Core-Shell Composite as the Racemization Catalyst in the Dynamic Kinetic Resolution of Secondary Alcohols

Article abstract of DOI:10.1002/cctc.201200566

Beta-Silicalite-1 core-shell microcomposites with controllable shell thickness were synthesized and used as racemization catalysts in the one-pot dynamic kinetic resolution (DKR) of secondary alcohols by using lipase-catalyzed transesterification. The inert Silicalite-1 shell covered the external acidic sites of the Beta zeolite core, suppressing dehydration and non-enantioselective transesterification of the alcohol. The alcohols could penetrate the Silicalite-1 shell to access the acidic sites at the core Beta for racemization, however, the enzymatically formed (R)-esters were excluded owing to their larger size. As a result, the high ee of the (R)-ester products was conserved and dehydration side products were minimized. Owing to the shape selective nature of the composite racemization catalyst, small and readily available acyl donors could be used in the enzyme-catalyzed transesterification to obtain the esters with high enantiopurity. The DKR of 1-phenylethanol with isopropenyl acetate using an optimized core-shell catalyst, CS-60, gave 92% selectivity to ester formation and the desired (R)-1-phenylethyl acetate was formed with 94% ee.

Full text of DOI:10.1002/cctc.201200566

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DOI: 10.1002/cctc.201200566
Core–Shell Composite as the Racemization Catalyst in the
Dynamic Kinetic Resolution of Secondary Alcohols
Jie Wang, Dong-Minh Do, Gaik-Khuan Chuah, and Stephan Jaenicke*[a]
Beta–Silicalite-1 core–shell microcomposites with controllable
shell thickness were synthesized and used as racemization cat-
alysts in the one-pot dynamic kinetic resolution (DKR) of sec-
ondary alcohols by using lipase-catalyzed transesterification.
The inert Silicalite-1 shell covered the external acidic sites of
the Beta zeolite core, suppressing dehydration and non-enan-
tioselective transesterification of the alcohol. The alcohols
could penetrate the Silicalite-1 shell to access the acidic sites
at the core Beta for racemization, however, the enzymatically
formed (R)-esters were excluded owing to their larger size. As
a result, the high ee of the (R)-ester products was conserved
and dehydration side products were minimized. Owing to the
shape selective nature of the composite racemization catalyst,
small and readily available acyl donors could be used in the
enzyme-catalyzed transesterification to obtain the esters with
high enantiopurity. The DKR of 1-phenylethanol with isopro-
penyl acetate using an optimized core–shell catalyst, CS-60,
gave 92% selectivity to ester formation and the desired (R)-1-
phenylethyl acetate was formed with 94% ee.
Introduction
Methods that generate enantiomerically pure compounds are
of great interest as the importance of asymmetric synthesis is
growing in the pharmaceutical and agrochemical industry.[1]
Secondary alcohols are an important class of chiral synthons
for the assembly of active intermediates. Over the decades,
many methods have been developed to acquire optically pure
chiral secondary alcohols, such as asymmetric reduction of ke-
tones and selective hydrolysis of epoxides.[2] Chiral catalysts
based on noble metal centers with chiral ligands, as well as
biocatalysts, have been developed for asymmetric syntheses.[3]
Kinetic resolution of racemic mixtures offers another approach
to enantiomerically pure compounds.[4] Enzymes are excellent
chiral catalysts. Lipases have the advantage that they do not
require cofactors and are active in both aqueous and nonaqu-
eous environments. Hence, lipases are widely used in the ki-
netic resolution of secondary alcohols, in which they catalyze
stereospecific esterification or transesterification reactions.
However, by starting with an inexpensive racemic mixture, the
yield of the desired product is limited to 50% because only
one enantiomer is transformed.
emization catalyst. A number of homogeneous catalysts based
on Rh, Ir, Al, V, and Ru metal complexes have been studied ex-
tensively for the racemization of secondary alcohols through
an oxidation–reduction mechanism.[7] However, these catalytic
systems suffer from the disadvantages common to homogene-
ous catalysts, that is, difficulties in separation and regeneration
of the catalyst. Hence, heterogeneous catalysts based on noble
metals,[8] zeolites,[9] and acidic resins[10] have been investigated
for racemization activity. Of the zeolites screened, H-Beta was
found to be the most promising because of its acidity and size
of the pore openings. Jacobs et al. designed a biphasic system
in which the racemization occurred in the aqueous phase
whereas the enzyme-catalyzed transesterification occurred in
an organic phase.[9a,b] However, the acyl donor had to be
added in considerable stoichiometric excess because of its de-
pletion through hydrolysis. We have reported previously that
the DKR of aromatic secondary alcohols in a single organic
phase could be performed efficiently with high silica-contain-
ing Beta zeolites with Al3+ or Zr4+ [9c]
Because of the absence
.
