Heteropoly acid catalysts in the valorization of the essential oils: Acetoxylation of β-caryophyllene

Article abstract of DOI:10.1016/j.apcata.2009.11.032

H₃PW₁₂O₄₀ (PW), the strongest heteropoly acid in the Keggin series, is an active and environmentally friendly catalyst for the liquid-phase conversion of β-caryophyllene (1) to β-caryolanyl acetate (2) in homogeneous and heterogeneous systems. An efficient and clean method for the synthesis of 2, providing a mixture containing two stereoisomeric β-caryolanyl acetates 2a and 2b, 2a/2b = 80/20 mol/mol, with 100% GC yield, has been developed using PW as a homogeneous catalyst under mild reaction conditions. The reaction occurs at 25 °C with a catalyst turnover number of 2000. The catalyst can be recovered without neutralization and reused without loss of activity and selectivity.

Full text of DOI:10.1016/j.apcata.2009.11.032

Applied Catalysis A: General 374 (2010) 87–94
Contents lists available at ScienceDirect
Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
Heteropoly acid catalysts in the valorization of the essential oils:
Acetoxylation of
b-caryophyllene
a
a
b
a,
*
´
Kelly A. da Silva Rocha , Nathalia V.S. Rodrigues , Ivan V. Kozhevnikov , Elena V. Gusevskaya
a Departamento de Quı´mica, Universidade Federal de Minas Gerais, AV Antonio Carlos 6627, 31270-901, Belo Horizonte, MG, Brazil
b Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
H3PW12O40 (PW), the strongest heteropoly acid in the Keggin series, is an active and environmentally
friendly catalyst for the liquid-phase conversion of -caryophyllene (1) to -caryolanyl acetate (2) in
homogeneous and heterogeneous systems. An efficient and clean method for the synthesis of 2,
providing a mixture containing two stereoisomeric -caryolanyl acetates 2a and 2b, 2a/2b = 80/20 mol/
Received 9 September 2009
Accepted 23 November 2009
Available online 27 November 2009
b
b
b
mol, with 100% GC yield, has been developed using PW as a homogeneous catalyst under mild reaction
conditions. The reaction occurs at 25 8C with a catalyst turnover number of 2000. The catalyst can be
recovered without neutralization and reused without loss of activity and selectivity.
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
Acetoxylation
b-Caryophyllene
Acid catalysis
Heteropoly acid
1. Introduction
geneous systems. Such an opportunity is provided by high
solubility of HPAs in polar solvents, on the one hand, and low
Terpenes are naturally occurring substances that can be used as
renewable hydrocarbon feedstock to replace the present
solubility in non-polar solvents (e.g., hydrocarbons), on the other
hand, so that they can be recovered from polar organic solutions by
precipitating with a non-polar solvent.
Within our program aimed at the valorization of natural
ingredients of renewable essential oils, we choose to study the HPA
a
petroleum-based source of hydrocarbons. In particular, these
compounds represent a sustainable supply of intermediates for
several segments of the fine chemical industry, e.g., the manufac-
ture of flavors and fragrances [1–4]. Various terpenic compounds
used in the fine chemicals industry are produced by acid-catalyzed
transformations of more abundant mono- and sesquiterpenes. In
these reactions, mineral acids are used as catalysts, often in large
amounts, which lead to serious environmental problems.
Heteropoly acids (HPAs), especially those of the Keggin series,
are attractive acid catalysts for the clean synthesis of fine and
specialty chemicals [5,6]. Recently, HPAs have been applied in
various reactions of terpenoids, such as hydration, acetoxylation
[7–9], and isomerization [10–15]. Due to their stronger acidity,
HPAs generally exhibit higher catalytic activities compared to
conventional catalysts, such as mineral acids, ion-exchange resins,
mixed oxides, zeolites, etc. Furthermore, HPA catalysis lacks side
reactions, such as sulfonation and chlorination, which frequently
occur with mineral acids. Economic and environmental advantages
of using solid acid catalysts in liquid-phase reactions are clearly
apparent. It should be noted that HPAs can, in some cases, be
recovered and recycled without neutralization even from homo-
catalyzed transformations of
terpene compound containing two olefinic bonds.
-Caryophyllene is one of the most abundant sesquiterpenes
b-caryophyllene – a bicyclic sesqui-
b
found in many essential oils. For example, it is the main
hydrocarbon component of clove (Eugenia caryophyllata) and
copaiba (Copaifera) oils [4,16,17]. Various synthetic derivatives of
b-caryophyllene find use as woody ingredients in perfumes, as
aromatic additives for tobacco and food products, and as odor
fixatives [4,16]. Furthermore, it is known that natural caryophyl-
lene compounds often show a biological activity, for example, the
copaiba extract is used for years in folk medicine and occupies an
important place in the Brazilian pharmaceutical export [17].
