Functionalization of the naturally occurring linalool and nerol by the palladium catalyzed oxidation of their trisubstituted olefinic bonds

Article abstract of DOI:10.1016/j.molcata.2016.07.033

Linalool and nerol, bio-renewable terpenic alkenyl alcohols found in many essential oils, were selectively oxidized by molecular oxygen in the presence of the chloride-free Pd(OAc)₂/p-benzoquinone catalytic system. An efficient dioxygen-coupled

Full text of DOI:10.1016/j.molcata.2016.07.033

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Functionalization of the naturally occurring linalool and nerol by the
palladium catalyzed oxidation of their trisubstituted olefinic bondsଝ
Luciana A. Parreiraa,b, Ana F. Azevedoc, Luciano Meninic, Elena V. Gusevskayaa,∗
a Departamento de Química, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil
b Departamento de Química e Física, Campus de Alegre—CCA, Universidade Federal do Espírito Santo, 29500-000 Caixa Postal 16, Alegre, ES, Brazil
c Campus de Alegre Instituto Federal de Educac¸ ão, Ciência e Tecnologia do Espírito Santo, 29500-000 Caixa Postal 47, Alegre, ES, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Linalool and nerol, bio-renewable terpenic alkenyl alcohols found in many essential oils, were selec-
tively oxidized by molecular oxygen in the presence of the chloride-free Pd(OAc)2/p-benzoquinone
catalytic system. An efficient dioxygen-coupled catalytic turnover was achieved in the absence of auxil-
iary electron-transfer mediators under 5–10 atm of oxygen pressure. In both substrates, only one of two
olefinic bonds was involved in the interaction with palladium, whereas the other one remained intact. Pri-
mary allylic acetates were formed as major reaction products: 8-linalyl acetate and 8-neryl acetate from
linalool and nerol, respectively. In the case of linalool, the intramolecular cyclization product (known as
herboxide), also resulted from the oxidation of the internal double bond, was also formed in significant
amounts. All monoterpenic compounds obtained in the present work are natural products found in exotic
plants or grape wines and are potentially useful as fragrance ingredients due to their pleasant scents.
© 2016 Published by Elsevier B.V.
Received 30 May 2016
Received in revised form 15 July 2016
Accepted 19 July 2016
Available online xxx
Keywords:
Bio-renewables
Linalool
Nerol
Oxidation
Oxygen
Palladium
1. Introduction
obtained from coniferous trees [2]. Nerol, another monoterpenic
allylic alcohol, is also widely used as a fragrance ingredient in many
Terpenes are secondary metabolites present in the essential
oils of many plants and flowers, frequently in high concentra-
tions. A large variety of terpenes are employed commercially due
to their pleasant olfactory characteristics or interesting biological
properties, such as anti-inflammatory, antimycotic, and anti-tumor
activities. Although terpenes have found a lot of direct applications
as ingredients in perfume, pharmaceutical and cosmetic products,
the use of these compounds as substrates in chemical reactions, in
particular, in catalytic reactions, opens promising routes to other,
often more stable, compounds with new aroma and/or with more
interesting properties [1–3].
Linalool, a monoterpenic tertiary allylic alcohol found in many
essential oils, such as Brazilian rosewood and lavender oils, is
widely used in the industrial synthesis of various vitamins and
fragrance chemicals and also in cosmetics, household cleaning
products and fine perfumery due to its pleasant lily aroma [4,5]. A
high demand for this compound is currently not supplied by natural
sources. The main part of commercially used linalool is manufac-
tured from ␣-pinene, a cheap major ingredient of turpentine oils
cosmetic, perfumery and household products [6]. Nerol is available
from various essential oils, such as geranium, neroli and rose oils,
including essential oils of medicinal plants with recognized biolog-
ical activities [7–9]. The catalytic oxidation of the linalool and nerol
molecules can extend the commercial use of these inexpensive bio-
renewable substrates opening new entries to poly-functionalized
value-added compounds.
The palladium catalyzed oxidation of alkenes is a very attractive
route to a variety of oxygen-containing compounds as these reac-
tions are usually characterized by excellent selectivities and can
involve molecular oxygen as a stoichiometric final oxidant [10–13].
In the original process, the oxidation of ethylene to acetalde-
hyde (Wacker process), PdCl2 is used as the catalyst and CuCl2 as
the co-catalyst to perform the reoxidation of reduced palladium
species before the irreversible formation of palladium black [14].
