl2 and CH4. Single
crystals of Hm-TPA, suitable for X-ray diffraction, were
obtained by slow diffusion of Et2O in a CH2Cl2 solution of
the cage. Interestingly, the corresponding XRD structure
reveals one encaged CH2Cl2 molecule, which appears to be
wrapped by the C3 structure of Hm-TPA. This observation
confirms the ability of the hydrophobic pocket of Hm-TPA to
bind small hydrophobic guests in the solid state. We then
investigated the interaction between Hm-TPA and CH4 by 1H
NMR using C2D2Cl4 as the solvent.28 Upon methane bubbling,
the signals of some aromatic protons of the CTV and TPA
moieties of Hm-TPA display moderate high-field shifts (Figure
2a, signals a−c, g, and h), while aromatic protons
corresponding to the phenyl spacers (Figure 2a, signals e
and f) exhibit slightly more marked downfield shifts, attesting
to the interaction of one (or more) molecule of CH4 with the
host Hm-TPA (Table S1). Furthermore, the high-field shift
(1.92 Hz) of the CH4 resonance observed in the presence of
Hm-TPA (Figure 2d) is in good agreement with its
encapsulation within the hemicryptophane cavity. It should
be noted, however, that the observed shifts remain modest,
indicating a weak interaction in C2D2Cl4, which might result
from (i) a fast exchange process between bound and free CH4
molecules at 298 K or/and (ii) the competitive encapsulation
of this hydrophobic solvent.
Figure 1. ORTEP (ellipsoids, 50% probability) diagrams of the X-ray
crystal structure of (CH3CN)2 ⊂ CuII(Hm-TPA)(SO3CF3)2. Triflate
counterions have been omitted for the sake of clarity.
of the caged complex shows one copper center that adopts a
trigonal bipyramidal geometry, wherein the trigonal plane
comprises the three pyridine nitrogen atoms (N1−N3). The
axial positions are occupied by the tertiary amine nitrogen
(N4) and an acetonitrile molecule, which is pointing toward
the inside of the Hm-TPA cavity. A well-defined cavity,
encaging a second molecule of acetonitrile, is observed just
above the copper center, attesting to an endohedral
functionalization of the hemicryptophane, which simultane-
ously hosts the metal ion in its southern part (TPA unit) and
one guest molecule (CH3CN) in its northern cavity (CTV
unit).
Oxidation of Methane. We then investigated the
reactivity of different catalytic sites in the oxidation of
methane. The influence of the metal (Cu, V, or Fe), the first
coordination sphere provided by the non-heme ligand, and the
hemicryptophane structure was probed using the complexes
shown in Scheme 1.
Methane, having very inert C−H bonds with a bond
dissociation energy (BDE) of 104.9 kcal mol−1, can be oxidized
only by strong oxidizing species. When organic solvents
The related iron complex FeII(Hm-TPA)(ClO4)2 was
prepared by reacting Hm-TPA with 1 equiv of iron(II)
perchlorate at room temperature in acetonitrile. The metal-
ation occurred immediately, and the encaged complex was
precipitated with diethyl ether, isolated by filtration, and
characterized by ESI-HRMS (Figure S4) and UV−vis (Figure
C
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typically containing more active C−H bonds are used, e.g.,
CH3CN and CH2Cl2, their oxidation and the formation of C1
oxidation products cannot be excluded because the organic
solvent is in a huge excess with respect to dissolved CH4,
typically in the millimolar concentration range. To avoid
possible oxidation of organic solvents by the metal-based
oxidizing species that would mask the target reaction, the
oxidation of CH4 was studied in water. To this end, the
complexes were supported on silica and applied in heteroge-
neous oxidation of methane by H2O2, a clean and industrially
relevant oxidant. It is noteworthy that this oxidant can also be
used by monooxygenases for the generation of active high-
valence metal−oxo species via shunted pathways. The
reactions were performed in slightly acidic water (0.07 M
H2SO4) for 20 h at 60 °C using an autoclave containing 50 mg
of a SiO2-supported catalyst (1 μmol of complex) and 0.33 M
H2O2 oxidant, and the mixtures charged with methane (30
bar).29 The catalytic performances of “encaged” and “naked”
catalysts were evaluated by the direct comparison of (i) the
selectivity for primary oxidation products (percentage of
CH3OH and CH3OOH produced with respect to the total
amount of oxidized products) and (ii) the turnover number
(TON, micromoles of oxidation products per micromole of
catalyst).
