Mild oxidative C?H functionalization of alkanes and alcohols using a magnetic core-shell Fe3O4@mSiO2@Cu4 nanocatalyst

Article abstract of DOI:10.1016/j.molcata.2016.06.028

A new hybrid Fe₃O₄@mSiO₂@Cu₄ material was constructed by loading a bio-inspired tetracopper(II) coordination compound [Cu₄(μ₄-O){N(CH₂CH₂O)₃}₄(BOH)₄][BF₄]₂ (Cu₄) onto the Fe₃O₄@mSiO₂ core-shell nanoparticles (NPs) composed of a magnetite (Fe₃O₄) core and mesoporous silica (mSiO₂) shell with perpendicularly aligned channels. The obtained Fe₃O₄@mSiO₂@Cu₄ magnetic nanoparticles were characterized by transmission electron microscopy (TEM), FT-IR spectroscopy, thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), and field-dependent magnetization. This hybrid material acts as a magnetically recoverable C?H functionalization nanocatalyst, namely for the mild oxidation, by t-butyl hydroperoxide at 50–70?°C in acetonitrile medium, of cycloalkanes (cyclopentane, cyclohexane, cycloheptane, and cyclooctane) to the corresponding alcohols and ketones (with up to ～15% yields based on cycloalkane; TON 335). A related oxidation process using cyclohexanol as a more reactive substrate leads to the formation of cyclohexanone in up to ～25% yield (TON 570). The Fe₃O₄@mSiO₂@Cu₄ nanocatalyst can be recycled five times without an appreciable loss of activity. The bond-, regio-, and stereoselectivity parameters were investigated in the oxidation of different alkane substrates (n-hexane, n-heptane, n-octane, methylcyclohexane, adamantane, cis- and trans-1,2-demethylcyclohexane), and the obtained results were compared with the homogeneous systems based on the Cu₄ catalyst. In particular, the high bond selectivity parameters detected in the oxidation of methylcyclohexane (1°:2°:3° of 1:8:142) and adamantane (2°:3° of 1:21) catalyzed by Fe₃O₄@mSiO₂@Cu₄ suggest that the reactions possibly occur in hydrophobic pockets of the nanocatalyst.

Full text of DOI:10.1016/j.molcata.2016.06.028

Accepted Manuscript
Title: Mild Oxidative C−H Functionalization of Alkanes and
Alcohols using a Magnetic Core-Shell Fe3O4@mSiO2@Cu4
Nanocatalyst
Author: Marina V. Kirillova Carla I.M. Santos Wenyu Wu Yu
Tang Alexander M. Kirillov
PII:
S1381-1169(16)30250-3
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.06.028
MOLCAA 9934
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
30-4-2016
25-6-2016
27-6-2016
Please cite this article as: Marina V.Kirillova, Carla I.M.Santos, Wenyu Wu, Yu Tang,
Alexander M.Kirillov, Mild Oxidative C−H Functionalization of Alkanes and Alcohols
using a Magnetic Core-Shell Fe3O4@mSiO2@Cu4 Nanocatalyst, Journal of Molecular
Catalysis A: Chemical http://dx.doi.org/10.1016/j.molcata.2016.06.028
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

1
Mild Oxidative C−H Functionalization of Alkanes and Alcohols using a Magnetic
Core-Shell Fe3O4@mSiO2@Cu4 Nanocatalyst1
Marina V. Kirillova a, Carla I. M. Santos a, Wenyu Wu b, Yu Tang b,* Alexander M. Kirillov a *
a
Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Universidade de Lisboa,
Av. Rovisco Pais, 1049-001, Lisbon, Portugal. E-mail: kirillov@tecnico.ulisboa.pt
b State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000,
P.R. China. E-mail: tangyu@lzu.edu.cn
1This article is dedicated to Prof. Georgiy B. Shul’pin on the occasion of his 70th birthday.
Graphical abstract
Research highlights:
Magnetic core-shell nanoparticle catalyst was assembled and fully characterized;
This hybrid Fe3O4@mSiO2@Cu4 material bears catalytically active tetracopper(II) unit;
Magnetically recoverable nanocatalyst is active for mild oxidation of cycloalkanes;
Effects of various reaction parameters were investigated;
Different selectivity parameters were studied.

