Manganese complex catalyst for valencene oxidation: The first use of metalloporphyrins for the selective production of nootkatone

Article abstract of DOI:10.1016/j.ica.2020.120031

This work describes the oxidation of valencene, a sesquiterpene easily obtained from citrus fruits, and responsible for the fresh odor of oranges. The reactions were catalyzed by manganese porphyrins derived from 5,10,15,20-tetrakis(3,5-dimethoxyphenyl)porphyrin (H₂T3,5DMPP): [Mn^III(T3,5DMPP)Cl] (MnP1) and [Mn^III(Br₁₂T3,5DMPP)Cl] (MnP2), using iodosylbenzene (PhIO), iodobenzene diacetate [PhI(OAc)₂], and molecular oxygen as oxidants. The systems MnP1/O₂/acetonitrile and MnP1/O₂/diethyl carbonate led to higher yields of valencene oxidation products (44% and 48%, respectively) as compared with MnP2 (9% and 7%, respectively), with nootkatone being the major product. The addition of a small amount of imidazole (molar MnP1: imidazole ratio of 1:5) to the MnP1/O₂/diethyl carbonate led to superior yields (64%) as compared with systems without the additive. A mechanism for the formation of the two products obtained was also proposed.

Full text of DOI:10.1016/j.ica.2020.120031

Inorganica Chimica Acta 515 (2021) 120031
Contents lists available at ScienceDirect
Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Research paper
Manganese complex catalyst for valencene oxidation: The first use of
metalloporphyrins for the selective production of nootkatone
a
a
b
Carla Nunes de Melo , Alexandre Moreira Meireles , Vinicius Santos da Silva ,
a
a,⁎
Patrícia Robles-Azocar , Gilson DeFreitas-Silva
a
b
Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, 31.270-901 Belo Horizonte, MG, Brazil
Centro de Formação de Professores, Universidade Federal do Recôncavo da Bahia, 45.300-000 Amargosa, BA, Brazil
A R T I C L E I N F O
A B S T R A C T
Keywords:
This work describes the oxidation of valencene, a sesquiterpene easily obtained from citrus fruits, and re-
sponsible for the fresh odor of oranges. The reactions were catalyzed by manganese porphyrins derived from
Valencene oxidation
Molecular oxygen
Green solvent
Mn-porphyrins
Nootkatone
III
III
5
,10,15,20-tetrakis(3,5-dimethoxyphenyl)porphyrin (H
2
T3,5DMPP): [Mn (T3,5DMPP)Cl] (MnP1) and [Mn
(
Br12T3,5DMPP)Cl] (MnP2), using iodosylbenzene (PhIO), iodobenzene diacetate [PhI(OAc) ], and molecular
2
oxygen as oxidants. The systems MnP1/O
2
/acetonitrile and MnP1/O /diethyl carbonate led to higher yields of
2
valencene oxidation products (44% and 48%, respectively) as compared with MnP2 (9% and 7%, respectively),
with nootkatone being the major product. The addition of a small amount of imidazole (molar MnP1: imidazole
ratio of 1:5) to the MnP1/O /diethyl carbonate led to superior yields (64%) as compared with systems without
2
the additive. A mechanism for the formation of the two products obtained was also proposed.
1
. Introduction
Valencene (1, Fig. 1), the chemical responsible for the fresh odor of
as biomimetic models of cytochrome P450 in oxidation reactions of
organics substrates [13,14]. Metalloporphyrin catalysts are classified
into first, second, and third-generation, based on the catalytic activity
of these compounds in the reaction medium and their ability to resist
oxidative processes [15]. Complexes derived from tetra-
phenylporphyrin are classified as first-generation catalysts, while
second and third-generation catalysts are characterized by having
oranges, is a sesquiterpene that is easily obtained from citrus fruits [1].
It is an inexpensive raw material that can be oxidized into high value
products such as nootkatone [2,3] (2, Fig. 1). Nootkatone is an allylic
ketone first isolated from the heartwood of Alaskan yellow cedar [4,5].
Currently, this substance is widely used in the food industry, as a
beverage flavoring, and the fragrance industry [1]. Recent studies have
also demonstrate its potential use as a natural repellent against mos-
quitoes and other pathogenic insects to humans and animals [6,7].
Despite the great industrial demand for this molecule, its most
common extraction source, the grapefruit, contains a low concentration
of this substance (0.05 to 0.2%), causing the process to be costly
substituents (such as –Cl, –Br, –NO
2
, and –OCH ) in the aryl group of
3
the meso-positions or the β-pyrrolic positions of the macrocycle, re-
spectively.