RESULTS
■
Copper Complexes. In the initial experiments, the tris(2-
aminoethyl)amine (TREN) copper-based supramolecular
complex CuII(Hm-TREN)(ClO4 )2 and its “naked” analogue
−
CuII(TREN)(ClO4 )2 (Scheme 1) were compared in the
−
heterogeneous oxidation of CH4 by H2O2. The positioning of
the hemicryptophane hydrophobic cavity above the CuII-based
active site of CuII(Hm-TREN)(ClO4 )2 has recently been
−
described as an efficient strategy for enhancing the activity and
selectivity of cyclohexane oxidation. Higher product yields and
an increase in the selectivity for cyclohexanol were observed.19
This improvement originates from the positive conjunction of
two factors. (i) The supramolecular architecture better
protects the catalyst from oxidative degradation because
another catalyst molecule cannot fit inside the hemi-
cryptophane cavity and access the active species, and (ii) the
affinity of the hemicryptophane host for hydrophobic cyclo-
hexane is higher than that of the more hydrophilic cyclo-
hexanol. However, when applied to the oxidation of CH4,
Figure 2. (a) Diagram of the X-ray crystal structure of CH2Cl2 ⊂
Hm-TPA with space-filling representation of CH2Cl2 (left) and
HmTPA (right). (b) Partial 1H NMR spectra (C2D2Cl4, 300 MHz) of
the cage Hm-TPA at 298 K before (top) and after (bottom) bubbling
of methane (3 equiv). (c) Schematic representation of the cage Hm-
TPA. (d) H NMR resonance of CH4 in C2D2Cl4 in the absence
(top) and presence (bottom) of Hm-TPA.
1
−
caged CuII(Hm-TREN)(ClO4 )2 and “naked” CuII(TREN)-
−
(ClO4 )2 display low TONs of 1.8 and 0.6, respectively,
a
Table 1. Oxidation of CH4 by H2O2 Catalyzed by Supported Copper(II) Complexes
b
c
b
b
d
catalyst
HCOOH TON
HCHO TON
CH3OOH TON
CH3OH TON
total TON
CuII(TREN)
0.5
1.3
1.4
0.7
−
0.1
−
−
−
0.3
−
−
0.6
1.8
1.5
0.7
CuII(Hm-TREN)
0.2
0.1
−
CuII(Hm-TPA)
CuII(Hm-TREN-COO−)
−
a
Reaction conditions: reaction time of 20 h, 60 °C, solvent of H2O, 2 mL; 0.33 M H2O2, 0.07 M H2SO4, PCH = 30 bar, 50 mg of silica-supported
4
b
catalyst containing 1.0 μmol of complex. TONs of CH3OH, CH3OOH, and HCOOH were determined by 1H NMR and are the average of at least
three experiments. The yield of HCHO was determined by the Nash colorimetric method. Moles of (CH3OH + CH3OOH + HCOOH +
HCHO)/moles of catalyst. The estimated error for the TON was 20%.
c
d
D
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indicating the difficulty of reaching an efficient CH4 oxidation
using the TREN-CuII active site in combination with H2O2
(Table 1). Nevertheless, the supramolecular complex
CuII(Hm-TREN)(ClO4 )2 provided a TON 3-fold higher
−
−
than that of “naked” CuII(TREN)(ClO4 )2 (Table 1). This
positive confinement effect is in line with the results obtained
in the cyclohexane oxidation.19 Unfortunately, the low yields of
oxidized products preclude the direct comparison of the
selectivity of these complexes for CH3OH and CH3OOH.
Similarly, the CuII(Hm-TPA)(ClO4)2 complex showed a low
activity in methane oxidation (TON = 1.5).