2
ABSTRACT
A new hybrid Fe3O4@mSiO2@Cu4 material was constructed by loading a bio-inspired
tetracopper(II) coordination compound [Cu4(µ4-O){N(CH2CH2O)3}4(BOH)4][BF4]2 (Cu4) onto the
Fe3O4@mSiO2 core-shell nanoparticles (NPs) composed of a magnetite (Fe3O4) core and
mesoporous silica (mSiO2) shell with perpendicularly aligned channels. The obtained
Fe3O4@mSiO2@Cu4 magnetic nanoparticles were characterized by transmission electron
microscopy (TEM), FT-IR spectroscopy, thermogravimetric analysis (TGA), powder X-ray
diffraction (PXRD), and field-dependent magnetization. This hybrid material acts as a magnetically
recoverable C−H functionalization nanocatalyst, namely for the mild oxidation, by t-butyl
hydroperoxide at 50–70 °C in acetonitrile medium, of cycloalkanes (cyclopentane, cyclohexane,
cycloheptane, and cyclooctane) to the corresponding alcohols and ketones (with up to ~15% yields
based on cycloalkane; TON 335). A related oxidation process using cyclohexanol as a more
reactive substrate leads to the formation of cyclohexanone in up to ~25% yield (TON 570). The
Fe3O4@mSiO2@Cu4 nanocatalyst can be recycled five times without an appreciable loss of activity.
The bond-, regio-, and stereoselectivity parameters were investigated in the oxidation of different
alkane substrates (n-hexane, n-heptane, n-octane, methylcyclohexane, adamantane, cis- and trans-
1,2-demethylcyclohexane), and the obtained results were compared with the homogeneous systems
based on the Cu4 catalyst. In particular, the high bond selectivity parameters detected in the
oxidation of methylcyclohexane (1°:2°:3° of 1:8:142) and adamantane (2°:3° of 1:21) catalyzed by
Fe3O4@mSiO2@Cu4 suggest that the reactions possibly occur in hydrophobic pockets of the
nanocatalyst.
Keywords: C−H Functionalization; Oxidation catalysis; Magnetic nanoparticles; Nanocatalysis;
Cycloalkane oxidation; Multicopper compounds.
1. Introduction
Within the sweeping research progress in the field of nanocatalysis [1–3], the design of
novel hybrid materials incorporating magnetically recoverable nanoparticles (NPs) decorated with
catalytically active units has received an increased attention [4–7]. In fact, magnetic separation of
nanocatalysts and their easy isolation from the reaction medium and reutilization in subsequent
batches constitute very powerful features, which can lead to the development of new and more
efficient catalytic protocols [1–7]. The use of magnetically recoverable NPs is particularly attractive
when dealing with expensive catalysts or in the catalytic processes that involve inert substrates and
show low conversions, thus justifying frequent catalyst and substrate recycling procedures [5–7]. A
notable example of such a class of inert substrates concerns alkanes, which are typically involved
into low-conversion transformations, including various C–H functionalization processes [8–10].

3
Despite alkanes are very highly abundant in nature and can be considered as inexpensive
substrates, an intrinsic inertness of these hydrocarbons limits their application as raw materials in
different oxidative C–H functionalization processes that undergo efficiently and under mild
conditions [8–13]. However, there are a good number of homogeneous catalytic systems and
protocols for the mild alkane oxidation based on different bio-inspired or bio-mimetic metal
complexes, which are highly active when combined with a certain oxidant and under tuned reaction
conditions [14–16]. In this regard, the heterogenization of such metal complexes on various
supports or carriers and, in particular, on magnetic nanoparticles (e.g., based on magnetite, Fe3O4
[5a,d]) represents a perspective research direction [5–7]. It should be noted that the application of
magnetically recoverable nanocatalysts for the mild oxidative C–H functionalization of alkanes still
remains very little explored [17], thus motivating further research in this field.
Our recent studies were focused on the design of homogeneous multicopper(II) catalytic
systems for the mild oxidation of alkanes [18] and on the fabrication of functional materials based
on hybrid magnetic nanoparticles [19]. Aiming at merging these two research directions, the main
objectives of the present work consisted of (i) assembling a novel magnetic core-shell nanoparticle
catalyst bearing a loaded catalytically active unit, and (ii) evaluating the generated material as a
magnetically recoverable catalyst for the mild oxidation of alkanes and alcohols. As a catalytically
active unit for loading, we have selected a bio-inspired tetracopper(II) triethanolaminate [Cu4(µ4-
O){N(CH2CH2O)3}4(BOH)4][BF4]2 (Cu4) complex (Scheme 1) on account of its high stability as
well as remarkable and versatile catalytic behavior in the homogeneous oxidation of alkanes and
other substrates [16,20].
Hence, we report herein the fabrication, characterization, and catalytic application in an
oxidative C–H functionalization of a novel hybrid Fe3O4@mSiO2@Cu4 nanocatalyst, generated via
the loading of an active Cu4 unit onto the core-shell Fe3O4@mSiO2 nanoparticles that comprise a
magnetite (Fe3O4) core and a mesoporous silica (mSiO2) shell with perpendicularly aligned
channels. The obtained material acts as a magnetically recoverable nanocatalyst for the mild
oxidation, by t-BuOOH at 50–70 °C, of various C5–C8 cycloalkanes to the corresponding alcohols
and ketones and, in turn, for the oxidation of a more reactive model substrate, cyclohexanol, to give
cyclohexanone.
2. Experimental
2.1. Materials and methods
All chemicals were obtained from commercial sources and used as received. Compound
[Cu4(µ4-O){N(CH2CH2O)3}4(BOH)4][BF4]2 (Cu4) was synthesized according to a reported

