Peroxidative oxidation of alkanes and alcohols under mild conditions by Di- and TetranuclearCopper (II) Complexes of Bis (2-Hydroxybenzylidene) Isophthalohydrazide

Article abstract of DOI:10.3390/molecules23102699

Bis(2-hydroxybenzylidene)isophthalohydrazide (H₄L) has been used to synthesize the dinuclear [Cu₂(1_κNO²:2_κN′O′2-H₂L)(NO₃)₂(H₂O)₂] (1) and the tetranuclear [Cu₄(μ-1_κNO²:2_κN′O₂- H₂L)₂(μ-NO₃)₂(H₂O)₄]·2C₂H₅OH (2) complexes. The solvent plays an important role in determining the ligand behaviour in the syntheses of the complexes. An ethanol-acetonitrile mixture of solvents favours partials enolization in the case of 2. Both complexes have been characterized by elemental analysis, infrared radiation (IR), single crystal X-ray crystallography and electrochemical methods. The variable temperature magnetic susceptibility measurements of 2 show strong antiferromagnetic coupling between the central nitrato-bridged Cu (II) ions. The catalytic activity of both 1 and 2 has been screened toward the solvent-free microwave-assisted oxidation of alcohols and the peroxidative oxidation of alkanes under mild conditions. Complex 1 exhibits the highest activity for both oxidation reactions, leading selectively to a maximum product yield of 99% (for the 1-phenylethanol oxidation after 1 h without any additive) and 13% (for the cyclohexane oxidation to cyclohexyl hydroperoxide, cyclohexanol and cyclohexanone after 3 h).

Full text of DOI:10.3390/molecules23102699

molecules
Article
Peroxidative Oxidation of Alkanes and Alcohols
under Mild Conditions by Di- and Tetranuclear
Copper (II) Complexes of Bis
(2-Hydroxybenzylidene) Isophthalohydrazide
Manas Sutradhar 1,*, Elisabete C.B.A. Alegria 1,2,
Cai-Ming Liu 3 and Armando J. L. Pombeiro 1
* * ,
, M. Fátima C. Guedes da Silva 1,
1
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais,
1049-001 Lisboa, Portugal; pombeiro@tecnico.ulisboa.pt
Chemical Engineering Departament, Instituto Superior de Engenharia de Lisboa,
Instituto Politécnico de Lisboa, R. Conselheiro Emídio Navarro, 1, 1959-007 Lisboa, Portugal
National Laboratory for Molecular Sciences, Center for Molecular Science, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, China; cmliu@iccas.ac.cn
2
3
*
Correspondence: manas@tecnico.ulisboa.pt (M.S.); ebastos@deq.isel.ipl.pt (E.C.B.A.A.);
fatima.guedes@tecnico.ulisboa.pt (M.F.C.G.d.S.); Tel.: +351-21-841-9237 (M.F.C.G.d.S.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 27 September 2018; Accepted: 15 October 2018; Published: 19 October 2018
Abstract: Bis(2-hydroxybenzylidene)isophthalohydrazide (H4L) has been used to synthesize the
dinuclear [Cu2(1 ) and the tetranuclear [Cu4( -1
NO2:2 N0O02-H2L)(NO3)2(H2O)2] ( NO2:2 N0O2-
H2L)2( -NO3)2(H2O)4] 2C2H5OH ( ) complexes. The solvent plays an important role in determining
the ligand behaviour in the syntheses of the complexes. An ethanol-acetonitrile mixture of solvents
favours partials enolization in the case of . Both complexes have been characterized by elemental
analysis, infrared radiation (IR), single crystal X-ray crystallography and electrochemical methods.
The variable temperature magnetic susceptibility measurements of show strong antiferromagnetic
coupling between the central nitrato-bridged Cu (II) ions. The catalytic activity of both and has
been screened toward the solvent-free microwave-assisted oxidation of alcohols and the peroxidative
oxidation of alkanes under mild conditions. Complex exhibits the highest activity for both oxidation
κ
κ
1
µ
κ
κ
µ
·
2
2
2
1
2
1
reactions, leading selectively to a maximum product yield of 99% (for the 1-phenylethanol oxidation
after 1 h without any additive) and 13% (for the cyclohexane oxidation to cyclohexyl hydroperoxide,
cyclohexanol and cyclohexanone after 3 h).
Keywords: Cu (II) complexes; microwave assisted oxidation of alcohols; oxidation of alkanes; solvent
free process; magnetism
1. Introduction
The oxidation of alcohols to carbonyl-containing compounds [
reactions in organic synthesis [ ], with a great interest due to the application of carbonyl compounds
in research and industrial manufacturing, e.g., in the production of new materials [ ] and energy
sources [ ]. In view of their central role in synthetic chemistry and expected further applications,
these reactions continue to attract great attention in order to develop environmentally benign
processes [ ] disclosing new efficient catalysts [10 11], substrates or oxidation agents which could
1–3] is one of the fundamental
4,5
6
7
8,
9
,
successfully be used in the near future and make a difference in terms of efficiency, selectivity,
economy and/or sustainability of the processes. The metal-catalyzed aerobic and peroxidative
oxidations of alcohols, in particular of benzylic alcohols, are typical model reactions due to their
Molecules 2018, 23, 2699; doi:10.3390/molecules23102699
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2699
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importance and generality; inexpensive primary oxidants such as O2, H2O2 or tert-butylhydroperoxide
(TBHP) and simple procedures are usually explored [ ]. The accelerating effect of microwave
(MW) irradiation in the synthesis of ketones from secondary alcohols with TBHP as an oxidant has
been largely reported [12 18]; this technology is a useful alternative source in organic synthesis,
1–5
–
with an environmentally friendly nature.
The mild oxidation of cycloalkanes by hydrogen peroxide to the corresponding alkyl hydroperoxides,
alcohols and ketones, a highly significant reaction in terms of industrial interest, remains a challenge
in modern catalysis [19–24].
It has been shown that copper (II) complexes are useful catalysts towards the MW assisted
oxidation of alcohols and also the functionalization of inert alkanes into valuable organic products,
using readily available and cheap oxidants [22
and the subject requires further exploration. Moreover, aroylhydrazone complexes are potentially
important as oxidation catalyst and some of them also showed interesting magnetic properties [29 32].
,25–28]; however, such applications are still limited
–
Continuing our research on the syntheses of aroylhydrazone metal complexes and their
application in catalysis, herein we report the syntheses and characterization of new dinuclear and
tetranuclear Cu(II) complexes derived from the aroylhydrazone Schiff base bis(2-hydroxybenzylidene)
isophthalohydrazide (H4L), their electrochemical behaviour and magnetic properties (2), as well as
their catalytic activity in the solvent-free MW assisted peroxidative oxidation of alcohols and also in
the oxidation of alkanes under mild conditions, towards the development of environmentally friendly
catalytic systems.
2. Results and Discussion
2.1. Syntheses and Characterizations
The aroylhydrazone Schiff base bis(2-hydroxybenzylidene) isophthalohydrazide (H4L) has two
potential tridentate coordination pockets which can bind two metal centres simultaneously. It has
previously been observed [32–34] that the aroylhydrazone can act as ligand in two tautomeric (keto or
enol) forms. At room temperature, deprotonation of the phenolic –OH group from the aroylhydrazone
in the presence of a copper (II) source, in methanol, generates the H2L2− species and leads to the stable
dinuclear complex 1 (Scheme 1). When the reaction is carried out in a 2:1 acetonitrile-ethanol solvent
mixture, part of the aroylhydrazone remains in the keto form, the remaining undergoing enolization
and deprotonation during complexation. As a result, a HL3− species is formed in solution and provides
the tetranuclear complex
2 (Scheme 1). This compound 2 can be considered as a dimer of 1, where the
two central Cu (II) ions are bridged by two nitrate ions and one of the phenoxido groups of the organic
ligand. The IR spectra of complexes 1 and 2 contain all the characteristic bands of the corresponding
coordinated tridentate anion−ic1ligand viz., 3476, 3024, 1608, 1254 and 1159 cm−1 for
1 and 3388, 3226,
2978, 1611, 1252 and 1068 cm for 2. The electrospray ionization mass spectrometry (ESI-MS) spectra
of both compounds, in ethanol solution (see experimental section), display the molecular ion peaks at
m/z = 672 [1 + H]+ (100%) and at m/z = 1158 [2 + H]+ (100%).

