Reversible microencapsulation of pybox-Ru chiral catalysts: Scope and limitations

Article abstract of DOI:10.1016/j.tet.2005.07.117

Chiral Pybox-Ru catalysts can be microencapsulated into linear polystyrene as a method to recover and recycle the valuable catalyst. These catalysts allow 60-68% yields to be achieved with enantioselectivities in the range 75-85% ee in the benchmark cyclo

Full text of DOI:10.1016/j.tet.2005.07.117

Tetrahedron 61 (2005) 12107–12110
Reversible microencapsulation of pybox–Ru chiral catalysts:
scope and limitations
a
Alfonso Cornejo, Jos e´ M. Fraile, Jos e´ I. Garc ´ı a, Mar ´ı a J. Gil, V ´ı ctor Mart ´ı nez-Merino
b
b
a
a,
*
b,
and Jos e´ A. Mayoral
*
a
Departamento de Qu ´ı mica Aplicada, Universidad P u´ blica de Navarra, E-31006 Pamplona, Spain
Departamento de Qu ´ı mica Org a´ nica, Instituto Universitario de Cat a´ lisis Homog e´ nea, Instituto de Ciencia de Materiales de Arag o´ n,
Universidad de Zaragoza-CSIC, E-50009 Zaragoza, Spain
b
Received 28 June 2005; revised 8 July 2005; accepted 8 July 2005
Available online 19 October 2005
Abstract—Chiral Pybox–Ru catalysts can be microencapsulated into linear polystyrene as a method to recover and recycle the valuable
catalyst. These catalysts allow 60–68% yields to be achieved with enantioselectivities in the range 75–85% ee in the benchmark
cyclopropanation reaction between styrene and ethyl diazoacetate. The catalyst is soluble in the reaction solvent and is re-encapsulated at the
end of the reaction. The great advantage of this methodology is that the chiral ligand does not need to be modified, but the recycling is highly
solvent dependent—in contrast with the catalysts immobilized through covalent bonds.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
and this method does not require any modification of the
chiral ligand.
Immobilization on organic polymers is one of the most
widely used strategies to support chiral catalysts and is a
way to make them recoverable and reusable—with the
Our group is working in the field of chiral catalyst
immobilization, with special emphasis on oxazoline-contain-
ing ligands —particularly pyridinebis(oxazoline) ligands
1
8
associated practical advantages. The chiral catalyst can be
(
pybox). The immobilization of these systems through
linked to the polymeric support either through strong bonds/
interactions (e.g., covalent bond or electrostatic interaction)
or through weak interactions. Covalent bonding is by far the
covalent bonding to organic polymers was assessed in two
ways: polymerization and grafting (Fig. 1). The polymeri-
zation method involves functionalization of the chiral pybox
with a group that can polymerize with other monomers, such
2
most common method, but has the drawback of requiring
chemical modification of the chiral ligand to introduce
additional functionality to form the covalent bond with the
support. This requirement makes the preparation of the
catalyst more difficult, which is often a serious limitation
for the industrial application of the immobilized chiral
9
as styrene. In this case the synthetic effort is double because
the polymerizable ligand and the polymeric support with a
suitable morphology must be considered. In the case of
grafting (Fig. 1), well-characterized, commercially available
supports can be used, so the synthetic effort for this method
3
catalysts, in contrast with the recent applications described
4
for analogous non-chiral systems.
1
0
is restricted to the modified chiral ligand.
Given the attractiveness of the microencapsulation method-
ology (Fig. 2) we decided to investigate this area with the
same types of catalysts to evaluate the advantages and
disadvantages of this system in comparison with the
methods involving ligand-support covalent bonding.
In terms of immobilization through weak interactions, a
number of examples have been described for the entrapment
of chiral catalysts within polymers, either in cross-linked
polymers or in linear polymers to give microcapsules. In
both cases, the preparation of the catalyst is rather simple
5
6,7
2. Results and discussion
Keywords: Microencapsulation; Pybox–Ru chiral catalysts; Cyclopropana-
tion reaction.
*
Corresponding authors. Tel./fax: C34 976 762077;
e-mail: mayoral@unizar.es
One important limitation of the microencapsulation method
is compatibility with the solvent. Indeed, cyclopropanation
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.117

