Mild homogeneous oxidation and hydrocarboxylation of cycloalkanes catalyzed by novel dicopper(II) aminoalcohol-driven cores

Article abstract of DOI:10.1016/j.molcata.2016.07.050

N-benzylethanolamine (Hbea) and triisopropanolamine (H₃tipa) were applied as unexplored aminoalcohol N,O-building blocks for the self-assembly generation of two novel dicopper(II) compounds, [Cu₂(μ-bea)₂(Hbea)₂](NO₃)₂ (1) and [Cu₂(H₃tipa)₂(μ-pma)]·7H₂O (2) {H₄pma = pyromellitic acid}. These were isolated as stable and aqua-soluble microcrystalline products and were fully characterized by IR spectroscopy, ESI–MS(±), and single-crystal X-ray diffraction, the latter revealing distinct Cu₂ cores containing the five-coordinate copper(II) centers with the {CuN₂O₃} or {CuNO₄} environments. Compounds 1 and 2 were used as homogeneous catalysts for the mild oxidation of C₅–C₈ cycloalkanes to give the corresponding cyclic alcohols and ketones in up to 23% overall yields based on cycloalkane. The reactions proceed in aqueous acetonitrile medium at 50 °C using H₂O₂ as an oxidant. The effects of different reaction conditions were studied, including the type and loading of catalyst, amount and kind of acid promoter, and water concentration. Despite the fact that different acids (HNO₃, H₂SO₄, HCl, or CF₃COOH) promote the oxidation of alkanes, the reaction is exceptionally fast in the presence of a catalytic amount of HCl, resulting in the TOF values of up to 430 h^?1. Although water typically strongly inhibits alkane oxidations due to the reduction of H₂O₂ concentration and lowering of the alkane solubility, in the systems comprising 1 and 2 we observed a significant growth (up to 5-fold) of an initial reaction rate in the cyclohexane oxidation on increasing the amount of H₂O in the reaction mixture. The bond-, regio- and stereo-selectivity parameters were investigated in oxidation of different linear, branched, and cyclic alkane substrates. Both compounds 1 and 2 also catalyze the hydrocarboxylation of C₅–C₈ cycloalkanes, by CO, K₂S₂O₈, and H₂O in a water/acetonitrile medium at 60 °C, to give the corresponding cycloalkanecarboxylic acids in up to 38% yields based on cycloalkanes.

Full text of DOI:10.1016/j.molcata.2016.07.050

Accepted Manuscript
Title: Mild homogeneous oxidation and hydrocarboxylation of
cycloalkanes catalyzed by novel dicopper(II)
aminoalcohol-driven cores
ˆ
´
Author: Tiago A. Fernandes Vania Andre Alexander M.
Kirillov Marina V. Kirillova
PII:
S1381-1169(16)30309-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.07.050
MOLCAA 9984
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
1-6-2016
29-6-2016
27-7-2016
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Please cite this article as: Tiago A.Fernandes, Vania Andre, Alexander M.Kirillov,
Marina V.Kirillova, Mild homogeneous oxidation and hydrocarboxylation of
cycloalkanes catalyzed by novel dicopper(II) aminoalcohol-driven cores, Journal of
Molecular Catalysis A: Chemical http://dx.doi.org/10.1016/j.molcata.2016.07.050
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1
Mild homogeneous oxidation and hydrocarboxylation of cycloalkanes catalyzed
by novel dicopper(II) aminoalcohol-driven cores1
Tiago A. Fernandes, Vânia André, Alexander M. Kirillov,* Marina V. Kirillova*
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, kirillova@tecnico.ulisboa.pt
1This article is dedicated to Prof. Georgiy B. Shul’pin on the occasion of his 70th birthday.
Graphical abstract

2
Research highlights:
Two new dicopper(II) coordination compounds were synthesized and fully characterized;
These compounds catalyze the mild homogeneous oxidation of alkanes;
Effects of different reaction parameters were evaluated;
Unusual promoting role of water was detected and investigated;
The compounds also catalyze the hydrocarboxylation of alkanes to carboxylic acids.

3
ABSTRACT
N-benzylethanolamine (Hbea) and triisopropanolamine (H3tipa) were applied as unexplored
aminoalcohol N,O-building blocks for the self-assembly generation of two novel dicopper(II)
compounds, [Cu2(µ-bea)2(Hbea)2](NO3)2 (1) and [Cu2(H3tipa)2(µ-pma)]∙7H2O (2) {H4pma =
pyromellitic acid}. These were isolated as stable and aqua-soluble microcrystalline products
and were fully characterized by IR spectroscopy, ESI-MS(±), and single-crystal X-ray
diffraction, the latter revealing distinct Cu2 cores containing the five-coordinate copper(II)
centers with the {CuN2O3} or {CuNO4} environments. Compounds 1 and 2 were used as
homogeneous catalysts for the mild oxidation of C5–C8 cycloalkanes to give the
corresponding cyclic alcohols and ketones in up to 23% overall yields based on cycloalkane.
The reactions proceed in aqueous acetonitrile medium at 50 °C using H2O2 as an oxidant. The
effects of different reaction conditions were studied, including the type and loading of
catalyst, amount and kind of acid promoter, and water concentration. Despite the fact that
different acids (HNO3, H2SO4, HCl, or CF3COOH) promote the oxidation of alkanes, the
reaction is exceptionally fast in the presence of a catalytic amount of HCl, resulting in the
TOF values of up to 430 h−1. Although water typically strongly inhibits alkane oxidations due
to the reduction of H2O2 concentration and lowering of the alkane solubility, in the systems
comprising 1 and 2 we observed a significant growth (up to 5-fold) of an initial reaction rate
in the cyclohexane oxidation on increasing the amount of H2O in the reaction mixture. The
bond-, regio- and stereo-selectivity parameters were investigated in oxidation of different
linear, branched, and cyclic alkane substrates. Both compounds 1 and 2 also catalyze the
hydrocarboxylation of C5–C8 cycloalkanes, by CO, K2S2O8, and H2O in a water/acetonitrile
medium at 60 °C, to give the corresponding cycloalkanecarboxylic acids in up to 38% yields
based on cycloalkanes.
Keywords: C−H Functionalization; Oxidation; Hydrocarboxylation; Cycloalkanes;
Homogeneous Catalysis; Copper compounds.
1. Introduction
Different copper compounds constitute a vast variety of catalytic systems and are
widely applied in the areas of both heterogeneous and homogeneous catalysis [1–4]. The use
of Cu-containing catalysts is primarily governed by the versatile redox properties of this
metal, its natural abundance and relatively low cost, low toxicity, and rich inorganic and