Molecules 2018, 23, 2699
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OH
HO
O
O
N
N
N
N
H
H
H
N
N
N
H2O
OH2
N
O
O
O
O
Cu
O
Cu
O
N
O
O
O
Cu
HN
O
O
OH
2 O N
O
N
O
H2O
O
O
O
OH2
N
N
H
H2O
O
N
O
Cu
Cu
O
O
ONO2
N
N
2 EtOH
N
H
N
(2)
(1)
Scheme 1. Syntheses of 1 and 2.
2.2. General Description of the Crystal Structures
X-ray low quality (low diffracting) crystals of
of a methanolic (for 1) or an acetonitrile-ethanol solution mixture (for 2
1
and
2
were obtained upon slow evaporation
), at room temperature.
Crystallographic data are summarized in Table 1, representative plots are displayed in Figures 1
and 2, and selected dimensions are presented in Table 2. Cif files for Compound
are available as Supporting Information for this paper.
1 and Compound 2
The organic ligand in
a NO2 donor for each metal cation in
behaves as an Ophenolate-bridging species as well. The copper cations exhibit square pyramidal [Cu1:
τ5 = 0.08 ( ) and 0.06 ( )], distorted penta-coordinate (Cu2 in τ5 = 0.38) or distorted octahedral
geometries (Cu2 in
; quadratic elongation = 1.078, angle variance = 77.60 º2)). The relative orientation
of one of the nitrate ligands of Cu1 in caused a measured Cu-Onitrate bond distance of 2.69(1) Å which
is similar to those of 2.680 (7) and 2.709 (5) Å in , well below the sum on the van der Waals radii of
copper and oxygen (1.40 and 1.52 Å, respectively). Therefore, on this basis, the geometry of that cation
1
and
2
is almost planar, behaves as a hexadentate chelator and acts as
1
and for the outer ones in , while for the inner metals it
2
1
2
1,
2
1
2
in
1
may be thought as octahedral, although with a great distortion (quadratic elongation = 1.125,
2
angle variance = 272.62 º )).
Compound
2 can be considered as a dimer of 1, where dimerization took place at the level of
the metals bearing nitrates, leading to a central four-membered dicopper metalacycle. This process
affected not only the dimensions involving the central copper cations (Cu(nitrate), see Table 2), but also
the outer ones with water ligands bound to copper (Cu(water), see Table 2), which is probably related
to the observed change of geometry (see above the values of τ5 descriptor for such metals). Thus,
from
the metal with water ligands, and decreased slightly in the other. Concerning the Cu-Owater lengths,
they differ markedly in with the apical much longer than the equatorial one; in the dissimilarity
1 to 2, the Cu-Ophenolate increased in both types of metals, but the Cu-Oketone increased only in
2
1
is not so significant, but still the longer distance pertains to the water molecule more distant from
the least-square plane of the molecule. An influence has also been perceived in the Cu···Cu lengths;
in the molecule of
than in
2 the distance between the Cu(nitrate) and the Cu(water) is more than 0.100 Å shorter
, but the shortest intermolecular distance between the metal cations is higher in the former.
1
The effect on selected O-Cu-O and O-Cu-N angles in 1 and 2 (Table 2) is most probably related to the
aforementioned differences in geometry.
Moreover, the enolate forms are more strongly coordinated to the metal centres with shorter M–O
bond distances than the corresponding ones in the keto forms, as observed in other cases [32–34].