4
procedure [20]. Fourier transform infrared (FT-IR) spectra were measured within the 4000–400 cm–
1
range using a Nicolet 360 FT-IR spectrometer with the KBr pellet technique. Thermogravimetric
(TGA) analysis was performed on a Perkin-Elmer thermal analyzer, by heating the sample up to
800 °C at a rate of 10 °C/min under nitrogen atmosphere. Powder X-ray diffraction patterns
(PXRD) were determined on a Rigaku-Dmax 2400 diffractometer using Cu Kα radiation over the
2θ range of 10-80º. Transmission electron microscopy (TEM) images were taken on a Tecnai-G2-
F30 (300 kV). Dynamic light scattering (DLS) measurements were performed by a BI-200SM from
Brookhaven Corporation (America). Hydrodynamic particle diameters were obtained from
cumulate fits of the autocorrelation functions at 90 scattering angle. Gas chromatography (GC)
analyses were run on an Agilent Technologies 7820A series gas chromatograph (He as carrier gas)
equipped with the FID detector and BP20/SGE (30 m × 0.22 mm × 0.25 μm) capillary column.
2.2. Synthesis of Fe3O4@mSiO2 core-shell nanoparticles
Magnetite core Fe3O4 nanoparticles with a mean diameter of 90 nm were obtained via a
solvent thermal reaction using a previously described high-temperature hydrothermal method [21].
A mesoporous silica shell was generated through a surfactant involved solution sol-gel process [22]
by applying the obtained Fe3O4 particles as seeds [19]. More specifically, the as-prepared Fe3O4 (50
mg) and cetyltrimethyl ammonium bromide (CTAB, 500 mg) were mixed in deionized H2O by
ultrasonication for 30 min. Then, the resultant homogenous dispersion was diluted in a flask with
deionized H2O (400 mL) and an aqueous solution of NaOH (0.01 M, 50 mL), followed by further
ultrasonic treatment for 5 min. Afterward, the obtained basic dispersion was heated at 60 °C for 30
minutes under mechanical stirring to form a stable dispersion. Subsequently, 2.5 mL of
tetraethylorthosilicate (TEOS)/ethanol (v:v = 1:4) solution was injected into the stable dispersion,
and this was intensively stirred for about 1 min and then was left to stand undisturbed for 8 h [23].
After the coating process, the product was collected by magnetic separation. The surfactant was
removed from the obtained product via extraction with 40 mL ethanol and 0.15 mL HCl in soxhlet
extractor. After the extraction process, magnetic mesoporous silica microspheres (Fe3O4@mSiO2)
were collected and washed with deionized water at least 5 times and dried at 50 °C in vacuum.
2.3. Preparation of hybrid Fe3O4@mSiO2@Cu4 material
Loading process of [Cu4(µ4-O){N(CH2CH2O)3}4(BOH)4][BF4]2 (Cu4) onto a Fe3O4@mSiO2
matrix was performed as follows. A 10 mL ethanol/H2O (v:v = 9:1) solution containing 50 mg of
Cu4 was added into an ultrasonic suspension of Fe3O4@mSiO2 (50 mg) in EtOH (5 mL), under
vigorous stirring. The mixture was kept at 50 °C for 10 min, followed by annealing at room
temperature for 12 h. The product was purified by magnetic separation and re-dispersed in 10 mL

5
ethanol for three times, yielding the resulting Fe3O4@mSiO2@Cu4 material with a ~10 wt% content
of Cu4. Its characterization was carried out by field-dependent magnetization, Fourier transform
infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), thermogravimetric analysis
(TGA), and transmission electron microscopy (TEM).
2.4. Catalytic studies
The oxidation reactions were carried out in air atmosphere in thermostated glass vessels
equipped with a reflux condenser, under vigorous stirring (1000 rpm) at 50 or 70 °C and using
MeCN as solvent (up to 2.5 mL total volume). In a typical experiment, the Fe3O4@mSiO2@Cu4
catalyst (5 mg) and gas chromatography (GC) internal standard (MeNO2, 25 µL) were introduced
into MeCN solution, followed by the addition of alkane substrate (1 mmol, typically cyclohexane).
The reaction was started (0 min) upon addition of t-BuOOH oxidant (70% in H2O, 2.5 mmol) in one
portion. The formation of products was monitored by withdrawing small aliquots (50 µL) after
different periods of time, which were treated with PPh3 (following a method developed by Shul’pin
[24]) for reduction of remaining t-BuOOH and alkyl peroxides that are typically formed as primary
products in alkane oxidations. The samples were analyzed by GC using nitromethane as an internal
standard. Attribution of peaks was made by comparison with chromatograms of authentic samples.
In the catalyst recycling experiments, the Fe3O4@mSiO2@Cu4 nanocatalyst was recovered
magnetically, washed with ethanol three times, dried in air, and reused in subsequent batches.
For the oxidation of cyclohexanol, a similar general procedure was followed wherein the
alcohol substrate was used instead of alkane. Blank tests confirmed that both alkane and alcohol
oxidations do not proceed in the absence of the Fe3O4@mSiO2@Cu4 catalyst. In addition, the sole
magnetite Fe3O4 NPs and mesoporous silica shell Fe3O4@mSiO2 NPs were tested under standard
reaction conditions, showing that these materials do not catalyze the oxidation of alkanes and
alcohols.
3. Results and discussion
3.1. Preparation and characterization of Fe3O4@mSiO2@Cu4 nanocatalyst
The hybrid core-shell Fe3O4@mSiO2@Cu4 material was fabricated by loading, via a direct
sorption process in an EtOH/H2O medium (v:v = 9:1), a tetracopper(II) compound [Cu4(µ4-
O){N(CH2CH2O)3}4(BOH)4][BF4]2 (Cu4) onto the Fe3O4@mSiO2 matrix [19]; it is composed of a
magnetite (Fe3O4) core and a mesoporous silica (mSiO2) shell with perpendicularly aligned
channels (Scheme 2). After annealing and purification procedures, the resulting
Fe3O4@mSiO2@Cu4 material (with a Cu4 content of ~10 wt%) was obtained and characterized by