In reactions catalyzed by metalloporphyrins, several oxidants can be
used, including iodosylbenzene (PhIO), iodobenzene diacetate [PhI
(OAc)
2
], hydrogen peroxide (H
2
O
2
), and molecular oxygen (O )
2
[16–20]. The use of molecular oxygen in place of classical oxidants
typically used for catalyzing these reactions, such as PhIO, is an inter-
esting proposal [19–21]. This oxidant is attractive due to its low cost,
ready availability, and it is environmentally harmless because it gen-
erates water as a byproduct. The oxidation of olefins in value-added
[
2,8,9]. Studies on obtaining nootkatone are generally related to va-
lencene biotransformation. Although the commonly used processes lead
to satisfactory yields, it requires a long processing time, due to the need
for inoculation and cultivation of microorganisms, and results in the
formation of a large number of byproducts, which causes their in-
dustrial application to be unfeasible [1,5,10–12]. Therefore, investing
in simpler routes that can provide good yields of nootkatone in a shorter
time becomes a promising research field.
compounds using O is already widely used in several catalytic systems
2
[22–25]. Rayati and Nafarieh studied the oxidation of alkenes and al-
kanes with molecular oxygen in the presence of Fe(III)- and Mn(III)-
porphyrins supported onto multi‐wall carbon nanotubes as catalysts
[21]. The Mn‐catalyst was shown to have higher catalytic activity
Metalloporphyrin catalysts have been investigated in several studies
⁎
Corresponding author at: Departamento de Química – Instituto de Ciências Exatas – Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil.
E-mail address: gilsonufmg@ufmg.br (G. DeFreitas-Silva).
https://doi.org/10.1016/j.ica.2020.120031
Received 28 June 2020; Received in revised form 28 August 2020; Accepted 18 September 2020
Available online 24 September 2020
0020-1693/ © 2020 Elsevier B.V. All rights reserved.

C.N. de Melo, et al.
Inorganica Chimica Acta 515 (2021) 120031
distilled before use. PhIO was prepared according to a previously de-
scribed method and assayed periodically by iodometric titrations [32].
All the other reagents and solvents were analytical grade and used
without further purification unless stated otherwise.
2.2. Catalysts
III
III
The [Mn (T3,5DMPP)Cl] (MnP1) and [Mn (Br12T3,5DMPP)Cl]
MnP2) (Fig. 2) were obtained and characterized as previously reported
by Silva et al. [30].
Fig. 1. Structural representation of valencene (1) and nootkatone (2).
(
compared with the Fe‐catalyst in styrene oxidation. In this case, the
reactions were carried out with acetonitrile as a solvent at 40 °C and
resulted in the formation of styrene oxide with a conversion of 87% and
selectivity of 64% [21].
2
.3. Catalytic reactions
Reactions were carried out in a 100 mL homemade stainless-steel
In addition to the oxidant, the choice of solvent represents one of
the fundamental aspects within the principles of green chemistry since
it represents up to 90% of the total mass for the synthesis of many
products of industrial interest [26]. Thus, toxic solvents, whenever
possible, should be replaced by solvents with less toxicity in chemical
reactions. Organic carbonates, such as diethyl carbonate, have been
attractive as substitutes for volatile organic compounds (VOC) because
of their low toxicity and they do not bioaccumulate [27]. This solvent
has only been broadly employed in electrochemical and extraction
processes [26,27]. However, this scenario has been modified, and it is
already possible to find works in which catalyzed reactions such as
Heck [26] and hydrogenation [28] and even oxidation [29] are per-
formed using carbonates as solvents.
reactor with a magnetic stirrer. In a typical run, a mixture of valencene
(
(
1 mmol), dodecane (GC internal standard, 0.5 mmol), MnP1 or MnP2
1 µmol), and solvent (acetonitrile or diethyl carbonate, 4.8 mL) was
vigorously stirred (300 rpm) at 80 °C under an oxygen pressure of
1
0 atm. At appropriate time intervals, stirring was stopped, and samples
were collected from the reactor and analyzed by gas chromatography
(
GC) using a Shimadzu QP2010-Plus instrument fitted with an apolar
RTx −5MS (Crossbond –Carbowax –polyethylene glycol) capillary
column and a flame ionization detector. All the reactions were carried
out at least two times, and the data reported represent the average of
these reactions. The reactions that presented the best results were
performed two more times, and the data reported represent the average
of these four reactions. For these systems, the standard deviation was
In this context, we decided to evaluate the oxidation of the sesqui-
terpene valencene using second and third-generation manganese por-
2
% of the average value. The conversion of the substrate and the yield
of the reaction products were monitored over time. A time of 4 h
achieved the maximum conversion of the substrate. Control reactions,
in the absence of either oxidant or catalyst, were performed under the
same conditions as the catalytic runs.
