Factors influencing recyclability of Co(III)-salen catalysts in the hydrolytic kinetic resolution of epichlorohydrin

Article abstract of DOI:10.1016/j.molcata.2009.10.025

The recyclability of Co(III)-salen catalysts, where salen is defined by (R,R)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine, for the hydrolytic kinetic resolution (HKR) of racemic epichlorohydrin is a strong function of the counterion of the Co(III)-salen catalyst. The nature of the counterion determines whether the HKR reaction follows primarily a bimetallic or monometallic reaction path, which significantly affects catalyst recyclability. For example, Co(III)-salen initially containing the nucleophilic Cl^- counterion catalyzes the HKR of epichlorohydrin according to a bimetallic reaction path but loses activity upon recycle, as Cl^- is replaced with OH^- during the reaction. In contrast, a Co(III)-salen catalyst containing non-nucleophilic SbF₆^- counterion catalyzes the reaction according to a monometallic reaction path and is quite stable during multiple recycles, albeit at a low rate with less selectivity. A mixed catalyst system with Co(III)-salen initially containing Cl^- to which Co(III)-salen with SbF₆^- is later added demonstrates high activity and high stability to recycling. Additional experiments with Co(III)-salen initially containing the acetate counterion reveal a progressive decline in activity with multiple recycles even after regeneration with acetic acid between runs, suggesting a destructive role of the regeneration process.

Full text of DOI:10.1016/j.molcata.2009.10.025

Journal of Molecular Catalysis A: Chemical 316 (2010) 8–15
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Editor’s choice paper
Factors influencing recyclability of Co(III)-salen catalysts in the hydrolytic
kinetic resolution of epichlorohydrin
Surbhi Jaina, Krishnan Venkatasubbaiahb, Christopher W. Jonesb,∗, Robert J. Davisa,∗∗
a Chemical Engineering Department, University of Virginia, 102 Engineers Way, Charlottesville, VA 22904, USA
b School of Chemical & Biomolecular Engineering, Georgia Institute of Technology, 311 Ferst Dr., Atlanta, GA 30332, USA
a r t i c l e i n f o
a b s t r a c t
The recyclability of Co(III)-salen catalysts, where salen is defined by (R,R)-N,Nꢀ-bis(3,5-di-tert-
butylsalicylidene)-1,2-cyclohexanediamine, for the hydrolytic kinetic resolution (HKR) of racemic
epichlorohydrin is a strong function of the counterion of the Co(III)-salen catalyst. The nature of the
counterion determines whether the HKR reaction follows primarily a bimetallic or monometallic reac-
tion path, which significantly affects catalyst recyclability. For example, Co(III)-salen initially containing
the nucleophilic Cl− counterion catalyzes the HKR of epichlorohydrin according to a bimetallic reac-
tion path but loses activity upon recycle, as Cl− is replaced with OH− during the reaction. In contrast, a
Article history:
Received 28 September 2009
Accepted 22 October 2009
Available online 31 October 2009
Keywords:
Cobalt-salen
Homogeneous catalysis
Asymmetric synthesis
Hydrolytic kinetic resolution (HKR)
−
Co(III)-salen catalyst containing non-nucleophilic SbF6 counterion catalyzes the reaction according to
a monometallic reaction path and is quite stable during multiple recycles, albeit at a low rate with less
selectivity. A mixed catalyst system with Co(III)-salen initially containing Cl− to which Co(III)-salen with
−
SbF6 is later added demonstrates high activity and high stability to recycling. Additional experiments
with Co(III)-salen initially containing the acetate counterion reveal a progressive decline in activity with
multiple recycles even after regeneration with acetic acid between runs, suggesting a destructive role of
the regeneration process.
© 2009 Elsevier B.V. All rights reserved.
1. Introduction
complex with an acetate counterion [1]. With catalyst regenera-
tion, it was reported that the reaction could be recycled with no
The hydrolytic kinetic resolution (HKR) of epoxides catalyzed
by Co(III)-salen complexes, where salen is defined as (R,R)-N,Nꢀ-
bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine, is now
a pre-eminent method for the preparation of enantiopure terminal
epoxides and/or 1,2-diols [1,2]. Introduced by Jacobsen in 1997, the
reaction is both of synthetic significance and an intriguing reac-
tion for catalysis science [1]. As early as the first report of the
reaction, Jacobsen noted several unique features of the reaction
including the second order dependence on the catalyst concentra-
tion, suggestive of a cooperative bimolecular reaction mechanism
involving two Co-salen complexes in the rate-determining step of
the catalytic reaction [1]. The authors reported that the catalyst
was easily recoverable via evaporation of the volatile reactants and
products, with the non-volatile residue remaining after removal
of the reaction products containing the reduced catalyst (Co(II)-
salen). The reduced (deactivated) catalyst could be regenerated by
treatment in acetic acid under air, reproducing the Co(III)-salen
observable loss in activity or selectivity, based on what appears to
be reproducible yield and enantiomeric excess (ee) after 12 h of
reaction.1
The HKR reaction is closely related to the other metal-salen
catalyzed epoxide ring-opening reactions such as the Cr(III)-salen
catalyzed ring-opening of epoxides using azides as nucleophiles
[2]. Also, the HKR reaction is a cooperative one involving two salen
complexes activating both the epoxide and nucleophile. Jacobsen
demonstrated that designing ligands that promoted cooperativity
led to enhanced rates in most cases and also ee’s if the appropriate
transition state could be accommodated [2]. Konsler et al. showed
that a “head-to-tail” transition state was likely the appropriate
quasi-planar stacking structure for the catalytic reaction [3]. The
Jacobsen group further establishedthe generality ofthecooperative
mechanism in their subsequent studies of the epoxide ring-opening
reaction using alcohols and phenols as the nucleophiles and Co(III)-
salen complexes as catalysts [4,5].