The molecule of
b-caryophyllene is highly strained and
undergoes a variety of transformations with a remarkable facility.
Therefore, the development of reactions which are selective for a
single product is a challenging task. Probably for this reason, in
spite of the industrial importance of natural and synthetic
derivatives of
this compound are rare [18–21]. In particular, it has been reported
that acid-catalyzed transformations of -caryophyllene result in a
b-caryophyllene, selective catalytic reactions of
b
complex mixture of polycyclic products due to the involvement of
* Corresponding author. Tel.: +55 31 34095741; fax: +55 31 34995700.
E-mail address: elena@ufmg.br (E.V. Gusevskaya).
both double bonds in trans-annular reactions followed by a variety
0926-860X/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.apcata.2009.11.032

Table 1
Chemical shifts (
d
, ppm), coupling constants (J, Hz, in parenthesis) and HMBC correlations for b-caryophyllene 1, b-caryolanyl acetate 2a, and b-caryolanol 3.
Atoma
1
2a
3
d
(1H)b
d
(
13C)
HMBC
d
(1H)b
d
(
13C)
HMBC
d
(1H)b
d
(
13C)
HMBC
1a
1b
2
1.60–1.70 (m)
1.60–1.70 (m)
2.27–2.33 (m)
40.39
48.50
H-2, H-10, H-12, H-13
1.26–1.32 (m)
1.68–1.75 (m)
38.86
42.69
83.45
39.00
20.62
36.36
H-2, H-12, H-13
1.42–1.58 (m)
34.45
39.57
71.00
38.64
20.88
37.47
H-2, H-12, H-13
1.42–1.58 (m)
H-4a, H-4b, H-9a,
H-9b, H-15a, H-15b
H-4b, H-5a, H-5b,
H-10, H-15a
2.35 (qt, 9.3, H-1, H-10)
H-1a, H-1a, H-15a
2.28 (qt, 10.2, H-1, H-10)
H-9b, H-15a
3
154.45
34.82
H-1a, H-4b, H-15a, H-15b
H-2, H-6a, H-15b
H-1, H-15a, H-15b
4a
1.98–2.04 (m)
2.18–2.22 (m)
1.98–2.04 (m)
2.30–2.37 (m)
5.27–5.34 (m)
H-2, H-4a, H-4b
H-15a, H-15b
1.10–1.20 (m)
1.43–1.53 (m)
1.63–1.70 (m)
1.63–1.70 (m)
1.08–1.12 (m)
1.38–1.44 (m)
1.24–1.34 (m)
1.57–1.64 (m)
1.67–1.74 (m)
1.67–1.74 (m)
1.02–1.08 (m)
1.32–1.42 (m)
4b
5a
28.38
H-4a, H-4b
5b
6a
124.35
H-4a, H-4b, H-14
H-4a, H-5, H-14, H-15b
H-14
6b
7
135.24
39.99
H-5a, H-14
H-10, H-14
34.90
35.67
H-14, H-15
H-14
34.97
36.68
H-14
8a
1.85–1.95 (m)
2.07–2.13 (m)
1.47–1.53 (m)
1.47–1.53 (m)
1.65–1.75 (m)
1.43–1.53 (m)
2.42–2.50 (m)
1.30–1.35 (m)
1.43–1.53 (m)
1.78–1.86 (m)
1.07–1.14 (m)
1.50–1.68 (m)
1.30–1.40 (m)
1.42–1.48 (m)
1.78–1.86 (m)
H-14, H-15a
8b
9a
29.39
H-2
23.63
H-2
21.95
H-2
9b
10
53.62
32.74
30.10
22.62
16.30
111.67
H-1, H-5b, H-12, H-13
H-1, H-10, H-12, H-13
H-1, H-12
46.52
34.18
30.37
20.55
34.00
45.82
H-1a, H-1b, H-2, H-12, H-13
H-1, H-12, H-13
H-1a, H-13
44.82
34.80
30.54
20.83
33.26
48.78
H-8b, H-12, H-13
H-12, H-13
H-1, H-13
H-1, H-12
H-15a
11
12
1.00 (s)
0.97 (s)
1.61 (s)
4.82 (bs)
4.94 (bs)
0.98 (s)
1.01 (s)
13
H-1, H-13
0.98 (s)
H-1a, H-1b, H-12
H-6, H-15
1.00 (s)
14
0.91 (s)
0.89 (s)
15a
15b
C5O
C(O)CH3
H-2, H-4a, H-4b
1.30–1.35 (m)
1.92–2.00 (m)
H-14
1.04 (d, 14.8, H-15b)
1.70 (d, 14.8, H-15a)
169.95
22.18
1.97 (s)
a
For carbon numbering, see Scheme 1.
b
Resonance multiplicities, coupling constants (Hz), and coupled partners in parentheses: (s) singlet, (qt) quartet, (m) multiplet, (b) broad.