6
the field-dependent magnetization, FT-IR spectroscopy, PXRD, TGA, and TEM methods (Figure
1).
The magnetization saturation values of 49.9 emu·g–1 were observed for the Fe3O4
nanoparticles, which then turned to 21.8 emu·g–1 after being coated with a mesoporous silica layer
to give the Fe3O4@mSiO2 matrix (Figure 1a). As expected, after a loading process of Cu4, the
magnetization saturation decreased further to 8.9 emu·g–1. Nevertheless, this value allows a good
magnetic separation ability that was experimentally confirmed in the course of catalytic tests. In
fact, the Fe3O4@mSiO2@Cu4 NPs quickly respond to an external magnetic field and can easily
agglomerate and, when required, homogeneously redisperse upon shaking or stirring (Figure 1a,
inset). Such a magnetic behavior allows the use of this material as a magnetically recoverable
nanocatalyst [5–7].
The comparison of the FT-IR spectra of the resulting Fe3O4@mSiO2@Cu4 material,
Fe3O4@mSiO2 matrix, and Cu4 derivative confirms the loading of the latter (Figure 1b). Despite
becoming less intense, various characteristic ν(C–N) [664 cm–1], ν(Cu–O) [970 cm–1], ν(C–O)
[1031 cm–1], ν(B–O) [1389 cm–1], ν(C–H) [2981, 2933, 2881 cm–1], and ν(OH) [B–OH: 3464, 3390
cm–1] bands [20] correspond to the presence of Cu4 in the hybrid nanomaterial. The PXRD patterns
(Figure 1c) exhibit expectable diffraction peaks for the Fe3O4@mSiO2 matrix and hybrid
Fe3O4@mSiO2@Cu4 material, which can be exactly indexed to the diffractions of magnetite phase
(29.8°, 35.4°) and Cu4 (17.8°), suggesting a successful Cu4-loading process. The diffraction peak at
around 1.7° in Fe3O4@mSiO2 (Figure 1d) corresponds to the reflection of a two-dimensional
hexagonal ordered mesostructure owing to the mesopore alignment on the spherical surface; this
peak is not observed in Fe3O4@mSiO2@Cu4 possibly as the pores were essentially blocked upon
loading of Cu4. The comparison of the TGA plots for the Fe3O4@mSiO2 and Fe3O4@mSiO2@Cu4
NPs (Figure 1e) further corroborates the presence of Cu4 in the core-shell Fe3O4@mSiO2 matrix. In
fact, the Fe3O4@mSiO2@Cu4 material loses some absorbed moisture upon heating in the ~30–100
°C temperature range, and the sample is then stable up to ~190 °C, followed by the decomposition
of Cu4 in the ~190–310 °C interval. The concentration of Cu4 (~10 wt%) in Fe3O4@mSiO2@Cu4
was determined based on the TGA data (Figure 1e). The TEM image of the resulting
Fe3O4@mSiO2@Cu4 NPs (Figure 1f) showed that the Fe3O4@mSiO2 microspheres are decorated
with a compact core (approximately 90 nm in diameter), also revealing a lower density shell with an

7
approximate thickness of 20 nm. A slight particle aggregation after the catalyst loading process was
observed, resulting in the aggregates ranging from 150 to 220 nm in diameter (Fig. 1g).
3.2. Mild oxidation of cycloalkanes catalyzed by Fe3O4@mSiO2@Cu4
The hybrid Fe3O4@mSiO2@Cu4 nanoparticle material was tested as a nanocatalyst for the
mild oxidation of different C5–C8 cycloalkanes, by t-BuOOH in MeCN medium at 50–70 °C, to
produce a mixture of the corresponding cyclic alcohols and ketones. Cyclohexane was studied in
more detail as a model substrate (Scheme 3), given an importance of cyclohexanone and
cyclohexanol as intermediates in the nylon production [10,25].
The oxidation of cyclohexane at 50 °C results in the ~12% total yield (hereinafter all yields
are based on an alkane substrate) of cyclohexanol and cyclohexanone, with a catalyst turnover
number (TON) of 265 (Table 1, Figure 2a,). The product accumulation curves show that in the
beginning of the reaction, cyclohexanol is formed predominantly to cyclohexanone, but after some
time the accumulation of both products becomes comparable (Figure 2a). A slightly higher reaction
temperature of 70 °C accelerates the C6H12 oxidation which also turns to be more efficient, resulting
in the ~15% total product yield (Figure 2b) and TON of 340. It is important to mention that under
similar reaction conditions, the oxidation of cyclohexane in the presence of the parent
Fe3O4@mSiO2 matrix or magnetite Fe3O4 nanoparticles does not occur, thus confirming the
importance of the Cu4 catalytically active units in the obtained nanocatalyst. Aiming at exploring
the oxidant scope of the present reaction, we tested hydrogen peroxide (50% in H2O) instead of t-
BuOOH, but only traces of products were observed.
In order to check the substrate versatility of the Fe3O4@mSiO2@Cu4 nanocatalyst toward
different cyclolakanes, we also carried out the oxidation of cyclopentane, cycloheptane, and
cyclooctane by t-BuOOH at 50 °C (Table 1). Under these reaction conditions, cyclopentane turned
to be the most active substrate (~15% total yield, TON 335), followed by cycloheptane (~14% total
yield, TON 310) and cyclohexane (~12% total yield, TON 265). Cyclooctane was the least active
substrate (~9% total yield, TON 215). However, it should be mentioned that the obtained yields (9–
15% based on substrate) and TONs (215–335) can be considered as rather good in the field of
alkane functionalization, given the intrinsic inertness of these hydrocarbons and mild reaction
conditions [8–16]. In contrast, an industrial DuPont process for the oxidation of cyclohexane shows
only ~5% total yield of the cyclohexanol and cyclohexanone mixture, utilizes a homogeneous
cobalt naphthenate catalyst, and operates under harsher reactions conditions (~150 °C, 10 atm
pressure) [10]. Moreover, the TONs showed by the Fe3O4@mSiO2@Cu4 catalyst are better than

