Preparation and utilization of perillyl acetate

Article abstract of DOI:10.1007/s11164-012-0527-8

Perillyl acetate is a fragrance compound that was prepared by the reaction of β-pinenoxide with acetic anhydride and using acetic acid as an acid catalyst. Several selected catalysts were tested (homogenous: phosphoric acid, boric acid, acetic acid, and citric acid; heterogeneous: zeolite USY, SSA, and montmorillonite K-10) and the reaction conditions optimized for this reaction. The yield 78.7 % of perillyl acetate was obtained. Mayol (4- isopropylcyclohexylmethanol), a valuable fragrance compound, was further obtained by a two-step synthesis from perillyl acetate. Firstly, perillyl acetate was saponified to perillyl alcohol. The yield of alcohol was 94.4 %. The last step of the entire preparation was the hydrogenation of perillyl alcohol to Mayol. The yield of the desired product of this reaction was 94.6 %. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0527-8

Res Chem Intermed (2012) 38:2075–2084
DOI 10.1007/s11164-012-0527-8
Preparation and utilization of perillyl acetate
ˇ
Martina Stekrova Iva Paterova-Dudkova
•
•
´
Eliska Vyskocilova-Leitmannova Libor Cerveny
´
´
ˇ
•
ˇ
ˇ
´
´
´
Received: 27 June 2011 / Accepted: 3 March 2012 / Published online: 15 March 2012
Ó Springer Science+Business Media B.V. 2012
Abstract Perillyl acetate is a fragrance compound that was prepared by the
reaction of b-pinenoxide with acetic anhydride and using acetic acid as an acid
catalyst. Several selected catalysts were tested (homogenous: phosphoric acid, boric
acid, acetic acid, and citric acid; heterogeneous: zeolite USY, SSA, and montmo-
rillonite K-10) and the reaction conditions optimized for this reaction. The yield
78.7 % of perillyl acetate was obtained. Mayol (4-isopropylcyclohexylmethanol), a
valuable fragrance compound, was further obtained by a two-step synthesis from
perillyl acetate. Firstly, perillyl acetate was saponified to perillyl alcohol. The yield
of alcohol was 94.4 %. The last step of the entire preparation was the hydrogenation
of perillyl alcohol to Mayol. The yield of the desired product of this reaction was
94.6 %.
Keywords b-pinenoxide ꢀ Perillyl acetate ꢀ Perillyl alcohol ꢀ
Cis-4-isopropylcyclohexylmethanol (Mayol)
Introduction
Perillyl acetate is a fragrant compound whose use has been suggested especially in
perfumery, in particular as a modifier to selected essential oils (Bergamot, etc.) [1].
It is characterized by a spicy herbal odor suggestive of spearmint, whereas, in a
suitable dilution, it has a refreshing, fruity note. Perillyl acetate has also been used
in flavor compositions, mainly as a component of artificial spearmint and in spice
and condiment flavor blends.
ˇ
ˇ
´
´
´
ˇ
´
´
´
M. Stekrova (&) ꢀ I. Paterova-Dudkova ꢀ E. Vyskocilova-Leitmannova ꢀ L. Cerveny
Department of Organic Technology, Institute of Chemical Technology, Technicka 5,
16628 Prague 6, Czech Republic
e-mail: stekrovm@vscht.cz
123