4
coordination chemistry [1–5]. Besides, copper ions are present in the active sites of diverse
oxidation enzymes, such as catechol oxidase, laccase, multicopper oxidases, and particulate
methane monooxygenase (pMMO), thus justifying an extensive research in the fields of
copper bioinorganic chemistry and related areas of biomimetic and/or bioinspired catalysis
focused on the search for efficient C−H functionalization protocols [4–6]. Among the above-
mentioned enzymes, pMMO represents an especially interesting case given its multicopper
active site with an N,O-environment that is capable of catalyzing the hydroxylation of such
inert substrates as alkanes.7
In fact, alkanes are very abundant in nature and relatively inexpensive substrates for
the synthesis of various important oxidation products [8–10]. However, a high inertness of
alkanes toward the oxidative C−H functionalization under mild conditions prevents their
broad use as raw materials for the direct or single-step production of alcohols, ketones,
aldehydes, or carboxylic acids. [8,9,11]. Nevertheless, the design of new bioinspired metal
complex catalysts, incorporating metal ions with a recognized function in oxidation catalysis
as well as simple and commercially available ligands, can potentially result in the discovery
of active catalytic systems, capable of oxidizing alkanes with high efficiency and under mild
temperatures and pressures [4,8,11–16].
As a continuation of our recent research on the synthesis and catalytic application of
novel multicopper(II) cores [17] the main aim of the current work consisted of the self-
assembly generation of new dicopper(II) compounds bearing aminoalcohols as principal N,O-
ligands, and the investigation of their catalytic function toward the mild homogeneous
oxidation or hydrocarboxylation of cycloalkanes to give the corresponding cyclic alcohols
and ketones or carboxylic acids, respectively.
Thus, the present study reports the synthesis, characterization, crystal structures, and
application in oxidation catalysis of two novel dicopper(II) coordination compounds, [Cu2(µ-
bea)2(Hbea)2](NO3)2 (1) and [Cu2(H3tipa)2(µ-pma)]∙7H2O (2) (Scheme 1). Apart from
featuring aqueous solubility and having distinct dicopper(II) cores, the obtained complexes
act as homogeneous catalysts for (i) the oxidation of different C5–C8 cycloalkanes by
hydrogen peroxide to give a mixture of alcohols and ketones and (ii) the hydrocarboxylation
of C5–C8 cycloalkanes by carbon monoxide, peroxodisulfate oxidant, and water, to give the
corresponding cycloalkanecarboxylic acids with one additional carbon atom. For alkane
oxidations, the effects of various reaction parameters, substrate scope, different selectivity
features, and possible catalytically active species were studied in detail.

5
Scheme 1. Structural formulae of dicopper(II) compounds 1 (top) and 2 (bottom).
2. Experimental
2.1. Materials and methods
All chemicals were obtained from commercial sources and used as received.
Triisopropanolamine (racemic mixture) was purchased from Across Organics. The synthetic
work was performed in air and at room temperature (r.t., 25 °C). Infrared spectra (4000–400
cm–1) were recorded on a JASCO FT/IR-4100 instrument in KBr pellets (abbreviations: vs −
very strong, s − strong, m – medium, w – weak, br – broad, sh. − shoulder). ESI-MS(±)
analyses were run on a LCQ Fleet mass spectrometer with an ESI source (Thermo Scientific),
using 10−3 M solutions of 1 and 2 or their model mixtures with HNO3 and H2O2 in aqueous
solution. 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 and characterization of 1 and 2.
[Cu2(µ-bea)2(Hbea)2](NO3)2 (1). To a MeOH solution (10 mL) of Cu(NO3)2∙2.5H2O
(1.0 mmol, 233 mg) was added dropwise an aqueous 1 M solution of N-benzylethanolamine
(Hbea; 2.0 mmol, 2 mL) with continuous stirring at room temperature. Then, an aqueous 1 M
solution of NaOH (3.0 mmol, 3 mL) was introduced and the resulting mixture was stirred for
2 h and then filtered off. The filtrate was left to evaporate in a beaker at r.t. Blue X-ray
quality crystals were formed in 1–2 weeks, then collected and dried in air to furnish

6
compound 1 in 35% yield (based on copper(II) nitrate). Compound 1 is moderately soluble
in H2O (S25°C ~3 mg mL–1). FT-IR (KBr): 3230 (m) ν(OH), 3183 (m) ν(NH), 2940 (w), 2885
(w), and 2628 (w) ν(CH), 1455 (m), 1384 (vs br) and 1361 (sh) ν(NO3), 1076 (m), 1049 (m),
1015 (w), 755 (m), and 702 (m) cm–1. ESI-MS(+) (H2O), m/z: 853 [Cu2(µ-
H0.5bea)2(Hbea)2(NO3)2]+, 640 [Cu2(µ-bea)2(Hbea)(NO3)]+, 551 [Cu2(µ-H0.5bea)2(NO3)2]+,
364 [Cu2(µ-bea)2(Hbea)2]2+. ESI-MS(–) (H2O), m/z: 851 [Cu2(µ-bea)2(H0.5bea)2(NO3)2]–, 745
[Cu2(µ-bea)2(H0.5bea)(H2O)]–, 593 [Cu2(µ-bea)2(bea)(OH)]–, 576 [Cu2(µ-bea)2(bea)]–.
[Cu2(H3tipa)2(µ-pma)]∙7H2O (2). To a MeOH solution (10 mL) of Cu(NO3)2∙2.5H2O
(1.0 mmol, 233 mg) was added dropwise triisopropanolamine (H3tipa; 1.0 mmol, 191 mg)
and pyromellitic acid (1.0 mmol, 254 mg) as a solid, with continuous stirring at room
temperature. Then, an aqueous 1 M solution of NaOH (3.0 mmol, 3 mL) was introduced and
the resulting mixture was stirred for 2 h and then filtered off. The filtrate was left to evaporate
in a beaker at r.t., resulting in the formation of blue crystals (including those of X-ray quality)
in 2–4 weeks. These were collected and dried in air to furnish compound 2 in ~45% yield
(based on copper(II) nitrate). Compound 2 is slightly soluble in H2O (S25°C ~2 mg mL–1). FT-
IR (KBr): 3484 (s br), 3398, and 3277 (s br) ν(OH/H2O), 2973 (w) and 2930 (w) ν(CH), 1631
(w sh) δ(H2O), 1596 (s) and 1560 (w sh) νas(COO), 1483 (w), 1420 (w) and 1379 (vs)
νs(COO), 1174 (w), 1138 (s), 1034 (m), 977 (m), 867 (w) and 812 (w) cm–1. ESI-MS(+)
(H2O), m/z: 781 [Cu2(H3tipa)2(µ-pma) + Na]+, 759 [Cu2(H3tipa)2(µ-Hpma)]+, 742
[Cu2(H3tipa)2(µ-H2pma) – OH]+, 703 [Cu2(H3tipa)2(µ-H2pma) – C3H7OH]+, 552
[Cu2(H3tipa)(µ-H2pma) – OH]+. ESI-MS(–) (H2O), poor fragmentation, m/z: 779
[Cu2(H2tipa)2(µ-pma) + Na]–.
2.4. X-ray crystallography
Crystals of 1 and 2 suitable for X-ray diffraction study were mounted with Fomblin©
in a cryoloop. Data were collected on a Bruker AXS-KAPPA APEX II diffractometer with
graphite-monochromated radiation (Mo K,  = 0.71073 Å) at 273 K. The X-ray generator
was operated at 50 kV and 30 mA and the X-ray data collection was monitored by the
APEX2 program [18]. All data were corrected for Lorentzian, polarization and absorption
effects using SAINT and SADABS programs [18]. SIR97 [19] and SHELXS-97 [20] were
used for structure solution and SHELXL-97 [20] was applied for full matrix least-squares
refinement on F2. These three programs are included in the package of programs WINGX-
Version 1.80.05 [21]. Non-hydrogen atoms were refined anisotropically. A full-matrix least-