Thus, no significant changes in reactivity were observed
upon replacement of the three amine functions of the TREN
ligand with the more withdrawing pyridine units. The related
water-soluble cage complex CuII(Hm-TREN-COO−), an
analogue of CuII(Hm-TREN) in which the methoxy groups
of the CTV moiety are replaced by three carboxylate groups,
was then studied as a homogeneous catalyst. When applied
under identical catalytic conditions, but in a homogeneous
fashion, CuII(Hm-TREN-COO−) displays a catalytic efficiency
that is lower than that of its silica supported counterpart,
CuII(Hm-TREN), with total TONs of 0.7 and 1.8, respectively
(Table 1). These results confirm that the higher catalytic
efficiency observed for the silica-supported catalyst cannot
arise from a leaching of the catalyst from the silica. The
sluggish oxidation of CH4 mediated by catalytic amounts of
CuII(TREN)(ClO4)2, CuII(Hm-TREN)(ClO4)2, and
CuII(Hm-TPA)(ClO4)2 might be explained by the nature of
the active site. Although the involvement of the Cu(III)
oxidation state in biological and biomimetic oxidation
processes has been documented,30 the activation of H2O2 at
Cu(II) centers can lead to the generation of HOO• and HO•
radicals in a Fenton-like fashion.31 Therefore, in the presence
of a recalcitrant methane molecule, the freely diffusing HOO•
or/and HO• species might react preferentially with the weaker
C−H bonds found in the hemicryptophane scaffold, resulting
in the degradation of the complexes. This hypothesis was
confirmed by ESI-MS analysis of the CuII(Hm-TPA) solution
in CH3CN after addition of H2O2, where signals with m/z
values corresponding to the oxidized complex were observed
(Figure S8).
Vanadium Complexes. Oxido−vanadium(V) hemicryp-
tophane complexes bearing a trialkanol amine coordination
unit (TKA) have recently been described as efficient catalysts
for sulfoxidation reactions.20,22 Indeed, supramolecular V(V)-
based complexes V(Hm-TKA) and V(Hm-BINOL-TKA)
have shown enhanced selectivity, reactivity, and turnover
numbers compared to those of their related model complex
V(TKA) that is devoid of the cavity. This strong confinement
effect, derived from the hydrophobic cavity present in these
flexible systems, allows for both hydrophobic substrate
recognition and hydrophilic product release. On this basis,
we have first focused on exploring the ability of oxido−
vanadium supramolecular complexes to oxidize methane. The
importance of having a second coordination sphere is well
emphasized by comparing the supramolecular catalyst V(Hm-
TKA) and its “naked” analogue V(TKA) (Figure 3 and Table
S1). The introduction of a hydrophobic cavity above the metal
site leads to an increase in the yield of CH3OH and CH3OOH
(Table 2). Importantly, similar TONs of 6.6 and 7.4 were
found using V(Hm-TKA) and V(TKA), respectively, indicat-
ing that the caged catalyst did not suffer from undesired
product inhibition, which is commonly observed for supra-
Figure 3. Structures of oxido−vanadium complexes and comparison
of their TONs and selectivities to those of the initial oxidation
products of methane. Footnote a: moles of (CH3OH + CH3OOH +
HCOOH + HCHO)/moles of catalyst. Footnote b: (CH3OH +
CH3OOH)/(CH3OH + CH3OOH + HCOOH + HCHO) × 100.
For reaction conditions, see Table 1.
