Enantioselective cyclopropanation and aziridination catalyzed by copper(II) bis(oxazoline) anchored onto mesoporous materials

Article abstract of DOI:10.1016/j.poly.2014.05.025

The preparation of multipurpose asymmetric heterogeneous catalysts based on the immobilization of expensive privileged chiral ligands onto porous supports is essential for their use in industry. The benchmark cyclopropanation of styrene has been performed

Full text of DOI:10.1016/j.poly.2014.05.025

Accepted Manuscript
Enantioselective cyclopropanation and aziridination catalyzed by copper(II)
bis(oxazoline) anchored onto mesoporous materials
Hélio Albuquerque, Liliana Carneiro, Ana P. Carvalho, João Pires, Ana R. Silva
PII:
S0277-5387(14)00333-7
DOI:
http://dx.doi.org/10.1016/j.poly.2014.05.025
POLY 10739
Reference:
To appear in:
Polyhedron
Received Date:
Accepted Date:
25 March 2014
3 May 2014
Please cite this article as: H. Albuquerque, L. Carneiro, A.P. Carvalho, J. Pires, A.R. Silva, Enantioselective
cyclopropanation and aziridination catalyzed by copper(II) bis(oxazoline) anchored onto mesoporous materials,
Polyhedron (2014), doi: http://dx.doi.org/10.1016/j.poly.2014.05.025
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Corresponding Author:
Dr. Ana Rosa Silva
Departamento de Química, CICECO
Universidade de Aveiro
Campus Universitário de Santiago
3810-193 Aveiro, Portugal
Ph: +351 234 370 604
Fax: +351 234 401 470
e-mail: ana.rosa.silva@ua.pt
Enantioselective cyclopropanation and aziridination catalyzed by
copper(II) bis(oxazoline) anchored onto mesoporous materials
1
1
2
2
Hélio Albuquerque , Liliana Carneiro , Ana P. Carvalho , João Pires ,Ana R. Silva
1*
1
Departamento de Química, CICECO, Universidade de Aveiro, Campus Universitário
de Santiago, 3810-193 Aveiro, Portugal
2
CQB, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade
de Lisboa, 1749-016 Lisboa, Portugal
1

Abstract
The preparation of multipurpose asymmetric heterogeneous catalysts based on the
immobilization of expensive privileged chiral ligands onto porous supports is essential
for their use in industry. The benchmark cyclopropanation of styrene has been
performed using a copper(II) complex of a commercial chiral bis(oxazoline) anchored
onto ordered mesoporous silica materials (including SBA-15) and their carbon replicas
(
including CMK-3), and for the first time, we also report on the asymmetric
aziridination of styrene by anchored copper(II) bis(oxazoline). All the composites
prepared were active and enantioselective in these two organic transformations. In the
cyclopropanation of styrene the best heterogeneous catalyst gave higher
enantioselectivities and TON than in the corresponding homogeneous phase reactions.
In the aziridination of styrene the enantioselectivities for the best heterogeneous
catalysts were similar to the propylated bis(oxazoline). The mesoporous silica, prepared
by a straightforward one-pot procedure, was always among the best supports for the
functionalized bis(oxazoline) in all the asymmetric processes studied. However its
carbon replica was not a good support for the outcome of these asymmetric
transformations, always yielding the lowest enantioselectivities. Once again the
mesoporous materials surface properties were an important factor for the uniform
distribution of the homogeneous catalyst, as well as for the course of the asymmetric
organic reactions, together with the pore size. The best results presented herein are
comparable to the ones reported for copper(II) bis(oxazoline) (2) immobilized onto
other types of porous supports.
Keywords: homogeneous catalysis, heterogeneous catalysis, asymmetric catalysis,
immobilization, mesoporous materials.
2

1.
Introduction
Enantiomerically enriched cyclic compounds are valuable building blocks in organic
synthesis due to their highly regio- and stereoselective ring-opening reactions. As a
large majority of organic compounds contain carbon-nitrogen bonds, aziridines are
invaluable intermediates in the synthesis of pharmaceuticals and agrochemicals [1].
Cyclopropanes are also very important intermediates in organic synthesis and
cyclopropane rings are often found in a variety of natural products and biologically
active compounds [2]. However, the synthesis of enantiomerically enriched
cyclopropanes [2] and aziridines remains a considerable challenge [1].
As catalysis is one of the fundamental pillars of green chemistry and a source of low-
cost methodologies, due to its efficiency and selectivity, there is already a system that
catalyzes efficiently both cyclization reactions. Copper(II/I) complexes with
bis(oxazoline) ligands (Scheme 1) are versatile enantioselective and efficient
homogeneous catalysts in a number of asymmetric organic transformations [3-6],
including the cyclopropanation [3-7] and aziridination [8,9] of alkenes. These privileged
chiral ligands are available commercially, but at high cost. Thus a heterogeneous
version would be preferable due to several inherent practical advantages associated with
separation, handling, stability, recovery and re-use [3-6,10]. Most reports on the
heterogenization of copper(II) bis(oxazoline) are on organic polymers [3-6]. Ordered
mesoporous silicas present, however, higher specific surface area, mechanical
resistance, chemical robustness and thermal stability than polymers. Ordered
mesoporous carbons, prepared by making use of ordered mesoporous inorganic solids
as templates [11], also possess high surface areas and uniform mesopores, although
accompanied by a certain amount of micropores [11,12], and are still quite unexplored
as supports for homogeneous catalysts [17,18].
3