Molecules 2018, 23, 2699
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Figure 1. Molecular structure of
1 with partial atom numbering scheme. The O-atoms from solvent
water molecules are omitted for clarity.
Figure 2. Molecular structure of
2 with partial atom numbering scheme. The ethanol solvent molecule
is omitted for clarity. Symmetry operation to generate equivalent atoms (i): 3−x, −y, 1−z.
Table 1. Crystal data and structure refinement details for complexes 1 and 2.
1
2·2EtOH
Empirical formula
Formula Weight
Crystal system
Space group
Temperature/K
a/Å
C22H20Cu2N6O15
735.52
C48H50Cu4N10O20
1341.14
Triclinic
Triclinic
P−1
P−1
296 (2)
296 (2)
7.8618 (4)
10.1197 (6)
18.1173 (10)
102.605 (3)
98.203 (2)
90.384 (3)
1391.19 (13)
2
9.5722 (5)
10.0444 (5)
14.9699 (8)
71.735 (2)
76.323 (3)
80.058 (3)
1320.44 (12)
1
b/Å
c/Å
◦
α/
β/
γ/
◦
◦
V (Å3)
Z
Dcalc (g cm–3
)
1.756
1.615
1.687
1.677
µ (Mo Kα) (mm–1
)
Rfls. collected/unique/observed
Rint
15,443/4623/2087
0.1339
0.0718, 0.1441
0.996
17,480/4694/2675
0.0913
0.0607, 0.1326
1.039
Final R1 a, wR2 b (I ≥ 2σ)
Goodness-of-fit on F2
1
a
2
2
2
2
4
R = Σ||Fo|–|Fc||/Σ|Fo|; b wR (F ) = [Σw(|Fo| – |Fc| ) /Σw|Fo| ] .
2

Molecules 2018, 23, 2699
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Table 2. Selected bond distances (Å) and angles (º) in complexes 1–2.
Parameter
1
2
Cu(water)-Ophenolate
Cu(nitrate)-Ophenolate
Cu(water)-Oketone
1.881(6)
1.891(5)
1.964(6)
1.984(5)
1.961(7)
2.427(7)
2.69(1)
1.903(4)
1.925(4)
2.017(4)
1.919(4)
Cu(nitrate)-Oketone
2.680(7)
2.709(5)
Cu-Onitrate
2.019(8)
2.131(8)
1.935(7)
1.938(6)
1.379(8)
1.399(9)
1.970(4)
2.251(5)
1.905(5)
1.933(5)
1.373(7)
Cu-Owater
Cu-N
N-N
1.405(6)
Shortest
intramolecular Cu···Cu
intermolecular Cu···Cu
Largest
8.457 [Cu(water)···Cu(nitrate)
]
]
]
9.471 [Cu(water)···Cu(nitrate)
5.471 [Cu(water)···Cu(nitrate)
]
]
2.928 [Cu(nitrate)···Cu(nitrate)
6.120 [Cu(water)···Cu(nitrate)
O-Cu(water)-O
O-Cu(water)-N
O-Cu(nitrate)-O
O-Cu(nitrate)-N
172.3(3)
149.8(5)
171.6(2)
176.5(3)
170.53(18)
167.0(2)
174.01(18)
170.71(19)
2.3. Electrochemical Properties
Cyclic voltammograms of
1 and 2 exhibit a first single-electron (per metal atom) irreversible
red
reduction process (wave Ired) at IEp
−
0.27 or
−
0.43 V vs. SCE, for 1 or 2, respectively, followed,
at a lower potential, by a second single-electron (per metal atom) reduction (wave IIred) at
red
IIEp
=
→
−
1.12 or
−
1.08 V vs. SCE, for 1 or 2, respectively, which are believed to correspond to
the CuII
CuI (wave Ired) and CuI
→
Cu0 (wave IIred) cathodic processes, in this order. Upon scan
reversal following the first reduction wave, an irreversible oxidation at IEp
−
0.05 or 0.02 V vs. SCE,
ox
for 1 or 2, respectively, was detected and assigned to the oxidation of a novel Cu(I) species. By reversing
the direction of the potential scan after the formation of wave IIred, an adsorption wave was formed at
ox
IIEp 0.15 or 0.27 V vs. SCE for 1 or 2, respectively.
Expectedly, no genuine anodic waves have been detected for any of the complexes.
Bis(2-hydroxybenzylidene) isophthalohydrazide (H4L) was not redox active under our experimental
conditions, and hence the cyclic voltammetric waves of
transfer processes.
1 and 2 can be due to metal-based electron
2.4. Magnetic Properties
The dc magnetic susceptibilities of complex
2 have been determined under 2000 Oe from 2 K
to 300 K. As shown in Figure 3, the χMT value at 300 K is 1.48 cm3 K mol−1, slightly smaller than
the expected value for four noninteracting Cu2+ ions (g = 2.0). The χMT product decreases with the
decreased temperture until about 100 K, then drops slowly to about 10 K; below this temperature,
χMT further decreases. These results indicate that there are antiferromagnetic interactions between
copper(II) ions.
A linear tetranuclear copper (II) magnetic coupling model was adopted to analyze the magnetic
interaction [35]. Owing to the crystallographic inversion symmetry, four exchange coupling constants
J1, J2, J3 and J4 were used in the Hamiltonian, H =
−
2J1(S1S2+S10 S20
)
−
2J2 S2S20
−
2J3(S1S20 +S10 S2)
−
2J4(S1S10 ) [35]; they represent the magnetic interactions between Cu1 and Cu2 (or Cu1i and Cu2i),
Cu2 and Cu2i, Cu1 and Cu2i (or Cu1i and Cu2), and between Cu1 and Cu1i, respectively. Given
the high number of variables, fitting the magnetic data using all four coupling constants led to
unreasonable results. Since the distance between Cu1 and Cu2i (or Cu1i and Cu2) and the distance

Molecules 2018, 23, 2699
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between Cu1 and Cu1i are large enough, J3 and J4 could be considered as zero for a simplified mod−el1,
and better results were thus achieved. The best fitting gave g = 2.02, J1 =
−
5.1 cm−1, J2 =
−
172.8 cm
−5
−4
and N
α
= 4.8
×
10 with R = 5.5
×
10 (R =
Σ
[(χM
)
−
(χM) Σ[(χM)
calc]2/ obs]2). The large negative
obs
value of J2 reveals that there is a strong antiferromagnetic exchange between the Cu (II) ions mediated
by the Ophenolate and NO3– bridges.
1.6
1.4
1.2
1.0
0.8
χΤ
0.6
0.4
0
50
100
150
200
250
300
T/K
Figure 3. Plot of χMT versus T for complex 2. The solid line represents the best theoretical fitting.
2.5. Catalytic Studies
2.5.1. Solvent-Free Microwave (MW) Assisted Oxidation of Secondary Alcohols
Complexes and were tested as catalyst precursors for the homogeneous oxidation of
secondary alcohols [1-phenylethanol (model substrate), cyclohexanol, 2-hexanol and 3-hexanol]
to the corresponding ketones following our previously developed procedure [18 31 36 39] using
1
2
,
, –
tert-butylhydroperoxide (t-BuOOH, Equation (2), used as aq. 70%) as oxidizing agent, under typical
◦
conditions of 80–120 C, microwave (MW) irradiation (5–20 W), 0.5–3 h reaction time and in the
absence of any added solvent (Scheme 2 for 1-phenylethanol and cyclohexanol oxidation). Results are
summarized in Tables 3 and 4.
Scheme 2. Microwave (MW)-assisted solvent-free oxidation of 1-phenylethanol and cyclohexanol to
acetophenone and cyclohexanone, respectively, catalysed by 1 or 2.