of water, the hydrolysis of the acyl donors was no longer
a problem. The key parameters for high racemization activity
were strong Lewis acid sites, low Brønsted acidity, and a hydro-
phobic surface. Over these catalysts, the racemization of 1-phe-
nylethanol proceeded through an acid-catalyzed hydration–de-
hydration mechanism rather than the Meerwein–Ponndorf–
Verley–Oppenauer oxidation–reduction mechanism.[11] Howev-
er, the presence of acid sites means that styrene formation
through the dehydration of the alcohol could not be totally
eliminated and esters of small molecular size, such as 1-phenyl-
ethyl acetate, were racemized to a certain extent. Only by
using bulky acyl donors, such as vinyl octanoate, in the enzy-
matic transesterification was it possible to limit the diffusion of
the formed esters into the micropores, and as a result, up to
Combining kinetic resolution with racemization of the slow
reacting enantiomer in a one-pot system is referred to as “dy-
namic kinetic resolution” (DKR)[5] and offers the prospect to
obtain 100% yield of the desired stereoisomer from a racemic
starting material.[6] This method clearly requires an efficient rac-
[a] Dr. J. Wang, D.-M. Do, Prof. Dr. G.-K. Chuah, Prof. Dr. S. Jaenicke
Department of Chemistry
National University of Singapore
3 Science Drive 3, Kent Ridge, 117543 (Singapore)
Fax: (+65)6779-1691
E-mail: chmsj@nus.edu.sg
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201200566.
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98% ee of 1-phenylethyl octanoate could be achie-
ved.[9c] High ee values of 1-phenylethyl octanoate
[12]
were also reported if (VO)SO4 and nano-Beta zeoli-
te[9h] were used as the racemization catalysts.
Vinyl acetate and isopropenyl acetate are inexpen-
sive and more readily available than the bulky acyl
donors. In addition, enantiomerically pure esters with
small substitution groups at the aromatic ring are fa-
vored as intermediates for asymmetric synthesis. So
far, the highest ee reported for the formation of (R)-1-
phenylethyl acetate after DKR with Novozym 435 and
an H-USY acid zeolite as the racemization catalyst was
97%. However, an unusual biphasic system of an
ionic liquid and supercritical CO2 was used for the
transformation.[9g] We envisaged that a racemization
catalyst based on shape selectivity could be equally
effective in the DKR of secondary alcohols with small
acyl donors. Recently, core–shell structured hierarchi-
Scheme 1. Dynamic kinetic resolution of rac-1-phenylethanol.
cal materials have caught the attention of catalyst designers.[13]
The core–shell catalyst should readily racemize the unreacted
enantiomer to the racemic mixture of (R,S)-1-phenyethanol but
simultaneously prevent the (R)-ester produced by the enzymat-
ic reaction from reaching the acid sites, at which it could un-
dergo undesired racemization (Scheme 1, route c). Further-
more, covering the external acid sites by an inert shell should
minimize the byproduct formation owing to dehydration
(route d).
After establishing that high Si/Al Beta zeolite is a good cata-
lyst for racemization,[9c] we decided to use it as the “core” ma-
terial. Pure silica Silicalite-1 with the MFI framework was used
as the shell material. The MFI channels of 0.51ꢁ0.55 nm[14] are
adequate to accommodate 1-phenylethanol (approximate size
0.46ꢁ0.32ꢁ0.72 nm) but not large enough for the chiral ester
1-phenylethyl acetate (0.55ꢁ0.63ꢁ0.72 nm).[15]
Figure 1. XRD profiles of a) Beta (CP811C-300) with Silicalite-1 nanocrystals,
b) CS-15, c) CS-30, d) CS-60, and e) CS-120.
which limits long-range order. After hydrothermal treatment
for 15 min (Figure 1b), the more intense peaks of the MFI
phase at 2qꢀ7.5–9.58 and 23–248 appeared. The intensity of
these peaks increased with treatment time; hence, for the 60
and 120 min hydrothermally treated samples, the MFI lines ob-
scured the characteristic peaks of the BEA structure.
Results and Discussion
Material preparation and textural properties
The core–shell Beta–Silicalite-1 microcomposites were synthe-
sized by using a method similar to that described by Valtchev
et al.[13a,b] Commercial H-Beta (CP811C-300, Si/Al 150, Zeolyst)
was used as the core material. H-Beta carries a negative surface
charge at pH>2 and was, therefore, treated with a solution of
the cationic polyelectrolyte polydiallyldimethylammonium
chloride to enable the deposition of negative Silicalite-1 seeds.
This was followed by calcination at 6008C to ensure good ad-
herence of the seeds to the surface of the core. The Silicalite-
1 shell was grown by hydrothermal treatment at 2008C. The
shell thickness was controlled by varying the duration of this
treatment step. The samples were denoted as CS-x, in which
x represents the time of hydrothermal treatment (min), that is,
the extent of shell growth.