phyrins as biomimetic catalysts derived from 5,10,15,20-tetrakis(3,5-
III
dimethoxyphenyl)porphyrin,
H
2
T3,5DMPP:
[Mn (T3,5DMPP)Cl]
III
(
MnP1) and [Mn (Br12T3,5DMPP)Cl] (MnP2) (Fig. 2), which have
shown efficient catalytic activity for the activation of inert CeH bonds
in alkanes with high selectivity [30,31]. Based on these studies, the
oxidation of valencene was carried out using the classical oxidants PhIO
Gas chromatography (GC) mass balance was carried out using do-
decane as an internal standard. Deviations from the complete mass
balance were attributed to the formation of high boiling point products
from the polymerization reactions [33], which were not determined by
GC analysis. The details about the mass balance are given in the Sup-
plementary Material.
and PhI(OAc) . In an attempt to develop catalytic systems more sus-
2
tainable for this substrate oxidation, molecular oxygen as an oxidant
and diethyl carbonate as a solvent were also evaluated.
Reactions with PhIO or PhI(OAc) were similar to the described
2
2
. Materials and methods
process using molecular oxygen. In this case, a mixture of valencene
(
1 mmol), dodecane (GC internal standard, 0.5 mmol), MnP1 (1 μmol),
2
.1. Chemicals
PhIO (10, 25, 50, or 100 µmol) or PhI(OAc) (10 or 100 µmol), and
2
dichloromethane (4.8 mL) was vigorously stirred (300 rpm) at 80 °C,
and the reactor was kept under atmospheric pressure.
Analytical grade dichloromethane was obtained from Aldrich and
Fig. 2. Structural representation of the metalloporphyrin catalysts used in this work.
2

C.N. de Melo, et al.
Inorganica Chimica Acta 515 (2021) 120031
Fig. 3. Oxidation of valencene by different oxidants
(
PhIO, PhI(OAc)2, or O ) catalyzed by manganese
2
porphyrins (MnP).
2
.4. Product characterization
Table 1
Oxidation of valencene by PhIO and PhI(OAc)
.a
2
catalyzed by MnP1 in CH
2
Cl
2
Products 2 and 3 (Fig. 3) were isolated by column chromatography
b
c
d
Run Oxidant
Conversion Selectivity (%)
Yield
TON
TOF
(
Aprolab®, 60G, 70–230 Mesh) using mixtures of hexane and ethyl
−1
(
μmol)
(%)
(%)
(h
)
acetate (5:1) as eluents and identified by GC/MS (Shimadzu QP2010-
2
3
PLUS instrument, 70 eV). Product 2 was characterized by NMR (Bruker
e
f
1
2
3
4
5
6
7
8
9
PhIO (10)
–
7
Tr.
75
60
10
42
33
31
40
43
0
0
–
–
DRX-400 instrument, tetramethylsilane, CDCl
3
).
9
0
7
90
9
1
Nootkatone (2, Fig. 1): H NMR (400 MHz, CDCl
3
, 25 °C, TMS),
PhIO (10)
PhIO (10)
PhIO (25)
PhIO (50)
PhIO (100)
16
6
0
10
1.3
11
10
4
160
60
40
15
68
73
35
30
93
1
2
2
15
11
8
7
g
δ = 0.97 (d, 3H, C
H
3
, J = 6.78); 1.12 (s, 3H, C
H
3
); 1.24–1.28 (s,
11
0
2
8
10
27
29
14
12
270
290
140
120
370
1
H, C H); 1.74 (s, 3H, C , H
3
); 1.87–2.09 (m, 4H, C HH, C HH, C HH,
1
0
3
3
7
0
C
HH); 2.22–2.41 (m, 4H, C HH, C HH, C HH, C HH); 2.46–2.58(m,
9 15 15 5
0
1
H, C H); 4.71–4.76 (m, 2H, C HH, C HH); 5.78 (s, 1H, C H) ppm.
