Water-promoted kinetic separation of trans- and cis-limonene oxides

Article abstract of DOI:10.1002/cjoc.201100455

The efficient hydrolytic kinetic separation of trans/cis-(R)-(+)-limonene oxides was realized in a 1:1 mixed solvent of water and 1,4-dioxane without additional catalyst. Optically pure trans-(R)-(+)-limonene oxide was recovered in high yield (77%).

Full text of DOI:10.1002/cjoc.201100455

FULL PAPER
DOI: 10.1002/cjoc.201100455
Water-Promoted Kinetic Separation of trans- and
cis-Limonene Oxides
Xu, Zhao-Bing(徐招兵)
Qu, Jin*(渠瑾)
State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
The efficient hydrolytic kinetic separation of trans/cis-(R)-(＋)-limonene oxides was realized in a 1∶1 mixed
solvent of water and 1,4-dioxane without additional catalyst. Optically pure trans-(R)-(＋)-limonene oxide was re-
covered in high yield (77%).
Keywords trans/cis-(R)-(＋)-limonene oxides, kinetic separation, water, 1,4-dioxane
Introduction
Scheme 1 Hydrolytic kinetic separation of trans/cis-(R)-(＋)-
limonene oxides under acidic condition
Monoterpene epoxides, in particular limonene oxide,
serve either as starting material in synthesis of natural
products or as the chiral core of chiral auxiliaries in
O
O
hydrolytic kinetic separation
[
1]
+
asymmetric synthesis.
The direct epoxidation of
(R)-(＋)-limonene gave a diastereomeric mixture of
trans- and cis-(R)-(＋)-limonene oxides (1∶2＝1∶1)
trans-(R)-(+)-Limo- cis-(R)-(+)-Limo-
which were difficult to separate by fractional distilla-
nene oxides (1)
nene oxides (2)
[2]
tion. The chemical method employed to separate these
diastereomeric isomers is based on their different reac-
tion rates in epoxide ring-opening reactions. In the nu-
cleophilic ring opening of trans- and cis-limonene ox-
ides by secondary amines, the ring opening of the
trans-isomer 1 is more facile and the unreacted
cis-isomer 2 can be recovered after the complete con-
O
OH
OH
+
trans-(R)-(+)-Limo-
nene oxides (1)
trans-Diaxial-
diol (3)
[
3]
sumption of trans-isomer. However, in acidic condi-
tion, the hydrolysis of trans- and cis-(R)-(＋)-limonene
oxides leads to the same trans-diaxial diol 3 but in dif-
ferent reaction rate. The selective axial nucleophilic
attack to cis-isomer 2 is faster due to steric hindrance
and electronic effects that can be rationalized by the
focused on finding more environmentally friendly
[
11]
chemical processes.
The use of water as solvent or
co-solvent in organic reactions has attracted great atten-
tions from the organic community and a number of re-
[
12]
[13]
[4]
ports have emerged. Since Breslow et al. observed
an exceptional acceleration of the Diels-Alder reaction
in water in 1980, the rate-enhancing effect is widely
observed in organic reactions operated in water without
Fürst-Plattner rule (Scheme 1). It was reported that
[5]
Lewis acids (e.g. lanthanoid benzoate, β-ketophos-
[
6]
phonate complexes of molybdenum (VI)), photo-as-
[
7]
[8]
sisted Lewis acids, Brønsted acids (e.g. HClO
4
,
1
[14]
[
9]
[10]
additional catalyst. In our previous study, hot water
was found to exhibit similar property to that of near-
critical water, and it could act as a mild Brønsted acid
mol/L aq. NaHSO
3
,
acidic buffer solutions ), or
[3]
non-nucleophilic amines (triazole and pyrazole ) could
catalyze the hydrolytic kinetic separation of 1 and 2.
Some of the existing methods either suffered from haz-
ardous reagents used,
or low efficiency of separation.
[15]
catalyst in epoxide-opening reactions.
Here we re-
[6-8]
[6,9]
ported that the hydrolytic kinetic separation of trans-
and cis-(R)-( ＋ )-limonene oxides could be accom-
plished in refluxing mixed solvent of water and
1,4-dioxane without additional catalyst.
long reaction time needed,
[
9]
In recent years, green chemistry has become a
growing research area and much attention has been
*
E-mail: qujin@nankai.edu.cn; Tel.: 0086-(22)-23499247
Received October 6, 2011; accepted October 25, 2011; published online March 7, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100455 or from the author.
Chin. J. Chem. 2012, 30, 1133—1136
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1133