Recognizing that the cooperative epoxide ring-opening mech-
anism would allow supported catalysts to potentially achieve
∗
Corresponding author. Tel.: +1 404 385 1683; fax: +1 404 894 2866.
Corresponding author. Tel. +1 434 924 6284; fax: +1 434 982 2658.
E-mail addresses: cjones@chbe.gatech.edu (C.W. Jones), rjd4f@virginia.edu
∗∗
1
It should be noted that changes in reaction temperature may have been neces-
(R.J. Davis).
sary to achieve equivalent conversions and ee’s in a fixed reaction time [1].
1381-1169/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2009.10.025

S. Jain et al. / Journal of Molecular Catalysis A: Chemical 316 (2010) 8–15
9
Scheme 1. Co-existence of monometallic and bimetallic paths in the HKR of terminal epoxides.
higher reaction rates at a given catalyst loading as a result of
enhanced salen-salen interactions, Annis and Jacobsen reported
poly(styrene) resin and silica supported Co(III)-salen catalysts for
the HKR of epoxides [6]. The polymer resin supported catalyst
had rates and selectivities similar to the homogeneous catalyst.
Silica catalysts with a low density of grafted salen complexes dis-
played little to no activity, whereas those with higher densities
of salen complexes linked to the surface with long flexible link-
ers displayed activities similar to the homogeneous and polymer
supported catalysts. The catalysts were recovered and recycled,
with the authors again noting that regeneration of the catalyst
using a 9:1 toluene:acetic acid mixture under air was required. This
reactivation was suggested to reoxidize the catalyst, implying the
deactivated catalysts were reduced to Co(II) complexes [6].
reaction scheme that was kinetically consistent with the observed
results. The authors showed that the kinetics of the reaction were
consistent with the participation of two types of Co(III)-salen com-
plexes, one with a counterion X− introduced at the start of the
reaction [X = Cl−, OAc− (acetate), OTs− (tosylate), SbF6−, etc.] and
one, Co(III)-OH, that is generated in situ via counterion addition to
the epoxide (Scheme 1). Although the hypothetical Co(III)-OH com-
plex has not been isolated and characterized experimentally, both
kinetic and other evidence for its existence appears strong [8]. Asso-
ciated with the role of the counterion in the cooperative reaction,
Nielsen et al. [8] showed that the highest rates occurred when the
relative amounts of the Co(III)-X and Co(III)-OH salen were equal.
As a result, use of Co(III)-salen complexes with relatively nucle-
ophilic counterions such as Cl− or OAc− led to the rapid build-up
of Co(III)-OH and deactivation of the catalyst [8].
Building off the success of the solid supported catalysts [6] and
dimeric catalysts [3], Jacobsen and coworkers next developed den-
drimeric [7] and cyclic oligomeric [4] Co(III)-salen complexes for
epoxide ring-opening reactions. They showed that the dendrimeric
catalysts displayed higher activities than comparable dimeric ana-
logues, suggesting higher order catalyst interactions are possible
with structures with more than two salen units [7]. They reported
that the reactions using the oligomeric catalysts displayed a first
order dependence on catalyst concentration, unlike the unsup-
ported monomeric catalyst, supporting the cooperative bimetallic
mechanism proposed in their previous work [4]. Furthermore, they
demonstrated that a variety of alcohols and phenols could be
used as nucleophiles [4]. In another study on the cyclic oligomeric
catalysts, the authors suggested the possibility of two distinct reac-
tion paths, a more active and selective bimetallic pathway and
less active and less selective monometallic route when using the
monomeric catalyst [5]. However, no kinetic data in support of the
monomeric pathway were presented. Owing to the enhanced coop-
erativity imparted by the cyclic oligomeric catalysts, these catalysts
had enantioselectivities that were independent of catalyst load-
ing, an observation consistent with solely the bimetallic pathway
operating with the oligomeric systems [5].
Building on the work described above, we and coworkers have
sought to develop improved supported cooperative Co(III)-salen
catalysts for epoxide ring-opening reactions, with an eye towards
gaining insight into the preparation of more effective supported
catalysts for cooperative catalytic reactions [9–14]. The advantages
of supported catalysts for these reactions include: (i) ease of catalyst
separation from the products, (ii) the potential for easier catalyst
recycle, and (iii) improved catalytic activity and selectivity asso-
ciated with improved cooperative interactions among the salen
complexes. However, catalyst recycle requires not only recovery
of the catalyst, but also good catalyst stability as well as either
limited catalyst deactivation or an understanding of the deactiva-
tion process so that regeneration methods can be developed. As
noted above, Jacobsen and coworkers noted in their early work
that the prototypical catalysts such as Co(III)-OAc are sometimes
reduced to Co(II) after reaction, and they reported that these cat-
alysts are regenerated by an oxidative treatment using acetic acid
under air. The reports of catalyst reduction were often associated
with a change of the catalyst color from brown to brick red after
reaction and workup. Others have also reported that Co(III)-salen
catalysts are deactivated by reduction to Co(II) species after the
reaction. For example, Kim and coworkers, who developed a series
of dimeric and polymeric heterometallic Co-salen catalysts linked
with different Lewis acids [15,16], have reported that supported
and unsupported Co-salen catalysts are deactivated by reduction,
A breakthrough in the understanding of the reaction mech-
anism came from a collaborative work published in 2004 from
Jacobsen and Blackmond [8]. Detailed kinetic studies using a vari-
ety of different Co(III)-salen complexes allowed development of a

10
S. Jain et al. / Journal of Molecular Catalysis A: Chemical 316 (2010) 8–15
Scheme 2. HKR of epichlorohydrin using Co(III)-salen-X.
in some cases providing UV–vis spectroscopic evidence to support
this claim [17–19]. Seeking to understand the factors that affect
catalyst deactivation, we evaluated the deactivation and recycling
of soluble and supported Co(III)-salen HKR catalysts [20]. Our find-
ings were consistent with the work of Nielsen et al. [8] who first
suggested that the nature of the counterion (X− in Scheme 1) on
the Co(III)-salen catalyst is one of the most important factors in the
mechanistic understanding of the HKR reaction. They showed that
the nucleophilicity of the counterion X− as well as the stability of
X− (which depends on the pKa of its conjugate acid) influenced the
rates of HKR and recyclability of Co(III)-salen in this system. The
formation of the bimetallic transition state as depicted in Scheme 1
(lower pathway) illustrates how the observed kinetics of HKR are
statistically optimized with a 1:1 ratio of Co(III)-salen with OH− as
a counterion during the reaction [8].
