The influence of solvent choice, acid activation and surfactant addition on the hydrolytic kinetic resolution (HKR) of terminal epoxides

Article abstract of DOI:10.1016/j.tetasy.2004.11.024

The recently developed hydrolytic kinetic resolution (HKR) of epoxides catalysed by the Co-Jacobsen catalyst, is one of the most useful methods to obtain enantiomerically pure epoxides and/or diols. Several parameters can significantly influence the homog

Full text of DOI:10.1016/j.tetasy.2004.11.024

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 657–660
The influence of solvent choice, acid activation and
surfactant addition on the hydrolytic kinetic resolution (HKR)
of terminal epoxides
a,b
Sven Aerts, Anita Buekenhoudt, Herman Weyten, Ivo F. J. Vankelecom and
a
a
b,
*
b
Pierre A. Jacobs
a
Process Technology, Flemish Institute for Technilogical Research (VITO), Boeretang 200, 2400 Mol, Belgium
b
Faculty of Bio-engineering Sciences, Kasteelpark, Arenberg 23, 3001 Leuven, Belgium
Received 13 October 2004; accepted 10 November 2004
Available online 21 January 2005
Abstract—The recently developed hydrolytic kinetic resolution (HKR) of epoxides catalysed by the Co-Jacobsen catalyst, is one of
the most useful methods to obtain enantiomerically pure epoxides and/or diols. Several parameters can significantly influence the
homogeneous reaction. Several factors including the used solvent, the activation of the catalyst and the use of surfactants, are
investigated.
Ó 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
During the reaction, the immiscibility of certain epox-
ides with the water used in the HKR can pose problems
with regard to mass transfer. However, it is stated in lit-
erature that the addition of (±)-1,2-epoxyhexane ren-
The recently developed hydrolytic kinetic resolution
HKR) of epoxides, catalysed by the Co(III)-Jacobsen
catalyst, is one of the most elegant methods for the syn-
(
1
dered the reaction mixture homogeneous.
1
thesis of both enantiomerically pure epoxides and diols.
Water is an extremely appealing reagent for the resolu-
tion of epoxides, since it does not generate any waste,
it is cost effective, safe and environmentally benign.
These factors, which influence the activity and selectivity
of the HKR reaction, are investigated using 1,2-epoxy-
hexane and styrene oxide as test substrates. Differ-
ent solvents are used in the HKR of 1,2-epoxyhexane
to select the optimal solvent. The method of cata-
lyst activation and the influence of the addition of
a surfactant to the reaction mixture is investigated
for the HKR of styrene oxide under solvent-free
conditions.
The HKR is typically carried out using diethylether
2
3
(
Et O) or tetrahydrofuran (THF) as a solvent or under
2
1
solvent-free conditions. Prior to the reaction, the
Co(II)-Jacobsen complex, which is catalytically inactive,
has to be activated through a one-electron oxidation to
produce the active Co(III)-Jacobsen catalyst. Originally,
the Co(II)-complex was activated ex situ through oxida-
tion of the complex with acetic acid dissolved in tolu-
2. Results and discussion
1
ene. Lately however, it has been reported that in situ
activation of the Co(II)-Jacobsen complex in the pres-
2
3
The possibility to use Et O or THF as a solvent in the
2
4
HKR of epoxides has been suggested. Nevertheless, use
of other solvents for the HKR could be very interesting.
The results for 1,2-epoxyhexane are shown in Figure 1.
ence of epoxide is possible. The use of acetic acid is
an option, but it was shown recently that the use of elec-
5
tron-deficient aromatic acids afforded better results.
Figure 1 clearly shows that besides Et O the use of
2
IPA also resulted in good reactivity and selectivity. All
other tested solvents exhibit a significantly lower reactiv-
ity and besides THF, toluene and hexane, they also ex-
hibit a significantly lower ee for the formed diol. The
enantioselectivities of the remaining epoxides cannot
*
0
Corresponding author. Tel.: +32 16 321594; fax +32 16 321998;
e-mail: ivo.vankelecom@agr.kuleuven.ac.be
957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.024