Xu & Qu
FULL PAPER
Experimental
lytic separations. After cis-limonene oxide was totally
consumed, trans-limonene oxide was recovered in 8%
yield (recovered yield was based on the initial amount
of trans-limonene oxide in the mixture, Entry 1, Table
1
13
H NMR and C NMR spectra were recorded on a
1
Varian Mercury Plus 400 spectrometer at 400 MHz ( H
NMR) and 100 MHz ( C NMR) in CDCl . Chemical
3
13
1
). We assumed that extremely hydrophobic epoxides
shifts were reported down field from internal TMS. GC
analysis was recorded using SHIMADZU GC-2014
model equipped with an rtx-5 column. Phenyl n-butyl
ether was used as an internal standard. Organic solvents
used were purified by standard methods. trans/cis-(R)-
such as limonene oxide should reacted faster when a
suitable organic co-solvent was added as the dissolution
of the substrate was needed for their hydrolysis. Thus
several water soluble organic co-solvents were tested in
the reaction system and the results of the hydrolytic
separations were summarized in Table 1. In all cases,
the reaction was ceased after the total consumption of
the cis-limonene oxide monitored by GC analysis.
(＋)-Limonene oxides were synthesized from (R)-(＋)-
limonene with a 1∶1 mixture of two diastereomeric
[
16]
isomers.
3 3
When polar solvent like acetone, CH OH, CH CN, or
General procedure for preparation of trans-(R)-
(＋)-limonene oxide in gram scale
DMF was used as the co-solvent, the rate of the reaction
was similar compared with that performed in pure water
and the yield of the recovered trans-limonene oxide was
low (Entries 2—5, Table 1). The reaction rate was
largely increased in the 1∶1 mixture of water and eth-
ylene glycol and 58% of trans-limonene oxide was re-
covered (Entry 6). In the 1 ∶ 1 mixed solvent of
trans/cis-(R)-(＋)-Limonene oxides (5.8 g, 38 mmol),
distilled water (30 mL) and 1,4-dioxane (30 mL) were
added to a 100 mL of round-bottom flask equipped with
a magnetic stir bar and a reflux condenser. The reaction
mixture was heated to reflux and ceased until total con-
sumption of the cis-(R)-(＋)-limonene oxide occurred as
detected by GC analysis (1.5 h). The mixture was ex-
tracted by diethyl ether, washed with brine and then
dried over anhydrous sodium sulfate. The crude product
was purified by column chromatography to give
trans-(R)-(＋)-limonene oxide 1 (hexane∶diethyl ether
1
,4-dioxane and water, the hydrolysis of cis-limonene
oxide was completed in 2 h and trans-limonene oxide