The commercial Beta zeolite has a surface area of 496 m2 gÀ1
(Table 1). Before calcination, the surface area of the Silicalite-1-
Table 1. Textural properties of Beta zeolite and Beta/Silicalite-1 core–shell
samples.
Catalyst
Before calcination
After calcination
Coverage
[%]
SBET
Vmicro
[cm3 gÀ1
SBET
Vmicro
[cm3 gÀ1
]
[m2 gÀ1
]
]
[m2 gÀ1
]
Beta
496
471
254
133
59
0.154
0.147
0.058
0.031
0.010
0.005
0.002
496
–
0.154
–
–
–
Beta-TPA+
CS-15
483
532
536
476
469
0.106
0.191
0.133
0.145
0.139
48
73
88
93
95
The XRD profiles of the Beta zeolite with adsorbed nanocrys-
talline Silicalite-1 seeds showed only the characteristic peaks of
the BEA phase and not those for the MFI topology (Figure 1a).
This could owe to the small size of the adsorbed nanocrystals,
CS-30
CS-60
CS-120
CS-180
34
25
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coated samples was much lower than that of the core Beta
zeolite. Surface area and micropore volume of the uncalcined
Silicalite-1-coated samples decreased with longer hydrothermal
treatment time. This can be attributed to the nonporous over-
layer of the Silicalite-1 precursor covering the Beta zeolite core.
The possibility that the tetrapropylammonium (TPA+) template
used in the preparation of Silicalite-1 blocked the pores of
Beta zeolite was discounted because the surface area of Beta
zeolite exposed to a solution of TPAOH was still as high as
471 m2 gÀ1 after washing and drying at 808C. If the newly
formed Silicalite-1 were formed as a separate phase rather
than as a coating on the core Beta zeolite, the surface area
would not be reduced to such a degree. Considering the
weight of TPAOH and silica for forming Silicalite-1 in the gel
and assuming zero porosity for the grown silica, the maximum
decrease in surface area worked out to be 54%, which was far
less than the 95% observed in the uncalcined CS-180. Hence,
the ratio of surface areas between the Beta zeolite and the un-
calcined core–shell samples was used to estimate the coverage
(Table 1). A 15 min hydrothermal treatment resulted in 48%
coverage, whereas ꢁ88% coverage was obtained after 60 min.
After calcination at 4508C, the material blocking the pores in
the overlayer was removed and the core–shell samples had
high surface areas of 469–532 m2 gÀ1.
Figure 3. SEM images of a) Beta zeolite and b) core–shell CS-60.
morphology and crystal size of the CS-60 sample after the
growth of the shell remained unchanged, and no significant
MFI nanoparticles were observed.
Acidity measurements
The acidity of Beta zeolite and the resulting core–shell catalyst
CS-60 was studied by using temperature-programmed desorp-
tion of ammonia (Figure S2). The total acidity decreased from
41.5 mmolgÀ1 in the highly siliceous Beta zeolite (Si/Al 150) to
33.7 mmolgÀ1 in CS-60. The decrease in acidity was attributed
to a decrease in the overall aluminum content caused by the
coating of a pure silica shell onto the core Beta. In addition,
the siliceous Silicalite-1 shell replaced the external hydroxyl
groups with pure silanol groups, which thus decreased the
Lewis acidity of the core–shell catalyst.
The samples show the characteristic type 1 nitrogen adsorp-
tion–desorption isotherms of microporous solids with a steep
uptake in the low-pressure region (Figure 2). For the uncal-
To evaluate the accessibility of acid sites of the core Beta
zeolite, the bulky base 2,6-di-tert-butylpyridine (DTBPy) was
used as a probe.[16] As the kinetic diameter of the DTBPy mole-
cule is larger than 0.79 nm,[17] it cannot access the channels of
Beta zeolite, which has dimensions of 0.66ꢁ0.67 nm.[14] Hence,
the bulky base can only interact with acid sites located at the
external surface or the pore mouth region. The interaction
with accessible Brønsted acid sites resulted in the formation of
DTBPyH+, with characteristic IR bands at 3370, 1616, and
1530 cmÀ1 (Figure 4). The broad band around 2970 cmÀ1 was
due to physically adsorbed DTBPy at the surface. Compared to
Beta zeolite, all these bands decreased in intensity in CS-60. In
Figure 2. Nitrogen adsorption–desorption isotherms of a) Beta zeolite,
b) core–shell CS-60 after calcination, and c) CS-60 with an uncalcined TPA-
containing Silicalite-1 shell.
cined samples, the small uptake at low P/P0 corresponds to
low microporosity, as access to the channels of Beta zeolite
was blocked by the TPA+-filled Silicalite-1 shell. After calcina-
tion, the isotherms were comparable to those of Beta zeolite,
with only a slight decrease in nitrogen uptake at low values of
P/P0. A hysteresis loop at relative pressures between 0.55 and
0.80 indicated the presence of mesopores, which could be due
to void spaces between the core–shell particles.[13a]
The SEM images of commercial Beta zeolite and the calcined
core–shell sample CS-60 are shown in Figure 3. Beta zeolite
consists of spherical particles of 0.2–1 mm in diameter. The
Figure 4. IR spectra of a) Beta zeolite and b) core–shell CS-60 after DTBPy ad-
sorption–desorption at 1508C.