Molecules 2018, 23, 2699
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◦
Under typical reaction conditions (120 C and 0.5 h reaction time) ketone yields up to 37%
(TOF = 264 h−1) are obtained for the oxidation of 1-phenylethanol (Table 3, entry 3) by the
/TBHP/MW
1
system (catalyst/substrate molar ratio of 0.2%) and in the absence of any additive. For a longer reaction
time of 1 and 3 h, and for the same catalytic system, the oxidation by TBHP of 1-phenyletanol leads
to 75 and 95% of acetophenone, respectively (Table 3, entries 4 and 5). The acetophenone yield value
for 1 h reaction (Table 3, entry 4) is significantly higher than that obtained (17%, Table 3, entry 15)
◦
without MW assistance, for the same reaction time. Reactions performed at 120 C with 20 W of
MW irradiation and in the presence of complex 2 (2/TBHP/MW) resulted only in 28, 42 and 71% of
acetophenone after 0.5, 1 and 3 h of oxidation reaction, respectively (Table 3, entries 16–18, respectively).
The addition of the heteroaromatic 2-pyrazynecarboxylic acid (Hpca) or of trifluoroacetic acid (TFA)
to the 1/TBHP/MW system [n (acid)/n (catalyst 1) = 10], slightly improved the yield from 11 to 14%
(Table 3, entry 6) or to 18% (Table 3, entry 9), respectively, when the reaction was performed at 80 ◦C
for 0.5 h.
A major effect was observed in the presence of 2,2,6,6-tetramethylpiperydil-1-oxyl (TEMPO)
radical, an efficient promotor in aerobic oxidation of alcohols [11,40–48]. In fact, the oxidation of
1-phenylethanol by the
1
/TBHP/TEMPO/MW system afforded substantial increase in the yield of
◦
acetophenone achieving 99% after 1 h at 120 C (Table 3, entry 14) or 88% in only 0.5 h (Table 3, entry 13).
Under the oxidation conditions used, the TEMPO additive could be oxidized to the oxoammonium
species acting as oxidant, as well as acting as a hydrogen atom abstract from TBHP, enhancing the
formation of tert-BuOO• and t-BuO• [40
–48]. The 2/TBHP/TEMPO/MW system was not so effective
(Table 3, entries 23 and 24). The blank tests in the absence of metal catalyst (with and without TEMPO)
lead to very low conversion (up to 4% yield) of 1-phenylethanol to acetophenone (Table 3, entries 25
and 26).
Attempts to perform microwave-assisted oxidation of secondary alcohols in the presence of
in the absence of any additive and at room temperature, failed. Performing the reaction at 80 ◦C did
not allow yields beyond 27% in 3 h (with catalyst
), but at 120 ◦C the product was obtained in 95
(with ) or 71% yield (with ), in the same reaction time (Table 3, entries 5 and 20). The accelerating
1 or 2,
1
1
2
effect of the increase in temperature was also observed in the presence of the tested additives (Figure 4).
Thus, for example, in the presence of the TEMPO radical, one observes a change in the conversion
of 1-phenylethanol from 22 to 88% and in the TOF value from 168 to 1112 h−1 (Table 3, entries 12
◦
and 13) when going from 80 or 120 C, in 0.5 h. This feature also concerns the microwave power since
at 80 ◦C the power went up to 10 W in the first 10 s but then, after reaching the desired temperature,
it stabilized at ca. 5 W, while for the temperature of 120 ◦C, ca. 40 W were reached in the first 10 s
followed by stabilisation at 10–15 W for the remaining time.
Figure 4. Temperature effect on the yield of acetophenone from MW-assisted peroxidative oxidation of
1-phenylethanol by the 1/TBHP/MW catalytic system.

Molecules 2018, 23, 2699
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Table 3. Selected results for the MW-assisted oxidation of 1-phenylethanol by tert-butylhydroperoxide
(TBHP) with 1 and 2 as catalyst precursors a.
Yield b
(%)
Catalyst
Precursor
Reaction Time
(h)
Temperature
Additive
(µmol)
TOF c
Entry
◦
−1
( C)
(h
)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 d
16
0.5
3
0.5
1
80
80
120
120
120
80
120
80
80
120
80
80
120
120
120
120
-
-
-
-
11
27
37
75
95
14
70
5
18
79
6
22
88
99
17
42
108
74
264
494
222
118
538
64
182
501
89
3
-
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
Hpca (50)
Hpca (50)
Hpca (100)
TFA (50)
TFA (50)
TFA (100)
TEMPO (30)
TEMPO (30)
TEMPO (30)
-
1
168
1112
755
111
98
1
3
-
17
18
19
20
21
22
23
24
0.5
0.5
1
80
120
120
120
80
80
80
120
-
-
-
-
5
56
182
212
137
82
67
78
237
28
42
71
8
6
10
46
3
2
0.5
0.5
0.5
0.5
TFA (50)
Hpca (50)
TEMPO (30)
TEMPO (30)
25
26
None
None
1
1
120
120
-
1
4
6
TEMPO
21
a
Reaction conditions (unless stated otherwise): 2.5 mmol of substrate, 5 µmol of 1 or 2 (0.2 mol% vs. substrate),
5 mmol of t-BuOOH (aq. 70%), 80 or 120 ◦C, microwave irradiation (5–20 W). b Molar yield (%) based on substrate,
i.e., moles of product per 100 mol of substrate determined by G.C. c Turnover frequency = number of moles of
d
product per mol of metal catalyst per hour (turnover number per hour). Under conventional heating.
Complexes
1 and 2 were also tested towards the oxidation of aliphatic alcohols, namely
cyclohexanol and the linear 2- and 3-hexanols. As expected, they were less reactive than 1-phenylethanol
(benzylic alcohol derivative), leading to moderate yields in the 15–31% range (in 0.5 h reaction at
120 ◦C, without any additive (Table 4, entries 1, 4, 7, 10, 13 and 16). The efficiency of the oxidation of
those alcohols could also be enhanced by using TEMPO radical and the yields increased to 29–58% in
0.5 h (Table 4, entries 2, 5, 8, 11, 14 and 17). Extending the reaction time to 1 h and in the presence of
the same promoter, the conversions raised to 87% for cyclohexanol (Table 4, entry 3), 71% for 2-hexanol
(Table 4, entry 6) and 59% for 3-hexanol (Table 4, entry 9) with 1 as catalyst. The position (2 or 3) of
the OH group in the aliphatic chain of the linear alcohols (2-hexanol and 3-hexanol) appeared not
to influence significantly the efficiency of the system, in view of the obtained yields (compare, e.g.,
entries 4 and 7 or 6 and 9, Table 4, for complex
1). Blank tests were performed for all aliphatic alcohols
in the absence of any catalyst and residual conversions (up to 5%) were recorded.