was recovered in 71% yield (Entry 7). With another two
etheric solvent THF or DME, 2% or 38% of
trans-limonene oxide was recovered respectively (En-
＝
＞
95∶5, R
f
＝0.5) as a colorless oil (2.2 g, 74% yield,
Table 1 Hydrolytic kinetic separation of trans/cis-(R)-(＋)-
99% de, recovered yield was based on the initial
limonene oxides in water or a mixed solvent of water and organic
a
amount of trans-(R)-(＋)-limonene oxide in the
trans/cis-(R)-(＋)-limonene oxides) and trans-diaxial
co-solvent under refluxing condition
O
diol 3 (hexane∶EtOAc＝70∶30, R
f
＝0.25) as a white
H O: 1,4-dioxane = 1:1
2
solid (3.9 g, 95% yield, ＞99% de, this yield was cal-
culated based on the recovered trans-limonene oxide).
Reflux
[9]
trans-(R)-(＋)-Limonene oxide 1
Colorless oil;
20
[9]
25
trans/cis-Limonene oxides
[
α] ＋76 (c 0.98, CHCl
3
) [lit. [α]D ＋76 (c 0.98,
, 400 MHz) δ: 4.67 (s, 2H),
D
1
CHCl
3
)]; H NMR (CDCl
3
OH
OH
O
2
1
1
1
2
.99 (d, J ＝ 5.2 Hz, 1H), 2.05—2.00 (m, 2H),
.88—1.85 (m, 1H), 1.74—1.62 (m, 2 H), 1.67 (s, 3 H),
.39—1.36 (m, 2H), 1.33 (s, 3H); C NMR (CDCl ,
3
+
13
00 MHz) δ: 149.15, 109.03, 59.20, 57.44, 40.67, 30.68,
trans-Limonene oxide
trans-Diaxial diol
9.81, 24.27, 23.04, 20.16.
[
3]
trans-Diaxial diol 3
White solid, m.p. 70—71
trans-Limonene oxide
recovered /%
20
[10]
20
Entry Organic solvent
t/h
b
℃
; [α] ＋25.6 (c 1, CHCl
3
) [lit.
[α]D ＋18.1 (c
D
1
0
2
1
1
.01, CHCl
3
)]; H NMR (CDCl , 400 MHz) δ: 4.74 (s,
3
1
2
3
4
5
6
7
8
None
16
25
16
17
15
2.5
2
8
H), 3.65 (m, 1H), 2.31—2.23 (m, 1H), 1.97—1.90 (m,
H), 1.81—1.75 (m, 1H), 1.74 (s, 3H), 1.71—1.65 (m,
Acetone
5
1
3
CH
3
OH
14
10
12
58
71
2
H), 1.60—1.52 (m, 5H), 1.28 (s, 3H); C NMR
, 150 MHz) δ: 149.13, 108.97, 73.72, 71.43,
7.39, 33.84, 33.61, 26.35, 26.05, 21.06.
CH CN
3
(CDCl
3
3
DMF
Ethylene glycol
1,4-Dioxane
THF
Results and Discussion
17
3.5
The hydrolysis of trans/cis-(R)-(＋)-limonene oxides
was firstly tried in water. In pure water, the hydrolysis
of both trans- and cis-limonene oxides proceeded
slowly under refluxing condition. cis-Limonene oxide 2
reacted a little faster than trans-limonene oxide 1 which
was identical with that found in acid catalyzed hydro-
9
a
DME
38
Reaction condition: 0.2 mmol of trans/cis-(R)-(＋)-limonene
oxides were refluxed in 2 mL of water and 2 mL of organic
co-solvent for indicated time. The yield was determined by GC
with phenyl n-butyl ether as an internal standard.
b
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Chin. J. Chem. 2012, 30, 1133—1136