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particular, the band at 2970 cmÀ1 was significantly attenuated,
which showed the low external acidity of the core–shell
sample. Previous studies by the groups of Corma[16a] and Ler-
cher[16b] have established that the normalized peak intensity at
3370 and 1616 cmÀ1 correlates well with the concentration of
accessible Brønsted acid sites. For the CS-60 catalyst, the
number of accessible Brønsted acid sites was estimated to be
only 18% that of Beta zeolite, which supports the fact that an
overlayer of siliceous Silicalite-1 was grown as the shell entirely
covering the Beta zeolite core.
spect to the enzyme, and an initial rate of 1.05 mmolminÀ1 gÀ1
was measured. This rate is 5–7 times higher than the rate of
racemization by the core–shell catalysts, and a variation of the
enzyme to the core–shell catalyst ratio was done to match the
two reaction rates. The representative racemization catalyst
CS-60 was added after 1–6 h when the enzyme-catalyzed
transesterification had reached 50% conversion (Table 3, en-
Table 3. Variation of the enzyme/catalyst ratio in the transesterification of
rac-1-phenylethanol with isopropenyl acetate.[a]
Entry
Novozym
[mg]
CS-60
[mg]
t[b]
[h]
Conversion
[%]
Selectivity
[%]
ee[c]
[%]
Racemization of (S)-1-phenylethanol
(S)-1-Phenylethanol can be racemized by the core–shell acid
catalysts, with small amounts of styrene as the only byproduct.
An increase in the shell growth time from 15 to 180 min led to
a decrease in conversion from 97 to 56% over the reaction
time of 1 h (Table 2). This can be attributed to increasing diffu-
1
2
3
4
5
6
7
3
10
20
30
50
30
30
15
50
50
50
50
(6) 64
(2) 21
(2) 21
(1) 21
(1) 21
(1) 16
(1) 7
70
70
75
77
78
75
78
94
87
90
92
93
92
89
91
93
92
94
94
90
88
75
100
[a] Reaction conditions: T=608C, 1 mmol rac-1-phenylethanol, 2 mmol
isopropenyl acetate, Novozym 435, and CS-60; [b] Value in parentheses
refers to the time for the enzyme-catalyzed transesterification to reach
50%; [c] ee of (R)-1-phenylethyl acetate.
Table 2. Racemization of (S)-1-phenylethanol by Beta zeolite and Beta–
Silicalite-1 core–shell catalysts.[a]
Acid catalyst
Initial rate[b]
Conversion[c]
[%]
Selectivity
[%]
ee[d]
À1
À1
[mmolmin
g
]
[%]
cat
Beta
0.20
0.20
0.17
0.16
0.14
0.07
99
97
91
93
90
56
69
77
87
88
90
91
1.4
4.3
13
10
15
CS-15
CS-30
CS-60
CS-120
CS-180
tries 1–5). Using 3 mg of Novozym 435 and 15 mg of CS-60
with 122 mg (1 mmol) substrate, a conversion of 70% was ob-
tained after 64 h. The same conversion was obtained in a short-
er time of 21 h when the amount of the enzyme and the acid
catalyst was increased proportionately (Table 3, entry 2). How-
ever, the selectivity toward the ester was lower under these
conditions because the higher amount of CS-60 catalyzed the
undesired dehydration of phenylethanol to styrene. An in-
crease in the enzyme loading relative to CS-60 resulted in
a higher selectivity toward the ester. Owing to the higher con-
centration of Novozym 435, the rate of transesterification was
increased; hence, less 1-phenylethanol was present, which lim-
ited its dehydration to styrene. The ee of the product, (R)-1-
phenylethyl acetate, remained between 92 and 94%. The use
of 30 mg of Novozym 435 with 50 mg of CS-60 was sufficient
to achieve 77% conversion in 21 h, because an increase in the
enzyme loading to 50 mg did not lead to any significant im-
provement in the activity and selectivity of the reaction. In-
creasing the amount of the core–shell catalyst while keeping
the amount of Novozym 435 at 30 mg accelerated the reaction
and conversions >75% were obtained in a shorter time of 7–
16 h (Table 3, entries 6 and 7). However, the increased number
of acid sites of the core–shell catalyst resulted in more styrene
formation and also a slight decrease in the ee of (R)-1-phenyl-
ethyl acetate.