molecular systems. A shorter reaction time (6 h) resulted in a
TON of 1.9 for V(Hm-TKA). The supramolecular catalyst
V(Hm-BINOL-TKA), an analogue of V(Hm-TKA) in which
the phenyl spacers are replaced by biphenyl groups, displays an
improved catalytic efficiency (2 times higher) compared to that
of V(Hm-TKA) (Figure 3). Such a behavior is consistent with
a previous study of the sulfoxidation reaction in which V(Hm-
BINOL-TKA) was found to be ∼5 times more efficient than
V(Hm-TKA).20 However, this improvement in TON was
accompanied by an undesired decrease in the selectivity in
CH3OH and CH3OOH, which dropped from 15% to 5% when
passing from V(Hm-TKA) to V(Hm-BINOL-TKA) (Figure
3). Therefore, the nature, size, and shape of the hydrophobic
E
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a
Table 2. Oxidation of CH4 by H2O2-Supported Vanadium Complexes
Catalyst
HCOOHa TON
HCHOb TON
CH3OOHa TON
CH3OHa TON
totalc TON
V(TKA)
V(Hm-TKA)
V(Hm-BINOL-TKA)
V(Bz-BINOL_TKA)
6.6
4.8
10.1
13.8
0.2
0.8
2.4
3.7
0.3
1
-
0.3
-
0.7
0.8
7.4
6.6
13.2
18.3
-
a
See Table 1 for methods and reaction conditions.
cavity clearly impact the reaction outcome of CH4 oxidation at
the oxido−vanadium catalytic sites. This trend was further
confirmed by studying the catalyst V(Bz-BINOL-TKA) having
a bowl-shaped supramolecular structure. V(Bz-BINOL-TKA)
was previously reported as a particularly efficient sulfoxidation
catalyst due to its bowl-shaped hydrophobic pocket.22 When
V(Bz-BINOL-TKA) was applied to the oxidation of CH4, a
TON of 18.3 was obtained. This TON value is significantly
higher than those obtained with V(Hm-TKA) and V(Hm-
BINOL-TKA). As expected, the selectivity in CH3OH and
CH3OOH drastically dropped for this open structure [3.3
times lower than that of V(Hm-TKA)], confirming the crucial
role of endohedral functionalization (Figure 3 and Table 2).
Altogether, these results reveal that the oxidation of CH4 can
be tuned by controlling the second coordination sphere of
oxido−vanadium complexes. Depending on the supramolecu-
lar architecture, either selectivity or catalytic efficiency can be
improved but no simultaneous enhancement of both efficiency
and selectivity could be observed.
that the efficiency of the supramolecular complex was also 2
times higher than that of the model complex FeII(TPA)-
(ClO4)2 that is devoid of a cavity [TON = 4.7 (Table 3)].
Although the absolute yields of the over-oxidized products
formaldehyde and formic acid appear to be enhanced by a
factor of 1.7 when the supramolecular catalyst was used
[TONHCHO+HCOOH = 4 and 6.7 for FeII(TPA) and
FeII(HmTPA), respectively], these values are not indicative
of the reaction selectivity. Indeed, the selectivity toward the
primary product was determined by looking at the ratio of
mono-oxidized (CH3COOH and CH3OH) to over-oxidized
(HCOOH and HCHO) products (see Figure 4). The analysis
of the oxidation products revealed a 2-fold enhanced selectivity
toward CH3OH and CH3OOH for the caged catalyst
Iron Complexes. The well-documented activation of H2O2
by non-heme iron(II) complexes leads to the formation of
hydroperoxo−iron(III) Fe−OOH and oxo−iron(IV) FeO
(under acidic conditions) metal-based oxidants.32 Alterna-
tively, simple iron salts can catalyze the oxidation of the strong
C−H bonds via generation of hydroxyl radicals from H2O2.33
The formation of a well-defined metal-based oxidant inside the
hydrophobic cavity might lead to an oxidation reaction
oriented toward the substrate C−H bonds rather than on
the C−H bonds of the side arms of the ligand suprastructure.