8
those exhibited by a related homogeneous Cu4/t-BuOOH system [26a], thus indicating a positive
effect of the Cu4 loading onto the core-shell Fe3O4@mSiO2 NPs.
In order to evaluate a possible leaching of the Cu4 complex to the reaction solution from the
Fe3O4@mSiO2@Cu4 NPs, we performed the following experiment. The Fe3O4@mSiO2@Cu4
catalyst (5 mg) was treated with t-BuOOH (2.5 mmol) in acetonitrile solvent (conditions typical to
those of catalytic tests, Table 1), and the obtained mixture was incubated for 1 h at 50 °C under
vigorous stirring. Then, the nanocatalyst was separated magnetically from the mixture containing t-
BuOOH and MeCN. This mixture was additionally filtered to ensure a complete removal of any
remaining nanoparticles, and then combined with the cyclohexane substrate (1 mmol). The obtained
mixture was left to react for 5 h under vigorous stirring at 50 °C and then analyzed by GC. The
formation of cyclohexanol and cyclohexanone in low amounts (~0.5% total yield) was observed,
thus indicating that minor leaching of Cu4 takes place. Moreover, a similar incubation experiment
using the Fe3O4@mSiO2@Cu4 NPs suspension in CH3CN without t-BuOOH, followed by an
isolation of the catalyst and posterior introduction of cyclohexane substrate and t-BuOOH oxidant,
resulted in even lower yields (traces) of oxidation products. These data suggest that t-butyl
hydroperoxide is mainly responsible for a minor elution of the Cu4 species from the nanoparticles.
In fact, after standard catalytic experiments, the leaching of Cu4 was determined to be ~4% from the
amount of the complex in the Fe3O4@mSiO2@Cu4 NPs.
Despite detecting the above-described leaching, we were able to reuse the
Fe3O4@mSiO2@Cu4 nanocatalyst for up to five recycling batches (Figure 2c) in the cyclohexane
oxidation, wherein the catalyst essentially maintains an initial activity. Although Figure 2c shows
that the TON values slightly decline after each reaction cycle, their drop is not only explained by
partial leaching but is also associated with some loss of the catalyst quantity during recycling
experiments. We believe further optimization of the Fe3O4@mSiO2 matrix parameters and Cu4-
loading process can result in improved and more stable catalytic materials.
3.3. Mild oxidation of cyclohexanol catalyzed by Fe3O4@mSiO2@Cu4
Aiming at evaluating the catalytic potential of the Fe3O4@mSiO2@Cu4 nanocatalyst toward
the oxidation of more reactive substrates rather than alkanes, we selected cyclohexanol as a model
alcohol substrate and tested its oxidation by t-butyl hydroperoxide to give cyclohexanone (Scheme
3). As expected, the oxidation of cyclohexanol (Figure 3) is more efficient in comparison with that
of cyclohexane, giving rise to ~19% yield of cyclohexanone (TON 435) under standard conditions.
Similarly, the oxidation reaction is faster and more efficient at 70 °C, resulting in ~25% yield of

9
cyclohexanone (TON 570). Blank experiments indicated that neither the Fe2O3 nanoparticles nor
the Fe3O4@mSiO2 matrix catalyze the oxidation of cyclohexanol by t-BuOOH. As in the case of
cyclohexane, no oxidation of cyclohexanol was detected in the presence of H2O2 as an oxidant and
Fe3O4@mSiO2@Cu4 as a catalyst under the same reaction conditions.
3.4. Selectivity features in alkane oxidations catalyzed by Fe3O4@mSiO2@Cu4
In order to shed some light onto the reaction mechanism, we studied the oxidation of various
linear and substituted cyclic alkanes by t-BuOOH in the presence of the Fe3O4@mSiO2@Cu4
nanocatalyst. Different types of selectivity parameters were determined and compared with the
values obtained in related oxidation reactions catalyzed by the homogeneous Cu4/t-BuOOH and
Cu4/TFA/H2O2 (TFA, trifluoroacetic acid) systems [26,27]; the obtained data are summarized in
Table S1. Hence, the oxidation of n-hexane, n-heptane, and n-octane catalyzed by
Fe3O4@mSiO2@Cu4 undergoes with a slight preference to the secondary C(2) carbon atom of the
hydrocarbon chain, as attested by the regioselectivity C(1):C(2):C(3):C(n) parameters of 1:19:16,
1:19:11:16, and 1:22:12:12, respectively (Table S1). The oxidation of methylcyclohexane shows an
increased bond selectivity 1°:2°:3° parameter of 1:8:142, suggesting that the tertiary C atom is
oxidized with high preference over the secondary and primary C atoms. A similar trend is observed
in the oxidation of adamantine, with a comparable 2°:3° parameter of 1:21. The oxidations of both
cis- or trans-1,2-dimethylcyclohexanes proceed with a moderate stereoselectively, as confirmed by
the trans/cis ratios of 0.6 between the generated isomeric tertiary alcohols with the mutual trans and
cis orientation of the methyl groups. Interestingly, a partial inversion of the configuration was also
detected, with the cis isomers being predominant products in both cis- and trans-1,2-
dimethylcyclohexane oxidations.
The observed bond-, regio- and stereoselectivity parameters (Table S1) for alkane oxidations
by the Fe3O4@mSiO2@Cu4 / t-BuOOH system are generally well comparable to those of the
homogeneous Cu4/t-BuOOH system [26a], but are very different from those exhibited by the
Cu4/TFA/H2O2 system that operates with an involvement of hydroxyl radicals [26b]. These data and
prior literature background [15,16,28,29] suggest that the alkane oxidations with t-BuOOH
catalyzed by Fe3O4@mSiO2@Cu4 possibly occur in hydrophobic pockets (clefts) of the
nanocatalyst with an involvement of some intermediate copper species [26a]. This differs
significantly from the related Cu4/H+/H2O2 and other homogeneous multicopper(II) systems
[15,18], in which hydroxyl radicals act as active oxidizing species. Another distinctive feature of
the Fe3O4@mSiO2@Cu4 nanocatalyst is characterized by no need for an acid co-catalyst or