Molecules 2018, 23, 2699
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Table 4. MW-assisted oxidation of selected alcohols by TBHP with 1 and 2 as catalyst precursors a.
Catalyst
Precursor
Reaction
Time (h)
Additive
(µmol)
−1
)
Yield b (%)
TOF c (h
Entry
Substrate
1
2
3
4
5
6
7
8
9
0.5
0.5
1
0.5
0.5
1
0.5
0.5
1
-
31
58
87
21
45
71
20
43
69
380
568
471
204
426
726
194
398
321
cyclohexanol
TEMPO (30)
TEMPO (30)
-
TEMPO (30)
TEMPO (30)
-
1
2-hexanol
3-hexanol
TEMPO (30)
TEMPO (30)
10
11
12
13
14
15
16
17
18
a
0.5
0.5
1
0.5
0.5
1
0.5
0.5
1
-
22
34
59
17
31
49
15
29
51
222
382
285
176
368
225
168
358
255
cyclohexanol
2-hexanol
TEMPO (30)
TEMPO (30)
-
TEMPO (30)
TEMPO (30)
-
2
TEMPO (30)
TEMPO (30)
3-hexanol
Reaction conditions (unless stated otherwise): 2.5 mmol of substrate, 5 µmol of 1 or 2 (0.2 mol% vs. substrate),
5 mmol of t-BuOOH (aq. 70%), 120 ◦C, microwave irradiation (20 W power). Molar yield (%) based on substrate,
i.e., moles of product per 100 mol of substrate determined by GC. Turnover frequency = number of moles of
b
c
product per mol of metal catalyst per hour (turnover number per hour).
The catalytic mechanism may proceed through the metal-assisted generation of t-BuOO and
t-BuO radicals [40–
48], upon oxidation or reduction of t-BuOOH by a CuII or CuI centre (Equations (1)
and (2)), respectively, and is summed up in Equations (1)–(6).
Cu(II) + t-BuOOH → Cu(I) + t-BuOO• + H+
(1)
Cu(I) + t-BuOOH → Cu(II)-OH + t-BuO•
Cu(II)-OH + t-BuOOH → Cu(II)-OO-t-Bu + H2O
t-BuO• + R2CHOH → t-BuOH + R2C•-OH
(2)
(3)
(4)
(5)
(6)
t-BuOO• + R2CHOH → t-BuOOH + R2C•-OH
Cu(II)-OO-t-Bu + R2C•-OH → R2C=O + t-BuOOH + Cu(I)
2.5.2. Peroxidative Oxidation of Cyclohexane
Compounds
1
and
2
were also tested as catalyst precu◦rsors in the oxidation of cyclohexane by
H2O2 (Equation (2), used as 50% aqueous solution) at 50 C in MeCN/H2O medium (Scheme 3).
The reaction was monitored by Gas Chromatography (GC) to determine the amount of cyclohexanol
and cyclohexanone formed, typically after treatment with PPh3 (to reduce cyclohexyl hydroperoxide
to cyclohexanol) [29,30,49–51].
Scheme 3. Oxidation of cyclohexane to cyclohexyl hydroperoxide, cyclohexanol and cyclohexanone.