Ready and Jacobsen [5] have suggested that a less enantioselective
monometallic mechanism involving a single Co(III)-salen complex
in the transition state may play a role in HKR at low catalyst con-
centrations, no specific kinetic results were presented.3 We report
conclusive evidence of this less selective monometallic mechanism
and how it couples to the well-recognized bimetallic path of the
HKR of epichlorohydrin during the recycling of Co-salen catalysts
containing specific counterions at specified catalyst concentrations.
In addition, the influence of acetic acid regeneration on the recycla-
bility of Co-salen catalyst containing acetate counterion is explored
in the HKR of epichlorohydrin.
2. Results and discussion
2.1. Monometall−ic route to HKR with non-nucleophilic
Despite numerous reports suggesting reduction of Co(III) to
Co(II) to be the cause of catalyst deactivation, based on our pre-
vious work, we have shown that the deactivation of the Co-salen
catalysts upon multiple recycles was not attributed to reduction
of Co or to dimerization of the Co complexes in the HKR, under
our reaction conditions2 [20]. Instead, the rate of counterion addi-
tion to epichlorohydrin, which ultimately formed the less active
Co(III)-salen-OH complex, correlated to the loss in activity, as sug-
gested by Nielsen et al. [8]. In particular, we observed that on
recycling Co(III)-salen-X catalysts, the loss in catalyst activity dur-
ing HKR of epichlorohydrin occurred in the following order, with X:
iodide > chloride > acetate > tosylate [20]. However, the measured
activity of the fresh catalysts in the first run showed nearly the same
trend with the counterion, which contrasts the results reported ear-
lier by Nielsen et al. [8] with 1,2-epoxyhexane as the substrate.
This result suggests that, in addition to the Co-salen counterion,
the nature of the substrate may also affect the rate of change of
Co(III)-salen-X to Co(III)-salen-OH during the HKR reaction.
More recently, recycling studies of some supported Co(III)-
salen-OAc catalysts have suggested that catalyst deactivation can
also occur due to salen ligand hydrolysis during the HKR reaction
or regeneration [13]. Thus, three mechanisms appear in the liter-
ature that are associated with Co(III)-salen-X deactivation in HKR
reactions: (i) counterion exchange, (ii) reduction of Co(III) to Co(II)
and (iii) salen ligand hydrolysis. Here, we explore the kinetics of the
epichlorohydrin HKR during the recycling of various Co(III)-salen
catalysts to gain insight into the stability of Co-salen HKR catalysts.
A series of Co(III)-salen catalysts containing different counterions,
counterion (SbF6
)
The HKR of epichlorohydrin was evaluated in the presence
of Co(III)-salen-SbF6 since the non-nucleophilic SbF6 counterion
−
should not react with the epoxide to form the Co(III)-salen-OH
species. Therefore, the bimetallic reaction path should not be avail-
able when Co(III)-salen-SbF6 is used as a catalyst.
Various concentrations of Co-X salen complexes (0.1–2 mol%)
containing different counterions, namely, Cl− (1a) OAc− (1b), and
SbF6− (1c) were utilized in the HKR of epichlorohydrin using water
(0.7 eq.) as a nucleophile, as shown in Scheme 2.
In some cases, the solvent 2-propanol was used to make the
reaction mixture a single-phase [20], hence eliminating any induc-
tion period due to the presence of the initial biphasic reaction
mixture of epichlorohydrin and water in the absence of solvent.
A control experiment confirmed that 2-propanol does not partic-
ipate in the reaction but functions only as an inert solvent in the
reaction mixture.4 The initial rates were evaluated at various cat-
alyst loadings to evaluate the role of catalyst concentration on the
observed activity. Table 1 summarizes the observed reaction orders
for catalysts containing various counterions. The kinetic data and
experimental details of the determination of reaction order in cata-
lyst concentrations as a function of different counterions are given
in the supporting information. It should be noted that the catalysts
containing nucleophilic counterions (i.e. 1a and 1b) are contin-
uously undergoing chemical change during the reaction to form
ranging from non-nucleophilic SbF6 to a highly nucleophilic Cl−,
−
3
In early work, Jacobsen and coworker suggest that a less selective, slower
are examined in the HKR of epichlorohydrin. Although at one time
monometallic pathway exists [5]. Later work by Jacobsen and Blackmond suggested
(Fig. 1) that Co(III)-salen-SbF6 in the absence of Co-salen-OH is inactive [8]. Indeed,
they suggest that Co(III)-salen-SbF6 is inactive if purified carefully, in contrast to the
work of Kim et al. [17].
2
4
Recycling of the soluble molecular catalyst via recovery from reaction media by
2-propanol acts as an inert solvent except when Co(III)-salen-SbF6 complexes
distillation can lead to catalyst reduction if careful control of the distillation tem-
perature is not practiced. Limiting the heating to a maximum of 50–55 ◦C leads to
recovery of the unreduced Co(III) complex in our hands under typical conditions.
were used, in which case additional reactions occur. Thus, 2-propanol was not used
as a solvent when SbF6 complexes were used. These reactions were run in the
absence of solvent.