7
squares refinement was used for the non-hydrogen atoms with anisotropic thermal
parameters. All the hydrogen atoms were inserted in idealized positions and allowed to refine
in the parent carbon or oxygen atom, except for the OH and NH moieties that were located
from the electron density map. Water hydrogen atoms that were not accurately located from
the electron density map were not included. PLATON [22] and TOPOS [23] were used for
hydrogen bond interactions and topological analysis, respectively. Only one type of the
dicopper(II) unit was identified in the crystal structure of 2 that represents one
diastereoisomer. We believe, different diastereoisomers are present in the bulk sample of 2.
Crystal data for 1: C36H50Cu2N6O10, M = 853.90, λ = 0.71073 Å (Mo-Kα), T = 273(2)
K, monoclinic, space group P21/c, a = 22.536(2), b = 9.2705(9), c = 22.142(2) Å, β =
117.139(3)º, V = 4116.6(7) Å3, Z = 4, Dc = 1.378 g/cm3, μ = 1.093 mm1, 99706 reflections
collected, 5195 unique, I > 2σ(I) (Rint = 0.1571), R1 = 0.0639, wR2 = 0.1552. Crystal data for
2: C14H22CuNO14, M = 491.88, λ = 0.71073 Å (Mo-Kα), T = 273(2) K, monoclinic, space
group P21/n, a = 12.4448(7), b = 11.0336(6), c = 17.9095(10) Å, β = 108.936(2)º, V =
2326.1(2) Å3, Z = 4, Dc = 1.402 g/cm3, μ = 1.002 mm1, 31187 reflections collected, 4027
unique, I > 2σ(I) (Rint = 0.0398), R1 = 0.0444, wR2 = 0.1206. CCDC 1436749 and 1436750.
2.5. Alkane oxidation reactions
The alkane oxidation reactions were performed in air atmosphere in thermostated
glass reactors equipped with a condenser under vigorous stirring at 50 °C and using MeCN as
solvent (up to 5 mL total volume). In a typical experiment, catalyst 1 or 2 (10 µmol) and gas
chromatography (GC) internal standard (MeNO2, 50 µL) were introduced into the MeCN
solution, followed by the addition of an acid promoter (typically 0.1 mmol, optional) used as
a stock solution in MeCN. An alkane or alcohol substrate (2 mmol) was then introduced, and
the reaction started upon addition of hydrogen peroxide (50% in H2O, 10 mmol) in one
portion. The oxidation reactions were monitored by withdrawing small aliquots after different
periods of time, which were treated with PPh3 (following the Shul’pin’s method [24]) for the
reduction of remaining H2O2 and alkyl hydroperoxides 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. For comparative purposes, the oxidation of cyclohexanol to
cyclohexanone was also investigated, following the above-mentioned experimental

8
procedure. Blank tests confirmed that alkane oxidations do not proceed in the absence of
copper catalyst.
2.6. Alkane hidrocarboxylation reactions
The alkane hydrocarboxylation experiments were performed following a previously
developed protocol [12]. In a typical experiment the reaction mixtures were prepared as
follows: to 0.01 mmol of the compound 1 or 2 contained in a 20.0 mL stainless steel
autoclave, equipped with a Teflon-coated magnetic stirring bar, were added 1.50 mmol of
K2S2O8, 2.0 mL of H2O, 4.0 mL of MeCN (total solvent volume was 6.0 mL), and 1.00 mmol
of alkane. Then the autoclave was closed and flushed with CO three times to remove the air,
and finally pressurized with 20 atm of CO. CAUTION: Due to the toxicity of CO, all
operations should be carried out in a well-ventilated hood! The reaction mixture was typically
stirred for 4 h at 60 C using a magnetic stirrer and an oil bath, whereupon it was cooled in an
ice bath, degassed, opened and transferred to a flask. Diethyl ether (9.0 mL) and 45 L of
cycloheptanone (typical GC internal standard) were added. In the case of cycloheptane
hydrocarboxylation, cyclohexanone (45 L) was used as a GC standard. The obtained
mixture was vigorously stirred for 10 min, and the organic layer was analyzed by gas
chromatography (internal standard method), revealing the formation of the corresponding
monocarboxylic acids as major products Attribution of peaks was made by comparison with
chromatograms of authentic samples.
3. Results and discussion
3.1. Synthesis of catalysts 1 and 2.
Treatment of copper(II) nitrate with an excess of N-benzylethanolamine (Hbea) and
sodium hydroxide in MeOH/H2O medium at ~25°C led to the self-assembly generation of a
dicopper(II) complex [Cu2(µ-bea)2(Hbea)2](NO3)2 (1). A related synthetic procedure using a
mixture of Cu(NO3)2, triisopropanolamine (H3tipa), pyromellitic acid (H4pma), and NaOH
resulted in the self-assembly of a different dicopper(II) compound [Cu2(H3tipa)2(µ-
pma)]∙7H2O (2) (Scheme 1). Both products were isolated as blue air-stable microcrystalline
solids and were characterized by IR spectroscopy, ESI-MS(±), and single crystal X-ray
diffraction. The latter also shows the formation of H-bonded networks in the solid state
which, however, disaggregate upon the dissolution of the compounds. In fact, both complexes
1 and 2 are slightly soluble in water (S25°C ~2–3 mg mL–1) and relatively stable in solution, as