12108
A. Cornejo et al. / Tetrahedron 61 (2005) 12107–12110
Figure 3. FTIR spectra of the polystyrene matrix (a), the Ru–pybox
complex (b), and the microencapsulated the Ru–pybox complex (c).
Figure 1. Polymerization and grafting methods for pybox immobilization.
The asymmetric cyclopropanation reactions between
styrene and ethyl diazoacetate (Scheme 1) were carried
out in dichloromethane, with only one exception (MC3).
Under these conditions the encapsulated catalyst was
completely soluble in the reaction medium and behaved as
a homogeneous catalyst. However, the addition of a solvent
such as hexane or cyclohexane led to the formation and
hardening of the capsules, which were filtered off, washed
and reused. The reaction conditions, results and recycling
method are collected in Table 1. One set of experiments in
the homogeneous phase (Hom in Table 1) was conducted
under the same conditions for the sake of comparison.
Figure 2. Microencapsulation of pybox–Ru chiral catalyst.
reactions with pybox–Ru catalysts are usually carried out in
dichloromethane, a solvent in which linear polystyrene is
soluble. We therefore envisaged microencapsulation as a
reversible method for immobilization. The catalyst and
support will be soluble in the reaction medium (homo-
geneous catalysis) but can be recovered by re-encapsulation
Scheme 1. Asymmetric cyclopropanation reaction.
Comparison of MC1 and the homogeneous test clearly
shows that the use of polystyrene increases the recyclability
of the complex, which maintains good yield and enantio-
selectivity up to the fourth run. However, a small amount of
Ru is lost in each recycle, as shown by the colour of the
washings. However, the amount leached in each batch is so
small that it cannot be accurately analyzed, meaning that it
must be less than 5%. The analysis of joint mother liquors
after four batch reactions shows an overall loss of Ru of
about 15% (0.01 mmol). The worst property of this type of
complex is its mechanical weakness—the solid is ground by
the magnetic stirrer and is almost completely destroyed after
four runs. An interesting aspect is the higher stability of this
catalyst in comparison with the homogeneous one. All of
the recycling operations were carried out in air without
loss of activity or selectivity, in contrast with the grafted
1
1
at the end of the reaction.
The pybox–Ru complex 1 was prepared from pybox
ligand and [Ru(p-cymene)Cl ] in an ethylene atmosphere
2
2
1
2
using the method described by Nishiyama et al. Ethylene
plays an important role in the stability and efficiency of
7
the catalyst as it protects the ruthenium centre from
other strongly coordinating molecules such as oxygen.
A solution of pybox–Ru complex in dichloromethane was
added to a solution of the linear polystyrene in warm
cyclohexane and the solvents were slowly evaporated.
The Ru content was determined by plasma emission
spectroscopy and, in the fresh catalysts, was slightly lower
than the theoretical value (0.225–0.230 mmol/g vs
0.258 mmol/g). FTIR (Fig. 3) shows the presence of the
Ru catalyst in the solid.
1
0
catalysts. Despite this finding, all recycling operations in