Molecules 2018, 23, 2699
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The accumulation of oxygenated products (cyclohexanol and cyclohexanone) in the cyclohexane
oxidation catalysed by and , in the absence and in the presence of TFA, is given in Table 5.
Both complexes were active for this reaction in the absence of any additive (Figure 5) with
approximately 7 and 5% (for and , respectively) of total product yield after ca. 0.5 h (Table 5,
entries 3 and 15, for and , respectively). Further increase of the reaction time to 2 h slightly improved
the total yield of the products in the presence of and almost had not effect when was the catalyst.
The presence of TFA improved the catalytic performance of both copper compounds, more markedly
for with the total yield of cyclohexanol and cyclohexanone achieving ca. 13% in 1 h (Table 5, entry 11).
1
2
1
2
1
2
1
2
1
The promoting effect of an acid co-catalyst was already observed for other Cu-catalysed systems in
the oxidative transformation of alkanes and can be related to (i) its involvement in proton transfer
steps, (ii) catalyst activation by unsaturation of the Cu (II) centres upon ligand protonation or to the
(iii) facilitation of the formation of peroxo complexes [27,52–56].
The activity exhibited by compounds
1 and 2, even in the absence of TFA, is higher than that
shown, e.g., by [Cu(OTf)2(Py2S2)] (Py2S2 = 1,6-bis(20-pyridyl)-2,5-dithiahexane) (with 4.3% overall
yield) [57] and is comparable to those of the complexes bearing azathia macrocycles, e.g., [Cu(OTf)2(L3)]
(L3 = mixed 14-membered N2S2 azathia macrocycle) or [Cu(OTf)(L4)(H2O)](OTf) (L4 = nine-membered
NS2 macrocyclic ligand with a 2-methylpyridyl pendant arm) (overall yield of ca. 8%) [58].
Table 5. Total yield (cyclohexanol and cyclohexanone) with time in the oxidation of cyclohexane by
◦
H2O2 at 50 C in CH3CN catalysed by 1 or 2 a.
Entry
Precatalyst
Acid Co-Catalyst
Reaction Time (min)
Yield (%)
Total b
6.9
7.7
7.9
8.1
8.3
8.7
6.1
8.8
10.4
11.8
12.5
13.1
4.9
5.2
5.4
5.4
5.5
OL
3.7
4.1
4.2
4.3
4.5
4.8
3.8
5.3
5.9
6.6
7.2
7.8
3.3
3.5
3.5
3.6
3.7
3.9
2.9
3.6
4.1
4.4
4.8
5.1
ONE
3.2
3.6
3.7
3.8
3.8
3.9
2.3
3.5
4.5
5.2
5.3
5.3
1.6
1.7
1.9
1.8
1.8
1.6
2.2
1.9
2.0
1.9
2.0
2.5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
18
20
21
22
23
24
a
1
-
-
-
-
-
5
15
30
45
60
120
5
15
30
45
60
120
5
15
30
45
60
120
5
15
30
45
60
120
-
TFA
TFA
TFA
TFA
TFA
TFA
-
-
-
-
-
2
-
5.5
5.1
5.5
6.1
6.3
6.8
7.6
TFA
TFA
TFA
TFA
TFA
TFA
Reaction conditions: C6H12 (0.46 M),
1
or
2
(5
×
10−4 M), TFA (5
×
10−3 M), H2O2 (50% aq, 2.2 M), MeCN
(up to 5 mL total volume), 50 ◦C. Moles of products [cyclohexanol (OL) + cyclohexyl hydroperoxide (OOH)
b
c
+ cyclohexanone (ONE)]/100 mol of C6H12, determined by GC after treatment with PPh3. Moles of products
(cyclohexanol + cyclohexanone) per mol of catalyst precursor.

Molecules 2018, 23, 2699
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14
12
10
8
6
4
2
0
0
0.5
1
1.5
2
2.5
Time (h)
Figure 5. Total yield (cyclohexanol and cyclohexanone) along the time in the oxidation of cyclohexane
with aq. H2O2 catalyzed by in the absence of any additive ( , squares) or in the presence of TFA
in the absence of any additive ( , circles) or in the presence of TFA (1:10)
1
ꢀ
(1:10) (
×
, cross), or◦by
2
(N, triangles), at 50 C in CH3CN.
The formation of cyclohexyl hydroperoxide CyOOH was confirmed by GC-MS methods
and accounts for a free radica•l reaction mechanism, which conceivably involves the presence of
oxygen-centered radicals, HOO and HO , very reactive species, formed upon reaction of the catalyst
•
with hydrogen peroxide (Equations (7) and (8)) [50
radical. The HO radical abstracts hydrogen from cyclohexane CyH to produce cyclohexyl radical
Cy (Equation (9)), which is then trapped by dioxygen to give CyOO radical (Equation (10)).
The latter may react with the oxidant to form CyOOH (Equation (11)). Metal-assisted decomposition
of CyOOH to CyO and CyOO (Equations (12) and (13)) would then lead to cyclohexanol (CyOH)
,59–62] and enhanced by the presence of TEMPO
•
•
•
•
•
and cyclohexanone (Cy-H=O) products (Equations (14) and (15)) [61].
Cu(II) + HOOH → HOO• + H+ + Cu(I)
(7)
Cu(I) + HOOH → HO• + Cu(II) + HO−
HO• + CyH → ROH + Cy•
(8)
(9)
Cy• + O2 → CyOO•
(10)
(11)
(12)
(13)
(14)
(15)
CyOO• + HOOH → CyOOH + HOO•
CyOOH + Cu(I) → CyO• + Cu(II) + HO−
CyOOH + Cu(II) → CyOO• + H+ + Cu(I)
CyO• + CyH → CyOH + Cy•
2CyOO• → CyOH + Cy-H=O + O2
The coordination of the oxidant to the metal centre is dependent on the Lewis acidity of the
latter. The more Lewis acid metal centre should be easier to reduce. To correlate the electrochemical
and catalytic behaviours, the reduction potentials of both complexes were determined by cyclic