9
attested by ESI-MS data. These characteristics open up their possible use as homogeneous
catalysts (or pre-catalysts) for the mild oxidation reactions in aqueous medium [17,25].
3.2. Structures of compounds 1 and 2.
The crystal structure of 1 is composed of a dicopper(II) [Cu2(µ-bea)2(Hbea)2]2+ cation
and two nitrate anions. The Cu2 cation (Figure 1a) comprises two symmetry non-equivalent
copper(II) centers, a pair of terminal Hbea ligands, and two bridging deprotonated µ-bea(1–)
moieties. Both Cu1 and Cu2 atoms are five-coordinate and display well distorted {CuN2O3}
square-pyramidal geometries with the τ5 parameters of 0.33 and 0.39, respectively (parameter
5 = 0 for an ideal square-pyramidal geometry, 5 = 1 for an ideal trigonal-bipyramidal
geometry) [26]. The equatorial sites around the Cu1 center are taken by the N7, N8, O3, and
O60 atoms of the µ-bea/Hbea moieties [Cu1–N7 2.024(4), Cu1–N8 2.058(4), Cu1–O3
1.953(3), Cu1–O60 1.935(3) Å], while the axial position is occupied by the OH group of
Hbea [Cu1–O4 2.347(5) Å]. The coordination environment and bonding distances around the
Cu2 atom are similar to those of Cu1; the Cu1∙∙∙Cu2 separation of 3.0010(7) Å is rather short.
The bond distances and angles in 1 are in agreement with those encountered in some related
dicopper(II) aminoalcohol compounds [17a,27]. Furthermore, in 1 the Cu2 cations and nitrate
anions are assembled, via the repeating N–H∙∙∙O and O–H∙∙∙O hydrogen bonds, into a 2D H-
bonded network. From the topological viewpoint [23], this network can be classified as
uninodal 3-connected underlying net with the hcb topology (Fig. 1b).
(a)
(b)
Figure 1. Structural fragments of 1. (a) Dicopper(II) [Cu2(µ2-bea)2(Hbea)2]2+ unit with atom labelling
–
scheme; H atoms and NO3 anions are omitted for clarity; color codes: Cu (green balls), O (red), N
(blue), C (gray). (b) Topological representation of a 2D H-bonded underlying net showing a decorated
uninodal 3-connected layer with the hcb topology and point symbol of (63); centroids of 3-connected
–
[Cu2(µ2-bea)2(Hbea)2]2+ cationic nodes (green balls), centroids of 2-connected NO3 anionic linkers
(gray), view along the a axis.

10
(a)
(b)
Figure 2. Structural fragments of 2. (a) Dicopper(II) [Cu2(H3tipa)2(µ2-pma)] unit with atom labelling
scheme (representation of one diastereoisomer identified in the crystal structure); H atoms are omitted
for clarity; symmetry code: (i) –x, 2–y, –z; color codes: Cu (green balls), O (red), N (blue), C (gray).
(b) Fragment of a 2D H-bonded {(H2O)25}n network (gray colored) composed of repeating (H2O)8 and
(H2O)20 rings; this network was topologically classified as a uninodal 3-connected layer with the fes
topology and point symbol of (4.82); for simplicity, H-bonding interactions between [Cu2(H3tipa)2(µ2-
pma)] units (their centroids are shown as green balls) and {(H2O)25}n layer are omitted for clarity;
rotated view along the ab plane.
In contrast to 1, the structure of 2 is neutral and reveals a different type of dicopper(II)
block [Cu2(H3tipa)2(µ-pma)] (Fig. 2a); there are also seven water molecules of crystallization
per formula unit. The Cu2 block is built from two symmetry equivalent {Cu(H3tipa)}2+
moieties which are interconnected by the µ2-bridging and fully deprotonated pyromellitate(4–
) linker. The five-coordinate Cu1 center adopts a significantly distorted {CuNO4} square-
pyramidal environment (5 = 0.41) wherein the equatorial sites are filled by the N2, O9, and
O10 atoms from a neutral fully protonated H3tipa ligand and the carboxylate O66 atom from
a µ-pma(4–) moiety [Cu1–N2 2.010(3), Cu1–O9 1.951(2), Cu1–O10 1.967(2), Cu1–O66
1.909(2) Å]. The axial position is taken by the remaining O1 atom of H3tipa [Cu1–O1
2.298(2) Å]. The µ-pma(4–) moiety separates the adjacent copper(II) centers with the
Cu1∙∙∙Cu1i distance of 11.055(2) Å. An interesting feature of the crystal structure of 2
concerns the presence of numerous H2O molecules of crystallization, which are assembled
into intricate 2D {(H2O)25}n layers (Fig. 2b) [28]. These layers are composed of the repeating
(H2O)8 and (H2O)20 cyclic motifs and can be topologically classified as uninodal 3-connected
nets with the fes topology [23]. Furthermore, these {(H2O)25}n layers are extensively H-
bonded to [Cu2(H3tipa)2(µ-pma)] units, generating a very complex 3D supramolecular
network.

11
3.3. Catalytic activity of 1 and 2 in the oxidation of cycloalkanes
Following our general interest in the mild oxidative functionalization of alkanes
catalyzed by bioinspired copper compounds [12,17], we tested the dicopper(II) derivatives 1
and 2 as homogeneous catalysts for the oxidation of cycloalkanes to the corresponding
alcohols and ketones. The reactions proceed under mild conditions (50 °C, atmospheric
pressure) in aqueous MeCN medium and using H2O2 (50% in H2O) as an oxidant. The
oxidation of cyclohexane to a mixture of cyclohexanol and cyclohexanone (Scheme 2) was
studied in detail as a model reaction with industrial significance (e.g., one of the steps in
nylon production) [29].
Scheme 2. Oxidation of cyclohexane to cyclohexanol and cyclohexanone.
The cyclohexane oxidation catalyzed by 1 in the presence of a catalytic amount of
trifluoroacetic acid (TFA) as a promoter (Fig. 3a) proceeds with a maximum total product
yield of ~20% (hereinafter, all the yields are based on an alkane substrate), which is achieved
at 90 min reaction time. A slight yield decline due to an overoxidation is observed on
prolonging the reaction time. In the beginning of the reaction, cyclohexanol is formed
predominantly to cyclohexanone; however, after 2 h of the reaction the ketone yield
approaches that of the alcohol. Compound 2 is less active under the same reaction conditions,
resulting in ~16% total yield (Fig. 3b).

12
Figure 3. Kinetic curves of product accumulation in the cyclohexane oxidation by H2O2 catalyzed by
1 (a) and 2 (b) in the presence of TFA promoter. Reaction conditions: pre-catalyst 1 or 2 (5 µmol),
TFA (0.05 mmol), C6H12 (1.0 mmol), H2O2 (5.0 mmol), CH3CN (up to 2.5 mL of the total volume),
50 °C.
(a)
(b)
Figure 4. Effect of the type of acid promoter on the total yield of the products in the cyclohexane
oxidation with H2O2 catalyzed by 1 (a) or 2 (b). Reaction conditions: catalyst 1 or 2 (0.01 mmol), acid
promoter (0.1 mmol), C6H12 (2.0 mmol), H2O2 (10.0 mmol), CH3CN (up to 5.0 mL total volume), 50
°C.
Both catalysts 1 and 2 require the presence of a small amount of an acid promoter
(Fig. 4). Such a promoter activates the catalysts via partial protonation of ligands, facilitates
proton transfer steps, and enhances the oxidation properties of H2O2 [12,13,17]. We studied
the influence of different types of acid promoters and found a similar behavior of 1 and 2
(Fig. 4). The kinetic curves of products accumulation show a resembling trend when using
TFA, HNO3, or H2SO4 as promoters (acid-to-catalyst molar ratio of 10:1). In contrast, the