K.A.S. Rocha et al. / Applied Catalysis A: General 374 (2010) 87–94
89
of rearrangements [4,16]. For example, the hydration of
caryophyllene leads to the formation of up to 20 products,
although in some cases, -caryolanol is the main product (50–70%
selectivity) [20–25]. The hydration of -caryophyllene has been
performed in the presence of various acid catalysts, such as sulfuric
and chloroacetic acid, acidic alumina, and zeolites, which are often
used in over-stoichiometric amounts [20–25].
b
-
a Shimadzu 17 instrument fitted with a Carbowax 20 M capillary
column and a flame ionization detector. In homogeneous systems,
at appropriate time intervals, aliquots were taken, diluted with
hexane (1/10 v/v) to separate the heteropoly acid and analyzed by
GC. In heterogeneous systems, stirring was stopped and after quick
catalyst settling aliquots were taken as in homogeneous systems.
The mass balance, product selectivity and yield were calculated
using dodecane as internal standard. Any difference in mass
balance was attributed to the formation of oligomers, which were
GC unobservable, and referred to as ‘‘others’’.
In heterogeneous systems, to control catalyst leaching and the
possibility of a homogeneous reaction, the catalyst was removed
by centrifugation of the reaction mixture at the reaction
temperature to avoid re-adsorption of active components onto
silica, then the supernatant was added with portion of substrate
and allowed to react on. No further reaction was observed in such
experiments, indicating absence of PW leaching.
b
b
In the present work, we report the application of H3PW12O40
(PW), the strongest HPA in the Keggin series, as the catalyst for the
liquid-phase acetoxylation of
and heterogeneous systems. Our aim was to achieve high
selectivity towards -caryolanyl acetate (2) and -caryolanol
b-caryophyllene (1) in homogeneous
b
b
(3). As a result, we developed an efficient method for the synthesis
of acetate 2 with a virtually quantitative yield. To our knowledge,
no attempt to use HPA catalysts for this reaction has been made so
far. Moreover, none of the previous work has achieved such a high
selectivity.
The products were separated by a column chromatography
(silica gel 60) using mixtures of hexane and CH2Cl2 as eluents and
identified by GC–MS, 1H, and 13C NMR. The 1H and 13C NMR signals
were assigned using bidimensional techniques. NMR spectra were
recorded in CDCl3 using a Bruker 400 MHz spectrometer, with TMS
as an internal standard. Mass spectra were obtained on a Shimadzu
QP2010-PLUS instrument operating at 70 eV.
2. Experimental
2.1. Chemicals
All chemicals were purchased from commercial sources and
used as received, unless otherwise stated. H3PW12O40 hydrate was
from Aldrich and Aerosil 300 silica from Degussa.
b
-Caryophyllene
Data for b
-caryophyllene 1: MS (m/z/rel.int.): 204/7 (M+); 189/
´
´
was kindly donated by Prof. J.C. Bayon (Universidad Autonoma de
Barcelona).
27; 161/51; 147/41; 148/27; 133/100; 121/30; 120/50; 119/46;
107/50; 106/32; 105/71; 93/100; 91/82; 81/43; 79/71; 69/83; 67/
34; 59/3, 55/31. For NMR data see Table 1.
2.2. Characterization techniques
Data for b-caryolanyl acetate 2a: MS (m/z/rel.int.): 204/17
([MÀHOAc]+); 189/56; 166/35; 161/100; 148/42; 133/41; 123/39;
121/72; 119/42; 111/68; 107/33; 105/38; 95/41; 93/52; 91/34; 81/
45; 79/34; 69/43; 67/34; 59/3; 55/58. For NMR data see Table 1.
31P MAS NMR spectra were recorded at room temperature and
4 kHz spinning rate on a Bruker Avance DSX 400 NMR spectrome-
ter using 85% H3PO4 as a reference. Powder X-ray diffraction (XRD)
of the catalysts was measured using a Rigaku Geigerflex-3034
Data for
b-caryolanyl acetate 2b: MS (m/z/rel.int.): 204/34
([MÀHOAc]+); 189/100; 166/49; 161/98; 148/30; 135/22; 133/27;
diffractometer with CuK radiation. Surface area and porosity of
123/26; 119/30; 107/23; 105/29; 95/26; 93/28; 91/21; 81/30; 79/
a
the catalysts were measured by nitrogen physisorption at 77 K on
an Micromeritics ASAP 2000 instrument. Tungsten and phospho-
rus content in the catalysts was measured by inductively coupled
plasma (ICP atomic emission spectroscopy) on a Spectro Ciros CCD
spectrometer.