64
[a] Reaction conditions: T=608C, 1 mmol (S)-1-phenylethanol, 50 mg cat-
alyst; [b] Based on the first 10 min; [c] After reaction for 1 h; [d] ee of (S)-
1-phenylethanol.
sional resistance faced by the molecule in accessing the acid
sites of the core as the siliceous overlayer builds up. However,
all catalysts formed with shell growth times below 120 min
gave a conversion of >90% after 1 h. The initial rates of race-
mization estimated from the reaction rate within the first
À1
À1
10 min (Figure S3) decreased from 0.20 mmolmin
g
in
cat
À1
À1
Beta zeolite to 0.07 mmolmin
g
cat
in CS-60. Compared to
Beta zeolite, the core–shell samples gave less dehydration
product, styrene, as expressed by the higher selectivity toward
1-phenylethanol, which increased from 77 to 91%. This is con-
sistent with the fact that a more complete and/or thicker shell
is built around the core Beta zeolite as the shell growth time
increased.
DKR of rac-1-phenylethanol
Novozym 435, a commercially available immobilized lipase
preparation, was used to catalyze the chiral transesterification.
Owing to the pronounced preference of the enzyme for (R)-1-
phenylethanol, the reaction comes essentially to a standstill at
50% conversion. Varying the enzyme loading from 3 to 50 mg,
this final conversion was attained within 240 to 30 min, respec-
tively (Figure S4). The enzymatic catalysis is zero-order with re-
The progress of DKR of 1-phenylethanol with isopropenyl
acetate catalyzed by Novozym 435 and unmodified Beta zeo-
lite (Si/Al 150) is shown in Figure 5a. The selectivity toward the
ester was 72%, and styrene was the significant byproduct. Fur-
thermore, the ee of the desired product (R)-1-phenylethyl ace-
tate was only 48%. Hence, Beta zeolite is clearly not a suitable
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was less than half that measured over Beta zeolite (0.030 mmol
À1).
À1
min
g
cat
Core–shell catalysts formed with longer shell growth time
showed lower conversion, which supports the fact that the Sili-
calite-1 overlayer covers the external acid sites of Beta zeolite
and also limits the diffusion of molecules into the microporous
channels. For the core–shell catalyst prepared with 180 min of
shell growth time, CS-180, the conversion was only 57% after
21 h (Table 4). This is just above the conversion threshold of
Table 4. DKR of rac-1-phenylethanol with isopropenyl acetate by using
Novozym 435 and Beta zeolite or Beta–Silicalite-1 core–shell racemization
catalyst.[a]
Entry Racemization catalyst
t
[h]
Conversion Selectivity ee[b]
[%] [%] [%]
1
2
3
4
5
6
7
Beta
(1) 21 100
(1) 21 100
(1) 21 100
72 48
CS-15
CS-30
CS-60
CS-60
CS-120
CS-180
74
85
54
73
(1) 21
(1) 40
(1) 21
(1) 21
77
95
66
57
92
94
91
92
97
95
>99
>99
[a] Reaction conditions: T=608C, 1 mmol rac-1-phenylethanol, 2 mmol
isopropenyl acetate, 30 mg Novozym 435, and 50 mg catalyst; [b] ee of
(R)-1-phenylethyl acetate.
50% in the absence of any racemization catalyst. However, the
ee of (R)-1-phenylethyl acetate was >99%. In comparison, for
catalysts prepared with shorter shell growth times of 15 and
30 min, 100% conversion was obtained but the selectivity
toward the ester and the ee of (R)-1-phenylethyl acetate were
lower. A shell growth time of 60 min appears to be optimum
and a conversion of 95% could be obtained after 40 h with
>90% ester selectivity and ee of the (R)-enantiomer (Table 4,
entry 5).[18] Hence, the results show that a pure silica shell over
Beta zeolite covered the external acid sites, resulting in a high
selectivity toward 1-phenylethyl acetate. The lower reaction
rate can be compensated for by extending the reaction time.
Figure 5. Dynamic kinetic resolution of rac-1-phenylethanol over a) Beta zeo-
&
^
lite and b) CS-60. : Conversion of 1-phenylethanol, : selectivity toward 1-
!
~
phenylethyl acetate, : selectivity toward styrene, : ee of (R)-1-phenylethyl
acetate. Reaction conditions: T=608C, 1 mmol rac-1-phenylethanol, 2 mmol
isopropenyl acetate, 30 mg Novozym 435, 50 mg catalyst.
catalyst for the DKR of 1-phenylethanol with a small acyl trans-
fer agent such as isopropenyl acetate. The active sites in the
Beta zeolite not only catalyze the racemization of the alcohol
but also racemize (R)-1-phenylethyl acetate and catalyze non-
enantioselective transesterification. Therefore, high enantio-
meric purity is difficult to achieve with Beta zeolite as the race-
mization catalyst. In contrast, if CS-60 was used, a conversion
of 77% was obtained after 21 h with a high selectivity of 92%
to the ester (Figure 5b). The desired product, (R)-1-phenylethyl
acetate, was formed with an ee of 94%. The slight decrease in
the ee of (R)-1-phenylethyl acetate with time can be due to the
incomplete coverage of the core Beta zeolite. Hence, some
acid sites were still exposed, which then catalyzed the racemi-
zation of the chiral ester as well as non-enantioselective trans-
esterification. This was confirmed through separate experi-
ments (Figures S5 and S6) to investigate the non-enantioselec-
tive transesterification and the racemization of the chiral ester.