In our previous work on the encapsulation copper(II) bis(oxazoline) onto zeolites [13]
and also anchoring onto mesoporous silicas [14], we were attracted by the best
homogeneous catalyst for the cyclopropanation of alkenes. However, as reported
previously [3], when heterogenized, this copper(II) complex turned out to be very
unstable, yielding low enantioselectivities and weak recyclability.
In this work, a pre-formed copper(II) complex with the commercial bis(oxazoline) 2
(
Scheme 1) was anchored onto SBA-15 and its carbon replica CMK-3 using the
anchoring procedure represented in Scheme 2. This immobilization procedure was
already used to anchor Cu(2) onto mesoporous silicas, MCM-41 and MCM-48, which
were highly active in the enantioselective cyclopropanation of styrene with ethyl
diazoacetate with moderate enantioselectivities [15]. Another regular mesoporous silica
and its carbon replica prepared in a one step pathway were also used as supports. Their
efficiency and reusability as asymmetric heterogeneous catalysts in the kinetic
resolution of a 1,2-diol has already been shown previously [17]. Herein the
multipurpose catalytic properties of these heterogeneous catalysts will be exemplified
for more reactions: (i) the benchmark asymmetric cyclopropanation of styrene at room
temperature with ethyl diazoacetate (Scheme 3) and (ii) aziridination of styrene with (N-
(
p-tosylsulfonyl)imino)phenyliodinane (PhINTs), also at room temperature (Scheme 4).
So conclusions will also be withdrawn on the effect of the mesoporous support nature
on the catalytic performance and stability upon reuse of the immobilized Cu(2)
complex for each reaction. Because we have also been investigating eventual
confinement effects within the pores of materials [13,14], the Cu(2) complex was also
heterogenized onto smaller pore hexagonal mesoporous silica (HMS).
Scheme 1 and 2
4

2.
Experimental Section
2.1. Materials and solvents
2
Copper(II) trifluoromethanosulfonate (copper triflate, [Cu(OTf) ], 98%), (S)-(–)-2,2'-
isopropylidenebis(4-phenyl-2-oxazoline) (1, 97%), 2,2′-methylenebis[(4S)-4-phenyl-2-
oxazoline] (2, 97%), buthyl lithium solution 1.6 M in hexane (BuLi), 3-
iodopropyltrimethoxysilane (IPS, ≥ 95.0%), triethylamine (Et N, ≥ 99%), dry
3
tetrahydrofuran (THF, ≥ 99.9%), styrene (≥ 99%), n-undecane (≥ 99%),
ethyldiazoacetate (EDA, ≤ 15% dichloromethane), phenylhydrazine (97%), copper(II)
acetylacetonate (98%), iodobenzene diacetate (98%), p-toluenesulfanamide (98%),
potassium hydroxide (p.a.) and potassium bromide (FT-IR grade, ≥ 99%) were
purchased from Aldrich and used as received. Ethanol (p.a.) and methanol (p.a.) were
from Riedel de Häen. Dichloromethane, acetonitrile, n-hexane, isopropanol and ethyl
acetate were from Romil and were of HPLC grade. The Supplementary Data includes
details for the synthesis of the aziridines and their characterization procedures.
2.2. Physical and chemical methods
Elemental analysis was performed in duplicate by the “Servicio de Análisis
Instrumental”, CACTI Vigo, Universidade de Vigo, Spain. The copper ICP-AES was
performed in duplicate at the “Laboratório Central de Análises” of the University of
-
Aveiro, Portugal. FTIR spectra were collected in the range 400-4000 cm at room
1
-
1
temperature using a resolution of 4 cm and 256 scans, and were obtained by attenuated
total reflectance (ATR) using a Bruker Tensor 27 spectrophotometer or as KBr pellets
with a FT Mattson 7000 galaxy series spectrophotometer (carbon materials); the
samples were previously dried in an oven at 100 ºC for 6 hours. Thermogravimetry
coupled with Differential Scanning Calorimetry (TG-DSC) were performed under air
5

flux, except for the carbon materials where a nitrogen flux was used, with a ramp of 5
C/min in a TG-DSC apparatus, model 111 from Setaram. Nitrogen adsorption
°
isotherms at -196 ºC were measured in an automatic apparatus (Asap 2010;
Micromeritics). Before the adsorption experiments, the samples were outgassed under
vacuum for 2.5 hours at 150 ºC.
2.3. Catalysis experiments
All the catalytic reactions of the prepared materials were performed in batch reactors at
atmospheric pressure and with constant stirring. At the end of the reactions, the
materials were isolated by vacuum filtration and then washed extensively with the
appropriate solvent, dried under vacuum at 60 ºC and reused in another cycle with the
same experimental procedures. In order to compare with the heterogeneous phase
reactions, control experiments in the homogeneous phase were also performed using the
2
same experimental procedures and equimolar quantities of [Cu(OTf) ] plus1, 2 or 3.
2.3.1. Cyclopropanation of styrene
In the experiments, typically 2.4 mmol of styrene, 0.65 mmol of n-undecane, 70 mg of
heterogeneous catalyst in 10.0 ml of dichloromethane and 2 µl of phenylhydrazine were
used (Scheme 3). Finally, 2.75 mmol of ethyldiazoacetate was added to the reaction
mixture over 2 hours using a syringe pump. When the addition of ethyldiazoacetate was
completed, aliquots (0.05 ml) were periodically withdrawn from the reaction mixture
with a hypodermic syringe, filtered through PTFE 0.2 µm syringe filters and analyzed
by GC-FID by the internal standard method. The reaction mixture was analyzed by GC-
FID on a Varian 450 GC gas chromatograph equipped with a fused silica Varian
Chrompack capillary column CP-Sil 8 CB Low Bleed/MS (15 m x 0.25 mm id; 0.15 µm
6