13
presence of HCl dramatically increases the reaction rate of the C6H12 oxidation for both
catalysts 1 and 2, resulting in a very fast reaction with the total yields of 16–18% (TOFs =
380–430 h–1) that are achieved within several minutes.
(a)
(b)
(c)
Figure 5. Effect of H2SO4 (a, b) or TFA (c) amount on the total yield of the products in the
cyclohexane oxidation with H2O2 catalyzed by 1 (a) or 2 (b, c). Reaction conditions: catalyst 1 or 2
(0.01 mmol), acid promoter (H2SO4 or TFA, 0.01–0.15 mmol), C6H12 (2.0 mmol), H2O2 (10.0 mmol),
CH3CN (up to 5.0 mL total volume), 50 °C.
To get further insight into the promoting role of acids, we investigated the influence
of the amount of H2SO4 and TFA (Fig. 5). In the cyclohexane oxidation by the 1/H2SO4
system (Fig. 5a), both the product yield and the initial reaction rate (W0) grow on increasing
the amount of H2SO4 up to 5 equivalents relatively to catalyst. Further increase of the H2SO4
loading (up to 15 equivalents) has no effect on the W0 and final product yield. In the 2/H2SO4

14
system (Fig. 5b), only one equivalent of acid is required to promote the catalytic activity of
the complex, leading to ~10% total yield. By increasing an amount of H2SO4 up to 2.5
equivalents relatively to 2, the maximum total yield rises to 13%, without affecting the initial
reaction rate. A bigger H2SO4 loading (15 equivalents) does not have influence on the
reaction parameters. A similar behavior was observed in the 2/TFA system (Fig. 5c).
(a)
(b)
Figure 6. The effect of catalyst amount on (a) the total product yield and (b) the maximum initial
reaction rate (W0) in the cyclohexane oxidation with H2O2 catalyzed by 1/TFA. Reaction conditions:
catalyst 1 (0.0025–0.01 mmol), TFA promoter (0.1 mmol), C6H12 (2.0 mmol), H2O2 (10.0 mmol),
CH3CN (up to 5.0 mL total volume), 50 °C.
The effects of the catalyst amount on the total yield and the reaction rate of the
cyclohexane oxidation in the 1/TFA (Fig. 6) and 2/TFA (Fig. 7) systems are rather similar,
although the reaction is slightly faster in the case of 1/TFA. A gradual growth of the total
product yield on rising the catalyst amount from 0.0025 to 0.01 mmol was observed. The
initial reaction rates have a linear dependence on the concentration of 1 and 2 (Figs. 6b and
7b), thus indicating the first-order reaction kinetics with respect to catalyst and supporting a
probable involvement of one Cu-containing species in the rate-limiting step of the oxidation
reaction.
An unusual accelerating effect of water on the initial reaction rate was observed for
both catalysts 1 and 2 (Fig. 8). The increase in water concentration from 4.1 M
(corresponding to the amount of H2O present in 50% aqueous H2O2) to 12.9 M (via an
introduction of additional H2O into the reaction mixture) leads to a linear increase of the
initial reaction rate in both catalytic systems. In the 1/H2SO4 system (Fig. 8a), such a

15
behavior is also accompanied by a slight improvement of the maximum product yield;
however, upon a prolonged reaction time, an yield drop was observed. This process is more
evident at a high water concentration (12.9 M), thus suggesting that an additional amount of
water in the system may promote the overoxidation reactions. In fact, a detailed GC-MS
analysis of reaction mixtures containing a higher water content revealed the presence of
different isomeric dicyclohexanols, dicyclohexanones, hidrohycyclohexanones, and even
adipic acid. A similar trend was observed when studying the effect of water in the 2/TFA
(Fig. 8b) and 1/TFA (Fig. 8c) systems. For both the 1/H2SO4 and 2/TFA systems, a linear
dependence of W0 on water concentration was detected (Fig. 8d), revealing a 5- or 4-fold
growth of the W0 on increasing the H2O concentration from 4.1 to 12.9 M, respectively.
Figure 7. The effect of catalyst amount on (a) the total product yield and (b) the maximum initial
reaction rate (W0) in the cyclohexane oxidation with H2O2 catalyzed by 2/TFA. Reaction conditions:
catalyst 2 (0.0025–0.01 mmol), TFA promoter (0.1 mmol), C6H12 (2.0 mmol), H2O2 (10.0 mmol),
CH3CN (up to 5.0 mL total volume), 50 °C.
To get further insight, we performed additional experiments using the incubation of
the 1/TFA catalytic system (Fig. 8c). The addition of a high amount of water (up to 12.9 M
total) into the reaction mixture leads to the acceleration of the C6H12 oxidation but results in a
lower total yield (15% vs. 20%). The incubation of the reaction mixture containing 1/TFA,
H2O2, and H2O for 1 h at 50 °C with a posterior addition of C6H12 does not lead to
cyclohexane oxidation due to the consumption of peroxide (catalase activity). The addition of
a new portion of H2O2 to this reaction mixture restores the C6H12 oxidation. The incubation of
the reaction mixture containing 1/TFA and water for 1 h with a posterior addition of both
H2O2 and C6H12 results in a less efficient cyclohexane oxidation, which proceeds with the

16
same reaction rate as the reaction without incubation. This can be due to the shift of an
equilibrium toward the formation of different catalytically active species in the presence of a
high amount of water.
(a)
(b)
(c)
(d)
Figure 8. The effect of H2O amount on (a, b, and c) the total product yield and (d) the maximum
initial reaction rate (W0) of the cyclohexane oxidation with H2O2 catalyzed by (a) 1/H2SO4, (b) 2/TFA,
(c) 1/TFA, and (d) 1/H2SO4 and 2/TFA systems. Reaction conditions: catalyst 1 or 2 (0.01 mmol),
acid promoter (0.1 mmol), C6H12 (2.0 mmol), H2O2 (10.0 mmol), added H2O (up to 0.8 mL), CH3CN
(up to 5.0 mL total volume), 50 °C.
All the above-discussed effects of H2O indicate a direct involvement of water in the
rate-limiting step (generation of hydroxyl radicals) of the cycloalkane oxidation. In fact, the
H2O-assisted pathways for the generation of hydroxyl radicals in V- or Re-catalyzed alkane