The inert shell reduced the rate for the acid-catalyzed transes-
DKR with different acyl donors and acceptors
The kinetic resolution of rac-1-phenylethanol with the small
isopropenyl acetate works well with the racemization catalyst
CS-60 (Table 5, entry 1). In contrast, to obtain high yields of the
(R)-ester using Beta zeolite, bulkier acyl donors have to be
used (Table 5, entries 2 and 3). The use of vinyl butyrate over
Beta zeolite formed the (R)-ester with a selectivity of 84% and
an ee of 75%. Only by using vinyl octanoate was it possible to
obtain an ester selectivity and an ee greater than 90%. There-
fore, the kinetic resolution of a number of alcohols with isopro-
penyl acetate was tested using CS-60. With aromatic secondary
alcohols such as 1-(4-methylphenyl)-ethanol, 1-(4-chlorophen-
yl)-ethanol, and 1-phenylpropanol, the selectivity was >90%
and the ee of the corresponding (R)-ester was in the range of
86–95% (Table 5, entries 4–6). The DKR of rac-1-indanol with
isopropenyl acetate was very facile. After only 3 h, full conver-
À1
À1
terification from 0.11 mmolmin
g
over Beta zeolite to
cat
À1
À1
0.007 mmolmin
g
cat
over CS-60. The acid-catalyzed transes-
terification is much slower than the enzyme-catalyzed reaction
(1.05 mmolminÀ1 gÀ1). Similarly, the initial rate of racemization
À1
À1
of 1-phenylethyl acetate over CS-60 (0.014 mmolmin
g
)
cat
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Reusability of the catalysts
Table 5. DKR with various substrates and acyl donors.[a]
Entry Substrate
1
Acyl Catalyst t
Conversion Selectivity ee[b]
The reusability of the core–shell racemization catalyst CS-60 to-
gether with Novozym 435 was studied in the DKR of 1-phenyl-
ethanol with isopropenyl acetate. To explore the reusability of
each component, the enzyme was kept separate from the
core–shell catalyst in the reaction mixture, which enables the
easy recovery of the latter (Figure S7). Novozym 435 is a lipase
supported on acrylic resin spheres of 0.3–0.9 mm in diameter
(ꢀ20–50 mesh). The enzyme was placed in a basket made
from 120 mesh (0.125 mm) stainless steel wire gauze. A test
showed that the kinetics was essentially unchanged from
those in the one-pot enzyme–catalyst system, and no diffu-
sional problems or additional side reactions were observed.
Compared to fresh Novozym 435 in which the conversion for
the enzyme-catalyzed transesterification was 50% after 1 h, the
used enzyme showed slightly lower conversion of 43–48% in
subsequent runs (Figure S8 and Table S1).
donor
[h]
[%]
[%]
[%]
IA
Beta
(1) 14 100
79
67
CS-60 (1) 21 77
92
94
2
3
4
5
VB
VO
IA
Beta
CS-60 (1) 6
(1) 3 100
79
75
96
84
>99
Beta
CS-60 (1) 8
(1) 3 100
91
91
97
98
>99
Beta
CS-60 (1) 8
(1) 3 100
95
74
93
<1
90
IA
Beta
(1) 8 100
83
95
76
97
CS-60 (1) 24 75
The used racemization catalyst CS-60 was regenerated by
calcination at 5008C for 3 h. Almost full activity could be recov-
ered, and after three cycles with reused CS-60 and fresh
enzyme, the conversion decreased only slightly from 77 to
72% (Figure 6). The ee of (R)-1-phenylethyl acetate remained at
94–95%. The possibility to regenerate the core–shell catalyst
through calcination is due to its good thermal stability.
6
IA
IA
IA
IA
IA
Beta[c] (2) 16 97
CS-60[c] (2) 21 87
70
86
58
90
7
Beta[d] (0.5) 2 100
CS-60 (0.5) 3 100
78
91
>99
>99
8
Beta
(1) 16 53
>99
>99
>99
>99
CS-60 (1) 16 51
9
Beta
(1) 18 67
91
95
97
92
97
84
CS-60 (1) 18 59
CS-60[e] (1) 40 70
10
Beta
(1) 16 65
78
90
>99
>99
CS-60 (1) 16 57
[a] Reaction conditions: 1 mmol rac-alcohol, 2 mmol acyl donor, 30 mg No-
vozym 435, and 50 mg acid catalyst, 608C. IA=isopropenyl acetate, VB=
vinyl butyrate, VO=vinyl octanoate; [b] ee of the (R)-ester product;
[c] 50 mg Novozym 435 and 30 mg acid catalyst; [d] 30 mg Novozym 435
and 20 mg Beta zeolite (Si/Al 150); [e] 30 mg Novozym 435 and 75 mg CS-
60.