The method is very efficient for terminal olefins with short carbon
chains but for higher olefins the reaction is usually less selective
due to the CuCl2 promoted substrate rearrangements and forma-
tion of chlorinated products. Furthermore, the high Lewis acidity
of CuCl2 complicates the industrial application of the method due
to corrosion problems. Many efforts have been directed to substi-
tute CuCl2 by more benign alternatives, such as p-benzoquinone,
Cu(OAc)2, heteropoly acids or special ligands capable to stabilize
reduced palladium species in solutions [14–20].
ଝ
This paper is dedicated to Prof. Georgiy Shulpin on the occasion of his 70th
birthday.
∗
Corresponding author.
E-mail address: elena@ufmg.br (E.V. Gusevskaya).
http://dx.doi.org/10.1016/j.molcata.2016.07.033
1381-1169/© 2016 Published by Elsevier B.V.
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p-Benzoquinone (BQ) as a powerful oxidant can easily oxi-
dize reduced palladium species during the catalytic cycle, thus
representing a high potential to replace CuCl2 in Wacker type pro-
cesses [14,15]. However, the reduced form of BQ, p-hydroquinone
(BQH2), reacts with molecular oxygen very slowly under atmo-
spheric pressure. Cobalt, copper and manganese complexes were
used to accelerate the regeneration of BQ by molecular oxygen in
palladium catalyzed oxidations [13,15,21]. In particular, we have
preciously reported the oxidation of limonene and ␣-bisabolol
catalyzed by Pd(OAc)2 and BQ using Cu(OAc)2 as the co-catalyst
[22,23]. Recently, we have found that BQH2 can be re-oxidized
back to BQ without the use of additional metal co-catalysts under
superatmospheric oxygen pressure (5–10 atm), which allowed us
to develop environmentally more attractive catalytic oxidation
processes [24–26].
For several years, we have been studied the palladium catalyzed
aerobic oxidations of naturally occurring alkenes, including ter-
penes, aiming the valorization of these bio-renewable substrates.
Our particular interest was to involve in these reactions oxy-
functionalized terpenic compounds to produce poly-oxygenated
products, which would be hardly accessible by the methods
of conventional organic synthesis [23–25,27,28]. In the present
communication, we report the palladium/BQ catalyzed aerobic oxi-
dation of olefinic bonds in two terpenic alkenyl alcohols, linalool
and nerol, under mild chloride-free conditions.
To the best of our knowledge, the only example of the
palladium-promoted transformations of linalool was reported by
our group [27,28]. We have obtained from linalool in methanol or
ethanol solutions containing the catalytic amounts of Pd(OAc)2 and
Cu(OAc)2 the ethers of 7-hydroxyhotrienol (a natural ingredient
of Cinnamomum camphora oil). As concern to nerol, this primary
allylic alcohol was used (along with the corresponding trans iso-
mer, geraniol) as a model substrate in numerous studies on the
palladium catalyzed aerobic oxidation of alcohols to carbonyl com-
pounds [29–34]. In all the works we have found in the literature,
palladium catalysts promoted only the oxidation of the hydroxyl
group in the nerol or geraniol molecules to give citral, whereas both
of their trisubstituted olefinic bonds remained intact.
OH
OH
3
Pd/BQ
4
5
2
+
1
O
O2, HOAc
6
7
6
7
6
7
OAc
8
9
1a
1b
1c
Scheme 1. Oxidation of linalool (1a).
from the mixture by column chromatography (silica gel 60) using
hexane and dichloromethane as the eluents. The products were
identified by GC–MS (Shimadzu QP2010-PLUS instrument, 70 eV)
and NMR spectroscopy (Bruker 400 MHz spectrometer, CDCl3,
TMS).