17
oxidations were earlier suggested by DFT calculations [30]. Furthermore, H2O showed a
remarkable promoting behavior in some related Cu-containing catalytic systems [17a,b] as
well as acted as unusual hydroxylating reagent and solvent component in mild copper-
catalyzed alkane hydrocarboxylations [12,31]. However, such a promoting role of water is
still uncommon but may open a possibility of applying diluted in situ generated aqueous
solutions of H2O2 as a green oxidant in alkane oxidation processes.
The effect of the oxidant amount on the cyclohexane oxidation catalyzed by the
1/H2SO4 system was also investigated. As expected, the H2O2 concentration affects both the
initial reaction rate and total product yield (Fig. 9a). With a high H2O2 amount (10 mmol), the
oxidation of C6H12 is faster and more efficient, resulting in 17% total yield (vs. 10% with a
low oxidant loading, 2.5 mmol).
(a)
(b)
Figure 9. (a) The effect of H2O2 amount on the total product yield in the cyclohexane oxidation
catalyzed by 1/H2SO4. (b) The cyclohexane oxidation with H2O2 catalyzed by the 2/TFA system using
fresh and recovered catalyst. Reaction conditions: catalyst 1 (a) or 2 (b) (0.01 mmol), H2SO4 (a) or
TFA (b) promoter (0.1 mmol), C6H12 (2.0 mmol), H2O2 (2.5 (a) or 10.0 (a, b) mmol), CH3CN (up to
5.0 mL total volume), 50 °C.
A notable feature of the catalyst 2 consists in the possibility of its reuse. After a
standard cyclohexane oxidation reaction by the 2/TFA system (Fig. 9b), we recovered a solid
residue of the catalyst by filtration. It was washed by CH3CN, dried in air, and analyzed by
the IR spectroscopy, revealing a spectrum that is very similar to that of the parent compound
2. This experiment confirms the stability of 2 in the course of catalytic tests. In fact, the
cyclohexane oxidation using a recovered catalyst 2 reveals a similar product accumulation
curve (Fig. 9b), although with a slightly decreased total yield of 13%. Such a yield decrease

18
may be associated with the use of a decreased catalyst amount (due to a partial loss of the
catalyst during a recycling experiment).
To evaluate the substrate scope of the present catalytic systems, we tested the
oxidation of other cycloalkanes under selected reaction conditions, using the 1/TFA and
2/TFA systems (Table 1). Among the tested cycloalkanes, the highest activity (23% total
yield) was observed for the cycloheptane oxidation, followed by cyclooctane (22–18%) and
cyclohexane (19–15%) substrates. Cyclopentane oxidation is less efficient, leading to 9–6%
total product yields. For the oxidation of the C6–C8 cycloalkanes, the obtained product yields
are comparable to those attained in some other copper based catalytic systems [12,17].
Despite not being very high, the total yields of cyclohexanol and cyclohexanone achieved in
the present work are superior than those in an industrial DuPont process for the oxidation of
cyclohexane, which uses cobalt naphthenate as a homogeneous catalyst and proceeds under
harsher reaction conditions [10,29].
Furthermore, in spite of being more reactive substrate, cyclohexanol is not readily
oxidized into cyclohexanone by the present 1/TFA and 2/TFA systems (only 5–6% yields of
cyclohexanone were obtained), thus suggesting that possible overoxidation reactions of the
formed alcohol products in the course of the alkane oxidations do not proceed to a significant
extent, if avoiding prolonged reaction times. These data also confirm a rather high overall
selectivity (typically above 90% in the first hours of the reaction) toward the main products,
cyclohexanol and cyclohexanone, in the cyclohexane oxidation catalyzed by 1 and 2. It
should also be mentioned that both the 1/TFA and 2/TFA catalytic systems show a
significantly lower activity when using tert-butyl hydroperoxide (t-BuOOH) as oxidant
instead of hydrogen peroxide. In fact, the total yields of products in the oxidation of
cyclohexane by t-BuOOH do not exceed ~3%.
Table 1. Mild oxidation of C5–C8 cycloalkanes with H2O2 catalyzed by 1 and 2.a
Total product yield
(alcohol + ketone), %b
Cycloalkane
1
2
C5
C6
9
6
c,d
19
23
15
23
C7

19
C8
18
22
aReaction conditions: catalyst 1 or 2 (0.01 mmol), acid promoter (TFA, 0.1 mmol), cycloalkane (2 mmol), H2O2
(10 mmol), CH3CN (up to 5 mL total volume), 50 °C, 3 h. bYields are based on alkanes [(moles of products per
c
mol of cycloalkane)×100%]. Under similar reaction conditions, the oxidation of cyclohexanol with H2O2 leads
d
to ~6 or 5% yield of cyclohexanone when using 1 or 2, respectively. Under similar reaction conditions, the
oxidation of C6H12 by t-BuOOH (70% in H2O, 5 mmol) results in only 3 or 1% total yields of products
(cyclohexanol + cyclohexanone) when using 1 or 2, respectively.
3.4. Investigation of model solutions by ESI-MS.
To get additional information on possible species present in solution, we investigated the
parent compounds 1 and 2 and the corresponding 1/H+/H2O2 and 2/H+/H2O2 model catalytic mixtures
by the ESI-MS(±) method. The MS(+) spectrum of [Cu2(µ-bea)2(Hbea)2](NO3)2 (1) reveals a
characteristic peak of a doubly charged cation [Cu2(µ-bea)2(Hbea)2]2+ (m/z 364) and a molecular ion
[Cu2(µ-H0.5bea)2(Hbea)2(NO3)2]+ (m/z 853), followed by further fragmentation with the loss of
benzylethanolamine moieties, as confirmed by the detection of the [Cu2(µ-bea)2(Hbea)(NO3)]+ (m/z
640) and [Cu2(µ-H0.5bea)2(NO3)2]+ (m/z 551) peaks. The MS2 fragmentation of the molecular ion,
[Cu2(µ-H0.5bea)2(Hbea)2(NO3)2]+ (m/z 853), produced the following fragments: [Cu2(µ-
bea)2(H0.5bea)2(H2O)2]+ (m/z 765), [Cu2(µ-bea)2(bea)]+ (m/z 576), [Cu2(µ-H0.5bea)2(NO3)2]+ (m/z 551),
and [Cu2(µ-bea)2]+ (m/z 426). In the MS(–) mode, we were able to detect the molecular ion, [Cu2(µ-
bea)2(H0.5bea)2(NO3)2]– (m/z 851), and the derived adducts [Cu2(µ-bea)2(H0.5bea)(H2O)]– (m/z 745),
[Cu2(µ-bea)2(bea)(OH)]– (m/z 593), and [Cu2(µ-bea)2(bea)]– (m/z 576). Additional less characteristic
fragments corresponding to various nitrate adducts were also observed in both positive and negative
ESI modes. In acidic medium and after the introduction of hydrogen peroxide, we can still identify in
the ESI-MS(+) spectrum the molecular ion, [Cu2(µ-H0.5bea)2(Hbea)2(NO3)2]+ (m/z 853), and typical
derived dicopper fragments with expected isotopic distribution patterns, suggesting that such Cu2-
aminoalcohol cores can correspond to catalytically active species in the 1/H+/H2O2 system.
The ESI-MS(+) plot of [Cu2(H3tipa)2(µ-pma)]·7H2O (2) shows the characteristic peak
corresponding to the molecular ion [Cu2(H3tipa)2(µ-Hpma)]+ (m/z 759) and its adduct [Cu2(H3tipa)2(µ-
pma) + Na]+ (m/z 781), pursued by further fragmentation with the ESI-induced cleavage or loss of
triisopropanolamine moieties. This is confirmed by the detection of the ions: [Cu2(H3tipa)2(µ-H2pma)
– OH]+ (m/z 742), [Cu2(H3tipa)2(µ-H2pma) – C3H7OH]+ (m/z 703), and [Cu2(H3tipa)(µ-H2pma) –
OH]+ (m/z 552). Despite poor fragmentation in the MS(–) mode, an adduct of the molecular ion
[Cu2(H2tipa)2(µ-pma) + Na]– (m/z 779) was detected. In the MS(+) mode, some of the above
dicopper(II) fragments become more intense in acidic medium and after the introduction of H2O2,
suggesting a partial decoordination of triisopropanol moieties and further fragmentation of dicopper
cores in the course of catalytic reactions. However, these processes appear to be reversible given the