PhI(OAc)
2
2
(10)
0
5
1
3
4 6
C NMR (100 MHz, CDCl
3
, 25 °C, TMS), δ = 200.00 (C ); 170.7 (C );
PhI(OAc) (100) 37
0
16
1
3
5
15
10
3
1
49.3 (C ); 125.2 (C ); 109.5 (C ); 44.17 (C ); 42.29 (C ); 40.71
9 1 2 7 8 14
a
Conditions: valencene = 1.0 mmol; MnP1: 1 µmol; CH
2
2
Cl = 4.8 mL;
(
(
(
C ); 40.57 (C ); 39.58 (C ); 33.26 (C ); 31.88 (C ); 21.02 (C ); 17.08
1
+
1
12
+
80 °C, reaction time: 4 h. Conversion and selectivity were determined by GC.
C
); e 15.10 (C ) ppm. MS (m/z/rel. int.): 218/38 (M ); 203/40
Tr = traces.
M
−CH ); 175/50; 161/78; 147/100; 133/74; 121/80; 105/62; 91/
3
b
Theoretical yield calculated by the ratio: (conversion) × (selectivity
7
9; 79/78; 55/36.
2
+ 3)/100.
+
Valencene-1,10-epoxide (3, Fig. 3): MS (m/z/rel. int.): 220/35 (M );
c
TON (turnover number) was calculated as the amount of substance of va-
+
2
7
05/20 (M −CH
3
); 91/95; 121/96; 177/100; 105/93; 121/87; 107/
lencene (mol) reacted per amount of substance of MnP1 (mol).
5; 79/61; 135/59; 79/72; 67/50; 109/41; 55/73. The data are con-
d
e
f
TOF (Turnover frequency).
sistent with those reported by Sowden et al. [34].
Reaction in the absence of catalyst; reaction time: 10 h.
Reaction in the absence of oxidant; reaction time: 10 h.
Reaction in an argon atmosphere.
g
3
. Results and discussion
the system, the reaction was performed under an argon atmosphere
Run 4, Table 1). In this case, there was a significant decrease in the
3
.1. Oxidation of valencene employing MnP1 and MnP2 as catalysts
(
selectivity of 2 (10%), showing that the formation of this product
The oxidation of valencene results in products of great commercial
strongly depended on the presence of O
2
. Furthermore, according to
value, such as nootkatone, which is widely used in the flavor and cos-
metic fields due to its grapefruit odor. To the best of our knowledge,
this is the first work describing the use of manganese porphyrins as
catalysts for valence oxidation. The vast majority of reports employ the
use of various biocatalysts, which are characterized by low conversion
rate and yield, costly culture conditions, the formation of various by-
products, and inhibition of enzymes by these byproducts. These char-
acteristics hamper the industrial application of these biocatalysts
+
GC–MS data, an oxygenated product (m/z (%): 220 (35) [M ]) was
detected in a similar amount to ketone (selectivity of 10 and 11%, re-
spectively). The product was attributed to the transformation of en-
docyclic π-bond of valencene, resulting in the valencene-1,10-epoxide
formation (3, Fig. 3), the most common product reported in the lit-
erature for this transformation type [6,34]. This system indicated that
the formation of epoxide was favored in anaerobic conditions, although
the combined yield for the two oxygenated products was a little higher
than 1%. Thus, it is possible that higher yields were achieved when
[
10,12,35]. Therefore, we decided to evaluate valencene oxidation
using MnP1 as the catalyst. This compound was synthesized by our
group [30]. It showed good activity in linear and cyclic alkanes oxi-
dation, and the presence of methoxy-groups at the meso-aryl positions
of the porphyrinic macrocycle tends to be beneficial in systems invol-
ving the oxidation of alkenes [36–38].
there was both PhIO and atmospheric O in the reaction medium.
2
Nascimento et al. reported a similar system for cyclohexene oxidation
reactions. The high yields for the allylic products derived from cyclo-
hexene were attributed to the ability of PhIO to act as a radical chain
initiator in the presence of O
41].
2
, mediated (or not) by the MnP catalyst
The reaction was first evaluated using the classic oxidant, PhIO, and
[
employing dichloromethane (CH
2
Cl ) as the solvent (Table 1). This
2
In the attempt to obtain the highest yields and conversions, reac-
solvent is typically used in reactions catalyzed by metalloporphyrins
since it can efficiently solubilize the catalyst, and additionally, it is a
non-coordinating solvent [30,31,39,40].
tions were carried out with higher amounts of PhIO (Runs 5 to 7),
keeping the amounts of MnP1 and valencene fixed. When the reaction
was carried out with 25 and 50 µmol of oxidant, very little difference
was observed in the product yield (Runs 5 and 6 versus Run 3).