S. Jain et al. / Journal of Molecular Catalysis A: Chemical 316 (2010) 8–15
11
Fig. 1. (a) HKR of epichlorohydrin with different loadings of Co(III)-salen-SbF6 (1c) catalyst. Reaction conditions: Co(III)-salen-SbF6 (1c) (0.50, 0.75, 1.00, and 2.25 mol%,
respectively), 3 mmol racemic epichlorohydrin, distilled deionized water (0.7 eq., 126 ␮L), 120 ␮L chlorobenzene (as internal standard), room temperature. (b) Plot of ln r vs.
ln [cat] showing the reaction order in concentration of Co(III)-salen-SbF6 (1c) catalyst.
Table 1
repeated our reactions with two different samples of Co(III)-salen-
SbF6 prepared in different ways. The original sample used was the
product of oxidation of Co(II)-salen with AgSbF6, which was the
Observed order of reaction with respect to catalyst concentration in the HKR of
epichlorohydrin.
Catalyst
Counterion X
Order of reaction, n [catalyst]n
same synthetic method used by Kim et al. [17] A second sample
was made via the more laborious path used by Nielsen et al. con-
verting Co(III)-salen-OTs to Co(III)-salen-Cl followed by counter ion
exchange to Co(III)-salen-SbF6. [8] The Co(III)-salen-SbF6 was char-
acterized using different techniques including 1H NMR, elemental
analysis and single crystal X-ray diffraction. The molecular struc-
ture of Co(III)-salen-SbF6 is given in the supplementary material.
Both the Co(III)-salen-SbF6 catalysts behaved the same in the HKR
of epichlorohydrin, leading us to conclude that the Co(III)-salen-
SbF6 complex is indeed active for the HKR reaction. Furthermore,
the kinetic results suggest the reaction is first order with regard to
the concentration of the cobalt complex (Fig. 1). For the reaction
with 0.50 mol% catalyst loading, only 30 min was needed to reach
36% conversion and 59% ee of recovered S-epichlorohydrin with
1a, whereas 4 h were needed to reach the same level of conver-
sion and only 31% ee with 1c. Thus, the monometallic path for HKR
with Co(III)-salen-SbF6 (1c) was not only less active, but also less
selective compared to the bimetallic path presumably followed by
the Co(III)-salen-Cl (1a), which is consistent with the suggestion by
Ready and Jacobsen [5] that a hypothetical monometallic path has
poor enantioselectivity. It should be noted that these are the first
kinetic data that directly illustrate the presence of a monometallic
pathway in the Co-salen catalyzed HKR reaction (upper pathway in
Scheme 1).
1a
1b
1c
Cl−
1.95 (1.97)a
1.26a
1.02
OAc−
−
SbF6
a
Order when 2-propanol is used as a solvent.
Co(III)-salen-OH species. Thus, the orders of reaction with respect
to catalyst concentration as reported in Table 1 are not true orders,
but instead are observed orders of reaction that suggest a bimetallic
or monometallic reaction path.
Under our standard reaction conditions, the observed order of
reactionwithrespectto catalyst concentrationforCo(III)-salen con-
taining the highly nucleophilic chloride counterion was very nearly
2, which is consistent with the bimetallic HKR reaction mecha-
nism as reported by Nielsen et al. [8]. For a catalyst containing the
moderately nucleophilic acetate counterion, the reaction order was
1.26, suggesting neither the monometallic nor the bimetallic mech-
anism was the exclusive reaction path. Unfortunately, the fact that
the catalyst is changing throughout the reaction prevents a more
quantitative conclusion based on the data in hand. However, for the
catalyst with SbF6−, the reaction order was unity, which suggests
the reaction path is exclusively monometallic.
The observed reactivity with Co(III)-salen-SbF6 is interesting
because there is conflicting information in the literature with
regard to its reactivity. Kim et al. reported in 2003 that the Co(III)-
salen-SbF6 complex was active but relatively unselective [17].
Subsequently, Nielsen et al. suggested in a footnote that Co(III)-
salen-SbF6 was inactive when purified carefully [8]. To this end, we
2.2. Recycling Co-salen catalysts in the HKR of epichlorohydrin
The co-existence of two reaction paths (as described above)
can now be used to reconcile the trends observed in activity
Fig. 2. Recycling of Co(III)-salen-SbF6 in the HKR of epichlorohydrin (a) % conversion vs time and (b) % ee vs time. Reaction conditions: 1c (0.5 mol%, 0.05 mmol, ∼42 mg), (
epichlorohydrin (10 mmol, 784 ␮L), water (0.7 eq., 126 ␮L), chlorobenzene was used as an internal standard (120 ␮L), room temperature, 1st run was performed for 12 h.
)

12
S. Jain et al. / Journal of Molecular Catalysis A: Chemical 316 (2010) 8–15
Fig. 3. Recycling studies of Co(III)-salen-Cl in the HKR of epichlorohydrin followed by the addition of an equimolar amount of Co(III)-salen-SbF6 catalyst. Reaction conditions:
1a or 1c (0.25 mol%, 0.025 mmol), ( ) epichlorohydrin (10 mmol, 784 ␮L), water (0.7 eq., 126 ␮L), chlorobenzene as an internal standard (120 ␮L), room temperature. In the
4th run, 0.25 mol% (∼21 mg) of Co(III)-salen-SbF6 catalyst was added to the reaction mixture. The runs were performed for 8 h.
and recyclability with catalysts containing various counterions.
As mentioned earlier, the loss of activity of these catalysts is the
result of Co(III)-salen-OH formation during the HKR reaction [8,20].