A. Cornejo et al. / Tetrahedron 61 (2005) 12107–12110
Table 1. Asymmetric cyclopropanation reactions with microencapsulated catalysts
12109
a
b
Experi-
ment
Solvent (mL)
Run
Yield
b,c
%
trans/cis
%ee
trans
%ee
b
cis
Hexane
addition
Evapora-
d
tion
Washing solvent and
d
temperature
b
d
e
Hom
DCM (5C1)
1
2
3
49
50
13
88/12
90/10
87/13
81
84
74
52
63
41
15 mL
Yes
Yes
Hex (6!12 mL) rt
CHex (6!15 mL) rt
MC1
MC2
DCM (5.4C1)
DCM (10C2)
1
2
3
4
46
63
63
48
85/15
87/13
88/12
88/12
75
85
83
84
37
45
47
45
No
1
2
3
36
37
29
11
88/12
88/12
87/13
77/23
78
83
75
45
43
48
40
10
15 mL
Yes
Hex (6!12 mL) K20 8C
f
4
MC3
MC4
CHex (10C2)
DCM (10C2)
1
2
31
12
94/6
91/9
85
66
68
35
No
Yes
Yes
CHex (6!15 mL) rt
Hex (6!10 mL) 0 8C
1
2
3
1
2
3
4
44
41
25
42
51
32
8
88/12
89/11
88/12
88/12
88/12
86/14
76/24
84
86
84
81
82
75
23
50
61
54
50
43
40
5
15 mL
MC5
DCM (2C0.5)
DCM (2C0.5)
DCM
20 mL
20 mL
No
No
Hex (5!10 mL) 0 8C
MC6
1
2
3
4
62
68
61
18
88/12
86/14
87/13
72/28
83
80
73
20
52
35
30
2
Hex (5!10 mL) K20 8C
f,g
Grafted
1
2
3
4
38
47
41
36
86/14
88/12
88/12
84/16
77
83
81
56
43
54
50
23
h
Polym
DCM
1
2
3
4
5
52
67
70
68
32
88/12
90/10
90/10
90/10
88/12
85
91
89
87
74
54
67
64
63
63
a
DCMZdichloromethane; ChexZcyclohexane; HexZhexane. The two different quantities indicate the amount solvent used to dissolve the catalyst and
styrene and to dilute ethyl diazoacetate, respectively.
Determined by gas chromatography. 2R and 3R are the major products.
In all cases complete disappearance of ethyl diazoacetate is observed, therefore yields reflect chemoselectivity rather that catalyst activity.
Steps in recycling of the catalyst: addition of hexane to the reaction mixture, evaporation of the solvents and washing the solids with solvent at different
temperatures. The combined solutions were analyzed to determine the results and the resulting solid was reused under the same conditions.
Homogeneous reaction. Non-encapsulated catalyst.
b
c
d
e
f
Run not carried out under inert atmosphere.
g
h
4
4
-Vinylpybox immobilized on Merrifield’s resin. Data from Ref. 10.
-Vinylpybox polymerized with styrene and divinylbenzene. Data from Ref. 10.
the other experiments were carried out under an inert
atmosphere. In recovered catalysts ethylene must be
replaced by other molecule, most probably the reacting
alkene—styrene in this case—as it has been recently shown
extraction of the reaction products and by-products. In fact,
complexation of ruthenium by maleate and fumarate may
contribute to catalyst deactivation. Another method to
increase the mechanical stability is the use of orbital shaking
instead of stirring in the experiments from MC4.
1
3
in a theoretical study on the mechanism of this reaction.
An increase in the amount of reaction solvent seemed to
have a slightly negative effect on the yield, and cyclohexane
In another set of experiments, the amount of dichloro-
methane was markedly reduced in order to allow the
collapse of the capsules without the need for evaporation.
This method works effectively but a significant loss of
activity and enantioselectivity was observed in the fourth
run. In this case the collapse and extraction at lower
temperature (MC6) improve the yield with no significant
modification of the enantioselectivity, but again the
cyclopropane yields noticeably decrease after the third run.
(
MC3) proved more detrimental than dichloromethane. In
experiment MC2 hexane was added to the reaction mixture
to harden the capsules prior to evaporation and washing. In
this way recycling is experimentally easier and more
efficient. The fourth run was carried out without an inert
atmosphere in order to assess the stability of the system in
air. The poor result, both in terms of activity and stability,
shows that the enhanced stability is not effective when the
catalyst is under reaction conditions, probably because it is
homogeneous in nature.
The results and stability of the microencapsulated
catalysts were compared with those prepared by grafting
1
0
4-mercaptopybox or by polymerization of 4-vinylpybox.
The stability of the catalyst is improved by recovering it at
0
In both cases the catalysts covalently linked to the
polymeric support show enhanced stability—both chemical
8C instead of K20 8C, probably due to a more efficient