film thickness), using helium as the carrier gas. The enantiomeric excesses (% ee) of the
cyclopropanes (trans-6 and cis-6) were determined in the same chromatograph but
using a fused silica Varian Chrompack capillary column CP-Chiralsil-Dex CB (25m x
0.15 mm d.i. x 0.25 µm film thickness). Conditions used: 125 °C (40 min); injector
temperature, 200 °C; detector temperature, 230 °C. The several chromatographic peaks
were identified against commercially available samples and/or by GC-MS (Finnigan
Trace). The absolute configuration of the major cyclopropane enantiomer was
determined by performing the homogeneous phase reactions with 2,2′-
methylenebis[(4S)-4-phenyl-2-oxazoline] (2) of the same configuration and comparing
the results with the reported data [7,15].
2.3.2. Aziridination of styrene
Typically 0.24 mmol of (N-(p-tosylsulfonyl)imino)phenyliodinane (PhINTs, Scheme 4,
see Supplementary Data) was added to 1.22 mmol of styrene and 70 mg of
heterogeneous catalyst in 5.00 ml of acetonitrile and the reaction mixture was stirred for
48 hours. At the end of the reaction, the heterogeneous catalyst was recovered by
filtration and the filtrate evaporated under reduced pressure. The N-(p-tolylsulfonyl)-2-
phenylaziridine (5, Scheme 4) was purified by column chromatography using petroleum
ether (40-60)/ethyl acetate 9:2.5 as eluent and the enantiomeric excess was determined
by HPLC at 220 nm using a Chiralpak IC column (250 mm x 4.6 ID, 5µm) using 1
ml/min of n-heptane/isopropanol 7:3. The retention times of the (R)-5 and (S)-5
enantiomers (Scheme 4) were identified by comparison with those of a racemic
aziridine (see Fig. A1 and A2 Supplementary Data).
7

3.
Results and discussion
3.1. Preparation and characterization of the materials
The anchoring of Cu(2) onto two ordered mesoporous silicas, SBA-15 and SPSi, as
well as their carbon replicas, CMK-3 and SPC, respectively, has been described by us
previously [17]. This complex was also anchored onto a mesoporous silica with a much
smaller pore size, HMS, to check the effect of the material’s pore size on the catalytic
parameters [17]. This method has three main steps: (i) functionalization of 2, (ii)
coordination of copper(II) onto the chiral ligand 2 and (iii) anchoring onto the surface of
the material (Scheme 2) [17]. Epimerization of the bis(oxazoline) does not occur upon
its functionalization with trimethoxypropylsilane under strongly basic conditions,
because the prepared heterogeneous catalysts have already shown moderate to high
enantioselectivities in the kinetic resolution of 1,2-diol [17]. Moreover, the di-propyl
functionalized bis(oxazoline) 3 showed even higher enantioselectivity in this reaction in
the homogeneous phase than the original bis(oxazoline) 2, and slightly lower than the
best bis(oxazoline) 1 [17]. In order to prevent the creation of non-enantioselective active
sites by direct coordination to the mesoporous silica silanols, as we found previously
[
14], or to the carbon oxygen groups, copper(II) coordination took place before the
anchoring step (ii, Scheme 2). An eventual negative interaction between LiI and the
immobilized copper(II) bis(oxazoline) complex can be also ruled out due to the
efficiency of these heterogeneous catalysts in the kinetic resolution of hydrobenzoin
[
17]. As these materials have been extensively characterized by us, only the results from
their characterization that are relevant to the catalytic experiments will be discussed; the
data are summarized in Table 1.
Table 1
8

Evidence for the effective anchorage of the functionalized Cu(2) complex was obtained
by elemental analysis, copper ICP and nitrogen isotherms at 77 K. Since the molecule
of 2 possesses two nitrogen atoms (Scheme 1), the chiral ligand loading was calculated
based on the nitrogen content of the materials determined by elemental analysis (Table
1
). Despite the lower superficial area (Table 1), curiously the mesoporous materials
prepared using the one-pot procedure (SPC and SPSi) have a higher 2 loading than
SBA-15 and its carbon replica, CMK-3. The SPC mesoporous carbon material has
higher 2 loading than the corresponding SPSi mesoporous silica, whereas SBA-15 and
CMK-3 possess similar 2 loadings (Table 1). With the exception of HMS, the amounts
of copper determined by ICP-AES are lower than the ones of 2 for the materials, and
they are not in line with them (Table 1). This result suggests that the constant of
formation of the complex Cu(2) is not high and that the complexation of copper(II) by
the ligand 2 is weak.
The TG-DSC shows that Cu(2) complex anchored onto the SPSi material decomposes
more sharply and at higher temperature (365 ºC) than when anchored onto the SBA-15
and HMS mesoporous silicas (325 ºC, Fig. 1). Like already observed by us [18], this
may suggest a more uniform distribution of the Cu(2) functionalized complex onto the
SPSi mesoporous silica. Furthermore, for the SBA-15 and SPSi materials, the results of
the nitrogen chemical analysis (Table 1) agree well with the TG data in Fig. 1, taking
into consideration the molecular mass of the organic part of the complex and subtracting
the mass loss for the initial materials. The expected mass loss due to complex oxidation
in air is 11.3 and 12.6% for SBA-15 and SPSi, respectively. For the carbon replicas
CMK-3 and SPC, the TG curves for the samples functionalized with Cu(2) (not shown,
see supporting information of [17]), an inflexion in the TG curve is noticed for
9