sion was obtained with >99% selectivity toward the ester and
91% ee of the (R)-enantiomer (Table 5, entry 7). In comparison,
over Beta zeolite, the selectivity and the ee of the esters were
poor owing to unhindered access to acid sites on the external
surface and in the pore channels. The results show that the
acid-catalyzed dehydration–hydration mode of racemization
works well for chemically labile alcohols, in which the phenyl
group is attached to the chiral carbon. For nonchemically
labile alcohols such as 4-phenyl-2-butanol, 1-cyclohexylethanol,
and 2-pentanol, the racemization by dehydration–hydration is
slow and the conversion was only between 51 and 59% after
16–18 h (Table 5, entries 8–10). To obtain higher conversion, it
was necessary to increase the catalyst loading. By increasing
the amount of CS-60 from 50 to 75 mg, 70% conversion of 1-
cyclohexylethanol was achieved after 40 h; however, the ee of
the (R)-ester was decreased. As a proof of concept, the design
of a core–shell composite is effective in the racemization of
secondary alcohols but further work is needed to improve the
activity and selectivity.
Figure 6. Reusability of the racemization catalyst CS-60 in the DKR of rac-1-
phenylethanol. Reaction conditions: T=608C, 1 mmol rac-1-phenylethanol,
2 mmol isopropenyl acetate, 30 mg Novozym 435, and 50 mg CS-60.
Conclusions
Microcomposites with a Beta zeolite core and a Silicalite-1 shell
have been prepared. The shell thickness could be controlled
by varying the synthesis time. The medium-pore Silicalite-
1 shell covered the external acid sites of Beta zeolite, which
suppressed yield-reducing side reactions such as alcohol dehy-
dration and non-enantioselective transesterification. By using
the bulky base 2,6-di-tert-butylpyridine as a probe for acid
sites, we confirmed that the density of external Brønsted acid
sites of the core–shell microcomposite CS-60 was only 18% of
that on Beta zeolite. Once formed by the enzyme-catalyzed
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oven at 2008C until the time it was taken out and kept at ambient
temperature to cool down. Growth times of 15, 30, 60, 120, and
180 min were used. After cooling, the composites were treated
with NH3 solution (5m) in an ultrasonic bath for 10 min to remove
loosely attached crystals. After washing and drying, the composites
were calcined at 4508C for 6 h in air.
transesterification, the chiral ester molecules are prevented by
the narrow pore channels in the Silicalite-1 shell from reaching
the acid sites located on the core Beta zeolite. Microcompo-
sites formed with longer shell growth time gave a lower con-
version but less side reactions, whereas those formed with
a shorter shell growth time had higher conversion but formed
more styrene as a byproduct. Optimum activity was observed
for catalysts prepared with a shell growth time of 60 min. The
core–shell microcomposites were compatible with an immobi-
lized lipase. In the dynamic kinetic resolution of secondary al-
cohols by lipase-catalyzed transesterification, selectivities of 86
to >99% to the desired esters were achieved in a system with
a single liquid phase. Even with the low molecular mass acyl
donor, isopropenyl acetate, the ee of the (R)-esters was high. In
contrast, the selectivity and ee were much lower if the uncoat-
ed Beta zeolite was used as the racemization catalyst. The ef-
fectiveness of the Silicalite-1 shell in conserving the high enan-
tiopurity of the formed ester is seen in the reduced rates for
acid-catalyzed transesterification and ester racemization over
CS-60 compared with Beta zeolite. The core–shell catalyst
could be easily recovered through filtration and regenerated
through calcination. Owing to its thermal stability, full activity
was restored.
Characterization
The surface area and textural properties of the samples were deter-
mined by using the nitrogen adsorption method (Micromeritics
Tristar 3000). Prior to each measurement, the sample was thor-
oughly degassed under a nitrogen flow for 4 h. The degassing
temperatures for the as-prepared core–shell catalysts and the cal-
cined catalysts were 100 and 3008C, respectively. The presence of
crystalline phase was determined by powder XRD analysis (Sie-
mens D5005 equipped with the copper anode and variable slits).