However, the selectivity for nootkatone decreased considerably (42 and
The control reaction, in the absence of MnP1 (Table 1, Run 1),
exhibited a small conversion of valencene (7%). Moreover, only traces
of nootkatone (2, Fig. 3) were detected. These results demonstrated the
need for a catalyst to obtain functionalized products. In Run 2, the
oxidation of valencene was carried out in the absence of PhIO, and
nootkatone (2) was formed with high selectivity (75%) and a yield of
3
3%, respectively) when compared to the experiment with 10 µmol of
PhIO (60%; Run 3, Table 1). The increase in the amount of PhIO
(
100 µmol) did not lead to more efficient systems for obtaining oxidized
products (yield of 4%, Run 7). Based on these results, we hypothesize
that with higher amounts of PhIO, there should be an increase in the
catalyst destruction process, leading to a decrease in the amount of
active catalytic species available for the oxidation of the substrate [42]
or by the occurrence of by-side reactions, responsible for consuming
7
%. This result suggests the incorporation of molecular oxygen in the
substrate, even in the absence of PhIO as the oxidant. The experiment
under aerobic condition, employing a molar MnP1:PhIO:valencene
ratio of 1:10:1000 (Run 3), led to a yield of 10% for nootkatone with
the selectivity of 60%. To verify the influence of atmospheric oxygen in
3

C.N. de Melo, et al.
Inorganica Chimica Acta 515 (2021) 120031
part of the oxidant [39,43]. Additionally, PhIO is a very strong oxidant,
which can lead to the formation of products with higher molar mass
was 48%, with the highest value of TON values (860) among the stu-
died systems.
(
polymerization) that are not detectable by GC [44]. These data present
When we employed the green solvent diethyl carbonate (DEC) in the
the drawback of using PhIO as an oxygen source for the valencene
oxidation reaction. It is poorly soluble in most of the organic solvents,
toxic, potentially explosive [45], and not recommended by Green
Chemistry principles [46,47].
presence of O , there was a slight decrease in reaction yield (44%) when
2
compared to the system with acetonitrile and a TON value (740) was
verified (Run 12, Table 2). The high TON values showed the stability of
the catalyst under the conditions employed. The slight decrease in re-
action yield could be related to the lower solubility of MnP1 in DEC
than acetonitrile since we verified that the catalyst was not completely
solubilized at the beginning of the reaction; however, the catalyst was
solubilized during the reaction, and at the end of 4 h we verified a
homogeneous system in the reactor vessel. These solvents present dis-
tinct properties, such as the dielectric constant (37.5 and 2.82 for
acetonitrile and DEC, respectively) and the dipole moment (3.75 and
1.07 D for acetonitrile and DEC, respectively), which could justify the
difference between these two systems. Guimarães and co-workers ver-
ified that in solvents with higher dielectric constants, the active species
responsible for transferring the oxygen atom to the substrate could be
formed faster than those present in the solvents with lower dielectric
constants [31]. In this way, acetonitrile could promote a more effective
system for the oxidation of valencene. However, DEC has the advantage
of being a biodegradable solvent that fits in the Green Chemistry
principles when compared to acetonitrile [46,52]. Thus, the replace-
ment of acetonitrile by DEC can ensure a greener system for valencene
oxidation, in addition to not promoting large losses in the total reaction
yield.
We also evaluated the catalytic efficiency of MnP1 using PhI(OAc)
2
as the oxidant (Table 1). This oxidant has the advantage of being so-
luble in most of the organic solvents commercially available and safer
than PhIO [48,49]. Under aerobic conditions and employing a molar
MnP1: PhI(OAc) :valencene ratio of 1:10:1000, the yield and se-
2
lectivity for nootkatone were 5% and 40%, respectively (Run 8,
Table 1). This system was less effective for valencene oxidation than the
one using PhIO (Run 3, Table 1). This could be due to the fact that the
reactions with PhI(OAc) are slower than those with PhIO [48]. This
2
observation could explain the lower catalytic efficiency of this system.