The observed order of deactivation, Co(III)-salen-Cl > Co(III)-salen-
OAc > Co(III)-salen-OTs, is related to the order of reactivity of the
counterions with the epoxide to form the Co(III)-salen-OH species
[20]. A catalyst such as Co(III)-salen-SbF6 with a non-reactive coun-
terion should therefore not suffer activity loss. To test this hypoth-
esis, 0.5 mol% of catalyst 1c (∼42 mg) was recycled in the HKR
of epichlorohydrin (10 mmol) using water (0.7 eq.) as the nucle-
ophile. The reaction was performed for a period of 12 h followed
by the evaporation of products under vacuum and addition of fresh
reagents to the recovered catalyst to perform the 2nd run. The con-
version and enantiomeric excesses of the residual epichlorohydrin
for both runs are summarized in Fig. 2. As seen in the figure, approx-
imately 41% conversion and 36% ee were obtained after 5 h reaction
time with both fresh Co(III)-salen-SbF6 catalyst (1st run) and the
catalyst recycled after 12 h (2nd run). The negligible activity loss
of this catalyst upon recycle is completely consistent with the pro-
posed idea that the counterion addition to epoxide and subsequent
formation of Co(III)-salen-OH causes catalyst deactivation [8].
In contrast to the Co(III)-salen-SbF6 complex, the Co(III)-salen-
Cl catalyst is quite active and selective, but undergoes substantial
activity loss upon recycle by conversion to the OH− form through-
out the reaction. Simple addition of Co(III)-salen-SbF6 to the system
containing Co(III)-salen-OH should promote the reaction via the
bimetallic reaction path involving the OH− complex [8]. There-
fore, the Co(III)-salen-Cl catalyst (1a) was recycled in the HKR
of epichlorohydrin followed by the addition of Co(III)-salen-SbF6
(1c) to the deactivated Co(III)-salen-Cl (which should be mostly
Co(III)-OH at that point [8]) recovered after the HKR reaction. The
recyclability of 1a during HKR of epichlorohydrin is illustrated in
the reaction profiles shown in Fig. 3, where 0.25 mol% of catalyst 1a
(∼16 mg) was utilized in the HKR of ( ) epichlorohydrin (10 mmol)
using water (0.7 eq.) as a nucleophile. In the first run, 47% conver-
sion and 94% ee were obtained after 2 h. After allowing the reaction
to continue for a total of 8 h, products were removed under vacuum
and fresh reagents were added to allow the 2nd run to be performed
under similar reaction conditions.
the products and residual reagents under vacuum. At this point,
the inactive catalyst should be primarily Co(III) in the ineffective
OH− form [8]. This inactive catalyst5 should be useful in a reac-
tion that follows the bimetallic reaction path (Scheme 1) as long as
additional Co(III)-salen catalyst is added in a non-OH− form. The
profile for the 4th run in Fig. 3 illustrates the high activity and
selectivity of a reaction in which an equimolar amount of Co(III)-
salen-SbF6 1c (0.25 mol%, ∼21 mg) was added to the deactivated
catalyst obtained after the 3rd run using 1a. Approximately 49%
conversion and 91% ee were obtained after 2 h with the mixed cat-
alyst system (4th run), results that were quite similar to the values
obtained in the 1st run and are better than the results obtained
with 0.5 mol% of fresh Co(III)-salen-SbF6 alone in 2 h. Evidently,
the electronic structure around the Co metal center with an OH−
counterion prevents significant participation in the monometallic
path. These results are completely consistent with those of Nielsen
et al. [8] who reported that the rate of the HKR increased sub-
stantially in a mixed catalyst system operating via the bimetallic
mechanism. However, the Cl− form of Co-salen under their condi-
tions with 1,2-epoxyhexane as substrate was proposed to undergo
complete conversion to the OH− form very early in the reac-
tion. The apparently slower replacement of Cl− with OH− during
our studies illustrates the important role of the epoxide in deter-
mining the form of the catalyst. According to the above results,
once Co(III)-salen-X (X = nucleophilic counterion such as Cl−, OAc−,
OTs−) has converted to the OH− form, addition of Co(III)-salen-
SbF6 should create a system that does not deactivate significantly.
Fig. 3 illustrates the repeated runs with a 50:50 mixture of deac-
tivated Co(III)-salen-Cl with Co(III)-salen-SbF6 (runs 5 and 6). The
−
system was quite stable since the non-nucleophilic SbF6 coun-
terion does not react with epichlorohydrin. These results suggest
a possible catalyst design strategy for enhanced durability under
recycling conditions. Recent works by several groups have shown
how immobilizing Co(III)-salen in flexible oligomers or on solid
supports can dramatically enhance the reaction rate by facilitating
the bimetallic reaction path [4,5,9,10,12,13,21,22]. However, these
systems still lose activity by counterion replacement as described
above. The results of the current study as well as those of Nielsen
et al. [8] suggest that a mixed catalyst containing both nucleophilic
and non-nucleophilic counterions (such as SbF6−) could provide a
new highly active HKR system, where the catalyst can be repeatedly
recycled without suffering from loss in the activity and selectivity.
In the 2nd run, the partially deactivated catalyst produced about
26% conversion and 33% ee after 2 h. After allowing the 2nd run to
continue for 8 h, the catalyst was recycled again to allow the 3rd
run of the HKR of epichlorohydrin to be performed under iden-
tical reaction conditions as those of the 1st and the 2nd runs. In
the 3rd run, the catalyst was deactivated even more, producing
only about 11% conversion and 10% ee after 2 h. After perform-
ing the 3rd run (for 8 h), the catalyst was recovered by removing
5
The Co(III)-salen-OH catalyst should be essentially inactive when it is present
alone without any other Co(III)-salen-X where X is for example, Cl−, OAc−, etc.,
according to Ref. [8].