Compound 1b (8-linalyl acetate), trans isomer: MS (70 eV, EI):
m/z (%): 152 (1) [M-HOAc]+, 137 (15) [M+-HOAc-CH3], 119 (31), 93
(22), 91 (28), 82 (38), 81 (22), 79 (30), 71 (61), 68 (48), 67 (100),
55 (50); 1H NMR (400 MHz, CDCl3, 25 ◦C, Me4Si): ␦ = 1.29 (s, 3H;
C10H3), 1.55–1.65 (m, 2H; C4H2), 1.65 (s, 3H; C9H3), 2.06 (s, 3H;
OCOCH3), 2.05–2.15 (m, 2H; C5H2), 4.44 (br.s, 2H; C8H2), 5.07 (dd,
3J = 10.8 Hz, 2J = 1.2 Hz, 1H; C1HH), 5.22 (dd, 3J = 17.4 Hz, 2J = 1.2 Hz,
1H; C1HH), 5.47 (td, 3J = 7.2 Hz, 4J = 1.1 Hz, 1H; C6H), 5.91 ppm (dd,
3J = 17.4 Hz, 3J = 10.8 Hz, 1H; C2H); 13C NMR (100 MHz, CDCl3, 25 ◦C,
TMS): ␦ = 14.06 (C9), 21.12 (OCOCH3), 22.63 (C5), 28.03 (C10), 41.70
(C4), 70.34 (C8), 73.34 (C3), 112.02 (C1), 129.64 (C6), 130.41 (C7),
145.02 (C2), 171.18 ppm (OCOCH3). Atom numbering is shown in
Scheme 1. Compound was described by Weyerstahl et al. [35]
(extracted from natural sources).
Compound 1b (8-linalyl acetate), cis isomer: MS (70 eV, EI): m/z
(%): 152 (1) [M-HOAc]+, 137 (15) [M+-HOAc-CH3], 119 (31), 93 (22),
91 (28), 82 (38), 81 (22), 79 (30), 71 (61), 68 (48), 67 (100), 55 (50);
1H NMR (400 MHz, CDCl3, 25 ◦C, Me4Si): ␦ = 1.28 (s, 3H; C10H3),
1.55–1.65 (m, 2H; C4H2), 1.73 (s, 3H; C8H3), 2.06 (s, 3H; OCOCH3),
2.05–2.15 (m, 2H; C5H2), 4.58 (br.s, 2H; C9H2), 5.06 (d, 3J = 10.8 Hz,
1H; C1HH), 5.21 (d, 3J = 17.4 Hz, 1H; C1HH), 5.40 (t, 3J = 7.2 Hz, 1H;
C6H), 5.90 ppm (dd, 3J = 17.4 Hz, 3J = 10.8 Hz, 1H; C2H); 13C NMR
(100 MHz, CDCl3, 25 ◦C, TMS): ␦ = 21.12 (OCOCH3), 21.53 (C8), 22.63
(C5), 28.03 (C10), 42.23 (C4), 63.34 (C9), 73.34 (C3), 112.02 (C1),
129.97 (C7), 130.84 (C6), 145.02 (C2), 171.18 ppm (OCOCH3). Atom
numbering is shown in Scheme 1.
2. Experimental
All reagents were acquired from commercial sources and used
without an additional treatment except p-benzoquinone. Nerol
[cis-3,7-(dimethyl-2,6-octadien-1-ol)] and racemic linalool [( )-
3,7-dimethyl-1,6-octadien-3-ol] were purchased from Aldrich. The
reactions were conducted in the solutions of glacial acetic acid. The
purification of p-benzoquinone was performed by re-sublimation.
Catalytic tests were run in either a glass reactor (under oxy-
gen pressure of 1 atm) or in a homemade 100-mL autoclave (under
superatmospheric oxygen pressure) with magnetic stirring. The
glass reactor was equipped with a condenser and a gas burette to
measure oxygen consumption. The reaction solution was periodi-
cally sampled using an appropriate sampling system without the
depressurization of the reactor and analyzed by gas chromatog-
raphy (GC) on a GC-Shimadzu GC2010 instrument equipped with
a Rtx®-5MS capillary column and FID detector. The reactors were
placed in an oil bath and after reaching a required temperature
(40–100 ◦C) intensive stirring was started. The calculation of con-
version and selectivity values was based on the reacted substrate,
with dodecane being used as the internal standard. Initial turnover
frequencies (TOFs) were determined at low conversions (up to
20–30%).
Compound 1c (known as herboxide): MS (70 eV, EI): m/z (%):152
(0.5) [M]+, 137 (10) [M+-CH3], 82 (22), 68 (57), 67 (100), 55 (48) (iso-
mer with shorter retention time); m/z (%): 152 (0.5) [M]+, 137 (10)
[M+-CH3], 82 (22), 68 (57), 67 (100), 55 (48) (isomer with longer
retention time).