ˇ
´
M. Stekrova et al.
2076
The starting material for the preparation of perillyl acetate can be b-pinenoxide
[2, 3], limonene [4, 5], pinocarveol [6, 7], or some other substances [8–10]. The
compound can be prepared by the reaction of b-pinenoxide with acetic anhydride in
dichloromethane as a solvent and with montmorillonite K-10 as an acid catalyst [3].
Alternatively, it can be prepared by the reaction with sodium acetate, acetic acid,
and Amberlite (IRC-50) [2], obtaining p-ment-1-en-8-acetoxy-7-ol, which yields
perillyl acetate under vacuum thermolysis. Methods starting from other substances
resulted in lower yields of perillyl acetate, e.g., only up to 40 % using 4-(2-hydroxy-
2-propyl)cyclohexene-1-methyl acetate as the starting material [9]. In general, the
simplest method for the preparation of perillyl acetate is the reaction of
b-pinenoxide with acetic anhydride in the presence of an acid catalyst.
The use of perillyl acetate has certainly not been limited only to the perfume
chemistry as it has also been used as the starting material in preparations of other
valuable specialty chemicals. However, perillyl alcohol also belongs to the most
interesting products prepared from perillyl acetate, owing to its antimicrobial and
antineoplastic activity [2] (for the treatment of breast, pancreas, lung, and colon
carcinomas). Perillyl alcohol has also been used as the initial substance for the
preparation of a high demand fragrance compound, i.e., 4-isopropylcyclohex-
ylmethanol, the so-called Mayol.
The main aim of this work was finding the most effective method for the
preparation of perillyl acetate from b-pinenoxide. The reaction system and
conditions were optimized. The tested catalysts were selected based on former
experience. The prepared perillyl acetate was first saponified yielding perillyl
alcohol (the optimal method was selected), which was hydrogenated producing
4-isopropylcyclohexylmethanol. Scheme 1 shows the individual steps of the
reaction.
Experimental
Chemicals
b-Pinenoxide was supplied by Aroma and used as received. Acetic anhydride, boric
acid, and anhydrous magnesium sulfate were purchased from Lach-Ner. Phosphoric
acid (84 %), citric acid, sodium hydroxide, methanol, and isopropyl alcohol were
OAc
OH
OH
NaOH
H2O
O
Ac2O
H+
H2
Scheme 1 Reaction scheme of cis-4-isopropylcyclohexylmethanol synthesis from b-pinenoxide with the
intermediate perillyl acetate
123

Preparation and utilization of perillyl acetate
2077
Table 1 Composition of
Component
ZrO2
Al2O3
30–40
Sulfates
10
catalyst SSA
Content (%)
50–60
Table 2 Properties of zeolite
Ratio of Si/Al
˚
Pore size (A)
Structure
3D
USY (CVB 720)
15
7.4
purchased from Penta. Acetic acid (99 %), potassium carbonate, and anhydrous
sodium carbonate were purchased from Lachema. Catalysts SSA (Table 1) and
NiSAT 320 RS were supplied by Su¨d Chemie. Zeolite USY (CVB 720; Table 2)
was purchased from Zeolyst International, montmorillonite K-10 from Aldrich,
c-alumina from ICT Prague, and tert-butyl methyl ether from Fluka Analytical.
Preparation of perillyl acetate
The preparation of perillyl acetate was carried out in a 2-necked flask (25 ml)
equipped with a condenser. Stirring and heating was accomplished using a magnetic
stirrer. In a typical experiment, 2 g (0.066 mol) of b-pinenoxide and 10 g
(0.098 mol) of acetic anhydride were added to the flask and the acid catalyst was
then slowly added. Then, 2 g of a homogenous catalyst was added dropwise into the
reaction mixture (100 wt% to b-pinenoxide), or 0.4 g of a heterogeneous catalyst
was added (20 wt% to b-pinenoxide). The reaction was carried out at the
temperature of 80 °C, while the reaction progress was monitored by GC.
In the case of a heterogeneous catalysis, the catalyst had to be activated before
the reaction by calcination under air at 420 °C for 1.5 h.
A subsequent rectification was carried out using a laboratory glass column
(Sulzer filling) with 15 theoretical plates.
Saponification of perillyl acetate
The saponification of perillyl acetate was carried out by two methods adopted from
the literature [2, 8]. Both the reactions were carried out in a flask with a condenser
on a magnetic stirrer.
1. The obtained perillyl acetate and a 30 % aqueous solution of sodium hydroxide
[8] were put into the flask and the heating commenced. The reaction proceeded
under a mild reflux (135 °C) for 3 h. Subsequently, the top layer was separated
and distilled.
2. Perillyl acetate, water, methanol, and anhydrous sodium carbonate [2] were
mixed in the flask, and the reaction mixture was stirred at room temperature
for 13 h. Finally, the extraction and purification of perillyl alcohol was carried
out.
123