23; 67/21; 55/22. 1H NMR, H: 0.86 (s, 3H, C14H3); 1.05 (s, 3H,
d
C12H3); 2.03 (s, 3H, COCH3). 13C NMR, C: 21.05 (C5), 21.26 (COCH3),
d
31.65 (C12), 32.97 (C14), 44.62 (C15), 82.66 (C3), 170.99 (COCH3).
Data for
b
-caryolanol 3: MS (m/z/rel.int.): 204/5 ([MÀH2O]+);
161/25; 123/30; 121/18; 111/100; 95/25; 81/31; 69/21; 55/33. For
NMR data see Table 1; 13C NMR data are in agreement with those
published previously [21,29].
2.3. Catalyst preparation and characterization
Data for clovene 4: MS (m/z/rel.int.): 204/7 (M+); 189/43; 161/
100; 133/26; 119/27; 105/34; 93/20; 91/27.
The silica-supported catalysts, 20 wt% H3PW12O40/SiO2 (PW/
SiO2), were prepared by impregnating Aerosil 300 (SBET
,
300 m2 gÀ1
)
with an aqueous PW solution and calcined at
3. Results and discussion
130 8C/0.2–0.3 Torr for 1.5 h, as described elsewhere [26]. The
PW content was determined by ICP. The BET surface area was
200 m2 gÀ1 and average pore volume was 0.53 cm3 gÀ1. The
integrity of Keggin structure of PW was verified by 31P MAS
NMR; the catalysts showed only a single peak at ca. À15 ppm
characteristic of H3PW12O40 [27]. From XRD, the catalysts included
crystalline phase of PW on the silica surface. The acid strength of
silica-supported PW was characterized calorimetrically using
ammonia and pyridine adsorption and discussed in the previous
work [28].
3.1. Acetoxylation of
b
-caryophyllene in homogeneous systems
The results on transformations of
b
-caryophyllene (1)
in acetic acid solutions containing the dissolved PW catalyst
are presented in Table 2. All experiments were performed at
25 8C due to high reactivity of the substrate in the presence of
PW. In a blank reaction, with no catalyst added, only a 2%
conversion of
b-caryophyllene was observed in 8 h, giving
mainly high-boiling products, which were not determinable by
GC (run 1). The PW catalyst showed excellent performance
in this reaction. With 0.1 mol% catalyst, a nearly complete
2.4. Catalytic reactions
conversion of
b-caryophyllene was achieved in 4 h resulting in
The reactions were carried out in a glass reactor equipped with
the formation of two main products, 2a and 2b, in an 80/20
a magnetic stirrer. In a typical run, a mixture of
b
-caryophyllene
molar ratio (run 2). These were identified as two stereoisomers
(0.04–0.30 M), dodecane (0.10 M, internal standard) and
H3PW12O40 (0.07–0.35 mM) or PW/SiO2 (1.25–2.50 wt%) in a
specified solvent (acetic acid or cyclohexane, 10 mL) was intensely
stirred under air at a specified temperature (25–40 8C). The
reaction progress was followed by gas chromatography (GC) using
of b-caryolanyl acetate (Scheme 1). Isomers 2a and 2b differ by
the spatial position of the bridging methylene group. The total
selectivity for these two products was 58%, with the rest
attributed to oligomers. The determination of structures of 2a
and 2b is described below.

90
K.A.S. Rocha et al. / Applied Catalysis A: General 374 (2010) 87–94
Table 2
Homogeneous acetoxylation of
b
-caryophyllene (1) catalyzed by H3PW12O40 (PW) in acetic acid solutions at 25 8C.
b
Run
[1] (M)
[PW] (10À4 M)
Time (h)
Conversion (%)
Selectivity for 2a/2b (%)a
Rate (M hÀ1
)
TONc
1
2
0.15
0.30
0.15
0.07
0.04
0.15
0.15
0.05
0.07
None
3.5
3.5
3.5
3.5
1.7
0.7
0.7
5.3
8
2
98
0
58
–
–
840
420
200
114
882
2026
714
–
4
0.30
0.33
–
3
0.75
0.25
0.25
4
97
59
4
100
100
100
100
100
30
80
5
90
–
6
70
0.18
0.10
0.11
–
7
7
100
100
–
8
9d
3
6
a
2a/2b ꢀ 80/20 mol/mol.
b
c
Initial rate of the substrate conversion.
Turnover number: the number of substrate molecules converted per mol of PW.
H2SO4 was used as catalyst (5.3 Â 10À4 M).
d
Scheme 1. Acetoxylation of
b-caryophyllene (1).
Further studies revealed that the substrate oligomerization can
problems, the reaction was performed in cyclohexane as a solvent
with addition of small amounts of acetic acid, up to 10/1 mol/mol
of substrate (Table 3).