temperatures between 325 and 350 ºC, suggesting that the thermal stability of the
supported complex is similar with the silica materials and with their carbon replicas.
Fig. 1
In the materials containing the anchored Cu(2), besides the characteristic bands of the
materials, further very low intensity bands between 2930-2850 and 1460-1400 and at
-
1
7
00 cm can be seen which are due to vibrations characteristic of the ligand 2 (Figs. 2
and 3). These characteristic vibrations are generally low in intensity, due to the general
low content of the bis(oxazoline) at the surface of the materials. Hence it is very
difficult to detect clearly the characteristic bands of this molecule upon anchoring onto
the several solid supports. However, in the Cu(2)@SPSi material these characteristic
vibrations can be clearly observed, due to the higher ligand 2 loading than in the other
materials. The characteristic strong stretching C=N vibration of the ligand 2 can be seen
-1
-1
at 1655 cm , which shifts to 1520 cm upon copper(II) coordination. However it is
generally masked under the O-H large bending vibration of the water adsorbed on the
-1
surface of the silica based materials, centered at about 1625 cm . Nonetheless, in the
-
case of SPC, it can be clearly seen at 1614 cm , in accord with the vibration of the
1
-
1
Cu(2) complex [17]. Furthermore, the low intensity band at 3746 cm , due to the
stretching of the O-H groups from the isolated silanols of the mesoporous silicas,
disappeared which confirms that grafting between this group and the propylsilane
functionalized Cu(2) has taken place according to Scheme 2 (Figs. 2 and 3) [19].
Fig.2 and 3
1
0

The nitrogen adsorption-desorption isotherms of the materials at -196 ºC are of type IV,
as expected for mesoporous materials [17,20]. According to the literature, the specific
surface areas and pore volumes of the carbon replicas are higher than the respective
silica templates (Table 1) [16,21]. The mesoporous size distributions of the silicas are
more uniform than those of the respective replicas [17]. Upon anchoring of the Cu(2)
complex, a decrease in the adsorption capacity is clear for all the samples, but it is more
striking for the carbon replicas (Table 1). Additionally, upon anchoring, the mesopore
size distributions of both the silica and replicas are not significantly changed, except for
the CMK-3 material. For this solid, the relative intensities of the maxima near 8.5-10
and 4 nm are reversed after the inclusion of the complex [17]. This suggests that Cu(2)
is essentially located in the latter pores, justifying the drastic decrease of the porous
volume upon anchoring as these pores represent the highest proportion of the porosity in
CMK-3, as discussed in detail elsewhere [12].
3.2. Catalysis experiments
3.2.1. Cyclopropanation of styrene
Copper(I) complexes with bis(oxazoline) ligands are efficient homogeneous catalysts in
the asymmetric cyclopropanation of alkenes [3-7]. The nanostructured materials with
anchored Cu(2) were thus tested as heterogeneous catalysts in the asymmetric
cyclopropanation of styrene with ethyldiazoacetate (EDA) at room temperature
(
Scheme 3). EDA was added slowly to the reaction mixture over 2 hours [13,14,22-27]
in order to create a local deficit of this reagent in relation to styrene. Therefore the
dimerization of EDA was minimized along with the formation of diethyl maleate and
diethyl fumarate. Cu(II) was also reduced to Cu(I) by phenylhydrazine prior to the
asymmetric cyclopropanation of styrene.
1
1

Scheme 3 and Table 2
The results obtained with these materials are compiled in Table 2 and it can be seen that
they are active in the cyclopropanation of styrene, with moderate to low
enantioselectivities. The order of the values for this parameter is: SPSi > CMK-3 ≈
SBA-15 > HMS > SPC. Hence the ordered mesoporous silica SPSi gives rise to the
most enantioselective heterogeneous catalyst, with % ee(cis-4) and % ee(trans-4) of 42
and 47, respectively, which are higher than in the homogeneous phase reaction run
under the same experimental conditions and using the same amount of 2+Cu, or even
the best 1+Cu (0.2% mol, Table 2). The corresponding carbon replica yields the least
enantioselective heterogeneous catalyst, with % ee(cis-4) and % ee(trans-4) of 10. The
values for SBA-15 and its carbon replica are similar and are slightly above 20% for both
trans-4 and cis-4 diastereoisomers. Taking into consideration only the silica
mesoporous materials and since the reactions with these materials possess similar Cu
mol% (Table 2), it can be concluded that the lowest enantioselectivity values were
obtained for the material with the lowest pore size and catalyst density [17].
Nonetheless, the Cu(2)@HMS heterogeneous catalyst possesses more copper than
bis(oxazoline) ligand 2. Thus lowering of the enantioselectivity may have occurred
through non-enantioselective cyclopropanation involving only copper. Therefore the
positive effects on the enantioselection of the immobilized Cu(2) catalyst can only be
observed using the SPSi material. This cannot be fully attributed to the propylation of
the bridge bis(oxazoline) carbon atom (Scheme 2) as the homogeneous reaction with
1
+Cu (0.2% mol, Table 2) gives similar enantioselectivities as the one performed with
+Cu (0.2% mol, Table 2). The use of the other mesoporous silicas, SBA-15 and HMS,
2
1
2