In an attempt to increase the efficiency of the reactions with PhI
(
OAc) , we also verified the effect of the amount of oxidant in this
2
system, similar to the reactions of PhIO (Table 1). When a molar
MnP1:PhI(OAc) :valencene ratio of 1:100:1000 was employed, no
2
significant differences in the selectivity of 2 (43%) was observed
compared to lower amounts of oxidant; however, the reaction yield had
a considerable increase (16%, Run 9, Table 1). As proposed by In and
co-workers, the systems with PhI(OAc) can generate the active oxidant
2
PhIO in situ in the presence of a small amount of water [48]. This
controlled hydrolysis could avoid the side reactions responsible for
removing part of the active oxidant from the reaction. In this way, we
In an attempt to obtain a more effective catalytic system, imidazole
was used as an additive (Run 13, Table 2). The addition of imidazole at
a molar MnP:Im ratio of only 1:5 to the system led a total product yield
of 64% versus 44% in the system with an absence of this additive (Run
12, Table 2). As reported by the literature, the co-catalyst, imidazole (or
other axial ligands), is responsible for favoring the epoxidation of al-
kenes due to the intermediary type formed in the oxidation reactions by
single oxygen donors [53,54]. Surprisingly, we verified that the addi-
tion of imidazole promoted a more selective system for nootkatone
production. Gunter and Turner proposed that a second type of the in-
termediary is responsible for the high levels of allylic oxidations when
the catalyst presents a radical centered in the porphyrin ligand (a ty-
carried out the reaction with PhI(OAc) in the same conditions as Run
2
9
, with the presence of 5 μL of water as an additive. This system reached
a maximum total yield of 21% in only 2 h, while the system in the
absence of this additive presented a total yield of 16% in 4 h. At this
point, we could suggest that even in the absence of water (as observed
for the reactions in Run 8 and 9 (Table 1)), the PhI(OAc) could be
2
hydrolyzed by the presence of water from the solvent [40,50] since the
solvent was not previous dried.
However, the system with PhI(OAc) presents higher values of
2
catalyst destruction, favored by a large amount of oxidant used [51].
Also, one of the byproducts of this oxidant is acetic acid [48,49], which
reduced the atomic economy of the process [46].
%+
pical π-cation radical [Mn(IV)P]O] ) [54]. In this way, we suggest
that the formation of this radical intermediary could be responsible for
promoting an increase in nootkatone selectivity. Also, imidazole pulls
the metal into the plane of the porphyrin ligand, increasing steric
hindrance around the metal center and, therefore, decrease its re-
activity toward valencene (low epoxide yield). In another way, binding
of imidazole can modify the redox potential of the metal center [55],
The reactions with PhIO and PhI(OAc) in the presence of di-
2
chloromethane as the solvent exhibited low values of valencene con-
version and low yields for the oxidized products. These systems present
reagents that should be avoided, according to Green Chemistry prin-
ciples. In this way, searching to develop a more environmentally-
friendly system, we verified the effect of a green oxidant and solvents
for valencene oxidation reactions.
activate O , or weaken the oxygen bond to the metal center [56,57]
2
favoring the occurrence of the autooxidation reaction, which leads to
As an alternative to PhIO and PhI(OAc) , we evaluated the effi-
2
the formation of the ketone in the reaction medium. It is important to
ciency of MnP1 to catalyze the oxidation of valencene by molecular
emphasize that the effect of imidazole in systems employing O as the
2
oxygen, O
2
(Table 2). Oxidation of organic compounds with molecular
oxidant (without co-oxidant) has not been extensively studied and the
amount of imidazole employed in this work was very small, showing
that it is not necessary to use a large excess of this additive [40].
In previous studies, it has been demonstrated that third-generation
metalloporphyrins usually present better catalytic efficiency than
second-generation complexes [30,37]. Therefore, we decided to eval-
uate the catalytic efficiency of MnP2.
oxygen has the advantages of promoting an eco-friendly environment
and being an abundant reagent. Initially, we carried out the reaction in
the presence of acetonitrile. This solvent, besides being safer than di-
chloromethane (boiling point 82 versus 39.6 °C, respectively, and it is
not a halogenated solvent), is also able to solubilize the catalyst and the
substrate, which facilitates the interaction between the components of
the reaction.
The reactions were carried out under the same conditions as em-
ployed in Runs 11 and 12 (Table 2). When acetonitrile was used as the
solvent (Run 16, Table 2), the combined yield for the products 2 and 3
was only 9%. With the green solvent DEC (Run 8, Table 2), the com-
bined yield for the products showed no significant difference (yield of
7%). Thus, it was verified that the introduction of bulky electron-
withdrawing bromine substituents in the β-pyrrolic positions of MnP2
led to a less efficient catalyst than the second-generation MnP1 to
oxidize valencene, counteracting results obtained by our group when it
was used for the oxidation of alkanes [30]. Low reaction yields may be
The oxidation of valencene under 10 atm of O was firstly evaluated
2
in the absence of a catalyst (Run 10, Table 2). In this system, almost no
conversion was observed, and only traces of nootkatone (2) were de-
tected, indicating that the presence of the catalyst has an important role
in the reaction.
The reaction in the presence of the second-generation manganese
porphyrin MnP1 and with acetonitrile as the solvent (Run 11, Table 2),
led to the formation of nootkatone (2) and product 3 (in smaller
amounts). In this reaction, the total yield of the oxygenated products
4

C.N. de Melo, et al.