In blank tests, with no catalyst or pure silica added, practically
no reaction was observed at 25 8C (runs 1 and 2). On the other
be controlled by choosing appropriate reaction conditions. With a
decrease in the initial concentration of substrate, the selectivity for
2a and 2b gradually increased from 58 to 90% at the expense of
oligomers (runs 2–5). This can be explained by a higher reaction
order in substrate for oligomerization compared to the desired
hand, a nearly complete conversion of
b-caryophyllene was
acetoxylation of
b
-caryophyllene.
attained in 2 h in the presence of PW/SiO2 catalyst (run 3). Acetate
2 and the corresponding alcohol 3 accounted for 65% of the
converted substrate (Scheme 2). It is noteworthy that acetate 2
formed mainly as isomer 2a, with only trace amount of isomer 2b
detected. This result is different from that observed for the
homogeneous system, where the 2a/2b molar ratio was about 80/
The catalyst efficiency in terms of turnover number (TON) was
improved significantly by decreasing the amount of PW catalyst
(cf. runs 3, 6, and 7), however at the expense of reaction rate. Thus,
a virtually 100% selectivity to acetate 2, with a 2a/2b molar ratio of
80/20 and a TON of more than 2000, were achieved under
optimized conditions (runs 7 and 8).
20. Other products observed were attributed to
b-caryophyllene
isomers due to the characteristic GC retention times and the
presence of the molecular ion peak with m/z = 204 in their mass
spectra. Clovene (4) was identified as the predominant isomer,
which amounted to more than 50% of the isomer products. A
difference in the GC mass balance of 10% was observed and
attributed to high-boiling products (runs 3 and 5). With increasing
the concentration of acetic acid the selectivity to 2 and 3 drastically
3.2. Acetoxylation/hydration of
systems
b-caryophyllene in heterogeneous
The high solubility of PW in acetic acid prevents direct use of
silica-supported PW catalysts for the acetoxylation of -caryo-
phyllene in this solvent due to PW leaching. To avoid leaching
b
Table 3
a
Transformations of
b-caryophyllene (1) catalyzed by 20 wt% H3PW12O40(PW)/SiO2 .
Run
Catalyst (wt%)
HOAc (M)
T (8C)
Time (h)
Conversion (%)
Selectivity (%)b
Isomersb
2c
3d
Others
1
2
None
0.70
0.70
0.35
0.70
0.70
None
0.70
25
25
25
25
40
40
40
6
6
0
2
–
–
–
–
–
–
100
10
69
11
46
–
SiO2
–
30
9
3e
4
PW/SiO2 (2.50)
PW/SiO2 (2.50)
PW/SiO2 (1.25)
PW/SiO2 (1.25)
Amberlyst (0.5)
2
100
80
97
92
0
25
15
23
28
–
35
7
2
5
1
42
–
24
26
–
6
1
7
10
–
a
[1] = 0.07 M, in cyclohexane as a solvent.
b
c
Isomers of
b-caryophyllene, mainly clovene (4).
Mostly 2a, only trace of 2b.
d
e
Oligomeric products.
After reaction, the catalyst was separated by centrifugation, the supernatant was added with a fresh portion of substrate and allowed to react for 3 h, with no conversion
observed thereupon. The separated catalyst was reused 2 times without loss of activity and selectivity.

K.A.S. Rocha et al. / Applied Catalysis A: General 374 (2010) 87–94
91
Scheme 2. Acetoxylation/hydration of
b-caryophyllene (1).
decreased due to
b-caryophyllene oligomerization (run 4). In run 2,
Amberlyst-15 acidic resin was also tested in
b
-caryophyllene
the catalyst was separated and, after washing with hexane, reused
two times without any loss in its activity and selectivity.
conversion in cyclohexane solutions of acetic acid, but no catalytic
activity was observed (run 7).
Generally, water was not added to the reaction system. The
amount of hydration water present in the PW catalyst and
commercial reagents was sufficient for the formation of 3. It should
be noted that HPA crystalline hydrates could bear up to about 30
water molecules per Keggin unit. In addition, water could be
present inside SiO2 pores of the catalyst which had a pore volume
3.3. Product characterization
The chemical nature of major product 2a has been firstly
elucidated by GC–MS and then confirmed by NMR spectroscopy. In
the mass spectrum of 2a, peaks at m/e = 59, due to the formation of
acetate ion, and at m/e = 204, corresponding to the loss of acetic
acid molecule, are observed. This gives for the original molecule
the molecular weight of 264 corresponding to the product of the
of 0.53 cm3 gÀ1
.
Although PW is insoluble in non-polar solvents, the presence of
acetic acid in the reaction mixture could promote PW leaching
from the catalyst. To prove the absence of any contribution of
homogeneous catalysis, the catalyst was removed from the
reaction system after reaction completion, fresh substrate was
added to the supernatant and the reaction was allowed to proceed
further (run 2). No activity was observed in this experiment, which
indicates that PW did not leach from silica into the reaction
medium under the conditions used.
addition of acetic acid to
However, a significant difference in the relative intensities of the
mass peaks of -caryophyllene and 2a suggests that the carbenium
b-caryophyllene (M.M. = 204 g/mol).
b
ion derived from the substrate molecule undergoes isomerization
before the addition of the nucleophile. In the 1H NMR spectrum of
2a, a singlet at
d 1.97 corresponding to the methyl protons of the
acetate group was observed, without –CHO– signal present. This
indicates that the compound was a tertiary acetate.