Compound 2bꢀ (8-neryl acetate): MS (70 eV, EI): m/z (%): trans
isomer: 152 (1) [M-HOAc]+, 134 (31) [M+-HOAc-H2O], 119 (84),
105 (22), 93 (38), 92 (21), 91 (38), 84 (100), 81 (27), 79 (35), 69
(25), 68 (39), 67 (53), 55 (30); cis isomer: 152 (1) [M-HOAc]+, 134
(20) [M+-HOAc-H2O], 119 (52), 93 (40), 91 (30), 84 (100), 83 (40),
81 (39), 79 (35), 71 (34), 69 (42), 68 (39), 67 (54), 55 (40); 1H NMR
(400 MHz, CDCl3, 25 ◦C, Me4Si): trans isomer: ␦ = 1.65 (s, 3H; C9H3),
1.75 (s, 3H; C10H3), 2.07 (s, 3H; OCOCH3), 2.00–2.10 (m, 4H; C4H2,
C5H2), 4.09 (d, 3J = 7.2 Hz, 2H; C1H2), 4.45 (br.s, 2H; C8H2), 5.44 ppm
(t, 3J = 6.4 Hz, 2H; C6H, C2H); 13C NMR (100 MHz, CDCl3, 25 ◦C, TMS):
trans isomer: ␦ = 14.05 (C9), 21.27 (OCOCH3), 23.48 (C10), 26.29 (C5),
31.58 (C4), 59.20 (C1), 70.27 (C8), 125,17 (C2), 129.14 (C6), 130.96
(C7), 138.95 (C3), 171.30 ppm (OCOCH3). Atom numbering is shown
in Scheme 2.
The mixture of reaction products was separated by the neutral-
ization of reaction solutions with sodium bicarbonate followed by
the extraction with diethyl ether. Individual products were isolated
Compound 2bꢀꢀ (1,8-neryl diacetate): MS (70 eV, EI): m/z (%):
trans isomer: 134 (70) [M+-2HOAc], 119 (93), 105 (20), 93 (38), 92
(24), 91 (32), 85 (40), 84 (100), 68 (37), 67 (49), 55 (24); cis isomer:
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the reaction solutions as a mixture of two isomers with almost
identical mass spectra, both identified by NMR spectroscopy as
8-linalyl acetate with different geometry around the internal dou-
ble bond (Scheme 1). The ratio between trans and cis isomers was
85–90/15–10 in all the runs, i.e., the thermodynamically more sta-
ble trans isomer was predominantly formed at the oxidation of
linalool. Minor product 1c was identified as a substituted tetrahy-
drofuran compound known as herboxide (Scheme 1). Two isomers
of product 1c were detected in the reaction solutions formed in
comparable amounts. The isomers, which showed very similar
mass spectra, probably differ from each other by the relative posi-
tion of the alkenyl groups with respect to the tetrahydrofuran ring.
Both products 1b and 1c are the result of the oxidation of
the sterically encumbered internal double bond in the linalool
molecule. It is remarkable that the terminal double bond remained
intact, similarly to what was observed in the reactions in methanol
and ethanol solutions [27]. The main difference is that in alcohols
the oxidation of linalool occurred exclusively at carbon C7, whereas
in acetic acid at carbon C8. Possible reasons for the enhanced reac-
tivity of the internal double bond as compared to the terminal one
in linalool were discussed in our previous publication [27]. The
terminal double bond is deactivated towards the interaction with
palladium by the electron withdrawing hydroxyl group in the allylic
position so that in spite of steric crowding the internal double bond
appears to be more reactive in ␩2-bonding with palladium due to
higher electron density. Calculated by Ishii et al. HOMO coefficients
for the internal double bond in the linalool molecule were near six
times higher than for the terminal double bond [36].
3
4
2
1
Pd/BQ
+
5
5
O2, HOAc
O
OH
OR
6
7
6
7
6
7
OAc
8
9
2a
2b' R=H
2b'' R=Ac
2c
Scheme 2. Oxidation of nerol (2a).
134 (55) [M+-2HOAc], 119 (1090), 105 (21), 93 (33), 92 (24), 91
(46), 79 (30), 85 (26), 84 (77), 69 (64), 68 (28), 67 (44), 55 (27) ();
1H NMR (400 MHz, CDCl3, 25 ◦C, Me4Si): trans isomer: ␦ = 1.58 (s,
3H; C9H3), 1.70 (s, 3H; C10H3), 1.97 (s, 3H; OCOCH3), 2.00 (s, 3H;
OCOCH3), 1.85–2.10 (m, 4H; C4H2, C5H2), 4.37 (br.s, 2H; C8H2), 4.48
(d, 3J = 7.4 Hz, 2H; C1H2), 5.30 (t, 3J = 7.4 Hz, 1H; C2H), 5.37 ppm (br.s,
1H; C6H); 13C NMR (100 MHz, CDCl3, 25 ◦C, TMS): trans isomer:
␦ = 14.02 (C9), 21.03 (OCOCH3), 21.09 (OCOCH3), 23.51 (C10), 26.38
(C5), 31.68 (C4), 61.10 (C1), 70.11 (C8), 119.77 (C2), 128.56 (C6),
130.92 (C7), 142.00 (C3), 171.05 (OCOCH3), 171.13 ppm (OCOCH3).