658
S. Aerts et al. / Tetrahedron: Asymmetry 16 (2005) 657–660
1
00
100
9
0
90
8
0
7
0
80
70
60
6
0
5
0
4
0
50
3
0
4
0
2
0
3
0
1
0
0
2
0
ee β-hydroxyether [%]
ee diol [%]
ee epoxide [%]
conversion [%]
10
0
ee epoxide [%]
Conversion [%]
MeOH
EtOH
n-PrOH
Figure 1. Conversions and selectivities for the HKR of 1,2-epoxy-
hexane in different solvents (S/C = 100, H O/S = 0.56 at rt after 24 h).
Figure 3. Conversion, ee of the epoxide and of the b-hydroxyether for
,2-epoxyhexane in different primary alcohols after 24 h.
2
1
be compared because of the conversion dependency of
the ee of the epoxide.
reaction rate decreased with increasing chain length of
the primary alcohol (Fig. 3).
Use of IPA in the HKR of epoxides offers the advantage
that the reaction mixture becomes one-phase since the
water dissolves completely in the IPA solution, whereas
As mentioned earlier, the inactive Co(II)-Jacobsen cata-
lyst has to be activated via acid treatment in the presence
of air to the active Co(III)-complex. Four aromatic
acids, namely benzoic acid (BA), 4-toluic acid (4-TA),
use of Et O results in a two-phase system. This is one of
2
the reasons why the reaction in IPA proceeds faster than
the reaction in Et O. A disadvantage of the use of
4
(
-fluorobenzoic acid (4-FBA) and 4-nitrobenzoic acid
4-NBA), were tested in the in situ activation of the
2
IPA as solvent is the faster deactivation of the Co(III)-
Jacobsen catalyst compared to Et O, but the deactivated
Co(II)-Jacobsen catalyst for the HKR of styrene oxide
and the obtained results are shown in Figure 4 (conver-
sion) and Table 1 (enantioselectivities).
2
Co(II)-Jacobsen catalyst can be easily reactivated by
acid treatment in the presence of air.
5
Figure 4 confirms the results obtained by Liu et al. The
Besides IPA several other alcohols were screened,
namely methanol (MeOH), ethanol (EtOH) and n-
propanol (PrOH). Use of these primary alcohols as sol-
vents resulted in the formation of the corresponding
b-hydroxyethers instead of the desired diol (Fig. 2).
Primary alcohols are used as the nucleophile in this
case. Use of IPA as solvent on the other hand resulted
in the formation of the desired alcohol and formation
of the corresponding b-hydroxyether was not observed.
The formation of the hydroxyethers proved to be regio-
selective, since only the formation of the 1-alkoxy-2-
hydroxy products was observed. The reactions with
the different alcohols furthermore revealed that the
in situ activation by 4-TA clearly affords the slowest
reaction, while the activation by the two aromatic acids
with an electron withdrawing group in the para-position
shows the highest reaction rate, with 4-NBA the most
Table 1. Obtained ee for styrene oxide and 1-phenyl-1,2-ethanediol for
different aromatic acids after 4 h
Acid
Eeepoxide (%)
Eediol (%)
BA
53
45
71
84
96
97
96
95
4-TA
4-FBA
4-NBA
H
H
N
O
N
O
Co
t-But
t-But
OAc
O
O
t-But
t-But
RO
OH
C4H9
+
C4H9
C4H9
ROH
Figure 2. Formation of b-hydroxyethers through ARO with primary alcohols.

S. Aerts et al. / Tetrahedron: Asymmetry 16 (2005) 657–660
00
659
100
1
8
6
4
2
0
0
0
0
0
8
0
0
0
0
0
6
4
2
No surfactant
Brij 30
Bis-2-ehss Na salt
Tween 20
Igepal CA 630
4
4
4
-NBA
-FBA
-TA
BA
0
1
2
3
4
5
6
Time [h]
0
1
2
3
4
5
Time [h]
Figure 4. Conversion as a function of time for the HKR of styrene
oxide with the catalyst activated by means of four different aromatic
acids.
Figure 6. Comparison of the conversion obtained in the HKR of
styrene oxide after the addition of different surfactants.
Table 2. Obtained ee for styrene oxide and 1-phenyl-1,2-ethanediol for
the different surfactants after 4 h
reactive. The rate enhancing effect of electron deficient
acids can be ascribed to the fact that the activation of
the nucleophile by the Co-Jacobsen complex occurs
more rapidly in the presence of these acids. Indeed, they
draw electrons away from the Co centre, making it more
susceptible to nucleophilic attack.
Surfactant
Eeepoxide (%)
Eediol (%)
––
Brij 30
84
81
24
95
95
77
Bis-(2-ethylhexyl)-
sulfosuccinate sodium salt
Tween 20
48
53
93
93
The immiscibility of certain epoxides with the water
used in the HKR can pose problems with regard to mass
transfer. Tokunaga et al. stated that the addition of (±)-
Igepal CA 630
1
,2-epoxyhexane rendered the reaction mixture homo-
1
possibly be explained by an interaction between the io-
nic surfactant and the Co-Jacobsen catalyst.
geneous. Several surfactants (Fig. 5) were screened in
the HKR of styrene oxide to determine whether they
had a beneficial effect on the reaction rate. Figure 6
shows the conversions as a function of time for the dif-
ferent surfactants. None of the tested surfactants in-
creased the reaction rate of the HKR of styrene oxide.
In fact, Brij 30 was the only surfactant, which did not
result in a decreased reaction rate. All other surfactants
had an unfavourable effect on the reaction rate, possibly
attributable to the drastic increase in viscosity of the
reaction mixture. The ionic bis-(2-ethylhexyl)-sulfosucci-
nate sodium salt afforded the worst results in combining
the lowest conversion after 4 h and the lowest enantio-
selectivity (Table 2). The lower enantioselectivity can
3. Conclusion
Solvent screening revealed that besides Et O, IPA was
2
also a suitable solvent for the HKR of epoxides. The
use of IPA as a solvent increased the reaction rate com-
pared to Et O. In contrast to the other alcohols tested,
2
no formation of the corresponding b-hydroxyether was
observed. Use of IPA did result in a faster deactivation
of the catalyst, but re-activation of the catalyst by acid
treatment is possible. The best results for the in situ acti-
vation of the catalyst were obtained using electron defi-
cient aromatic acids. In an attempt to solve the
problems with the immiscibility of water and the epox-
ide under solvent-free conditions, several surfactants
were tested, but none of these afforded good results.
+
Na
O
O
O
O
O
O
HO
b.
w
x OH
y OH
S
O
O
O
O
O
O
O
C11H23
z
4. Experimental
O
O
O
n
OH
4.1. Materials
a.
The commercially available reagents (1,2-epoxyhexane
Acros Organics, 97%) and styrene oxide (Acros Organ-
(
O
ics 98%) were used without further purification. The dif-
ferent solvents were bought from Merck, except
tetrahydrofuran, ethyl acetate (Acros Organics) and tolu-
ene (Aldrich); all solvents were used without further
purification. The Co-Jacobsen catalyst was bought from
Strem Chemicals.
O
O
HO
c.
O
d.
Figure 5. Different surfactants [(a) bis-(2-ethylhexyl)-sulfosuccinate
sodium salt, (b) Tween 20 (w + x + y + z = 20), (c) Brij 30, (d) Igepal
CA 630 (n = 8)] used in the HKR of styrene oxide.