ˇ
´
M. Stekrova et al.
2078
Hydrogenation of perillyl alcohol
Perillyl alcohol (2.4 g), nickel catalyst NiSAT 320 RS (0.24 g), and isopropyl
alcohol (80 ml) were introduced into the stainless steel autoclave Parr 4843 (volume
150 ml). The following reaction conditions were used: temperature 80 °C and
pressure 10 MPa. Samples were collected and analyzed using GC.
Analytical
The Agilent Technologies 6890 Network GC System gas chromatograph was used
with flame ionization detection to analyze all samples. A non-polar HP-5 column
was used (length 30 m, inside diameter 0.32-mm and stationary phase film thickness
0.25 lm).
The Saturn 2000 gas chromatograph combined with a mass spectrometer (GC/
MS) with an ion trap and 1177 injector was used for the identification of compounds
in the reaction mixture. The gas chromatograph contained a non-polar Cp-Sil 8 CB
Low Bleed MS column (length 30 m and inside diameter 0.25 mm).
Results and discussion
Preparation of perillyl acetate
The work was dedicated to the study of perillyl acetate formed from b-pinenoxide.
An optimal catalyst was identified, capable of opening both the rings (epoxidic and
carbonic) of the initial b-pinenoxide. The opening of only the epoxidic ring led to
the production of undesired products, in particular myrtenyl acetate (Scheme 2),
whereas the desired product was perillyl acetate and its isomers.
The reaction was carried out without any solvent. Similar reactions had been
carried out in N,N-dimethylformamide in previous research [11], but it was found
that this solvent could initiate undesirable polymerization reactions. Dichlorometh-
ane, recommended in the previous work [3], was not tested.
The influence of temperature was studied using reaction conditions with the same
reagent mass ratios as described in the experimental section (1 g of b-pinenoxide :
1 and 5 g of acetic anhydride : 5 g of catalyst and 1 g of acetic acid). The temperature
OAc
OAc
O
Ac2O
H+
+
myrtenyl acetate
perillyl acetate
Scheme 2 Reaction scheme of perillyl acetate preparation
123

Preparation and utilization of perillyl acetate
2079
range was from room temperature to 140 °C (reflux). The reaction proceeded very
quickly at both temperatures (Fig. 1 shows the course of the reaction). The yield of
perillyl acetate was almost the same in all cases. The main difference in using different
temperatures was in the composition of the reaction mixtures. Different isomers of
perillyl acetate were observed, while the highest yield of the sum of perillyl acetate and
its isomers was at 50 °C.
The optimum ratio of b-pinenoxide:acetic anhydride was for the reactions
determined at 80 °C using acetic acid as the catalyst. The optimum ratio was found
to be 1:5 b-pinenoxide:acetic anhydride by weight (Table 3). Using this ratio, the
highest yield of perillyl acetate was obtained (78.7 %). Higher and lower amounts of
acetic anhydride caused an increased formation of undesired products, in particular
myrtenyl acetate in higher amounts and unidentified polymeric by-products in lower
amounts.
In the following sections, the temperature of 80 °C and the ratio of b-pinenoxide
to acetic anhydride 1:5 were used.
Fig. 1 Reaction course of perillyl acetate preparation (reaction conditions: 1:5:1 b-pinenoxide:acetic
anhydride:acetic acid, 50 °C)
Table 3 Influence of the
Ratio
b-pinenoxide:
acid
Yield of
perillyl
acetate (%)
Yield of
myrtenyl
acetate (%)
Conversion of
b-pinenoxide
(%)
amount of acetic anhydride on
the composition of the reaction
mixture (reaction conditions:
2 h, 80 °C, 1:1 of b-
1:10
1:5
1:3
76.8
78.7
74.1
54.6
6.9
4.0
4.5
4.9
97.0
94.2
92.3
92.1
pinenoxide:acetic acid)
Bold type shows the highest
yield
1:1
123