leads to a decrease in the enantioselectivity when compared to the homogeneous phase
reaction, run using the same amount of Cu and with the same experimental conditions.
We have already found that the surface acidity of these mesoporous materials is an
important parameter in the asymmetric cyclopropanation of styrene by anchored
copper(II) aza-bis(oxazoline). The least acidic materials (SPSi and CMK-3) yielded the
most enantioselective heterogeneous catalysts [18]. This is also the case for the present
heterogeneous catalysts with the anchored commercial copper(II) bis(oxazoline) on
SPSi and CMK-3, although the heterogeneous catalysts bearing the CMK-3 support is
not as enantioselective as the one with the SPSi support. As the Cu(2)@SPSi
heterogeneous catalyst also possesses a more uniform distribution of the anchored
copper(II) bis(oxazoline) when compared to the other mesoporous materials (Fig. 1), it
may be an important factor for the course of the asymmetric cyclopropanation, together
with the lowest support acidity [18].
On the other hand, the immobilization of the Cu(2) catalyst on these mesoporous silica
materials leads to better styrene conversions and TON than the homogeneous phase
reactions (0.2% mol Cu). The order for the styrene conversions is CMK-3 > SBA-15 ≈
SPC > SPSi > HMS, which agrees well with the materials copper contents (Table 1).
The heterogeneous catalysts with the mesoporous carbons as supports convert more
styrene than with their corresponding silica templates, which must be due to their higher
copper contents (Table 1). The TON of the heterogeneous phase reactions are high and
are in the order: SBA-15 > SPSi > SPC > CMK-3 > HMS. Thus it can be concluded that
the ordered mesoporous silicas SBA-15 and SPSi yield more active heterogeneous
catalysts than when the corresponding mesoporous carbon replicas are used as
homogeneous catalyst supports. This could be due to the effect of the type of matrix
support, i.e. carbon vs silica, and also due to the pore size of the materials, since the
1
3

ordered mesoporous carbon possess a pore size of 4 nm, whereas their silica templates
possess pore sizes around 7 nm. The latter is sustained by the fact that the Cu(2)
catalyst supported onto the HMS mesoporous silica, with a pore size of 2.5 nm (Table
1
), is the least active heterogeneous catalyst (Table 2). It is noteworthy that the 4
trans/cis ratios for all the heterogeneous catalysts (1.8-1.6) are lower than the ones for
the homogeneous phase reactions (2.3).
Although a deficit of EDA was used in the catalytic experiments of a reported
heterogenized Cu(2) complex onto MCM-41 and MCM-48 mesoporous silicas with 3
nm pores [15], it showed slightly higher enantioselectivities and yields than the present
best Cu(2)@SPSi heterogeneous catalyst. Also using also a deficit of EDA and a
2
similar homogeneous complex, CuPh Box, immobilized onto mesoporous TUD-1
through non-covalent interactions, lower enantioselectivities and yields were obtained
than the results reported herein [22]. For a Cu(1) complex exchanged into a clay, higher
enantioselectivities and yields were obtained using regular mesoporous materials as
supports under similar experimental conditions [23]. In comparison with our previous
attempts to immobilize the best homogeneous catalyst, Cu(1) [13,14], better
enantioselectivities were achieved with Cu(2) and SBA-15. This is in accordance with
previous reports that the best homogeneous catalyst (ligand) will not always give the
best heterogenized catalyst [3].
Heterogenization of a chiral homogeneous catalyst may increase stability upon single
site isolation on a porous material, but the main aim of their immobilization is easy
separation from the reaction media at the end of the reaction and the possibility of
further use in more catalytic cycles. Hence the nanostructured materials were reused in
two more successive catalytic cycles after filtration from the solution, washing with
dichloromethane and drying. The results are also compiled in Table 2 and it can be
1
4

concluded that most of the materials deactivate upon reuse. This has been attributed to
the low stability of the chiral complex under the cyclopropanation reaction conditions,
because the bis(oxazoline) ligands are only bidentate and thus heterogeneous catalyst
deactivation is also highly dependent on the nature of the chiral ligand used [3].
However the carbon materials present a much sharper loss of enantioselectivity upon
reuse than the mesoporous silicas. Moreover, the FTIR spectra of the heterogeneous
catalysts at the end of the recycling experiments (Fig.2) show a very intense band at
-
1
around 1726 cm . This band is typical of the carbonyl moiety in an ester group, as can
be confirmed in Fig.2.f, which represents the spectra of the reagent EDA and the
products styrene cyclopropane and the by-products diethyl fumarate and diethyl
maleate. The vibration of the carbonyl band in the recycled heterogeneous catalysts is
closer to that of styrene cyclopropane and the diethyl maleate and diethyl fumarate by-
products, formed from EDA dimerization. Therefore, as observed by us previously, with
the presence of more nitrogen and carbon (EA) on the recycled catalysts [13], catalyst
poisoning through strong adsorption of the products cannot be ruled out, as it would
also justify the lowering of the catalytic activity of the heterogenized catalysts upon
reuse [24,26]. Ligand degradation has also been reported [28].
Nevertheless, the TON of the reused heterogeneous catalysts is still generally higher or
comparable to the homogeneous phase reaction run with a comparable amount of
Cu(2). Deactivation upon reuse was also observed in the Cu(2) catalyst anchored onto
2
MCM-41 and MCM-48 [15], CuPh Box immobilized onto a mesoporous TUD-1
through non-covalent interactions [22] and Cu(1) catalyst exchanged into clays [23]. It
is also commonly observed for other copper bis(oxazoline) catalysts immobilized onto
mesoporous silica materials [3,14,27]. Only when immobilized onto siliceous
mesocellular foam, which possesses ultra-large pores of 25 nm, do these commercial
1
5