Indeed, the catalytic oxidation of CH4 mediated by FeII(Hm-
TPA)(ClO4)2 was found to be significantly more efficient than
that of its copper(II) counterpart with a higher TON of 9.2
compared to a TON of 1.5 (Tables 1 and 3). A shorter
reaction time (6 h) resulted in a TON of 2.8. It is noteworthy
Table 3. Oxidation of CH4 by H2O2 Catalyzed by the
a
Supported Iron-Based Complexes
b
c
b
b
d
HCOOH
TON
HCHO
TON
CH3OOH
TON
CH3OH
TON
total
catalyst
TON
FeII(TPA)
FeII(Hm-
TPA)
1.7
4.7
2.3
2.0
0.7
1.4
−
1.1
4.7
9.2
a
Reaction conditions: reaction time of 20 h, 60 °C, solvent of H2O (2
mL), 0.33 M H2O2, PCH = 30 bar, 50 mg of silica-supported catalyst
Figure 4. Comparison of TON and selectivity toward primary
products of methane oxidation for iron catalysts FeII(Hm-TPA)-
(ClO4)2 and FeII(TPA) (ClO4)2. Footnote a: moles of (CH3OH +
CH3OOH + HCOOH + HCHO)/moles of catalyst. Footnote b:
(CH3OH + CH3OOH)/(CH3OH + CH3OOH + HCOOH +
HCHO) × 100. For reaction conditions, see Table 1.
4
b
containing 1.0 μmol of complex. TONs of CH3OH, CH3OOH, and
HCOOH were determined by 1H NMR and are the average of at least
c
three experiments. The yield of HCHO was determined by the Nash
d
colorimetric method. Moles of (CH3OH + CH3OOH + HCOOH +
HCHO)/moles of catalyst.
F
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Inorganic Chemistry
Article
FeII(Hm-TPA)(ClO4)2 (27% selectivity) compared to that of
the “naked” complex FeII(TPA)(ClO4)2 (15% selectivity).
This selectivity in primary oxidation products was the highest
observed among all bioinspired complexes screened during this
study. Thus, the oxidation of CH4 mediated by FeII(Hm-
TPA)(ClO4)2 was reinforced by a strong confinement effect.
The incorporation of the hydrophobic cavity above the TPA−
iron(II) active center enhances the yield of mono-oxidized
products by a factor of 3.6 with TONCH OH+CH OOH values of
2.5 and 0.7 for FeII(Hm-TPA)(ClO4)2 and FeII(TPA)-
(ClO4)2, respectively (Figure 4 and Table 3). Such a
confinement effect can be explained by the existence of
host−guest interaction between CH4 and the hemicryptophane
hydrophobic cavity, leading to (i) proximity between the
substrate and active site and (ii) release of the hydrophilic
oxidized products (CH3OH and CH3OOH) from the
hemicryptophane hydrophobic cage. Importantly, similar
behaviors are reported for the oxidation of cyclohexane,19
and thioanisole,20 inside the hydrophobic cavity of hemi-
cryptophane-based catalysts.
were associated with an undesired decrease in selectivity
toward initial oxidation products. Thus, it appears that in these
cases the molecular cage catalysts show a higher efficiency also
favoring the over-oxidation of methane, as supported by the
TON in over-oxidation products. This highlights how
challenging it is to develop catalytic systems featuring both
high activity and selectivity in methane oxidation. On the other
hand, the confinement effect observed for hemicryptophane
complex V(Hm-TKA) (where binaphthyl spacers are replaced
by phenyl moieties) results in improved selectivity, while its
catalytic efficiency remains similar to that of its parent model
complex. Remarkably, controlling the microenvironment above
a non-heme iron(II)(TPA) active site clearly improves both
the efficiency and the selectivity of the catalytic oxidation of
CH4. The intrinsic inertness of methane compared to its
mono-oxidized analogues (such as methanol) makes the single
oxidation of CH4 a particularly challenging task. Athough
formic acid is the major product with all of the cage complexes
tested, a strong improvement in selectivity is observed using
the new supramolecular catalyst FeII(Hm-TPA). Indeed, the
yield in target mono-oxidized products (CH3OH and
CH3OOH) was successfully increased (by 3.6-fold) compared
to that of its “naked” model. We propose that such a
confinement effect arises from the encapsulation of CH4 within
the organic hydrophobic cavity located above the iron(II)
catalytic center, along with the release of the more hydrophilic
mono-oxidized products to the bulk solution. To the best of
our knowledge, this represents the first example of methane
oxidation catalyzed by well-defined bioinspired catalysts inside
the cavity of a molecular receptor.