ˇ
´
M. Stekrova et al.
2080
Homogenous catalysis
From inorganic acids, phosphoric acid (84 %) and boric acid were tested as
homogenous catalysts, whereas acetic and citric acids were selected from organic
acids.
Table 4 summarizes the results from experiments carried out with different
amounts of acetic acid (99 %) used as the catalyst. The highest yield of perillyl
acetate was achieved using acetic acid in 1:1 ratio to b-pinenoxide.
Two ratios of citric acid to b-pinenoxide (100 and 5 wt% acid to b-pinenoxide)
were tested: 100 % conversion of b-pinenoxide was achieved using the higher ratio,
but a large amount of myrtenyl acetate (33.4 %) was formed. Using the smaller ratio
of the acid, the reaction yielded 58.1 % of perillyl acetate and 17.5 % of myrtenyl
acetate at 91.6 % conversion of b-pinenoxide. It conspicuously demonstrated that
the use of citric acid was associated with a high content of myrtenyl acetate.
H3PO4 and H3BO3 were added to the reaction mixture in 1:1 weight ratio to
b-pinenoxide. In both cases, the formation of polymers was demonstrated by a
change in the reaction mixture color and viscosity. Due to the more vigorous
reaction using H3PO4 (very exothermic with an immediate color change), this acid
was excluded from further experiments. H3BO3 was used in a mass of 20 wt%
relative to b-pinenoxide. The yield of perillyl acetate was 74 % and the amount of
undesired myrtenyl acetate was 5 % after 2 h at 99.8 % conversion of b-pinenoxide.
Heterogeneous catalysis
The following heterogeneous catalysts were tested for their use in the preparation of
perillyl acetate: zeolite USY (CVB 720), SSA, montmorillonite K-10 [3], and
c-alumina. All these heterogeneous catalysts were added to the reaction at levels of
20 wt% relative to b-pinenoxide.
The best results were achieved using montmorillonite K-10 as the catalyst for the
reaction at 80 °C using 1:5 ratio of b-pinenoxide:acetic anhydride. The reaction
mixture immediately turned black after the addition of the catalyst. After 2 h, 100 %
conversion of b-pinenoxide was achieved yielding 70.4 % of perillyl acetate and 4.2
% of myrtenyl acetate; 100 % conversion of b-pinenoxide was also achieved using
the catalyst called SSA. The yield of perillyl acetate was only 63.9 % but there was
no myrtenyl acetate in the reaction mixture. An unidentified by-product was
detected in the reaction mixture at the level of 14.9 %. The same outcome was
Table 4 Influence of acetic
acid amount (reaction
Ratio
b-pinenoxide :
acid
Yield of
perillyl acetate
(%)
Yield of
myrtenyl
acetate (%)
Conversion of
b-pinenoxide
(%)
conditions: 80 °C, b-
pinenoxide:acetic anhydride 1:5)
1:5
57.4
78.7
73.7
63.6
15.2
4.0
95.8
94.2
95.4
92.9
1:1
1:0.5
1:0.2
7.8
Bold type shows the highest
yield
13.1
123