Inorganica Chimica Acta 515 (2021) 120031
Table 2
Oxidation of valencene by O
2
catalyzed by MnP1 and MnP2.a
b
TONc
d
Run
Catalyst
Solvent
Conversion
Selectivity (%)
2
Yield
(%)
TOF
−
(
%)
(h 1)
3
e
10
11
12
13
14
15
16
17
–
CH
3
3
CN
CN
9
Tr.
35
38
68
–
0
0
–
–
MnP1
MnP1
MnP1
MnP1
MnP1
MnP2
MnP2
CH
86
74
75
12
63
46
42
21
21
17
–
48
44
64
–
860
740
750
–
215
185
188
–
DEC
DEC
DEC
DEC
f
g
h
–
89
3
56
9
630
460
420
158
115
105
CH
3
CN
17
11
DEC
5
7
a
Conditions: valencene = 1.0 mmol; Catalyst: 1 µmol; solvent = 4.8 mL; 80 °C, 10 atm of O , reaction time: 4 h. Conversion and selectivity were determined by
2
GC. Tr = traces.
b
Theoretical yield calculated by the ratio: (conversion) × (selectivity 2 + 3)/100.
c
d
e
f
g
h
TON (turnover number) was the amount of substance of valencene (mol) reacted per amount of substance of MnP1 or MnP2 (mol).
TOF (Turnover frequency).
The reaction in the absence of the catalyst.
The reaction in the presence of imidazole as additive; molar MnP1:imidazole ratio of 1:5.
The reaction was performed at room temperature (25 °C).
The reaction was performed with butylated hydroxytoluene (BHT) as a radical scavenger.
attributed to the difficulty for interactions between valencene and
MnP2 due to the presence of bulky groups, such as the bromine atoms,
in β-pyrrolic positions of the porphyrinic macrocycle. Besides, the high-
valence active species [MnP=O] has a different reactivity when com-
paring second and third-generation catalysts, as already observed by
Bartoli et al. [36], with MnP1 being more active for alkenes oxidation
and MnP2 for alkanes oxidation. The greater activity of MnP1 can be
explained by the higher electronic density of this catalyst, compared to
MnP2 [36–38].
PhIO or PhI(OAc)
2
as the oxidants and dichloromethane as the solvent,
as oxidant and acetonitrile and
Table 1) and the green system (i.e., O
2
DEC as solvent) were different, preventing a direct comparison between
these two systems. The classical system produced a higher amount of
nootkatone (2) than valencene-1,10-epoxide (3), although low con-
versions and total yields were obtained employing the iodosylarenes.
The green systems had higher conversion values and total yields, with
higher productions of 2 and 3 simultaneously. In this sense, the results
obtained indicated that the replacement of a classical system by a green
To the best of our knowledge, no studies have reported valencene
oxidation by manganese porphyrins similar to this work. Most studies
involved substrate biotransformation. Kolwek et al. recently obtained
nootkatone in a combined system using a unique dye–decolorizing
peroxidase (Ftr-DyP) obtained from basidiomycetes Funalia trogii. In
this system, the authors reached a yield of 36% for nootkatone after
system employing O as the oxygen source and imidazole as an additive
2
can generate a positive effect on the formation of products derived from
valencene. This also shows the potential for a green solvent (DEC) and
molecular oxygen to be used in oxidation systems of other terpenes
catalyzed by metalloporphyrins aiming at the valorization of the raw
material.
2
4 h of incubation and 48 h of reaction [35]. In the work of Palmerín-
Carreño et al., the efficiency of several microorganisms that can convert
valencene into nootkatone using different bioconversion systems such
as water, organic and biphasic systems was evaluated. It was noted that
Botryodiplodia theobromae, Yarrowia lipolytica, and Phanerochaete chry-
sosporium have oxidized valencene to nootkatone, reaching maximum
yields of 25%, 29%, and 27%, respectively after 4 days of incubation
and 5 days of reaction [12]. Although the reported works have shown
satisfactory yields, the need for inoculation and cultivation of micro-
organisms can make the process relatively slow.
3
.2. Mechanism for the oxidation of valencene employing manganese
porphyrins as catalysts
The proposed mechanisms for MnP1 catalyzing the oxidation of
valencene by molecular oxygen are presented in Figs. 4 and 5. The
variations in quantities of the obtained products (2 and 3) can be ex-
plained by different radical mechanisms. The first mechanism (Fig. 4)
involves a preferred route that explains the higher yields of nootkatone
(
2) in relation to valencene epoxide (3). This mechanism is consistent
The oxidation system proposed in our study is capable of generating
ketone with yields comparable to previous systems in the literature.