systems present high enantioselectivity, activity and excellent recyclability [24,25]. It is
noteworthy, however, that these catalytic studies were always performed using 2% mol
of Cu in relation to the substrate [24,25], double than the necessary amount in
homogeneous phase reactions [7], whereas in ours catalytic experiments the Cu and 2
contents were between 0.2-0.5% and 0.1-0.8% mol, respectively.
3.2.2. Aziridination of styrene
Evans et al. also reported in 1991 that copper(II) bis(oxazoline) complexes acted as
homogeneous catalysts for the enantioselective aziridination of alkenes at room
temperature, with a maximum 63% ee for the industrially important and challenging
styrene [8,9]. There are a few reports on asymmetric heterogeneous aziridination, just
by bis(oxazoline) ligands added to the reaction mixture containing copper exchanged
zeolites [29-33] and copper(II) bis(oxazoline) immobilized by electrostatic interactions
2 3
onto clays, silica Nafion nanocomposite and silica-CF SO H [34]. However it was
recently reported that the enantioselectivities of some of the aziridines obtained with the
former copper exchanged zeolites were higher than reality due to the enrichment in one
of the enantiomers as the racemate precipitated in n-hexane rich eluents [35]. There are
no reports on the asymmetric heterogeneous aziridination by anchored copper(II)
bis(oxazoline) complexes. The previous experience for the preparation of efficient
heterogeneous catalysts for the aziridination of styrene [19,36] prompted us to test the
prepared heterogeneous catalysts in this reaction as well (Scheme 3). The results are
compiled in Table 3, which were obtained after an initial analytical method
development with the styrene aziridine racemate and n-hexane free eluent (see Fig.A1
and A2 of the Supplementary Data for the HPLC chromatograms) [35].
1
6

Scheme 3 and Table 3
All the materials prepared were active in the aziridination of styrene with moderate
yields (6-33%) and low enantioselectivities (7-20%). The order of the
enantioselectivities were: SBA-15 (20) ≈ SPSi (19) > CMK-3 (14) > HMS (10) > SPC
(
7). Therefore, like in the kinetic resolution/monobenzoylation of 1,2-diphenyl-1,2-
ethanediol [17], the mesoporous silicas bearing 7 nm mesopores yield the most
enantioselective heterogeneous catalysts [17], whereas Cu(2)@HMS, with a smaller
pore size, yields lower enantioselectivity. So, definitely, smaller mesopores in the silicas
are detrimental for the course of these asymmetric organic transformations by anchored
copper(II) bis(oxazoline). The maximum enantioselectivity achieved is similar to the
homogeneous phase reaction run with the copper(II) complex with bis-propylated
bis(oxazoline) 3 (Scheme 1) [17] that mimics the anchored bis(oxazoline) 2 (Scheme 2).
Looking at the homogeneous phase reactions performed with ligands 1, 2 and 3
(
Scheme 1 and Table 3), it may be concluded that, under the experimental conditions
used, Cu(2) is more enantioselective than Cu(1) and Cu(3). Hence contrary to what has
been observed for kinetic resolution/monobenzoylation of 1,2-diphenyl-1,2-ethanediol,
the propylation of 2 upon anchoring onto the mesoporous materials (Scheme 3) has a
detrimental effect on the enantioselection capacity of the anchored Cu(2) complex in
the aziridination of styrene. Despite 48 hours being allowed for the heterogeneous phase
reactions to take place, the yields were lower than with the corresponding homogeneous
phase reactions under similar experimental conditions. This may be due to the
dissolution of the solid nitrogen source PhINTs limiting step and the heterogeneous
nature of the catalyst making the formation of the intermediate species difficult.
Nevertheless, Cu(2)@HMS is the most active catalyst (TON 15), followed by
1
7

Cu(2)@SBA-15 (10) and Cu(2)@SPSi (8); the least active heterogeneous catalysts are
both mesoporous carbons as supports, Cu(2)@CMK-3 (4) and Cu(2)@SPC (2). The
best enantioselectivities presented herein are comparable to Cu(1) immobilized by
electrostatic interactions onto silica-Nafion nanocomposite (21%) and slightly lower
than Cu(1) immobilized using the same process onto clays (25%) and silica-CF
2
SO
26%) [34]. The yields reported herein are nevertheless much lower than these catalysts
58-75%). Recycling experiments were not performed for these heterogeneous catalysts,
3
H
(
(
with electrostatic immobilization being highly susceptible to leaching.
Upon recycling of our Cu(2) anchored onto several mesoporous materials, a decrease in
the activity and enantioselectivity is observed upon reuse, with the exception of
Cu(2)@SPC and Cu(2)@SPSi; this last one nevertheless showing a small decrease in
enantioselectivity. The FTIR spectra of the reused mesoporous silicas are similar to the
original heterogeneous catalyst, but the mesoporous carbon shows a new band, which
might suggest ligand degradation under the aziridination conditions (Fig.3).
4.
CONCLUSIONS
Multipurpose asymmetric heterogeneous catalysts based on the anchoring of a
copper(II) complex with a commercial chiral bis(oxazoline) (Cu(2)) onto ordered silica
mesoporous materials and their carbon replicas were prepared. All the composites were
active and enantioselective in (1) the benchmark asymmetric cyclopropanation of
styrene with low to moderate enantioselectivities (TON 78-96, 10-42% eecis and 10-
47% eetrans) and (2), for the first time, the less studied aziridination of styrene with low
yields and enantioselectivities (6-33% yield and 7-20% ee). Furthermore, higher
enantioselectivity and activity than in the homogeneous phase was obtained with
Cu(2)@SPSi for the cyclopropanation of styrene, suggesting that propylation of 2 is
1
8