Preparation and utilization of perillyl acetate
2081
observed using zeolite USY (CVB 720). After 2 h, the yield of perillyl acetate was
55 % and myrtenyl acetate was not found in the final reaction mixture. The ring
opening catalyzed by c-alumina did not show a satisfactory performance, only a low
conversion of b-pinenoxide was achieved (58.9 %) and the yield of perillyl acetate
was only 33.7 %.
Table 5 summarizes the best results obtained using different catalysts.
Next, an experiment was carried out on a larger scale (2 l). The reaction
conditions for perillyl acetate formation were: 1:3:1 ratio of b-pinenoxide:acetic
anhydride:acetic acid at the temperature of 80 °C. The yield of perillyl acetate was
74.8 % after 2 h.
Saponification of perillyl acetate
As mentioned above, two saponification processes were adopted from the literature.
The first [8] uses an aqueous solution of sodium hydroxide and the second [2] uses a
methanolic solution of sodium carbonate and water. The obtained perillyl alcohol
was purified by vacuum distillation at 1.2 kPa, b.p. 130 °C.
Table 6 shows the comparison of both utilized methods.
Hydrogenation of perillyl alcohol
The next step was the hydrogenation of perillyl alcohol to cis-4-isopropylcyclohex-
ylmethanol (Mayol). The reaction was carried out using the nickel supported
catalyst NiSAT 320 RS under the reaction conditions provided in the ‘‘Experi-
mental’’ section. After 3 h, the yield of both isomers of 4-isopropylcyclohex-
ylmethanol was 87.1 % (48.2 % of cis-isomer and 39 % of trans-isomer) at 100 %
conversion of perillyl alcohol. Dihydroperillyl alcohol (7 %, equal to the sum of all
isomers of dihydroperillyl alcohol) was also contained in the reaction mixture. After
6 h, the composition of the reaction mixture consisted of 94.6 % of 4-isopropylcy-
clohexylmethanol (54.1 % of cis-isomer and 40.5 % of trans-isomer) and 2.4 % of
dihydroperillyl alcohol (Fig. 2).
Table 5 Summary of the best results obtained using homogenous and heterogeneous catalysts
(reaction conditions: 80 °C, 1:5 b-pinenoxide:acetic anhydride)
Catalyst
Yield of perillyl
acetate (%)
Yield of myrtenyl
acetate (%)
Conversion of
b-pinenoxide (%)
Acetic acid (100 wt%)
Boric acid (20 wt%)
Montmorillonite K-10 (20 wt%)
SSA (20 wt%)
78.7
73.5
70.4
63.9
58.1
55.0
33.7
4.0
5.1
94.2
99.8
4.2
100.0
100.0
91.6
0.0
Citric acid (5 wt%)
17.5
0.0
USY (CVB 720) (20 wt%)
c-Alumina (20 wt%)
92.9
13.9
58.9
123

ˇ
´
M. Stekrova et al.
2082
Table 6 Summary of results for both saponification methods
The saponification using
30 % water solution Methanol solution of Na2CO3
of NaOH
Content of perillyl acetate (%)
0.0
0.7
100
93.4
5.9
13
Catalyst amount (wt% to perillyl acetate) 120
Yield of perillyl alcohol (%)
Yield of unknown by-products (%)
Reaction time (h)
94.0
6.0
3
Reaction temperature (°C)
Final processing of reaction mixture
135
85
Separation of water
phase and vacuum
distillation
Filtration of Na2CO3, elimination
of methanol, extraction with
terc-butyl methyl ether, drying
with magnesium sulfate, filtration
of magnesium sulfate, and
vacuum distillation
Fig. 2 Reaction course of perillyl alcohol hydrogenation (10 wt% of the catalyst, 80 °C, 10 MPa)
Various isomers of dihydroperillyl alcohol formed in the reaction mixture during
the hydrogenation of perillyl alcohol. Most of these isomers were further
hydrogenated. Only one of these isomers (4-(1-methylethylidene)cyclohexanemeth-
anol, Scheme 3) remained in the reaction mixture at the level of 2.4 % after 6 h of
reaction time. This isomer was resistant to hydrogenation under the selected
reaction conditions.
123