Our attempt to minimize
b-caryophyllene isomerization and
oligomerization by varying reaction parameters had a limited
success. The best combined yield of 2 and 3 obtained was 66%, with
a TON of about 100 per mol of PW (Table 3, run 5). About 15% of
substrate isomerized to clovene in this run.
In the absence of acetic acid, the PW/SiO2 catalyst promoted the
isomerization and hydration of b-caryophyllene. However, under
Based on the 1H and 13C NMR spectroscopy data we suggested
the structure for product 2a is shown in Scheme 1. The
stereochemistry of 2a is shown in Scheme 3. The assignment of
the hydrogen and carbon resonances (Table 1) was carried out by
COSY (1H, 1H), HMQC (1H, 13C), HMBC (1H, 13C), and DEPT NMR. The
study of the HMBC spectra was decisive for building the molecular
skeleton of 2a. It was confirmed that the cyclobutane ring of the
substrate remains intact in this product. The strong cross peak
such conditions most of the converted substrate transformed into
unidentified high-boiling products (46% of the mass balance).
Scheme 3. Acid-catalyzed transformations of caryophyllene (1).

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K.A.S. Rocha et al. / Applied Catalysis A: General 374 (2010) 87–94
Scheme 4. Acid-catalyzed transformations of
b-caryophyllene (1).
observed in the COSY spectrum of 2a shows that the methine
proton at C-2, which appears in the 1H NMR as a quartet, is coupled
with both the methine proton at C-10 and the methylene protons
at C-1. On the other hand, in the HMBC spectrum, carbon C-10
correlates with both protons at C-1 via 3JCH. Furthermore, carbon C-
12 correlates with methyl protons at C-13 via 3JCH, whereas carbon
C-13 with methyl protons at C-12. This result indicates that both
methyl groups C-12 and C-13 are attached to the same carbon C-
11, which correlates, in its turn, with protons at C-12 and C-13 as
well as with protons at C-1 via 2JCH. Finally, both carbons C-12 and
C-13 correlate with the methylene protons at C-1 via 3JCH, whereas
with 2a (2a/2b ꢀ 2.5/1) because it is formed in the reaction as a
minor product. For this reason, we could not perform a complete
characterization of 2b by NMR. In the 1H NMR spectrum of the 2a/
2b mixture, most of the signals are overlapped and only the signals
from the methyl groups could be assigned to 2b. In the 13C NMR
spectrum, the signals from 2a and 2b are also very close or
overlapped. For example, the signal from the quaternary carbon C-
3 in 2a, which is bound to the acetate group, appears at
d 83.45 and
the corresponding carbon in 2b at 82.66. Thus, we believe that
d
products 2a and 2b are stereoisomeric acetates with the same
carbon skeleton, resulting from the different possibilities for the
position of the methylene C-15 bridge. The results of the NOESY
experiments suggest that in a major isomer 2a the proton at C-10
and the methylene C-15 bridge are at the same side of the nonane
ring, as shown in Scheme 3, because there is a strong correlation
signal between the protons at C-2 and C-4. Molecular modeling of
the structures shows that the proton at C-2 is spatially proximate
to protons at C-4 in 2a, but it is not in 2b. It should be mentioned
carbon C-10 with the methyl protons at both C-12 and C-13, also
3
via JCH
.
The formation of a bridge between carbons C-3 and C-7 through
carbon C-15 has been also unambiguously proved by the analysis
of long-range cross signals in HMBC spectra (Table 1). One of the
methylene protons at C-15 correlates via 3JCH with carbons C-2 and
C-4, on the one hand, and with carbon C-14, on the other hand.
Moreover, carbon C-15 also correlates with the protons of methyl
that the butane and nonane carbon rings in natural b-caryophyl-
lene are trans-linked, i.e., the protons at C-2 and C-10 are in a trans
position, as it is shown in Schemes 1–4.
3
group C-14 via JCH. Formally, the formation of this new tricyclic
skeleton from the bicyclic molecule of
b-caryophyllene can be
rationalized as the formation of the new C-7–C-15 bond and the
saturation of the C-6–C-7 olefinic bond. To facilitate the discussion
and signal comparison, carbon numbering used for 1 (according to
[30]) is maintained for 2a, 2b, and 3.
The mass spectra of 2a and 2b are very similar indicating that
these compounds seem to be closely related isomers. Compound
2b has been isolated from the reaction solutions only in a mixture
Product 3 was isolated from the reaction mixture as a pure
compound and characterized by GC–MS and NMR spectroscopy.