beneficial to the course of the reaction and the surface properties of this support. These
results are in accordance with what we observed previously in the cyclopropanation of
styrene by immobilized copper(II) aza-bis(oxazoline) [18]. In the aziridination of
styrene the maximum enantioselectivity obtained was similar to the homogeneously
catalyzed reaction with the bis-propylated bis(oxazoline) 3 (Scheme 1), which mimics
the immobilized bis(oxazoline) 2. Moreover, for all the reactions the ordered
mesoporous silicas SBA-15 and SPSi yield generally more active heterogeneous
catalysts than when the corresponding mesoporous carbon replicas are used as
homogeneous catalyst supports. This could be due to the effect of the type of matrix
support, i.e. carbon vs silica but, apparently, for the type of enantioselective reactions
studied in the present work, more uniform mesopore size distributions of the silica
materials are revealed to be a more relevant factor than, for instance, the total pore
volume. Among the silica materials, the heterogeneous catalysts with smaller
mesopores (HMS) showed much lower enantioselectivities.
The Cu(2)@SPSi heterogeneous catalyst can be recycled for the aziridination of
styrene, with almost quantitative recovery, by simple filtration. For the
cyclopropanation of styrene a noticeable deactivation upon reuse of the heterogeneous
catalysts is observed, probably due to the combination of the reported low stability of
the copper(II) bis(oxazoline) complexes and competing deactivating process by binding
of by-products[1]. However, the TON remains generally higher than the corresponding
homogeneous phase cyclopropanation reaction. Generally, the carbon materials present
a sharper loss of enantioselectivity upon reuse than the mesoporous silicas. Therefore
the ordered mesoporous silicas are better supports for the Cu(2) homogeneous catalyst
than the ordered carbon materials.
1
9

With this work we were able to show that a copper(II) complex of an expensive
commercial bis(oxazoline) anchored onto a mesoporous silica (SPSi), prepared using a
simple one-pot procedure, is a stable heterogeneous catalyst for at least two asymmetric
organic transformations, as well as the kinetic resolution/monobenzoylation of 1,2-
diphenyl-1,2-ethanediol [17]. As in the kinetic resolution of 1,2-diphenyl-1,2-ethanediol
we could recycle and reuse one of the heterogeneous catalysts for 4 consecutive cycles
without significant loss of activity, enantioselectivity or selectivity [17]. We can also
conclude that the stability of these heterogeneous catalysts on reuse is highly dependent
on the reaction experimental conditions.
Acknowledgements
This work was funded by the Fundação para a Ciência e a Tecnologia (FCT) through
the project PTDC/QUI/64770/2006, which was co-financed by the EU under the
programs COMPETE, QREN and FEDER. ARS thanks FCT, FSE and POPH for the
contract under the programs Ciência 2008 and Investigator FCT 2012 (IF/1300/2012),
as well as for financing under the program Pest-C/CTM/LA0011/2013 (CICECO) and
PEst-OE/QUI/UI0612/2013 (CQB/FC/UL).
We would also like to acknowledge Dr. Mónica Valega and Prof. Fernando Domingues
from the Department of Chemistry of the University of Aveiro for the initial help in the
HPLC analytical method development for the analysis of the aziridines.
Appendix
SupplementaryData: synthesis of the PhINTs, racemic aziridine and HPLC
chromatograms.
2
0

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2
3

Table 1
Chemical and textural characteristics of the materials.
Concentration
µmol/g)
Textural
properties
(
Sample
a
Cu
b
A
BET
V
total
2
Cu/2
2
m /g) (cm /g)
3
(
SBA-15
CMK-3
SPSi
SPC
756
0.99
1.26
0.84
1.23
0.72
0.79
0.65
0.62
0.75
0.50
1396
571
1140
994
556
529
404
719
667
HMS
Cu(2)@SBA-15
Cu(2)@CMK-3
Cu(2)@SPSi
Cu(2)@SPC
aCu(2)@HMS
101
175
74
104
80
187
180
209
277
46
0.5
1.0
0.4
0.4
1.7
Determined by ICP-AES, media of duplicate analyze [17].
b
Determined by elemental analysis from the nitrogen content, media of
duplicate analyze [17].
2
4