20
possibility of recovering the catalyst 2 in the solid form after catalytic tests. Hence, in both systems
containing 1 and 2, the obtained data confirm a partial decoordination of aminoalcohol ligands in the
course of catalytic tests, leading to the generation of dicopper active species, wherein the adjacent
copper atoms are interlinked via benzylethanolamine or pyromellitate bridging ligands.
3.5. Investigation of different selectivity parameters in alkane oxidation.
Aiming at evaluating the type of the reaction mechanism and nature of the involved
oxidizing species, we carried out the oxidation of different linear and cyclic alkanes in the
presence of both 1/TFA and 2/TFA systems and measured various selectivity parameters
(Table 2). Interestingly, the oxidation of a linear alkane, n-hexane, proceeds with some
specific preference to the third C(3) secondary carbon atom, as attested by the regioselectivity
C(1):C(2):C(3) parameters of 1:8:15 or 1:10:18 for the 1/TFA or 2/TFA systems,
respectively. In the case of n-heptane, an increased reactivity of the forth C(4) carbon atom
was also observed, with the respective C(1):C(2):C(3):C(4) parameters of 1:12:16:26
(1/TFA) or 1:10:12:15 (2/TFA). Besides, the oxidation of n-octane proceeds with some
preference to the C(3) and C(4) atoms (Table 2). Within all the tested C6–C8 linear alkanes,
the secondary atoms are oxidized with an increased preference over the primary C atoms. The
oxidation reactions of methylcyclohexane and adamantane result in moderate bond
selectivities, with the 1°:2°:3° parameters of 1:5:27 (1/TFA) and 1:8:31 (2/TFA) in the case
of methylcyclohexane. If both cis- or trans-1,2-dimethylcyclohexanes are used as substrates,
the oxidation reactions are non-stereoselective, as evidenced by the trans/cis ratios of 0.6–0.9
between the generated isomeric tertiary alcohols with the mutual trans and cis orientation of
the methyl groups. The cis isomers are predominant products in the oxidation of trans-1,2-
dimethylcyclohexane, suggesting a partial inversion of the configuration.
Table 2. Selectivity parameters in the oxidation of various alkane substrates.a

21
catalyst
Selectivity parameter
1
2
Regioselectivity
C(1):C(2):C(3)b (n-C6H14)
C(1):C(2):C(3):C(4)b (n-C7H16)
C(1):C(2):C(3):C(4)b (n-C8H18)
1:8:15
1:12:16:26
1:15:18:18
1:10:18
1:10:12:15
1:12:16:16
Bond selectivity
1°:2°:3° (methylcyclohexane)c
2°:3° (adamantane)d
1:5:27
1:1.6
1:8:31
1:1.6
Stereoselectivity
trans/cis (cis-dimethylcyclohexane)e
trans/cis (trans-dimethylcyclohexane)e
0.6
0.9
0.7
0.8
aReaction conditions: catalyst 1 or 2 (0.005 mmol), TFA (0.05 mmol), alkane (1.0 mmol), H2O2 (5.0 mmol),
MeCN up to 2.5 mL total volume, 3 h, 50 °C. All parameters were calculated based on the ratios of isomeric
alcohols. The calculated parameters were normalized, i.e., recalculated taking into account the number of H
b
atoms at each carbon atom. Parameters C(1):C(2):C(3):(C(4)) are the relative reactivities of hydrogen atoms at
c
carbons 1, 2, 3, (and 4) of the n-hexane, n-heptane or n-octane chain. Parameters 1°:2°:3° are the relative
normalized reactivities of the hydrogen atoms at primary, secondary and tertiary carbon atoms of
d
methylcyclohexane. Parameters 3°/2° are the relative normalized reactivities of the hydrogen atoms at tertiary
and secondary carbon atoms of adamantane, determined as the ratio of the formed tertiary and secondary alcohol
isomers. eParameter trans/cis is determined as the ratio of the formed tertiary alcohol isomers with mutual trans
and cis orientation of the methyl groups.
The above-discussed selectivity parameters in the alkane oxidations with H2O2
catalyzed by the 1/TFA and 2/TFA systems (Table 2) as well as prior literature data12,13,17,32
indicate an involvement of a powerful and rather indiscriminate oxidizing species such as
HO• radicals. A somewhat increased regioselectivity in the oxidation of linear alkanes can be
associated with some bulkiness of the dicopper catalysts. On the basis of the obtained
selectivity data, observed kinetic features, and literature background for related Cu-
containing catalytic systems [12,13,17] a number of simplified mechanistic steps can be
mentioned. (1) Hydrogen peroxide reacts with a Cu2 catalyst generating hydroxyl radicals;
(2) they abstract hydrogen atoms from alkane to give alkyl radicals R•; (3) these radicals react
further with O2 (e.g., from air or via partial H2O2 decomposition) to furnish ROO• radicals;
(4) the latter are transformed to alkyl hydroperoxides (ROOH) as primary intermediate
products; and finally (5) ROOH rapidly decomposes (eventually via a Cu-catalyzed processes
and additionally after the treatment by PPh3) to result in alcohols and ketones as oxidation
products [12,17].

22
3.6. Catalytic activity of 1 and 2 in the hydrocarboxylation of cycloalkanes
In addition to the oxidation of cycloalkanes by H2O2, we also investigated the
catalytic performance of the compounds 1 and 2 in the mild hydrocarboxylation of
cycloalkanes to give carboxylic acids with one more carbon atom (Scheme 3). This method
consists of the reaction of Cn alkane with CO (carbonyl source), potassium peroxodisulfate
(oxidant), and H2O (hydroxyl source) to form directly a Cn+1 carboxylic acid, Cn–COOH.
Cyclic ketones and alcohols are also formed as minor products as a result of the competing
alkane oxidation reaction. The hydrocarboxylation reactions were carried out under
optimized conditions [12,31], namely at 60 °C in water-acetonitrile medium (v/v 1:2) and
using p(CO) of 20 atm. The obtained results are summarized in Table 3.
Scheme 3. Hydrocarboxylation of Cn cycloalkanes into Cn+1 cycloalkanecarboxylic acids.
Both compounds 1 and 2 act as rather efficient catalysts toward the
hydrocarboxylation of C5C8 cycloalkanes (cyclopentane, cyclohexane, cycloheptane, and
cyclooctane) into the corresponding C6C9 cycloalkanecarboxylic acids with yields up to
38% based on the cyloalkane (Table 3). The catalytic activity of compound 1 is comparable
or slightly higher than that of 2. The hydrocarboxylation of cycloalkanes results in the
formation of one monocarboxylic acid product due to the presence of a single type of carbon
atom in their molecules. No dicarboxylic acid formation was detected in these tests. The
highest activity for both 1 and 2 catalysts is observed for the hydrocarboxylation of
cyclohexane, leading to a 38% yield of cyclohexanecarboxylic acid (C6H11COOH), followed
by cycloheptane (24–26% of C7H13COOH) and cyclopentane (21–27% of C5H9COOH). The
yield of carboxylic acid drops to 13% and 10% when using cyclooctane as a substrate in the
presence of 1 or 2, respectively.
Table 3. Single-pot hydrocarboxylation of Cn (n = 5−8) cycloalkanes into the corresponding Cn+1
cycloalkanecarboxylic acids catalyzed by 1 and 2.a