10
promoter, which is typically required by the majority of homogeneous copper based catalysts for
the mild alkane oxidation [15,24,27].
4. Conclusions
In the present work, we designed, fabricated, and fully characterized a novel hybrid material,
Fe3O4@mSiO2@Cu4, as well as applied it as a magnetically recoverable and recyclable
nanocatalyst for oxidative C–H functionalization, namely for the mild oxidation of cycloalkanes
and an alcohol (cyclohexanol). In this nanocatalyst, the catalytic function is played by a bio-inspired
tetracopper(II) triethanolaminate complex, which was loaded onto the Fe3O4@mSiO2 core-shell
nanoparticles composed of a magnetite (Fe3O4) core and mesoporous silica (mSiO2) shell.
The obtained hybrid material not only widens the family of magnetically recoverable
nanocatalysts [5–7], but also represents rare example of such materials that find a noteworthy
application in oxidative C–H functionalization of alkanes [17], which are very inert hydrocarbons
for oxidation under mild temperatures and pressures [8–13]. In fact, Fe3O4@mSiO2@Cu4 acts as a
versatile and efficient nanocatalyst for the mild oxidation by t-BuOOH of various cycloalkanes to
the corresponding alcohols and ketones. Overall turnover numbers (TONs) up to 335 were attained
and the effects of various reaction parameters were investigated, including the magnetically-assisted
catalyst recycling that is easily achievable due to the presence of a magnetite Fe3O4 core. It was
shown that the nanocatalyst maintains almost the same level of activity in cyclohexane oxidation
even after five reaction cycles. Besides, the substrate scope of Fe3O4@mSiO2@Cu4 can be extended
from alkanes to alcohols and the nanocatalyst is active for the oxidation of cyclohexanol as a more
reactive model substrate, resulting in the formation of cyclohexanone with a TON of 570.
The study also extends the application of bio-inspired multicopper(II) compounds
[14,16,30,31] toward the development of supported and recyclable oxidation catalysts. In fact, the
µ4-oxo Cu4 complex with triethanolaminate N,O-environment can show some relevance to the
catalytic function of particulate methane monooxygenase, a prominent enzyme bearing a
multicopper active site with an N,O-surrounding and capable of catalyzing the hydroxylation of
alkanes [32].
We expect that further research will focus on (i) designing related magnetically recoverable
nanocatalysts with a higher loading capacity of catalytically active species and superior
performance, (ii) broadening the substrate scope to other alkanes and alcohols, (iii) optimizing the
reaction conditions to achieve better yields and TONs, and (iv) probing the obtained nanocatalysts
in other types of oxidative C–H bond transformations involving alkanes. These research directions
are currently in progress.