Molecules 2018, 23, 2699
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voltammetry (see above). In fact, complex
1
, the most active one in both oxidation reactions, is easier
red
to reduce than 2 (reduction at a less negative potential, i.e., IEp −0.27 V versus −0.43 V vs. SCE).
3. Experimental Section
3.1. General Materials and Equipment
All synthetic work was performed in air. Commercially available reagents and solvents were
used as received, without further purification or drying. Cu(NO3)2
for the synthesis of the complexes.
·
5H2O was used as a metal source
C, H, and N elemental analyses were carried out by the Microanalytical Service of Instituto
Superior Técnico. Infrared spectra (4000–400 cm–1) were recorded on a Bruker Vertex 70 instrument in
KBr pellets; wavenumbers are in cm–1. The 1H NMR spectra were recorded at room temperature on
a Bruker Avance II + 400.13 MHz (UltraShieldTM Magnet, Rheinstetten, Germany) spectrometer.
Tetramethylsilane was used as the internal reference and the chemical shifts are reported in
ppm. Mass spectra were run in a Varian 500-MS LC Ion Trap Mass Spectrometer equipped with
an electrospray (ESI) ion source. For electrospray ionization, the drying gas and flow rate were
optimized according to the particular sample with 35 p.s.i. nebulizer pressure. Scanning was
performed from m/z 100 to 1200 in methanol solution. The compounds were observed in the positive
mode (capillary voltage = 80–105 V). The catalytic tests were performed under microwave (MW)
irradiation using a focused Anton Paar Monowave 300 microwave fitted with a rotational system
and an IR temperature detector, using a 10 mL capacity reaction tube with a 13 mm internal diameter.
Gas chromatographic (GC) measurements were carried in a FISONS Instrument GC 8000 series gas
chromatograph with a capillary DB-WAX column (30 m
×
0.32 mm), a FID detector, helium as the
carrier gas and using the Jasco-Borwin v.1.50 software. The magnetic susceptibility measurements were
carried out on polycrystalline samples with a Quantum Design MPMS-XL5 SQUID magnetometer in
the temperature range of 2–300 K and at an applied field of 2000 Oe. Diamagnetic corrections were
estimated from Pascal’s constants for all constituent atoms [63]. The electrochemical experiments were
performed in an EG&G PAR 273A potentiostat/galvanostat connected to a personal computer through
a GPIB interface.
Syntheses of the pro-ligand H4L: The aroylhydrazone Schiff base pro-ligand bis(2-hydroxybenzylidene)
isophthalohydrazide (H4L) (Scheme 1) was prepared by a reported method [64,65] upon condensation
of the 2-hydroxybenzohydrazide with isophthalohydrazide.
Yield: 84%. Anal. Calcd for H4L C22H18N4O4: C, 65.66; H, 4.51; N, 13.92. Found: C, 65.60; H, 4.48;
N, 13.87. IR (KBr pellet, cm−1): 3212 (C=O). 1H NMR (DMSO-d6,
(OH), 3055 (NH), 1653 ): 12.09
(s, 2H, OH), 11.18 (s, 2H, NH), 8.09 (s, 2H, -CH=N), 7.58–6.94 (m, 12H, C6H4).
Synthesis of [Cu2(1 ): 0.402 g (1.0 mmol) of H4L was
NO2:2 N0O2-H2L)(NO3)2(H2O)2] (
suspended in 25 mL of methanol and 0.525 g Cu(NO3)2 5H2O (2.05 mmol) were added. The resultant
ν
ν
ν
δ
κ
κ
1
·
mixture was stirred at room temperature for 15 min; a dark green solution was obtained. The solution
was then filtered and the solvent was allowed to evaporate slowly. After 3–4 days, single crystals
suitable for X-ray diffraction were isolated, washed 3 times with cold methanol and dried in open air.
Yield: 0.443 g (66%, with respect to Cu). Anal. Calcd for C22H20Cu2N6O12: C, 38.43; H, 2.93; N,
12.22. Found: C, 38.36; H, 2.90; N, 12.14. IR (KBr; cm−1): 3448
ν(OH), 1612 ν(C=N), 1250 ν(C–O)enolic
and 1159 ν( N–N). ESI-MS (+): m/z 672 [M+H]+ (100%).
0
Synthesis of [Cu4(
µ-1
κ
NO2:2
κ
N O2-H2L)2(
µ-NO3)2(H2O)4]
·
2C2H5OH (
2): To a 20 mL acetonitrile
solution of H4L (0.402 g, 1.00 mmol), a 20 mL ethanol solution of Cu(NO3)2
·
5H2O (0.525 g, 2.05 mmol)
was added and the reaction mixture was stirred for 20 min at room temperature. The resultant dark
green solution was filtered and the filtrate was kept in open air. Dark green single crystals suitable for
X-ray diffraction analysis were isolated after 4 days. Crystals were washed 3 times with cold ethanol
and dried in open air.

Molecules 2018, 23, 2699
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Yield: 0.800 g (64%, with respect to Cu). Anal. Calcd for C48H52Cu4N10O20
(
2
): C, 42.92; H, 3.90;
N, 10.43. Found: C, 42.87; H, 3.84; N, 10.39. IR (KBr; cm−1): 3456
ν(OH), 2986 ν(NH), 1609 ν(C=O),
and 1168 ν(N–N). ESI-MS (+): m/z 1158 [(M-2EtOH)+H]+ (100%).
3.2. X-Ray Measurements
Good quality single crystals suitable for X-ray diffraction of
mounted in Nylon loops and measured at a temperature of 296 K. Intensity data were collected
using a Bruker AXS PHOTON 100 diffractometer with graphite monochromated Mo-K 0.71073)
1 and 2 were immersed in cryo-oil,
α (λ
radiation. Data were collected using omega scans of 0.5◦ per frame and full spheres of data were
obtained. Cell parameters were retrieved using Bruker SMART [66] software and refined using Bruker
SAINT [66] on all the observed reflections. Absorption corrections were applied using SADABS [66].
Structures were solved by direct methods by using SIR97 [67] and refined with SHELXL2014 [68].
Calculations were performed using WinGX version 2014.1 [69]. All non-hydrogen atoms were refined
anisotropically. The H-atoms bonded to carbons were included in the model at geometrically calculated
positions and refined using a riding model. Uiso(H) values were defined as 1.2Ueq of the parent aromatic
and methylene groups and 1.5Ueq of the parent methyl ones. The other hydrogen atoms (O–H and
N–H) were located in the difference Fourier synthesis and refined, in some cases with the help of
distance and angle restraints, their isotropic thermal parameter set at 1.5 times the average thermal
parameter of the parent oxygen or nitrogen atom. The structure of
1 appears to have three water
molecules per unit cell, but their hydrogen atoms could not be ascertained and the Calc-OH routine
of WinGX led to unreasonable locations. The possibility of disordered solvent molecules in a void
was taken into consideration and Platon/Squeeze [70] was used to establish a void of 158 Å3 with
56 electrons; removing such content in the void did not lead to any improved solution, the reason why
such strategy was not followed. Least square refinements with anisotropic thermal motion parameters
for all the non-hydrogen atoms and isotropic for the remaining atoms were employed.
3.3. Electrochemical Studies
Cyclic voltammetry (CV) and controlled-potential electrolyses (CPE) were undertaken in 0.2 M
[nBu4N][BF4]/DMSO electrolyte solutions, saturated with N2 before each run, at room temperature.
They were performed in a three-electrode cell equipped with a Luggin capillary connected to a silver
wire pseudo-reference electrode. Platinum disc (for CV; d = 1 mm) or gauze (CPE) working electrodes
were used, as well as platinum wire (CV) or gauze (CPE) counter electrodes. In CPE experiments,
the working and counter compartments were separated by a sintered glass frit and the studies
were monitored regularly by CV. The redox potentials were measured using ferrocene as internal
standard, and their values are quoted relative to the SCE by using the [Fe(η
5-C5H5)2]0/+ redox couple
(E1O/X2 = 0.44 V vs. SCE for DMSO) [71–76].
3.4. Typical Procedures and Product Analysis for Catalysis
The microwave-assisted (MW) solvent-free peroxidative catalytic oxidation of 1-phenyethanol
was performed in a focused Anton Paar Monowave 300 reactor using a 10 mL capacity cylindric Pyrex
tube with a 13 mm internal diameter, fitted with a rotational system and an IR temperature detector.
The tube was charged with the alcohol (2.5 mmol), 5 µmol catalyst precursor 1 or 2 (0.2 mol% vs.
substrate) and a 70% aqueous solution of t-BuOOH (5 mmol), sealed, placed in the microwave reactor
and the system left stirring under irradiation (5 or 20 W) at 80 or 120 ◦C for 0.5–3 h. After cooling to
room temperature, 150 µL of benzaldehyde (internal standard) and 2.5 mL of MeCN (to extract the
substrate and the organic products from the reaction mixture) were added. The obtained mixture was
stirred for 10 min and then a sample (1 µL) was taken from the organic phase and analysed by GC.
The peroxidative oxidations of cyclohexane were performed in round bottom flasks with vigorous
stirring and using MeCN as solvent (up to 5.0 mL total volume), under air. The catalyst precursors
1
and and trifluoroacetic acid (TFA, optional), in the form of a stock solution in acetonitrile, were mixed,
2