SEM images were recorded on a Philips XL-30 microscope operat-
ing at 30 kV. The total acidity was measured by using temperature-
programmed desorption of ammonia. The sample was pretreated
at 5508C for 2 h in a flow of helium (flow rate: 50 mLminÀ1). After
the sample was cooled down to 1008C, NH3 gas was introduced
for 15 min, followed by flushing with helium for another 2 h. The
sample was heated to 5508C in helium (heating rate: 108CminÀ1),
and the desorbed NH3 was monitored by a quadrupole mass spec-
trometer (Balzers Prisma 200). The IR spectra of adsorbed DTBPy
were recorded to investigate the external acid sites. The sample
was pressed into a self-supporting disk (10–20 mg) and pretreated
in a glass cell with NaCl windows at 3008C for 2 h under a vacuum
pressure of <10À4 kPa. After cooling to RT, a background spectrum
was recorded. DTBPy was introduced into the cell at a partial pres-
sure of approximately 2ꢁ10À3 kPa. After 30 min, the cell was evac-
uated and the sample was heated to 1508C for 1 h before measur-
ing the IR spectra. The IR spectra were recorded on a Bio-Rad Exca-
Experimental Section
Synthesis of core–shell Beta–Silicalite-1 microcomposites
The core–shell Beta–Silicalite-1 microcomposites were synthesized
as in the literature.[13a,b] Commercial H-Beta with Si/Al=150
(CP811C-300, Zeolyst) was used as the “core” material. Silicalite-
1 nanocrystals were synthesized from a solution with molar com-
position (TPA)2O/SiO2/H2O/EtOH=4.5:25:480:100. The reactants
used were tetrapropylammonium hydroxide (40% solution, Merck)
and tetraethylorthosilicate (Merck). After prehydrolysis at RT for
2 h, the gel was transferred to an autoclave and kept at 808C for
4 h. The solid was recovered by centrifugation and resuspended in
water for several times (6000 rpm, 30 min each time) before drying
overnight in an oven at 808C.
libur FTIR spectrometer with a resolution of 4 cmÀ1
.
Racemization of (S)-1-phenylethanol
The racemization of (S)-1-phenylethanol was performed in a two-
neck round bottom flask equipped with a reflux condenser. (S)-1-
Phenylethanol (0.25 mmol, ee>99.5%, Fluka) was dissolved in tolu-
ene (5 mL) and heated to 608C. The acid catalyst (50 mg) was
added to the reaction mixture. Aliquots were taken and monitored
by using GC (HP-6890) with a Supelco BetaDex 325 chiral capillary
column. Only the two isomers of 1-phenylethanol and the byprod-
uct styrene were observed.
Before use, the nanocrystals were redispersed in distilled water.
The pH of the suspensions was adjusted to 9–10 with 5m NH3 so-
lution. The zeolite content in the seeding suspension was about
3%.The negative surface charge of BEA-type crystals was reversed
by using a 0.5 wt% aqueous solution of the polycationic agent pol-
ydiallyldimethylammonium chloride (molecular mass 2ꢁ105–3.5ꢁ
105 gmolÀ1, 20% aqueous solution, Sigma–Aldrich) to form the
core suspension. The weight ratio of polydiallyldimethylammonium
chloride to Beta zeolite was 1:5. The above as-prepared Silicalite-
1 nanocrystals were redispersed in distilled water to form a 3%
suspension. After adjusting to pH 9–10 with NH3 solution (5m), the
suspension was added dropwise to the core suspension so that
the weight ratio of the nanocrystalline Silicalite-1 to Beta zeolite
was 1:10. The mixture was stirred for 2 h and calcined at 5008C for
8 h to ensure adherence of the nanoseeds to the surface of the
core material.
DKR of secondary alcohols
Typically,
a reaction mixture of racemic (R,S)-1-phenylethanol
(1 mmol, Fluka), isopropenyl acetate (2 mmol, Sigma–Aldrich), tolu-
ene (5 mL), and Novozym 435 (30 mg) was stirred and heated to
608C. After 1 h, the racemization catalyst (50 mg) was added. The
progress of the reaction was monitored by using GC with a Supelco
BetaDex 325 chiral capillary column. The identity of the products
was verified by comparing the retention times and GC–MS spectra
with those of authentic samples, wherever possible. In addition to
isopropenyl acetate and 1-phenylethanol, other reagents such as
1-(4-methylphenyl)-ethanol (Sigma–Aldrich), 1-phenylpropanol
(Sigma–Aldrich), 1-(4-chlorophenyl)-ethanol (Sigma–Aldrich), 1-in-
danol (Fluka), 4-phenyl-2-butanol (Sigma–Aldrich), 1-cyclohexyle-
The secondary growth of the Silicalite-1 shell was performed at
2008C for different times. The molar ratio of the gel composition
was (TPA)2O/SiO2/H2O/EtOH=1.5:25:1500:100. After stirring at RT
for 2 h, the mixture was transferred to an autoclave. The growth
time was taken from the moment the autoclave was placed in the
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Acknowledgements
Financial support for this work from the National University of
Singapore (grants R-143-000-476-112 and R-143-000-418-112) is
gratefully acknowledged.
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Keywords: alcohols · enantioselectivity · enzyme catalysis ·
heterogeneous catalysis · transesterification
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[18] For extended one-pot DKR reaction, to minimize evaporation of isopro-
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20 h.
Received: August 18, 2012
Published online on November 13, 2012
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ChemCatChem 2013, 5, 247 – 254 254