Atom numbering is shown in Scheme 2.
Compound 2c (nerol oxide): MS (70 eV, EI): m/z (%): 152 (0.5)
[M]+, 85 (30), 83 (82), 68 (100), 67 (98), 55 (24), 53 (25).
3. Results and discussion
Experiments with the catalytic amounts of BQ were performed
in the presence of Cu(OAc)2 to promote the regeneration of BQ
under 1 atm of oxygen. At 60 ◦C, the reaction occurred gradually
without any stagnation but slowly and showed only 27% conver-
sion in 10 h (Table 1, run 2). To ensure reasonable reaction rates,
the reaction temperature was increased to 80 ◦C resulting in ca. 60%
conversion in 10 h (Table 1, run 3). Products 1b and 1c were formed
in this run in comparable amounts with 85% combined selectivity.
It is noteworthy that the contribution of the cyclization product
(1c) was much higher in the presence of Cu(OAc)2 (Table 1, runs
2 and 3 vs. run 1). In blank reactions without the palladium salt,
no formation of products 1b and 1c and no or a very slow linalool
conversion were detected (Table 1, runs 4 and 5).
The rate of the linalool oxidation in the presence of the catalytic
amounts of BQ was significantly lower than in the stoichiometric
reaction (Table 1, cf. runs 2 and 1) implying that the re-oxidation
of BQH2 probably was the rate-determining step of the whole pro-
cess. Indeed, the increase in oxygen pressure to 10 atm significantly
accelerated the reaction (Table 1, run 6 vs. run 2). Although the ini-
tial rate was slightly lower than with the stoichiometric amounts
of BQ, both reactions progressed successfully to high conversions
following similar kinetic curves (Table 1, cf. runs 6 and 1). The reac-
tions in runs 3 and 6 showed a dioxygen coupled turnover, in other
words, the process was catalytic in palladium, copper and BQ.
The combined selectivity for products 1b and 1c in the pres-
ence of Cu(OAc)2 was lower than in the stoichiometric reaction
(Table 1, cf. runs 6 and 1) due to the formation of minor non-
identified products, some of them having the same GC retention
times as the products formed in the blank reaction with Cu(OAc)2
(Table 1, run 5). Indeed, removing Cu(OAc)2 from the reaction solu-
tions improved reaction selectivity without a significant kinetic
impact (Table 1, cf. runs 7 and 6). Thus, a further process opti-
mization was performed using the two-component Pd/BQ catalytic
system.
3.1. Oxidation of linalool
The molecule of linalool (1a) has two olefinic bonds: the ter-
minal monosubstituted bond having a hydroxyl group in the
allylic position and the internal trisubstituited C6-C7 double bond
(Scheme 1). The attempts to perform the oxidation of linalool
with the conventional Wacker system (PdCl2/CuCl2) have failed
due to the low reaction selectivity [27]. Most of the GC detected
products had the same retention times as those formed in the
absence of the palladium salt. For this reason, our further efforts
in the work with linalool were directed to the development of
CuCl2–free catalytic systems. In methanol or ethanol solutions con-
tacting the chloride free Pd(OAc)2/Cu(OAc)2 catalytic combination,
we successfully converted linalool in the corresponding ethers of
7-hydroxyhotrienol, thus reporting the first chemical synthesis of
these natural fragrant compounds found in exotic plants and grape
wines. Only the internal double bond of the linalool molecule was
involved in the reaction, with the terminal one remaining intact. In
acetic acid solutions, the reaction regioselectivity was completely
switched to the oxidation at terminal carbon C8 rather than C7.