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S. Aerts et al. / Tetrahedron: Asymmetry 16 (2005) 657–660
4
.2. General method
ments 20 mol % (to styrene oxide) of the surfactant
was added. The reactor was pressurised with compressed
air to 6 bar and conversions and ee were determined via
GC analysis.
Reactions were carried out in stainless steel reactors
Premex) with a volume of 100 mL and equipped with
a mechanical stirrer (1100 rpm). Experiments were per-
formed on a 20 mL scale and samples were analysed
via GC. The efficiency of the catalyst is described
through the conversion and the enantiomeric excess
(
6
Acknowledgements
(
ee). A kinetic resolution reaction has a maximum con-
The Belgian Federal Government for an IAP-PAI grant
on Supramolecular Catalysis and the Flemish Govern-
ment for a grant from the Concerted Research Action
version of 50%, since only one enantiomer reacts. All
conversions are therefore rescaled to a 100% scale.
(GOA) are gratefully acknowledged. The author
4
.3. HKR of 1,2-epoxyhexane
acknowledges VITO for a grant as a doctoral research
fellow. The authors would also like to thank L. Willems
and W. Adriansens for technical support.
A mixture of (S,S)-Co(II)-Jacobsen (0.1 g, 0.17 mmol)
and acetic acid (20.4 mg, 0.34 mmol) in toluene (3 mL)
was stirred under air for 2 h at room temperature. The
solvent was removed under reduced pressure. After-
wards, 0.1 g (0.17 mmol) of the activated catalyst was
added to the reactor and subsequently 1,2-epoxyhexane
References
1. Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 277, 936–938.
(
1.6 g, 16 mmol), water (0.16 g, 8.9 mmol) and 20 mL
solvent were added. The reactions were carried out at
room temperature. The conversion and the enantiomeric
excess (ee) were determined via GC analysis.
2. Savle, P. S.; Lamoreaux, M. J.; Berry, J. F.; Gandour,
R. D. Tetrahedron: Asymmetry 1998, 9, 1843–1846.
3
. Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org.
Chem. 1998, 63, 6776–6777.
4
. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.;
Hansen, K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E.
N. J. Am. Chem. Soc. 2002, 124, 1307–1315.
4
.4. HKR of styrene oxide
The (S,S)-Co(II)-Jacobsen (0.5 g, 0.8 mmol) catalyst
was put directly into the reactor. Subsequently, the acid
5
. Liu, Y.; Dimare, M.; Marchese, S. A.; Jacobsen, E. N.;
Jasmin, S. WO 03/018520 A, 2003.
(
(
1.6 mmol), styrene oxide (21 g, 175 mmol) and water
6 g, 333 mmol) were added. For the surfactant experi-
6. GC-analysis was performed on a CP-Chirasil-Dex CB
column (Chrompack) with H as carrier gas.
2