Results obtained in our catalytic system led to a yield of nootkatone in
with that proposed by Melodnicka [61]. In this case, the initiation oc-
curs via a direct reaction of MnP with valencene via an initial electron
transfer followed by the loss of a hydrogen ion and formation of an
alkyl radical (Step Ia). It is interesting to note that the allylic position to
the valencene double terminal bond remained unchanged. The transfer
of an allylic hydrogen atom from valencene to the alkylperoxide radical
depends on the CeH bond reactivity. In the case of valencene, the
allylic hydrogen of the endocycle double bond appears to be more re-
active than the allylic hydrogen at the terminal double bond, since no
products derived from the transformation of that position were ob-
served. The regeneration of the catalyst (Step IIa) is carried out directly
by molecular oxygen that leads to the formation of the superoxide anion
2
8% and 16% for the epoxide, resulting in a combined yield of 44% in
only 4 h of reaction employing the green solvent diethyl carbonate.
When small amounts of imidazole were added to the system, yields of 2
and 3 increased to 51% and 13%, respectively, leading a combined
yield of 64%, also in 4 h of reaction.
It is interesting to highlight that although epoxide 3 has been pro-
duced in smaller amounts, the epoxidation of olefins has received
considerable attention, because they are key intermediates in the or-
ganic synthesis of fine chemicals [19,58–60]. As far as we are con-
cerned, the few studies present in the literature related to the epox-
idation of valencene employ environmentally harmful oxidants and the
product is obtained via slower methodologies [1,34]. Thus, the use of
second-generation metalloporphyrin, MnP1, might be an alternative to
obtain this product using green and sustainable chemistry principles.
In this work, the conditions employed in the classical system (i.e.,
%
2
–
(
O
). The termination step (IIIa) occurs via reaction of the superoxide
anion and the alkyl radical that, in the presence of hydrogen ion, leads
to the formation of alkyl hydroperoxide. The decomposition of alkyl
hydroperoxide leads to nootkatone (2) and water.
The mechanism for the epoxidation of valencene is described in
Fig. 5. The oxidation of organic substrates by O in the presence of
2
5

C.N. de Melo, et al.
Inorganica Chimica Acta 515 (2021) 120031
Fig. 4. Proposed mechanism for the formation of nootkatone (2) by molecular oxygen and MnP as the catalyst.
synthetic metalloporphyrins remains a challenge since the literature
reports the autooxidation pathway as the major route for oxidized
product obtention [62–66] and no evidence of high-valence [Mn(V)P]
O] species formation.
is facilitated by high temperatures [68], and the alkyl radical generated
could be responsible for nootkatone formation. The reduced form of the
catalyst is a fundamental intermediary responsible for generating the
•
–
O
2
anion, its able to coordinate to the catalyst as observed in Step IIb,
−
As reported in the literature, Fe(II)- and Mn(II)-porphyrins can bind
resulting in the [Mn(III)P(O
2
)] complex. Then, the coordination of
the O
2
(similar to the monooxygenase CIP450 pathway) [67]. In the
another [Mn(II)P] to the terminal oxygen atom leads to the mixed-va-
lence oxo-dimer complex in Step IIIb. This species has been character-
ized by EPR spectroscopy in systems involving Mn(II)-porphyrins and
proposed catalytic cycle, the first step involves the reduction of [Mn(III)
P] catalyst by the substrate, as observed in the step Ia (Fig. 4). This step
Fig. 5. Proposed mechanism for the formation of valencene epoxide (3) by molecular oxygen and MnP as the catalyst.
6

C.N. de Melo, et al.
Inorganica Chimica Acta 515 (2021) 120031
O
2
[62,69,70]. At this point, the OeO bond in the dimeric complex can
gratefully acknowledged.
be cleaved, generating the high-valence [Mn(IV)P]O] species (Step
IVb). In our work, we suggest that the [Mn(IV)P]O] is responsible for
transferring the oxygen atom to the endocyclic double bond of the
valencene, resulting in the formation of 3 (Step Vb). In step Vb, a me-
chanism involving the concerted insertion of an “oxene” into the en-
docyclic double bond of the substrate has been proposed [54]. Hyun
and co-workers proposed that different active species are responsible
for oxidizing alkenes, with the [Mn(IV)P]O] may be formed in the
presence of aprotic solvents and when the catalyst presents electron-
donating groups in the macrocycle periphery [49,71].
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