Table 2
Benchmark cyclopropanation of styrene with Cu(2) anchored onto various porous
a
supports and in the homogeneous phase (Scheme 3).
b
e
%
mol
c
4
% ee
trans/cis cis-4 trans-4
f
t(h)
Run
%C
d
TON
Cu Box
0.2 0.2
0.2 0.2
0.5 0.5
1.0 1.0
0.3 0.5
0.2 0.5
0.2 0.4
0.5 0.5
0.4 0.4
0.4 0.4
0.2 0.6
0.2 0.5
0.2 0.5
0.3 0.8
0.3 0.8
0.3 0.7
0.2 0.1
0.2 0.1
0.2 0.1
st
1
2
2
2
+[Cu(OTf)
+[Cu(OTf)
+[Cu(OTf)
+[Cu(OTf)
2
2
2
2
]
]
]
]
24
24
24
3
1
16
8
2.5
2.3
2.3
2.3
1.8
1.9
1.8
1.6
1.8
2.0
1.8
1.7
2.0
1.7
1.7
1.9
1.7
1.6
1.5
31
31
41
36
21
10
18
22
5
42
38
51
51
22
9
18
23
5
84
41
99
57
96
66
33
82
56
29
93
38
58
90
70
67
78
38
66
st
1
1
1
st
49
58
28
16
6
st
st
Cu(2)@SBA-15 24
1
2
3
nd
2
2
4
4
rd
st
Cu(2)@CMK-3 24
1
2
3
41
24
10
22
7
10
27
22
19
19
9
nd
2
2
4
4
rd
2
2
st
Cu(2)@SPSi
Cu(2)@SPC
24
1
2
3
42
25
17
10
3
47
25
18
10
3
nd
2
2
4
4
rd
st
24
1
2
3
nd
2
2
4
4
rd
2
3
st
Cu(2)@HMS
24
1
2
13
12
12
14
10
5
nd
2
2
4
4
rd
3
15
a
Reactions performed at room temperature using 2.40 mmol styrene, 0.65 mmol n-undecane (internal
standard), 70 mg of (S,S)-Cu(2)@MM heterogeneous catalyst or (S,S)-Cu(2) or (R,R)-Cu(2)
homogeneous catalysts, 2 µl phenylhydrazine and 2.75 mmol of EDA in 10.0 ml of CH
b
2
Cl
2
.
% of copper and Box ligand in the catalyst in relation to styrene (see Table 1); for the recycling
experiments corrected for the loss of heterogeneous catalyst weight, after filtration and drying.
c
Conversion of styrene determined by CG-FID.
Ratio trans/cis for 4.
d
e
Cis-4 and trans-4enantiomeric excesses determined by chiral GC-FID.
TON = moles of styrene converted/moles of Cu.
f
2
5

Table 3
Aziridination of styrene with Cu(2) anchored onto various porous supports and
a
in the homogeneous phase (Scheme 4).
b
%
Cu
1.9
0.4
0.6
0.5
0.6
0.5
1.0
1.0
0.4
0.4
0.6
0.5
0.4
0.5
mol
5
Box %yield
d
e
t(h) Run
c
% ee
TON
st
(
(
(
(
R,R)-1+[Cu(OTf)
R,R)-1+[Cu(OTf)
2
2
]
]
2
1
1
1
1
1
2.1
0.4
0.6
0.8
1.1
0.9
1.0
1.0
1.2
1.1
1.6
1.4
0.3
0.3
40
71
66
60
30
21
18
13
18
20
6
18 (S)
24 (S)
31 (R)
21 (R)
20 (R)
7 (R)
4
32
22
24
10
8
st
st
st
st
48
48
48
48
S,S)-2+[Cu(OTf)
2
]
S,S)-3+[Cu(OTf)
2
]
Cu(2)@SBA-15
Cu(2)@CMK-3
Cu(2)@SPSi
nd
st
48
2
48
1
14 (R)
11 (R)
19 (R)
12 (R)
7 (R)
4
nd
48
2
1
3
st
48
8
nd
st
48
2
10
2
Cu(2)@SPC
48
1
nd
48
2
1
5
10 (R)
10 (R)
2 (R)
2
st
Cu(2)@HMS
48
33
14
15
6
nd
48
2
a
Reactions performed at room temperature using 1.22 mmol of styrene, 70 mg of heterogeneous
catalyst and 0.24 mmol of PhINTs in 5.00 ml of acetonitrile.
b
%
of copper and Box ligand (Scheme 1) in the catalyst in relation to styrene (see Table 1); for the
recycling experiments corrected for the loss of heterogeneous catalyst weight, after filtration and
drying.
c
Isolated yield of 5 aziridine.
Enantiomeric excess of 5 aziridine and configuration of the major enantiomer in brackets (Scheme
d
4
), determined by HPLC.
TON = moles of aziridine 5 /moles of Cu.
e
2
6

Figures Captions
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Fig.1
2 2
Bis(oxazoline) ligands (1) Me PhBox, (2) PhBox and (3) Pr PhBox.
Anchoring procedure for the Cu(2) complex.
Cyclopropanation of styrene with ethyldiazoacetate.
Aziridination of styrene with PhINTs.
Thermo analysis curves for silica based samples. Solid lines for
thermogravimetric data (TG) and broken lines for Differential Scanning
Calorimetry (DSC) data.
Fig.2
FTIR spectra (KBr pellets) of the heterogeneous catalysts before and
after cyclopropanation of styrene reactions: (a) SBA-15, (b) CMK-3, (c)
SPSi, (d) SPC and (e) HMS materials and (f) reagents and products
(
Scheme 3).
Fig.3
FTIR spectra (ATR silicas and KBr pellets carbon materials) of the
heterogeneous catalysts before and after aziridination of styrene
reactions: (a) SBA-15, (b) CMK-3, (c) SPSi, (d) SPC and (e) HMS
materials and (f) PhINTs and styrene aziridine (5) (Scheme 4).
2
7

Scheme 1
H C CH3
3
O
O
O
O
O
O
N
N
N
N
N
N
1
2
3
2
8

Scheme 2
2
9