The corresponding product, 8-linalyl acetate, was obtained only in
low yields (20–40%) [27]. All our attempts to improve the selec-
tivity of the linalool oxidation in acetic acid solutions with Pd/Cu
or Pd/Cu/BQ catalytic systems were fruitless at that time. Latter,
we have found that BQ can be regenerated under 5–10 atm of
oxygen in the absence of metal co-catalysts [26] and successfully
applied the two-component Pd(OAC)2/BQ catalytic system for the
aerobic oxidation of limonene, ␣-terpineol and ␣-bisabolol [24,25].
These achievements encouraged us to get back to linalool in a
hope to develop more selective and more environmentally benign
processes for its oxidation. Representative results are collected in
Table 1. Reaction times included in Table were selected to facilitate
comparison between the runs.
The reaction of linalool in acetic acid solutions with 2 equiv.
of BQ at 60 ◦C and 1 atm of oxygen resulted in 82% conversion
in 10 h to give compounds 1b and 1c in 85 and 15% selectivity,
respectively (Table 1, run 1). Major product 1b was isolated from
The increase in the reaction temperature did accelerate the
linalool conversion; however, negatively affected the reaction
selectivity (Table 1, runs 8 and 9 vs. run 7). On the other hand, the
increase in the BQ concentration significantly accelerated the reac-
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Table 1
Aerobic oxidation of linalool (1a) with molecular oxygen catalyzed by Pd(OAc)2.a
Run
[BQ]
[Cu(OAc)2]
P
T
Time
Conversionb
Selectivityb (%)
TOFc
(M)
(M)
(atm)
1
1
1
1
(◦C)
60
60
80
60
60
60
60
70
80
60
80
40
60
(h)
10
10
10
10
10
10
10
5 10
3 5 10
5 7 10
3 5
25
(%)
82
27
63
0
4
87
76
64 100
60 90 100
65 77 97
83 92
70
1b
85
45
47
–
–
63
70
58 59
60 54 40
71 70 66
69 65
70
1c
15
36
38
–
–
18
20
20 19
20 18 16
18 18 19
19 18
20
(h−1
3.6
0.6
2.4
–
)
1
2
3
0.40
0.05
0.05
0.20
0.05
0.05
0.05
0.05
0.05
0.10
0.10
0.10
0.10
none
0.05
0.05
none
0.05
0.05
none
none
none
none
none
none
none
4d
5d
6
1
–
10
10
10
10
10
10
10
5
2.8
2.4
4.4
7.0
3.4
10.0
1.2
3.2
7
8
9
10
11
12
13
5 10
59 98
74 70
16 18
a
Reaction conditions: solvent: glacial acetic acid, [linalool] = 0.20 M, [Pd(OAc)2] = 0.01 M, gas phase: molecular oxygen.
Conversion and selectivity were determined by GC and calculated based on the reacted substrate.
Turnover frequency: initial rate of the linalool conversion per mol of palladium.
No Pd(OAc)2 was added.
b
c
d
spontaneous esterification to give neryl acetate (Table 2, run 1),
differently from what has been observed with linalool. In the calcu-
lations of the reaction conversion and selectivity neryl acetate was
considered as the non-reacted substrate. We were very pleased to
observe that the stoichiometric reaction of nerol with BQ catalyzed
by Pd(OAc)2 did result in the oxidation of the olefinic bond rather
than the hydroxyl group (Table 2, run 2). The characterization of
isolated products by NMR spectroscopy confirmed the structure of
8-neryl acetate for product 2bꢀ and corresponding diacetate (1,8-
neryl acetate) for product 2bꢀꢀ (Scheme 2). Each of these acetates
was predominantly formed with a trans geometry around the C6-
C7 double bond (85–90%). Along with acetates 2bꢀ and 2bꢀꢀ, formed
with a 90% combined selectivity, small amounts of the cyclization
product (compound 2c, known as nerol oxide) were detected in run
2 (Table 2). Nerol oxide 2c is also the product of the allylic oxidation
of the C6-C7 bond; however, differently from acetates 2bꢀ and 2bꢀꢀ,
it is formed with the participation of the internal hydroxyl group
resulting in the cyclization of the nerol molecule.
In attempts to make the reaction catalytic in BQ under atmo-
spheric pressure, Cu(OAc)2 was added to the reaction solutions
(Table 2, run 3). Indeed, the reaction occurred with a dioxygen
coupled turnover showing a 60% conversion in 10 h and 84% selec-
tivity for acetates 2b. The amounts of diacetate 2bꢀꢀ relatively to
monoacetate 2bꢀ were gradually increased with reaction time due
to the spontaneous esterification of the hydroxyl group in both
the original substrate and primarily formed monoacetate 2bꢀ. The
reaction with 0.25 equiv. of BQ was significantly slower than the
stoichiometric reaction even at the very beginning when the BQH2
re-oxidation step could not affect yet the rate of the substrate con-
version (Table 2, cf. the initial TOFs in runs 3 and 2).