Water-Promoted Kinetic Separation of trans- and cis-Limonene Oxides
tries 8 and 9). Overall, the fastest reaction led to the
highest recovered yield of trans-limonene oxide, and
dissolution of the substrate increased, but excessive
amount of 1,4-dioxane was harmful to the reaction since
1,4-dioxane could disturb the ionization of water and
1
,4-dioxane was the most suitable organic co-solvent.
Then the ratio of water to 1,4-dioxane in the mixed
[17]
the reaction system became less acidic. It seemed that
the concentration of the substrate was not crucial in the
reaction (Entries 3, 5—7). The highest recovery of
trans-limonene oxide was obtained at the concentration
of 0.025 mol/L in which trans-isomer 1 (purity＞99%)
was recovered in 77% yield (Entry 6, Table 2). Fur-
thermore, when this reaction was scaled-up to gram
level, trans-limonene oxide could also be recovered in
high yield (＞70%). The amounts of trans-limonene
oxide 1, cis-limonene oxide 2, and trans-diaxial diol 3
in the reaction process plotted as functions of time were
shown in Figure 1.
solvent and the concentration of the substrate were fur-
ther studied (Table 2). The amount of the recovered
trans-limonene oxide increased when a small amount of
1
5
,4-dioxane was added initially, reaching a maximum at
0% volume ratio of 1,4-dioxane, then the reaction rate
decreased sharply with further addition of 1,4-dioxane
Entries 1—4, Table 2). This suggested that suitable
(
amounts of 1,4-dioxane made the reaction faster as the
Table 2 Hydrolytic kinetic separation of trans/cis-(R)-(＋)-
limonene oxides in mixed solvent of water and 1,4-dioxane under
a
reflux condition
O
H O/1,4-Dioxane
2
Reflux
trans/cis-Limonene oxides
OH
OH
O
+
trans-Limonene oxide
trans-Diaxial diol
cis/trans-Limonene
H
2
O∶1,4-
trans-Limonene
oxide recovered /%
Entry oxides concentr-
t/h
b
Figure 1 Reaction profile of the hydrolytic kinetic separation of
trans/cis-(R)-(＋)-limonene oxides 1 and 2 (0.2 mmol) in equal
volume of water (4 mL) and 1,4-dioxane (4 mL).
Dioxane
－
1
ation/(mol•L )
1
2
3
4
5
6
0.05
5∶1
2∶1
1∶1
1∶2
1∶1
1∶1
1∶1
70
56
68
71
58
70
77
69
0.05
75
The hydrolysis of trans/cis-(R)-(＋)-limonene oxides
0.05
75
[
4]
was consistent with the Fürst-Plattner rule. The epox-
ide was activated with proton from the ionization of
water. The axial nucleophilic attack of water at the
C-1-carbon atom of a chair-like transition state of
cis-(R)-(＋)-limonene oxide led to the trans-diaxial diol
3 rapidly. In contrast, the axial nucleophilic attack of
water at the C-1-carbon atom of trans-(R)-(＋)-limo-
nene oxide 1 was stereo-hindered, water can only attack
the C-2-carbon atom, affording the same product
0.05
420
105
120
60
0.033
0.025
0.02
7
a
Reaction condition: 0.2 mmol of trans/cis-(R)-(＋)-limonene
oxides were refluxed in a mixed solvent of water and 1,4-dioxane
for indicated time. The yield was determined by GC with phenyl
n-butyl ether as the internal standard.
b
Scheme 2 Selective opening of cis-(R)-(＋)-limonene oxide
H
O
1
O
H O+
3
δ+
Me
2
fast
Me
cis-(R)-(+)-Limonene oxide 2
H O
2
OH
OH
trans-Diaxial diol 3
H O
2
H O
3
Me
slow
+
δ
Me
O
1
2
O
trans-(R)-(+)-Limonene oxide 1
H
Chin. J. Chem. 2012, 30, 1133—1136
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www.cjc.wiley-vch.de
1135

Xu & Qu
FULL PAPER
trans-diaxial diol 3, but with very low reaction rate.
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Massi, M.; Tuck, K. L. Synthesis 2007, 1523.
[
1
Conclusions
[
[
In summary, we reported a simple and less hazard-
ous way to operate the hydrolytic kinetic separation of
trans/cis-(R)-( ＋ )-limonene oxides. This discovery
again suggested that hot water can act as a mild acid
catalyst to promote organic reactions. The roles water
played during the separation were solvent, reactant, and
Brønsted acid catalyst. This method was superior to the
existing methods for not using additional catalysts, high
yield and high purity of trans-(R)-(＋)-limonene oxide
recovered and relatively fast reaction rate.
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Natural Science Foundation of China (Nos. 20772065
and 21072098), Program for New Century Excellent
Talents in University. We thank Mr. Liang Yan-Liang at
Nankai University for helpful discussions.
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