Molecules 2018, 23, 2699
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cyclohexane (0.25 mL, 2.3 mmol) was included and the reaction started when hydrogen peroxide was
added (50% in H2O, 0.68 mL, 11 mmol). The concentrations of the reactants were thus as follows:
catalyst precursor (5
−1). The reaction mixture was stirred at 50 ◦C for 2 h and at 5, 15, 30, 45, 60 and 120 min, an aliquot
was taken and analysed by GC using nitromethane (50 L) as internal standard. Before the GC analysis
×
10−4 mol L−1), TFA (0.005 mol L−1), substrate (0.46 mol L−1) and H2O2 (2.2 mol
L
µ
an excess of triphenylphosphine was added, in order to reduce the formed cyclohexyl hydroperoxide
to the corresponding alcohol and hydrogen peroxide to water, following a method developed by
Shul’pin [49–51]. Blank experiments were performed and confirmed that no product of cyclohexane
oxidation was obtained unless the metal catalyst was used.
For the GC measurements, the ◦temperature of injection was 240 ◦C. The initial temperature of
◦
the column was maintain◦ed at 100 C (oxidation of cyclohexane) or 120 C (oxidation of alcohol)
◦
◦
for 1 min, then raised 10 C/min up to 180 C (oxidation of cyclohexane) or 200 C (oxidation of
alcohol), and held at this temperature for 1 min. Attribution of peaks was made by comparison with
chromatograms of genuine samples and, in some cases, by GC-MS analyses using a Perkin Elmer
Clarus 600 C instrument (He as the carrier gas), equipped with a 30 m
capillary column.
×
0.22 mm
×
25 µm BPX5 (SGE)
4. Conclusions
The dinuclear [Cu2(1
NO2:2 N0O02-HL)2(
-NO3)2(H2O)4] (
isophthalohydrazide (H4L) have been synthesized and characterized. The electrochemical studies
show two one-electron cathodic reductions [CuII CuI and CuI Cu0]. The variable temperature
show strong antiferromagnetic exchange between the Cu
κ
NO2:2
κ
N0O02-H2L)(NO3)2(H2O)2] (
) complexes derived from bis(2-hydroxybenzylidene)
1) and the tetranuclear [Cu4(µ-
1
κ
κ
µ
2
→
→
magnetic susceptibility measurements of
2
(II) ions meadiated by the O-phenolate and NO3– bridges.
Both complexes act as catalyst precursors towards the solvent-free microwave-assisted oxidation
of alcohols and the peroxidative oxidation of alkanes under mild conditions. The highest activity and
selectivity with a maximum product yield of 99% (for the 1-phenylethanol oxidation after 1 h without
any additive) were observed with
1. In the case of oxidation of cyclohexane, 1 also exhibits a better
activity (a maximum product yield of 13% after 3h) than 2.
The catalytic oxidations under microwave assisted and solvent-free conditions have significance
for the development of environmentally friendly catalytic systems and deserve further investigations.
Our study was an attempt to contribute to this aim.
Supplementary Materials: The following are available online, Cif: Compound 1 and Compound 2. CCDC 1858873
and 1858872 for
1 and 2 contain the supplementary crystallographic data for this paper. This data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Author Contributions: Conceptualization, M.S. and E.C.B.A.A.; Methodology, M.S. and E.C.B.A.A.; Software,
M.S., M.F.C.G.d.S. and C.M.L.; Validation, M.S., M.F.C.G.d.S. and C.M.L.; Formal Analysis, M.S. and E.C.B.A.A.;
Investigation, M.S.; Resources, M.S. and A.J.L.P.; Data Curation, M.F.C.G.d.S. and C.M.L.; Writing-Original Draft
Preparation, M.S. and E.C.B.A.A.; Writing-Review & Editing, M.F.C.G.d.S., C.M.L.and A.J.L.P.; Visualization, M.S.;
Supervision, M.S. and E.C.B.A.A. and M.F.C.G.d.S.; Project Administration, A.J.L.P.; Funding Acquisition, A.J.L.P.
Funding: This research was funded by Fundação para a Ciência e a Tecnologia, Portugal grant number
UID/QUI/00100/2013, PTDC/QEQ-ERQ/1648/2014 and PTDC/QEQ-QIN/3967/2014.
Acknowledgments: Authors are grateful to the Fundação para a Ciência e a Tecnologia: FCT (projects
UID/QUI/00100/2013, PTDC/QEQ-ERQ/1648/2014 and PTDC/QEQ-QIN/3967/2014), Portugal, for financial
support. M.S. acknowledges the FCT, Portugal for a postdoctoral fellowship (SFRH/BPD/86067/2012). Authors
are thankful to the Portuguese NMR Network (IST-UL Centre) for access to the NMR facility and the IST Node of
the Portuguese Network of mass-spectrometry for the ESI-MS measurements.
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2018, 23, 2699
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