S. Jain et al. / Journal of Molecular Catalysis A: Chemical 316 (2010) 8–15
13
Table 2
2.3. Effect of acetic acid regeneration on Co-salen
Influence of catalyst recycling on the initial TOF of the
homogeneous Co(III)-salen-OAc catalyst (1b) in the HKR
of epichlorohydrin with 2-propanol solvent and with
intermediate acetic acid regeneration.
A common method to overcome loss in activity of Co(III)-salen-
X catalyst systems that contain a single type of counterion is to
regenerate the catalysts after each run. Indeed, Co(III)-salen-OAc
is commonly regenerated after reaction by subsequent treatment
with acetic acid in air. This may accomplish two goals, replace-
ment of OH− counterions with OAc counterions in Co(III)-salen-X
complexes as well as reoxidation of Co(II)-salen complexes to
Co(III)-salen-X complexes, should any reduction of the cobalt occur
during the reaction or workup. Recently, Gill et al. [13] reported the
insoluble silica supported polymeric Co(III)-salen-OAc complexes
deactivated on repeated recycling with intermediate acetic acid
regeneration. In addition to metal leaching, polymer loss and coun-
terion exchange, salen ligand decomposition was observed to be an
underlying cause of deactivation in their system. They speculated
that cleavage of the imine bonds in the salen ligand might have
occurred in the presence of water and acetic acid used for regen-
eration. It should be noted that this observation contrasts previous
reports that suggest that catalysts can be recycled with interme-
diate acetic acid regeneration without loss of activity6 [23]. Such
observations led us to evaluate deactivation pathways that may be
associated with the regeneration process.
Run
Initial TOF (min−1
)
1
2
3
4
5
6
6.4
6.6
5.8
4.4
3.2
2.7
Table 3
Influence of catalyst recycling on the initial TOF of
Co(III)-salen-SbF6 catalyst (1c) in the HKR of epichloro-
hydrin without intermediate regeneration.
Run
Initial TOF (min−1
)
1
2
3
4
0.25
0.23
0.23
0.24
were removed under vacuum and catalyst was recycled in the 2nd
run. In a similar manner, a total of four runs were performed. In
all four runs, there was negligible loss in catalyst activity, which
is consistent with the stable monometallic path mentioned above
when using Co(III)-salen-SbF6 as a catalyst. The conversion versus
time data for the four runs are shown in supporting information.
This stability is associated with the non-nucleophilicity of the SbF6
counterion as well as the absence of the application of any regen-
eration process.
Although the calculated TOFs using the Co(III)-salen-SbF6 cat-
alyst (1c) (summarized in Table 3) were−lower than those of the
Co(III)-salen-OAc catalyst (1b), the SbF6 catalyst was quite sta-
ble to repeated recycling without regeneration. Thus, the decrease
in TOF of Co(III)-salen-OAc (1b) after acetic acid regeneration is
likely the result of catalyst decomposition in the presence of acetic
acid (and trace water), consistent with the results reported by Gill
et al. [13] These observations contrast previous reports that sug-
gest the Co(III)-salen-OAc catalyst can be recycled without activity
loss if regenerated, with most reports not including kinetic plots
of reaction recycles [9,23]. It appears under our conditions that
regeneration leads to stable activity for only a few cycles. These
results indicate a very important principle regarding the stability
of Co(III)-salen-X catalysts for long term use. Since intermediate
regeneration of used catalysts can lead to irreversible activity loss
after multiple recycles, the best strategy for prolonging catalyst
lifetime is to prepare the mixed Co(III)-salen-X system contain-
ing both nucleophilic and non-nucleophilic X counterions. These
very active mixed counterion systems do not require intermediate
regeneration (see Fig. 3).
In this work, as in the work of Gill et al. [13], we also observed
a small peak near 10.29 ppm in the 1H NMR spectrum of the deac-
tivated molecular Co(III)-salen catalyst recovered after the HKR
reaction, which is a characteristic of an aldehyde proton. The pres-
ence of this peak suggests partial decomposition of the salen ligand
in the HKR of epichlorohydrin, which may also account for some
part of the catalyst deactivation. To further study the modes of
activity loss in the Co(III)-salen-X system, we performed multiple
recycles of the catalyst 1b in the HKR of epichlorohydrin with inter-
mediate acetic acid regeneration. In addition, catalyst 1c was also
recycled repeatedly under identical reaction conditions without
intermediate regeneration. Since the Co(III)-salen-SbF6 complex
did not lose activity in the HKR reaction (Fig. 2), recycling of Co(III)-
salen-SbF6 served as a control experiment to investigate whether
catalyst decomposition occurred during the HKR reaction or during
the regeneration step.
1 mol% of Co(III)-salen-OAc catalyst 1b was utilized in the HKR
of epichlorohydrin. In the first run, almost 52% conversion and >99%
ee were obtained in about 30 min. After performing the reaction for
about 75 min, the products were removed under vacuum and the
catalyst was regenerated with acetic acid/dichloromethane mix-
ture (stirring in air for 30 min) prior to re-use. In a similar manner,
the catalyst was recycled five times after the HKR of epichloro-
hydrin with intermediate acetic acid regeneration after every run.
Although the enantioselectivity was retained after the five recy-
cles, the catalytic activity decreased, i.e. it took longer reaction
times to achieve >99% ee. The initial turnover frequency (TOF) in the
first run was 6.45 min−1, which decreased to 2.67 min−1 in the 6th
run. The values of initial TOF’s for the six runs are summarized in
Table 2.