12110
A. Cornejo et al. / Tetrahedron 61 (2005) 12107–12110
and mechanical. The grafted catalyst leads to slightly lower
yields than the microencapsulated one and has comparable
enantioselectivity, which begins to drop in the fourth run. In
contrast, the polymerized catalyst is as good as the
microencapsulated one, with higher enantioselectivity and
better recoverability—as shown by the excellent results in
the fourth run and the moderate loss of activity and
enantioselectivity only in the fifth run. Although polymeri-
zation is the best method for the immobilization of the
pybox–Ru system, microencapsulation is an interesting
alternative to grafting owing to its simplicity and similar
performance.
immobilized catalyst (ca. 0.06 mmol). A solution of ethyl
diazoacetate (114 mg, 1 mmol) in the same solvent was
slowly added (6 h). The solution was shaken for an
additional period of 17 h. The catalyst was collapsed by
the addition of hexane or cyclohexane. The exact method is
described in Table 1. The solid catalyst was washed with the
same solvent and the combined organic solutions were
analyzed by gas chromatography. The dried solid catalyst
was reused several times under the same conditions.
Acknowledgements
This work was made possible by the generous financial
support of the C.I.C.Y.T. (Project PPQ2002-04012) and the
Diputaci o´ n General de Arag o´ n.
3
. Conclusions
Microencapsulation allows the reversible immobilization of
enantioselective pybox–Ru catalysts. In this way the solid
catalyst is solubilized under the reaction conditions and can
be re-encapsulated at the end of the reaction. When compared
with the grafting and polymerization methods for covalent
bonding to the polymeric support, the microencapsulation
technique shows some advantages, for example, it is not
necessary to modify the chiral ligand and this leads to an
easier preparation. On the other hand, microencapsulation
leads to less stable catalysts in terms of mechanical attrition
and leaching, making recovery and reuse more difficult.
In conclusion, microencapsulation is an interesting method-
ology that should be taken into account when a chiral
immobilized catalyst has to be designed for a given
application. This approach requires almost no supplementary
synthetic effort in comparison with the polymerization or
grafting techniques, although for this particular case the
grafted catalyst performs better, and it would be interesting to
assess this method in immobilization work.
References and notes
1. Chiral Catalyst Immobilization and Recycling; De Vos, D. E.,
Vankelecom, I. F. J., Jacobs, P. A., Eds.; Wiley-VCH:
Weinheim, 2000.
2. (a) Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102,
3217–3274. (b) McNamara, C. A.; Dixon, M. J.; Bradley, M.
Chem. Rev. 2002, 102, 3275–3300. (c) Fan, Q.-H.; Li, Y.-M.;
Chan, A. S. C. Chem. Rev. 2002, 102, 3385–3466.
3. Pugin, B.; Blaser, H.-U. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; pp 1367–1375.
4. (a) Phan, N. T. S.; Brown, D. H.; Styring, P. Green Chem.
2004, 526–532. (b) Phan, N. T. S.; Brown, D. H.; Styring, P.
Tetrahedron Lett. 2004, 45, 7915–7919.
5
. See for example: (a) Vankelecom, I. F. J.; Tas, D.; Parton,
R. F.; Van de Vyver, V.; Jacobs, P. A. Angew. Chem., Int. Ed.
4. Experimental
1
996, 35, 1346–1348. (b) Vankelecom, I.; Wolfson, A.;
4
.1. Preparation of microencapsulated catalysts
Geresh, S.; Landau, M.; Gottlieb, M.; Hershkovitz, M. Chem.
Commun. 1999, 2407–2408.
0
isopropyloxazolin-2 -yl]pyridine (400 mg, 1.33 mmol) and
Ethylene was bubbled for 1 h into a solution of 2,6-[4 -(S)-
0
RuCl (p-cymene)] (408 mg, 0.67 mmol) in anhydrous
6. Kobayashi, S.; Akiyama, R. Chem. Commun. 2003, 449–460
and references cited therein.
[
7. For a recent example of an efficient microencapsulated non-
chiral catalyst, see: Lee, C. K. Y.; Holmes, A. B.; Ley, S. V.;
McConvey, I. F.; Al-Duri, B.; Leeke, G. A.; Santos, R. C. D.;
Seville, J. P. K. Chem. Commun. 2005, 2175–2177.
8. Rechavi, D.; Lemaire, M. Chem. Rev. 2002, 102, 3467–3493.
2
2
dichloromethane (15 mL). After purging with nitrogen, the
solution was added to n-heptane (HPLC grade, 100 mL) and
the resulting solid was collected by filtration and dried under
vacuum. Yield of 1 550 mg (82%).
9
. Cornejo, A.; Fraile, J. M.; Garc ´ı a, J. I.; Garc ´ı a-Verdugo, E.;
Gil, M. J.; Legarreta, G.; Luis, S. V.; Mart ´ı nez-Merino, V.;
Mayoral, J. A. Org. Lett. 2002, 4, 3927–3930.
10. Cornejo, A.; Fraile, J. M.; Garc ´ı a, J. I.; Gil, M. J.; Luis, S. V.;
Mart ´ı nez-Merino, V.; Mayoral, J. A. J. Org. Chem. 2005, 70,
5536–5544.
A suspension of linear polystyrene (MWZ280,000,
2
4
46 mg) in anhydrous cyclohexane (20 mL) was heated at
5 8C for 90 min until complete dissolution. A solution of
complex 1 (36.7 mg, 0.073 mmol) in anhydrous dichloro-
methane in (1.5 mL) was added and the resulting solution
was stirred at 30 8C for 1 h. The solvent was evaporated at
room temperature under reduced pressure and the solid was
used without further treatment.
11. A similar strategy was used in a non-asymmetric Pd catalyzed
Suzuki cross-coupling reaction, Lau, K. C. Y.; He, H. S.; Chiu,
P.; Toy, P. H. J. Comb. Chem. 2004, 6, 955–960.
1
2. Nishiyama, H.; Itoh, Y.; Sugawara, Y.; Matsumoto, H.; Auki,
K.; Itoh, K. Bull. Chem. Soc. Jpn. 1995, 68, 1247–1262.
3. Cornejo, A.; Fraile, J. M.; Garc ´ı a, J. I.; Gil, M. J.; Mart ´ı nez-
Merino, V.; Mayoral, J. A.; Salvatella, L. Organometallics
2005, 24, 3448–3457.
4
.2. Asymmetric cyclopropanation reactions
1
A solution of styrene (0.57 mL, 5 mmol) in the correspond-
ing anhydrous solvent (see Table 1) was added to the