Our further work was focused in the two-component Pd/BQ
catalytic system, i.e., without the additional electron transfer medi-
ator to promote the oxidation of BQH2. Really, under 10 atm, the
regeneration of BQ was successfully performed in the absence of
Cu(OAc)2, with the reaction following nearly the same kinetic curve
as with 1 equiv. of BQ albeit being slightly slower at the beginning
(Table 2, run 4 vs. run 2). This implies the absence of kinetic limita-
tions by the step of the regeneration of BQ from BQH2, at least under
the conditions used. The high selectivity of ca. 80% for acetates 2b
was observed until the complete substrate conversion in this run.
The reaction temperaturewas varied in the range of 60–100 ◦C, with
no overall selectivity for 2b and 2c neither the ratio between them
being significantly affected. (Table 2, runs 4, 5 and 6). At 100 ◦C, the
reaction was completed within 3 h showing 77% selectivity for 2b
and 6% for 2c (Table 2, run 6).
Scheme 3. Proposed mechanism for the oxidation of linalool (1a).
tion, which was still catalytic in BQ and showed ca. 85% combined
selectivity for products 1b and 1c even at 80 ◦C (Table 1, cf. runs 10
and 7; runs 11 and 9). At 40 ◦C, the oxidation of linalool occurred
with excellent selectivity, however, very slowly (Table 1, run 12 vs.
runs 11 and 10). The reactions under the oxygen pressure of 5 and
10 atm occurred with similar kinetics (Table 1, cf. runs 13 and 10).
Thus, 5 atm of oxygen is also sufficient to perform the regeneration
of BQ during the catalytic cycle at the linalool oxidation.
3.2. Oxidation of nerol
The molecule of nerol (2a) has the same fragment which was
involved in the oxidation of linalool so that we decided to apply
the Pd/BQ catalytic system for the oxidation of nerol (Scheme 2,
Table 2). As mentioned in the Introduction, all the works we have
found in the literature on the palladium catalyzed oxidation of nerol
described the oxidation of the hydroxyl group to give the corre-
sponding aldehyde (citral), with both trisubstituded olefinic bonds
remaining intact.
We have found that in acetic acid solutions at elevated tem-
perature, the hydroxyl group in the nerol molecule undergoes a
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Scheme 4. Proposed mechanism for the oxidation of nerol (2a).
Table 2
Aerobic oxidation of nerol (2a) with molecular oxygen catalyzed by Pd(OAc)2.a
Run
[BQ]
[Cu(OAc)2]
P
T
Time
Conversionb
Selectivityb (%)
TOFc
(M)
(M)
(atm)
1
1
(◦C)
80
80
80
80
60
100
60
80
80
(h)
5
5
5 10
3 7
7 10
2
7 10
5
(%)
0
82
47 60
65 100
65 82
93
90 95
95
2b (2bꢀꢀ/2bꢀꢀ)
–
90 (85/15)
82 (73/27) 84 (62/38)
88 (66/34) 82 (32/68)
91 (77/33) 73 (50/50)
77 (36/64)
70 (66/34) 67 (48/52)
88 (38/62)
2c
–
5
7 7
8 6
6 5
6
4 3
3
(h−1
–
)
1d
2
3
4
5
6
7
8
9
none
0.20
0.05
0.05
0.05
0.05
0.10
0.10
0.05
none
none
0.05
none
none
none
none
none
none
6.4
3.4
5.4
3.6
7.6
5.6
10.0
5.4
1
10
10
10
10
10
5
7 10
75 95
94 (42/58) 90 (28/72)
5 5
a
Reaction conditions: solvent: glacial acetic acid, [nerol] = 0.20 M, [Pd(OAc)2] = 0.01 M, gas phase: molecular oxygen.
Conversion and selectivity were determined by GC and calculated based on the reacted substrate. Nerol was partially acetoxylated to give neryl acetate under the reaction
b
conditions, with neryl acetate being considered as the non-reacted substrate.
c
Turnover frequency: initial rate of the substrate (nerol and neryl acetate) conversion per mol of palladium.