11
Acknowledgements
This work was supported by the Foundation for Science and Technology (FCT)
(IF/01395/2013/CP1163/CT005, UID/QUI/00100/2013, SFRH/BSAB/114190/2016), Portugal, and
National Natural Science Foundation of China (21471071, 21431002).
References
[1] (a) V. Polshettiwar, T. Asefa (Eds.), Nanocatalysis: Synthesis and Applications, Wiley, 2013. (b) A.
Dalai (Ed.), Nanocatalysis for Fuels and Chemicals, Oxford University Press, USA, 2012.
[2] (a) P. Serp, K. Philippot (Eds.), Nanomaterials in Catalysis, Wiley, 2012. (b) U. Heiz, U. Landman
(Eds.), Nanocatalysis, Springer, 2007.
[3] M.B. Gawande, A. Goswami, F.-X. Felpin, T. Asefa, X. Huang, R. Silva, X. Zou, R. Zboril, R.S.
Varma, Chem. Rev. 116 (2016) 3722.
[4] (a) V. Polshettiwar, R. Luque, A. Fihri, H.B. Zhu, M. Bouhrara, J.-M. Bassett, Chem. Rev. 111 (2011)
3036. (b) M.B. Gawande, R. Luque, R. Zboril, ChemCatChem 6 (2014) 3312.
[5] (a) R.K. Sharma, S. Dutta, S. Sharma, R. Zboril, R.S. Varma, M.B. Gawande, Green Chem. 18 (2016)
3184. (b) M.B. Gawande, Y. Monga, R. Zboril, R.K. Sharma, Coord. Chem. Rev. 288 (2015) 118. (c) J.
Govan, Y.K. Gun’ko, Nanomaterials 4 (2014) 222. (d) M.B. Gawande, P.S. Branco, R.S. Varma, Chem.
Soc. Rev. 42 (2013) 3371. (e) L.M. Rossi, N.J.S. Costa, F.P. Silva, R.V. Goncalves, Nanotechnol. Rev.
2 (2013) 597.
[6] (a) K.N. Trohidou (Ed.), Magnetic Nanoparticle Assemblies, CRC Press, 2014. (b) D. Astruc (Ed.),
Nanoparticles and Catalysis, Wiley, 2008. (c) J.M. Campelo, D. Luna, R. Luque, J. Marinas, A.A.
Romero, ChemSusChem 2 (2009) 18.
[7] (a) V.V. Costa, M.J. Jacinto, L.M. Rossi, R. Landers, E.V. Gusevskaya, J. Catal. 282 (2011) 209. (b) F.
Joo, Aqueous Organometallic Catalysis, Springer, 2006.
[8] (a) A.E. Shilov, G.B. Shul’pin, Activation and Catalytic Reactions of Saturated Hydrocarbons in the
Presence of Metal Complexes, Kluwer Acad. Publ., Dordrecht, 2000. (b) G.B. Shul’pin, Catalysts 6
(2016) 50.
[9] G.A. Olah, A. Molnar, Hydrocarbon Chemistry, Wiley, 2003.
[10] Ullmann's Encyclopedia of Industrial Chemistry, 6th ed., Wiley-VCH, Weinheim, 1999-2013.
[11] J.-E. Bäckvall (Ed.), Modern Oxidation Methods, Wiley, 2011.
[12] J.J. Li (Ed.), C-H Bond Activation in Organic Synthesis, CRC Press, 2015.
[13] P.J. Pérez (Ed.), Alkane C-H Activation by Single-Site Metal Catalysis, Springer, 2012.
[14] (a) R.S. Brissos, S. Garcia, A. Presa, P. Gamez, Comments Inorg. Chem. 32 (2011) 219. (b) P. Gamez,
P.G. Aubel, W.L. Driessen, J. Reedijk, Chem. Soc. Rev. 30 (2001) 376.
[15] A.M. Kirillov, G.B. Shul’pin, Coord. Chem. Rev. 257 (2013) 732.
[16] A.M. Kirillov, M.V. Kirillova, A.J.L. Pombeiro, Coord. Chem. Rev. 256 (2012) 2741.
[17] (a) F.B. Zanardi, I.A. Barbosa, P.C. de Sousa, L.D. Zanatta, D.L. da Silva, O.A. Serra, Y. Iamamoto,
Micropor. Mesopor. Mater. 219 (2016) 161. (b) G.M. Ucoski, F.S. Nunes, G. De Freitas-Silva, Y.M.
Idemori, S. Nakagaki, Appl. Catal. A.: Gen. 459 (2013) 121. (c) M.S. Saeedi, S. Tangestaninejad, M.
Moghadam, V. Mirkhani, I. Mohammadpoor-Baltork, A.R. Khosropour, Polyhedron 49 (2013) 158. (d)

12
A. Rezaeifard, M. Jafarpour, P. Farshid, A. Naeimi, Eur. J. Inorg. Chem. (2012) 5515. (e) B. Fu, H.C.
Yu, J.W. Huang, P. Zhao, J. Liu, L.N. Ji, J. Mol. Catal. A.: Chem. 298 (2009) 74.
[18] (a) T.A. Fernandes, C.I.M. Santos, V. André, J. Kłak, M.V. Kirillova, A.M. Kirillov, Inorg. Chem. 55
(2016) 125. (b) S.S.P. Dias, M.V. Kirillova, V. André, J. Kłak, A.M. Kirillov, Inorg. Chem. Front. 2
(2015) 525. (c) S.S.P. Dias, M.V. Kirillova, V. André, J. Kłak, A.M. Kirillov, Inorg. Chem. 54 (2015)
5204.
[19] W.Y. Wu, A.M. Kirillov, X.H. Yan, P.P. Zhou, W.S. Liu, Y. Tang, Angew. Chem. Int. Ed. 53 (2014)
10649.
[20] A.M. Kirillov, M.N. Kopylovich, M.V. Kirillova, M. Haukka, M.F.C.G. da Silva, A.J.L. Pombeiro,
Angew. Chem. Int. Ed. 44 (2005) 4345.
[21] H. Deng, X.L. Li, Q. Peng, X. Wang, J.P. Chen, Y.D. Li, Angew. Chem. Int. Ed. 44 (2005) 2782.
[22] K.L. Ding, B.J. Hu, G.M. An, R.T. Tao, H.Y. Zhang, Z.M. Liu, J. Mater. Chem. 19 (2009) 3725.
[23] J. Kim, H.S. Kim, N. Lee, T. Kim, H. Kim, T. Yu, I.C. Song, W.K. Moon, T. Hyeon, Angew. Chem.
Int. Ed. 47 (2008) 8438.
[24] (a) G.B. Shul’pin, J. Mol. Catal. A: Chem. 189 (2002) 39. (b) G.B. Shul’pin, C. R. Chim. 6 (2003) 163.
(c) G.B. Shul’pin, Mini-Rev. Org. Chem. 6 (2009) 95.
[25] U. Schuchardt, D. Cardoso, R. Sercheli, R. Pereira, R.S. da Cruz, M.C. Guerreiro, D. Mandelli, E.V.
Spinace, E.L. Pires, Appl. Catal. A: Gen. 211 (2001) 1.
[26] (a) M.V. Kirillova, A.M. Kirillov, D. Mandelli, W.A. Carvalho, A.J.L. Pombeiro, G.B. Shul'pin, J.
Catal. 272 (2010) 9. (b) M.V. Kirillova, Y.N. Kozlov, L.S. Shul’pina, O.Y. Lyakin, A.M. Kirillov, E.P.
Talsi, A.J.L. Pombeiro, G.B. Shul’pin, J. Catal. 268 (2009) 26.
[27] A.M. Kirillov, M.V. Kirillova, A.J.L. Pombeiro. Adv. Inorg. Chem. 65 (2013) 1.
[28] M. Costas, K. Chen, L. Que Jr., Coord. Chem. Rev. 200–202 (2000) 517.
[29] (a) G.B. Shul’pin, Dalton Trans. 42 (2013) 12794. (b) G.B. Shul’pin, Org. Biomol. Chem. 8 (2010)
4217.
[30] (a) A.M. Kirillov, Y.Y. Karabach, M.V. Kirillova, M. Haukka, A.J.L. Pombeiro, Cryst. Growth Des. 12,
(2012) 1069. (b) M.V. Kirillova, A.M. Kirillov, A.N.C. Martins, C. Graiff, A. Tiripicchio, A.J.L.
Pombeiro, Inorg. Chem. 51 (2012) 5224.
[31] (a) M.V. Kirillova, A.M. Kirillov, A.J.L. Pombeiro, Chem. Eur. J. 16 (2010) 9485. (b) M.V. Kirillova,
A.M. Kirillov, M.L. Kuznetsov, J.A.L. Silva, J.J.R. Fraústo da Silva, A.J.L. Pombeiro, Chem. Commun.
(2009) 2353.
[32] (a) R.A. Himes, K.D. Karlin, Curr. Opin. Chem. Biol. 13 (2009) 119. (b) R.L. Lieberman, A.C.
Rosenzweig, Nature 434 (2005) 177.