The mass spectrum of 3 also shows the heaviest peak at m/e = 204;
however, it is different from the spectra of 2a and 2b in the relative
abundance of the fragments. The data of 1H and 13C NMR
spectroscopy (Table 1) confirm that compound 3 is a tricyclic
alcohol with the same skeleton as acetate 2a (Scheme 2). In

K.A.S. Rocha et al. / Applied Catalysis A: General 374 (2010) 87–94
93
general, the NMR spectra of 3 are similar to those of 2a except the
absence of the signals corresponding to the acetate group and a
significant difference in the chemical shift of the signals from
products arise from the top attack. On the other hand, in 2b as well
as in clovene 4 the methylene bridge is oriented to the other side of
the nonane and octane ring, respectively, than the proton at C-10.
quaternary carbons C-3 bound with the hydroxyl group in 3 (
d
Therefore, these products arise from the bottom attack. A
71.00) and with the acetate group in 2a ( 83.45). Furthermore, the
d
nucleophilic attack of acetic acid or water on carbenium ions B
gives the corresponding addition products, whereas a rearrange-
ment of carbenium ion B exo via opening the four-membered ring
into carbenium ion C followed by the loss of a proton gives clovene
4.
GC retention time of 3 is slightly longer than that of 2a (less than
0.1 min), which is characteristic for the pair of the corresponding
alcohol and acetate.
The NOESY spectrum of alcohol 3 shows a strong correlation
signal between the protons at C-10 and C-15, showing their spatial
proximity. Thus, we can conclude that in alcohol 3, like in major
acetate 2a, the proton at C-10 and the methylene C-15 bridge are at
the same side of the nonane ring as shown in Scheme 2.
The protonation of the main ba-conformer as well as aa
-
conformer leads to carbenium ions incapable of cyclization
because of the unfavorable orientation of the exo-methylene
group. Therefore, it should be suggested that all b-caryophyllene is
pumped over to the conformers bb and aa where the exo-cyclic
double bond and carbon C-7 are spatially proximate and, therefore,
cyclization can occur. The bb-conformer (endo) originates
products 2a and 3 with the endo-oriented methylene bridge,
while the aa-conformer (exo) gives products 2b and 4 in which the
methylene bridge and proton at C-10 are in a ‘‘trans’’ position. The
relative amounts of the products do not correspond to the relative
amounts of the conformers: ba (75%), bb (21%), aa (3%), and ab
3.4. Reaction mechanism
b
-Caryophyllene is known to be one of the most remarkable
and versatile of terpenoids in its variety of skeletal transformations
[16]. The unusual structure of this compound contains trans-linked
butane and nonane carbon rings and a trans-substituted double
bond in the nonane ring. The molecule is extremely strained,
therefore, it is highly reactive, undergoing a variety of trans-
annular cyclizations to give more stable bi- and tricyclic systems.
(<1%). Thus, it has to be assumed that
a conformational
equilibrium is shifted toward the more reactive conformers, i.e.,
bb and aa, with the major products 2a and 3 resulting from the
more abundant conformer bb, as shown in Scheme 3.
Although the reactivity of the trisubstituted double bond in
b-
caryophyllene is usually higher than that of the exo-cyclic double
bond [16], the main products in acid-catalyzed reactions under
certain conditions can be originated from the protonation of the
exo-cyclic double bond [23].
It is interesting that in the homogeneous system, i.e., in pure
acetic acid, both acetates 2a and 2b are formed in ca. 80/20 ratio,
whereas the in heterogeneous system, i.e., at low acetic acid
concentrations, isomer 2b is detected only in trace amounts. On
the other hand, clovene 4 is formed in the heterogeneous system
instead of 2b, in approximately the same proportion to 2a and 3.
This can be explained suggesting that in pure acetic acid carbenium
ion B exo is rapidly captured by nucleophile to give acetate 2b,
whereas at low acetic acid concentrations it has enough time to
rearrange into more stable carbenium ion C and to lose a proton
(Scheme 4).
The higher selectivities for addition products 2 and 3 in pure
acetic acid, compared with those obtained in cyclohexane, can also
be explained by ion-solvating ability of acetic acid. In acetic acid
solution, solvated intermediate carbenium ions readily react with
the abundant nucleophilic solvent rather than with another
molecule of substrate, which would lead to oligomerization. In
contrast, non-polar non-basic cyclohexane is less capable to
prevent the nucleophilic attack of the substrate on cationic
intermediates, which favors the formation of high-boiling pro-
ducts.