3
3
DISCUSSION
■
In this study, a novel strategy for the development of
bioinspired catalysts for the oxidation of methane to methanol
was proposed and evaluated. To combine a reactive metal
catalytic site with an adjacent hydrophobic pocket for methane
binding, a series of iron, vanadium, and copper complexes
supported by trialkanolamine, tren, and tris(2-pyridylmethyl)
amine ligands bearing hemicryptophane moieties was
prepared. The interaction of methane with hydrophobic
1
CONCLUSION
cages of Hm-TPA was observed by the H NMR method.
■
We have shown that the positioning of a hemicryptophane
hydrophobic cavity above a metal-based oxidizing center
positively influences the way that methane C−H bonds are
catalytically oxidized by H2O2. Indeed, the functional duality of
the hemicryptophane structure allows for host−guest inter-
actions with hydrophobic substrates inside its well-defined
cavity (northern part), along with the simultaneous coordina-
tion of biologically relevant VV, CuII, and FeII metal ions
(southern part). The heterogeneous catalytic oxidation of
methane in water has been studied through the screening of six
vanadium-, copper-, and iron-based silica-supported complexes
bearing a supramolecular second coordination sphere.
Although the cage compounds could not be recycled because
of progressive decomposition during the reaction [as observed
for the CuII(Hm-TPA) complex (Figure S8)], the effect of
confinement on CH4 oxidation has been unambiguously
shown through the direct comparison between “encaged”
and “naked” complexes. Such catalyst breakdown accompanied
by the known decomposition of H2O2 into H2O and O2 leads
to undesired H2O2 consumption that justifies the elevated
amounts of H2O2 required to convert methane in our catalytic
systems. Although copper-based complexes were found to be
rather sluggish catalysts, their iron(II) and vanadium(V)
analogues display promising catalytic efficiencies with total
TONs ranging from 4.7 to 18.3. It was found that the
supramolecular complexes simultaneously holding an oxido−
vanadium active center, binaphthyl spacers, and either CTV
(hydrophobic cavity, Hm-BINOL-TKA) or a benzene unit
(open hydrophobic pocket, Bz-BINOL-TKA) were the most
efficient catalysts with total TONs of 13.2 and 18.3,
respectively. However, these improved catalytic efficiencies
The results obtained in this study highlight the relevance of the
hemicryptophane nanoreactors, which can be used as
homogeneous or heterogeneous supported catalysts. These
functional models combine the efficiency of heterogeneous
catalysis (in pure water) with the convenient character of
homogeneous systems (host−guest studies). Therefore, the
confinement of well-defined metal-based active centers that
can activate the green and cheap H2O2 oxidant should be
considered as a promising strategy for the further development
of highly active catalysts for the selective oxidation of methane
to methanol. Finally, in contrast to sluggish copper(II)
complexes, the encouraging results obtained with the iron-
(II)-based catalysts might account for the involvement of a
high-valence metal-based oxidant in a manner similar to that
involved for enzymatic systems (MMO). Future work will be
focused on the preparation of a catalyst with improved
oxidizing activity and stability.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b00199.
1
Synthetic procedures, H NMR, mass, UV, and EPR
spectra, and data related to the X-ray structures (PDF)
Accession Codes
CCDC 1891843−1891844 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
G
DOI: 10.1021/acs.inorgchem.9b00199
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Inorganic Chemistry
Article
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Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: alexander.sorokin@ircelyon.univ-lyon1.fr.
*E-mail: alexandre.martinez@centrale-marseille.fr.
■
ORCID
Thierry Brotin: 0000-0001-9746-4706
Jean-Pierre Dutasta: 0000-0003-0948-6097
Alexandre Martinez: 0000-0002-6745-5734
Author Contributions
⊥S.A.I. and C.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the French National Research
Agency (ANR, France, OH Risque Grant ANR-14-OHRI-
0015-03). Lhoussain Khrouz and Michel Giorgi are acknowl-
edged for the EPR measurements and X-ray structure
determination, respectively.
̇ ̈
(b) Isç i, U.; Faponle, A. S.; Afanasiev, P.; Albrieux, F.; Briois, V.;
Ahsen, V.; Dumoulin, F.; Sorokin, A. B.; de Visser, S. P. Site-selective
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