23
Product Yield, %b
Entry Cycloalkane
Catalyst
Acid
26.7
Ketone
0.5
Alcohol
0.1
Totalc
27.3
1
1
2
C5
2
20.9
0.3
0.1
21.3
3
1
2
38.4
38.2
1.5
2.1
0.3
0.4
40.2
40.7
C6
4
5
1
2
24.2
26.1
9.5
8.3
2.7
2.2
36.4
36.6
C7
6
7
1
2
13.4
10.1
11.8
10.4
4.8
3.6
30.0
24.1
C8
8
a Cyclic ketones and alcohols are also formed as by-products. Reaction conditions (unless stated otherwise):
cycloalkane (1.00 mmol), Cu catalyst (0.01 mmol), p(CO) = 20 atm, K2S2O8 (1.50 mmol), H2O (2.0
b
mL)/MeCN (4.0 mL), 60 ºC, 4 h in an autoclave (20.0 mL capacity). Moles of product/100 moles of alkane.
c Yield of all products.
The corresponding cyclic ketones and alcohols are also formed as minor products as a
result of partial oxidation of cycloalkanes. However, the total yield of oxygenates (ketone is
formed predominantly to alcohol) increases with the hydrocarbon size, namely from 0.5–
2.5% for C5H10 and C6H12 to 10.5–12.6% for C7H14 and C8H16.
Based on prior literature background [12,31] and the obtained experimental data, we
believe that the Cu-catalyzed hydrocarboxylation reactions proceed via the following main
steps. (1) The formation of the cycloalkyl radicals R• from a cycloalkane [generated via H
abstraction by sulfate radical SO4
derived from homolysis of K2S2O8]. (2) The
carbonylation of R• by CO to give the cycloacyl radicals RCO•. (3) The oxidation of RCO• by
copper(II) species to the cycloacyl cations RCO+ [via the Cu(II)/Cu(I) redox couple] and (3')
the regeneration of the Cu(II) form upon oxidation of Cu(I) by K2S2O8. (4) The hydrolysis of
RCO+ to yield the corresponding cycloalkanecarboxylic acid [12].
4. Concluding remarks
The present study has reported the synthesis, full characterization, and application in
homogeneous oxidation catalysis of two new water-soluble coordination compounds, [Cu2(µ-
bea)2(Hbea)2](NO3)2 (1) and [Cu2(H3tipa)2(µ-pma)]·7H2O (2). Their structures show distinct
types of dicopper(II) cores driven by N-benzylethanolamine or triisopropanolamine and
pyromellitate ligands, respectively. In spite of commercial availability and potential

24
coordination versatility of these aminoalcohol ligands, the obtained compounds also represent
the first examples of discrete copper complexes derived from Hbea and H3tipa [17a,33].
Other novelty features of the present compounds concern their catalytic versatility, since both
1 and 2 are capable of catalyzing two distinct reactions of the oxidative functionalization of
alkanes (i.e., oxidation and hydrocarboxylation).
Thus, both dicopper(II) compounds catalyze the mild homogeneous oxidation by
H2O2 of different cycloalkanes (cyclopentane, cyclohexane, cycloheptane, and cyclooctane)
to form the corresponding cyclic alcohols and ketones in up to 23% overall yields based on
substrate. Despite not being high, these yields can be considered as rather good especially in
view of the high inertness of saturated hydrocarbons and very mild reaction conditions that
were applied [34,35]. Besides, a notable feature of compound 2 consists in the possibility of
its recovery and reuse in further catalytic tests. Cyclohexane has been studied as a model
hydrocarbon [10,29] and the influence of various reaction parameters has been investigated,
including the kind and amount of an acid promoter, catalyst loading, and solvent composition
(water content).
Although water is known to inhibit alkane oxidation due to the reduction of oxidant
concentration and decrease of substrate solubility, we have detected a considerable increase
of an initial reaction rate in the cyclohexane oxidation by both 1/H+/H2O2 and 2/H+/H2O2
systems on rising the H2O content in the reaction mixture. The present work thus represents a
continuation of our efforts on widening a very limited family of copper based catalytic
systems [17a,b] that are active in the oxidative functionalization of alkanes and wherein water
can play an unusual promoting role. By extending a series of Cu-aminoalcohol catalysts it
should be possible to verify whether the type of aminoalcohol ligand and/or the nuclearity of
a copper core can correlate with the promoting role of water. We believe that by identifying
and studying more examples of such copper compounds, it would be possible to develop
more efficient water-assisted catalytic systems and better understand the promoting role of
water.
Furthermore, the compounds 1 and 2 act as efficient catalysts for the
hydrocarboxylation of C5–C8 cycloalkanes in the presence of CO, K2S2O8, and H2O, resulting
in the formation of the corresponding cycloalkanecarboxylic acids as principal products.
Cyclic alcohols and ketones are also formed in minor amounts as products of the competing
oxidation reaction. Highest yields of carboxylic acids were obtained when using cyclohexane
(38% of C6H11COOH), followed by cycloheptane (24–26% of C7H13COOH) and
cyclopentane (21–27% of C5H9COOH).

25
By having a N,O-environment around copper centers and being active in mild alkane
oxidations, the compounds 1 and 2 can also be considered as bioinspired homogeneous
catalysts with some relevance to the function of particulate methane monooxygenase [7]. The
design of novel multicopper cores driven by simple and low-cost aminoalcohol ligands as
well as the application of such compounds toward the oxidation of different alkanes under
mild conditions is currently in progress.
Acknowledgements
This work was supported by the Foundation for Science and Technology (FCT), projects:
IF/01395/2013/CP1163/CT005,
RECI/QEQ-QIN/0189/2012,
UID/QUI/00100/2013,
SFRH/BSAB/114190/2016, SFRH/BPD/78854/2011, and REM2013, Portugal. We thank Dr.
M. C. Oliveira and Ms. A. Dias for ESI-MS(±) measurements.
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