13
(a)
(b)
(c)
(e)
(g)
(d)
(f)

14
Figure 1. Characterization of the Fe3O4@mSiO2@Cu4 nanocatalyst and parent nanoparticle materials. (a)
Field-dependent magnetization of Fe3O4, Fe3O4@mSiO2 and Fe3O4@mSiO2@Cu4 at 300 K. (b) FT-IR
spectra of Cu4, Fe3O4@mSiO2@Cu4, and Fe3O4@mSiO2. (c) PXRD patterns of Cu4, Fe3O4@mSiO2, and
Fe3O4@mSiO2@Cu4; peaks (■) are attributed to Fe3O4@mSiO2 and peak (★) is attributed to Cu4 present in
the nanocatalyst. (d) Low-angle PXRD pattern of Fe3O4@mSiO2. (e) TGA plots of Fe3O4@mSiO2 and
Fe3O4@mSiO2@Cu4 (Δm of ~7.5% corresponds to ~10 wt% of Cu4 in the nanocatalyst assuming the
decomposition of Cu4 to copper oxide). (f) TEM image of the Fe3O4@mSiO2@Cu4 microspheres. (g) Particle
size distribution of Fe3O4@mSiO2@Cu4 (2 mg/L, suspended in aqueous medium), measured by DLS.

15
(a)
(b)
(c)
Figure 2. Oxidation of cyclohexane by t-BuOOH in the presence of the Fe3O4@mSiO2@Cu4 nanocatalyst.
(a) Accumulation of cyclohexanol and cyclohexanone with time. (b) Evolvement of the product amount with
time at 50 and 70 °C; maximum total yields were 12 and 15%, respectively. (c) TON per cycle in catalyst
recycling experiments. General reaction conditions: C6H12 (1 mmol), t-BuOOH (2.5 mmol), catalyst (5 mg),
50 °C (a, c) or 50 and 70 °C (b), CH3CN solvent (up to 2.5 mL of the total volume).

16
Figure 3. Accumulation of cyclohexanone with time in the oxidation of cyclohexanol by t-BuOOH in the
presence of the Fe3O4@mSiO2@Cu4 nanocatalyst at 50 and 70 °C; maximum yield of cyclohexanone was 19
and 25%, respectively; selectivity >95%. Reaction conditions: C6H11OH (1 mmol), t-BuOOH (2.5 mmol),
catalyst (5.0 mg), 50 or 70 °C, CH3CN solvent (up to 2.5 mL of the total volume).

17
Scheme 1. Structural formula (left) and X-ray crystal structure (right) of [Cu4(µ4-
O){N(CH2CH2O)3}4(BOH)4][BF4]2 (Cu4) [20]. In structural representation, H atoms and counter anions are
omitted for clarity; color codes: Cu, green balls; B, cyan; O, red; N, blue; C, gray.
Scheme 2. Simplified representation of the fabrication process of the Fe3O4@mSiO2@Cu4 nanocatalyst.
Scheme 3. Alkane and alcohol oxidation reactions catalyzed by magnetically recoverable
Fe3O4@mSiO2@Cu4 nanocatalyst: (top) oxidation of cyclohexane as a model substrate to cyclohexanol and
cyclohexanone; (bottom) oxidation of cyclohexanol to cyclohexanone.

18
Table 1. Mild oxidation of C5–C8 cycloalkanes by t-BuOOH in the presence of the Fe3O4@mSiO2@Cu4
nanocatalyst.a
Product yield, %b
Cycloalkane
TON
Alcohol
11.8
Ketone
2.9
Totalc
14.7
335
265
310
215
C5H10
C6H12
C7H14
C8H16
6.5
9.4
5.9
5.2
4.2
3.4
11.7
13.6
9.3
a Reaction conditions: cycloalkane (1.0 mmol), t-BuOOH (2.5 mmol), catalyst (5.0 mg), MeCN (up to 2.5 mL total
b
volume), 50 °C, 6 h. Yields are based on cycloalkane substrate: (moles of product per mol of cycloalkane)×100%.
d
cSum of the yields of alcohol and ketone products; selectivity to alcohol+ketone >90%. TON, catalyst turnover
number: (moles of products per mol of Cu4 in nanocatalyst).