−
The first few runs illustrate the reproducibility of the process
and the efficacy of the regeneration treatment. However, the later
runs (runs 4–6) clearly show a loss in activity. To explore the
reason for the decrease in TOF even after acetic acid regenera-
tion, Co(III)-salen-SbF6 catalyst 1c was repeatedly recycled without
intermediate regeneration under similar reaction conditions as
those used for Co(III)-salen-OAc catalyst 1b. Thus, 1 mol% of cat-
alyst 1c was utilized in the HKR of epichlorohydrin. After running
the reaction for a period of 8 h, all residual reagents and products
3. Conclusions
Activity loss upon recycling Co(III)-salen-X catalysts containing
nucleophilic X counterions such as Cl− and OAc− was primarily the
result of forming excess Co(III)-salen-OH. For a Co(III)-salen-OAc
catalyst, the activity could be initially recovered by regeneration
with acetic acid treatment, but the catalyst was eventually deac-
tivated irreversibly by the treatment conditions. Addition of an
equimolar amount of Co(III)-salen-SbF6, where SbF6 represents a
suitable non-nucleophilic counterion, to in situ generated Co(III)-
salen-OH, produced a mixed catalyst system that was recycled
without significant loss in activity or selectivity. The mixed Co-
salen system was the preferred form of the catalyst since it avoided
6
The catalyst could be recycled with constant reaction selectivity and yield.
Kinetic data were not presented, so reaction rates cannot be directly inferred.

14
S. Jain et al. / Journal of Molecular Catalysis A: Chemical 316 (2010) 8–15
the need for intermediate regeneration and thus catalyst decom-
position.
out twice). The solvent was removed using rotovap and the solid
was dried under vacuum for 4 h to get dark green solid. The green
solid was crystallized using dichloromethane and heptane at low
temperature. Yield: 1.0 g (86%). The crystallized material was char-
acterized using single crystal X-ray crystallography and 1H NMR
(400 MHz, (CD3)2SO, 25 ◦C) ı 7.80 (s, 2H), 7.45 (d, J = 2.4 Hz, 2H), 7.42
(d, J = 2.8 Hz, 2H), 3.59–3.57 (m, 2H), 3.06–3.03 (m, 2H), 2.00–1.98
(m, 2H), 1.90–1.87 (m, 2H), 1.72 (s, 18H), 1.59–1.54 (m, 2H), 1.28
(s, 18H). The crystallized material was used for kinetic studies.
4. Experimental section
4.1. General
Reagents were used as received unless otherwise noted. 1H
spectra were acquired with a Varian Mercury 400 MHz spectrom-
eter, and chemical shifts were reported in ppm with reference
to the corresponding residual nuclei of the deuterated solvents.
Enantiomeric excesses were determined by capillary gas-phase
chromatography (GC) analysis on a Shimadzu GC 14A instru-
ment equipped with a FID detector and a Chiraldex ␥-TA column
(40 m × 25 mm × 0.25 ␮m). Elemental analyses were performed by
Galbraith Laboratories (Knoxville, TN).
For single crystal X-ray diffraction, a suitable crystal of 1c was
coated with Paratone N oil, suspended in a small fiber loop, and
placed in a cooled nitrogen gas stream at 173 K on a Bruker D8
APEX II CCD sealed tube diffractometer with graphite monochro-
mated MoK␣ (0.71073 Å) radiation. Data were measured using a
series of combinations of phi and omega scans with 10 s frame
exposures and 0.5◦ frame widths. Data collection, indexing and
initial cell refinements were carried out using APEX II software
[24]. Frame integration and final cell refinements were done using
SAINT software [25]. The final cell parameters were determined
from least-squares refinement on 3626 reflections. The structure
was solved using Direct methods and difference Fourier tech-
niques (SHELXTL, V6.12) [26]. Hydrogen atoms were placed in
their expected chemical positions using the HFIX command and
were refined as riding atoms All non-hydrogen atoms were refined
anisotropically except the cyclohexyl group which was disordered.
The cyclohexyl group was split over two positions and refined
isotropically.
4.2.4. Hydrolytic kinetic resolution (HKR) of epichlorohydrin
Various loadings of Co-salen catalysts (1a–1c) (0.1–2 mol%)
were dissolved in racemic epichlorohydrin (as received from Acros,
10 mmol, 784 ␮L) in a 100 mL reaction flask immersed in a tem-
perature controlled water bath (∼300 K). An internal standard
chlorobenzene (as received from Sigma–Aldrich, 120 ␮L) and co-
solvent 2-propanol (as received from Acros, 1 eq., 760 ␮L) were
added to the reaction mixture via a micro liter pipette. One aliquot
(1–2 ␮L) of the reaction mixture was taken before starting the reac-
tion, passed through a Pasteur pipette plugged with silica gel and
diluted with diethyl ether (∼1–1.5 mL). Distilled, deionized water
(0.7 eq., 126 ␮L) was then added to the mixture to start the HKR
reaction. Approximately 1–2 ␮L samples were withdrawn periodi-
cally, passed through a Pasteur pipette plugged with silica gel and
diluted with diethyl ether. Reaction products were analyzed by gas
chromatography using ChiralDex GTA capillary column and an FID
detector. The percent conversion and percent ee of the recovered
epoxide (S-epichlorohydrin) were monitored as a function of time.
4.3. Catalyst recycling
The recycling studies were performed on various homogeneous
Co-salen catalysts (1a–1c) with or without intermediate regenera-
tion of the catalyst. After performing the HKR reaction for a period
of 8–12 h, all of the reaction products were removed by evacua-
tion (epoxide was removed at room temperature, ∼300 K, and diol
was removed at a temperature of 323–329 K). Fresh reagents were
then added to the recovered catalyst and a 2nd run was performed.
In a similar manner, the catalyst was recycled again to perform
subsequent runs. In some cases, catalyst 1b was recycled with inter-
mediate regeneration, where the recovered catalyst was treated
with an acetic acid/dichloromethane mixture prior to re-use.
4.2. Catalyst preparation
4.2.1. Synthesis of Co(III)-salen-Cl catalyst (1a)
The catalyst (1a) was synthesized as previously reported [8].