Preparation and utilization of perillyl acetate
2083
OH
Scheme 3 4-(1-Methylethylidene)cyclohexanemethanol
OAc
OAc
OAc
H2
+
+
+
a
c
b
d
Scheme 4 Scheme of perillyl acetate hydrogenation
Hydrogenation of perillyl acetate
An alternative method for the preparation of cis-4-isopropylcyclohexylmethanol is
the hydrogenation of perillyl acetate, followed by saponification. Hydrogenation of
perillyl acetate was performed under the same conditions as the hydrogenation of
perillyl alcohol (catalyst NiSAT 320 RS 10 wt%, 80 °C, 10 MPa of isopropyl
alcohol). The reaction mixture analysis showed that this alternative method was not
suitable for the preparation of cis-4-isopropylcyclohexylmethanol as high amounts
of undesired products were present in the reaction mixture. Moreover, the
hydrogenation itself proceeded with a lower rate. The final reaction mixture
(Scheme 4) contained 37.4 % of 1-methyl-4-(propan-2-yl)cyclohexane (a),
1-methyl-4-(propane-2-yl)cyclohexene (b), 12.5 % of [4-(propan-2-yl)cyclohexen-
1-yl]methyl acetate (d), and 32.1 % of the desired [4-(propane-2-yl)cyclo-
hexyl]methyl acetate (c).
Conclusion
The preparation of perillyl acetate from b-pinenoxide was carried out followed by
its conversion to perillyl alcohol and to the desired fragrant compound
4-isopropylcyclohexylmethanol (Mayol). The best results for the preparation of
perillyl acetate were obtained using acetic acid (1:1 ratio related to b-pinenoxide) as
the catalyst at 50 °C and an acetic anhydride ratio of 5:1 with respect to
b-pinenoxide. The yield achieved of perillyl acetate was 78.7 %. Myrtenyl acetate,
which was an undesired reaction product, was present in the reaction mixture at
123

ˇ
´
M. Stekrova et al.
2084
around 4 %, but the mixture was successfully distilled. After the separation steps,
the yield was 67 % of perillyl acetate with its purity of 98 %.
Perillyl alcohol was prepared by saponification followed by distillation. The yield
of perillyl alcohol was 94.4 at 100 % conversion of perillyl acetate. Finally,
4-isopropylcyclohexylmethanol was prepared. The yield of this desired fragrance
compound was 47.7 % calculated on the initial b-pinenoxide.
Acknowledgments This work was carried out with a financial support of the Grant Agency of the
Czech Republic (Grant No. 203/08/H032-1) and the Ministry of Education, Youth and Sports of the
Czech Republic, the research project #MSM 604 613 73 0.
References
1. S. Arctander, Perfume and Flavor Chemicals II, part 1 (Montclair, New Jersey, 1969)
2. D.E. Chastain, N. Mody, G. Majetich: US 5994598 (1999), CAN 132:3478
3. L.E. Tatarova, D.V. Korchagina, K.P. Volcho, N.F. Salakhutdinov, V.A. Barkhash, Russ. J. Org.
Chem. 39, 1147 (2003)
4. J.A. Goncalves, E.V. Gusevskaya, Appl. Catal. A-Gen. 258, 93 (2004)
5. A.D. Silva, E. D0Elia, H.R. Bizzo, L. Cardozo-Filho, O.A.C. Antunes, Ciencia & Engenharia 16, 41
(2007)
6. H. Miyawaki, Ch. Yukawa, Chem. Soc. Japan 23, 80 (1979)
7. Jpn. Kokai Tokkyo Koho, JP 56049339 (1981), CAN 95:169543
8. Ansari H. R., Fido P. E.: GB 1508602 (1974), CAN 84:122072
9. G. Majetich, R. Hicks, F. Okha, New. J. Chem 23, 129 (1999)
10. Miyawaki, H.: JP 54059253 (1979), CAN 91:175557
11. Q. Li, X. Wang, D. Yin, Y. Xiao, Ch. Duan, Xiangliao Xiangjing Huazhuangpin 2, 10 (2002)
123