No Pd(OAc)2 was added; ca. 40% of 2a was converted in neryl acetate for 5 h.
d
Similarly to the reaction with linalool, the increase in the BQ
amounts resulted in significant acceleration (Table 2, cf. runs 5
and 7; runs 4 and 8). At 80 ◦C, 88% selectivity for acetates 2b was
obtained at a virtually complete conversion, with the reaction being
catalytic in both Pd(OAc)2 and BQ. It is noteworthy that the cycliza-
tion product formed with the participation of the tethered hydroxyl
group was detected at the oxidation of nerol in much less amounts
as compared to linalool (products 2c and 1c, respectively). Prob-
ably the reason is a much longer distance between the hydroxyl
group and the double bond involved in the oxidation in the nerol
molecule than in linalool.
The oxidation of nerol can also be performed under 5 atm of oxy-
gen with high selectivity and catalytically in both palladium and BQ
(Table 2, runs 9 and 4). It is remarkable that only one of the trisub-
stituted acyclic double bonds of nerol is involved in the oxidation in
our system. Although we could not found in the literature the calcu-
lations of the relative electron density on the nerol double bonds as
we did for linalool [36], we suppose that the reason for so different
reactivity towards the interaction with palladium is the presence
of the electron withdrawing hydroxyl group in the position allylic
to the C2-C3 double bond.
position) is generally accepted to involve an oxypalladation step
[11,37–40]. In our previous works on the oxidation of ␣-bisabolol,
the molecule having a trisubstituted olefinic bond involved in the
interaction with palladium like nerol and linalool [23,25], we have
proposed the oxypalladation step as a key reaction step on the
route to the products derived from this interaction. Really, in all the
products resulted from the oxidation of the acyclic double bond of
␣-bisabolol, the attacking oxygen containing group became bound
to one of the carbon atoms of this bond. On the other hand, the oxi-
dation of linalool and nerol occurred predominantly at the carbon
atoms allylic to the original double bond (C8 or C5). To explain the
formation of these products we have to propose ␩3-allyl palladium
complexes shown in Schemes 3 and 4 as key reaction intermediates.
Only in the product of linalool cyclization, product 1c, the attacking
oxygen atom became linked to one of the originally olefinic carbons
− carbon C6 − so that we can suggest that its formation occurs
through the oxypalladation step. The intramolecular nucleophilic
attack of the hydroxyl group on the C6-C7 double bond coordi-
nated to palladium would give a ␴-alkyl palladium intermediate
as shown in Scheme 3. Then, a ␤-hydrogen elimination step would
result in two isomers of product 1c which probably differ from each
other by the geometry at carbon C6. Alternatively, product 1c can
be formed from the same ␩3-allyl palladium intermediate depicted
in Scheme 3 on the route to the major reaction product, compound
1b. The external nucleophilic attack of the acetate group on the
less hindered terminal carbon C-9 in the ␩3-allyl palladium com-
plex would result in allylic acetate 1b, whereas the intramolecular
3.3. Mechanistic aspects of the oxidation of linalool and nerol
Suggested mechanistic proposals for the oxidation of linalool
and nerol are presented in Schemes 3 and 4. The palladium pro-
moted oxidative cyclization of alkenyl alcohols having a hydroxyl
group in a certain proximity to the olefinic bond (mostly at the ␥-
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6
attack of the hydroxyl group would lead to the molecule cyclization
giving tetrahydrofuran compound 1c.
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can be rationalized within a similar mechanism shown in Scheme 4.
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external acetate group at carbon C8 would give major acetates 2b.
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The oxidation of linalool and nerol, bio-renewable terpenic
alkenyl alcohols found in many essential oils, can be performed
with the chloride-free Pd(OAc)2/p-benzoquinone catalytic system
under 5–10 atm of oxygen pressure in the absence of convention-
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only one of two olefinic bonds was involved in the interaction with
palladium, whereas the other one remained intact. The major prod-
ucts were primary allylic acetates along with minor heterocyclic
products resulted from the oxidative cyclization of the linalool and
nerol molecules with the participation of the tethered hydroxyl
group. All monoterpenic compounds obtained in the present work
are natural products found in exotic plants or grape wines and are
potentially useful as fragrance ingredients due to their pleasant
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Acknowledgments
We acknowledge CNPq, FAPEMIG, FAPES and INCT Catálise
(Brazil) for the financial support.
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Please cite this article in press as: L.A. Parreira, et al., J. Mol. Catal. A: Chem. (2016), http://dx.doi.org/10.1016/j.molcata.2016.07.033