The catalytic activities of PW and H2SO4 are compared in
Table 2 (run 4 vs. 9) under the same reaction conditions and with
the same total amount of protons. Being much stronger acid, PW
showed significantly higher catalytic activity and selectivity to
acetate 2 than H2SO4. Instead, the latter promoted the formation of
a variety of other products and oligomers. Besides its strong
acidity, the high effectiveness of PW can be related to a weak
interaction of the soft heteropoly anion with carbenium ion
intermediates [6]. This makes it unlikely for the heteropoly anion
to influence rearrangement of the carbenium ion intermediates. On
the contrary, the anions of conventional Brønsted acids are known
to affect such rearrangement, promoting side reactions.
At room temperature,
b-caryophyllene exists as a mixture of
four conformers separated by a low barrier of inversion, with two
of them, ba (75%) and bb (21%), amounting to 96% of the mixture
[31]. Two minor conformers are found in much smaller amounts:
aa (3%) and ab (<1%). Two pairs of conformers, ba
differ by the relative position of the hydrogen at C-10 and the
methyl group C-14 at carbon C-7. In exo conformers, ba and aa
/aa and bb/ab,
,
they are at the opposite sides of the nine-membered ring as shown
in Scheme 4, whereas in endo conformers, bb and ab, at the same
side, as shown in Scheme 3. The exo–endo rearrangement occurs
through the intramolecular rotation of the C-7–C-6–C-5–C-4
fragment. The difference between two conformers in each pair
is the orientation of the exo-methylene group (C-15). In major
conformers ba (exo) and bb (endo), the hydrogen at C-10 and the
exo-cyclic C-15 are at the same side of the nine-membered ring,
whereas in the minor conformers aa (exo) and ab (endo) at the
opposite sides (not shown in Schemes 3 and 4). Thus, in the
conformers bb and aa, the exo-cyclic double bond C-3–C-15 and
carbon C-7 are spatially proximate (carbons C-15 and C-14 are at
the same side of the nonane ring), whereas in the conformers ba
and ab they are not (carbons C-15 and C-14 are at the opposite
sides).
Suggested reaction pathways for the acid-catalyzed transfor-
mations of 1 into products 2–4 are presented in Schemes 3 and 4.
We suppose that products 2a and 3 are formed from one of the
endo conformers of b-caryophyllene (Scheme 3), whereas products
2b and 4 from one of exo conformers (Scheme 4), as described
below. The structure of the main products 2 and 3 suggests that
they arise from protonation of the internal double bond of the
substrate to give carbenium ions A endo and A exo followed by a
trans-annular ring closure to form a new C-7–C-15 bond. Two
isomers of acetate 2 arise from the different stereochemistry of the
nucleophilic attack of the exo-cyclic double bond at carbon C-7 in
the intermediate carbonium ion A: via the top side of the nonane
ring (with respect to the proton at C-10 as shown in Scheme 3) or
via the bottom side (Scheme 4). In major products 2a and 3, the
proton at C-10 and the methylene C-15 bridge are at the same side
of the nonane ring, as shown in Scheme 3. Therefore, these
4. Conclusions
Heteropoly acid H3PW12O40 (PW) is an active acid catalyst for
the liquid-phase acetoxylation of
b-caryophyllene to give b-
caryolanyl acetate (2) in homogeneous and heterogeneous
systems. An efficient and clean method for the synthesis of 2,
providing a mixture containing two stereoisomeric
b-caryolanyl

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K.A.S. Rocha et al. / Applied Catalysis A: General 374 (2010) 87–94
[12] K.A. da Silva Rocha, P.A. Robles-Dutenhefner, E.M.B. Sousa, E.F. Kozhevnikova, I.V.
Kozhevnikov, E.V. Gusevskaya, Appl. Catal. A 317 (2007) 171–174.
[13] K.A. da Silva, P.A. Robles-Dutenhefner, E.M.B. Sousa, E.F. Kozhevnikova, I.V.
Kozhevnikov, E.V. Gusevskaya, Catal. Commun. 5 (2004) 425–429.
[14] K.A. da Silva Rocha, J.L. Hoehne, E.V. Gusevskaya, Chem. Eur. J. 14 (2008) 6166–
6172.
acetates 2a and 2b, 2a/2b = 80/20 mol/mol, with 100% yield, has
been developed using PW as a homogeneous catalyst under mild
reaction conditions. The catalyst can be recovered without
neutralization and reused without loss of activity and selectivity.
[15] K.A. da Silva Rocha, P.A. Robles-Dutenhefner, I.V. Kozhevnikov, E.V. Gusevskaya,
Appl. Catal. A 352 (2009) 188–192.
Acknowledgments
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[18] N.V. Maksimchuk, M.N. Timofeeva, M.S. Mel’gunov, A.N. Shmakov, Y.A. Chesalov,
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M.S. Mel’gunov, Catal. Lett. 127 (2009) 75–82.
Financial support and scholarships from CNPq, CAPES, FAPE-
´
MIG, and INCT-Catalise (Brazil) are acknowledged.
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