2.5 g of Co-salen-OTs was dissolved in 100 mL dichloromethane in
a 500 mL separatory funnel. The organic layer was then rinsed with
saturated aqueous NaCl solutions (3 × 100 mL), dried over Na2SO4,
and concentrated in rotary evaporator. The residue was then re-
suspended in pentane and vacuum filtered to produce a very dark
green material. Elemental analysis for C37H55O2ClCoN2, calcd: C
67.93, H 8.47, N 4.28, Co 9.01, Cl 5.42 found C 67.25, H 8.12, N 4.37,
Co 9.67, Cl 5.85.
Acknowledgements
We acknowledge the U.S. Department of Energy, Basic
Energy Sciences, for financial support through Catalysis Sci-
ence Grant/Contract Nos. DE-FG02-03ER15459 and DE-FG02-
03ER15460. We also acknowledge Prof. Marcus Weck (New York
University) for helpful discussions.
4.2.2. Synthesis of Co(III)-salen-OAc catalyst (1b)
A solution of Co(II) salen catalyst (400 mg) was dissolved in
dichloromethane (13 mL) in a 25 mL round bottom flask after which
glacial acetic acid (as received from Aldrich,10 eq. with respect to
catalyst, 382.5 ␮L) was added via a micro liter pipette. After stirring
the mixture with a teflon stir bar for about 45 min, dichloromethane
was removed with a rotovap and the excess acetic acid was
removed under vacuum. The resulting catalyst 1b was a dark brown
residue used for reactions.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molcata.2009.10.025.
References
4.2.3. Synthesis of Co(III)-salen-SbF6 (1c)
[1] M. Tokunaga, J.F. Larrow, F. Kakiuchi, E.N. Jacobsen, Science 277 (1997) 936.
[2] E.N. Jacobsen, Acc. Chem. Res. 33 (2000) 421.
The catalyst (1c) was synthesized as previously reported [17]. To
a solution of AgSbF6 (0.48 g, 1.39 mmol) in dichloromethane (5 mL)
was added Co(II) salen (1) (0.84 g, 1.39 mmol) in dichloromethane
(10 mL) (the flask was wrapped with aluminum foil). The color of
the solution turned green within a few seconds followed by pre-
cipitates of silver. The solution was stirred for 2 h, filtered through
a frit that was loaded with celite (the filtration process was carried
[3] R.G. Konsler, J. Karl, E.N. Jacobsen, J. Am. Chem. Soc. 120 (1998) 10780.
[4] J.M. Ready, E.N. Jacobsen, J. Am. Chem. Soc. 123 (2001) 2687.
[5] J.M. Ready, E.N. Jacobsen, Angew. Chem. Int. Ed. 41 (2002) 1374.
[6] D.A. Annis, E.N. Jacobsen, J. Am. Chem. Soc. 121 (1999) 4147.
[7] R. Breinbauer, E.N. Jacobsen, Angew. Chem. Int. Ed. 39 (2000) 3604.
[8] L.P.C. Nielsen, C.P. Stevenson, D.G. Blackmond, E.N. Jacobsen, J. Am. Chem. Soc.
126 (2004) 1360.
[9] X.L. Zheng, C.W. Jones, M. Weck, Chem. Eur. J. 12 (2006) 576.

S. Jain et al. / Journal of Molecular Catalysis A: Chemical 316 (2010) 8–15
15
[10] X.L. Zheng, C.W. Jones, M. Weck, J. Am. Chem. Soc. 129 (2007) 1105.
[11] X.L. Zheng, C.W. Jones, M. Weck, Adv. Synth. Catal. 350 (2008) 255.
[12] K. Venkatasubbaiah, C.S. Gill, T. Takatani, C.D. Sherrill, C.W. Jones, Chem. Eur. J.
15 (2009) 3951.
[13] C.S. Gill, K. Venkatasubbaiah, N.T.S. Phan, M. Weck, C.W. Jones, Chem. Eur. J. 14
(2008) 7306.
[14] P. Goyal, X.L. Zheng, M. Weck, Adv. Synth. Catal. 350 (2008) 1816.
[15] S.S. Thakur, W.J. Li, S.J. Kim, G.J. Kim, Tetrahedron Lett. 46 (2005) 2263.
[16] S.S. Thakur, W.J. Li, C.K. Shin, G.J. Kim, Catal. Lett. 104 (2005) 151.
[17] G.J. Kim, H. Lee, S.J. Kim, Tetrahedron Lett. 44 (2003) 5005.
[18] M.A. Kwon, G.J. Kim, Catal. Today 87 (2003) 145.
[20] S. Jain, X.L. Zheng, C.W. Jones, M. Weck, R.J. Davis, Inorg. Chem. 46 (2007) 8887.
[21] H.Q. Yang, L. Zhang, L. Zhong, Q.H. Yang, C. Li, Angew. Chem. Int. Ed. 46 (2007)
6861.
[22] T. Belser, E.N. Jacobsen, Adv. Synth. Catal. 350 (2008) 967.
[23] S.E. Schaus, B.D. Brandes, J.F. Larrow, M. Tokunaga, K.B. Hansen, A.E. Gould, M.E.
Furrow, E.N. Jacobsen, J. Am. Chem. Soc. 124 (2002) 1307.
[24] APEX II, Bruker AXS, Inc., Analytical X-ray Systems, 5465 East Cheryl Parkway,
Madison WI 53711-5373.
[25] SAINT Version 6.45A, Bruker AXS, Inc., Analytical X-ray Systems, 5465 East
Cheryl Parkway, Madison WI 53711-5373.
[26] SHELXTL V6.12, Bruker AXS, Inc., Analytical X-ray Systems, 5465 East Cheryl
Parkway, Madison WI 53711-5373.
[19] G.J. Kim, D.W. Park, Catal. Today 63 (2000) 537.