Validity of inorganic nanosheets as an efficient planar substituent to enhance the enantioselectivity of transition-metal-catalyzed asymmetric synthesis

Article abstract of DOI:10.1002/chem.201301150

Effectively enhancing the enantioselectivity is a persistent challenge in heterogeneous asymmetric catalysis. Here, the validity of a layered double hydroxides (LDH) nanosheet as an efficient planar substituent to enhance the enantioselectivity has been i

Full text of DOI:10.1002/chem.201301150

DOI: 10.1002/chem.201301150
Validity of Inorganic Nanosheets as an Efficient Planar Substituent To
Enhance the Enantioselectivity of Transition-Metal-Catalyzed Asymmetric
Synthesis
Li-Wei Zhao, Hui-Min Shi, Zhe An, Jiu-Zhao Wang, and Jing He*[a]
Abstract: Effectively enhancing the enantioselectivity is a persistent challenge in
heterogeneous asymmetric catalysis. Here, the validity of a layered double hydrox-
ides (LDH) nanosheet as an efficient planar substituent to enhance the enantiose-
lectivity has been investigated theoretically; first in vanadium-catalyzed asymmet-
ric epoxidation of allylic alcohols, and then in zinc-catalyzed direct asymmetric
aldol addition. The computational predication is further confirmed experimentally
in zinc-catalyzed direct asymmetric aldol addition by controlling the location of
catalytic sites.
Keywords: asymmetric catalysis
density functional calculations
enantioselectivity · heterogeneous
catalysis · nanosheets
·
·
Introduction
close relationship to the location of vanadium centers. When
the vanadium centers were coordinated with the amino acid
anions situated at the center of LDH interlayer regions, a
remarkable ee increment was observed (from 56 to 91% ee
for the trans isomers and from 26 to 68% ee for the cis iso-
mers). When the vanadium centers were coordinated with
amino acid anions situated at the edges of LDH interlayer
regions, a moderate ee increment was observed (to 80% ee
for the trans isomers and 9% ee for the cis isomers). In this
case, the LDH layers themselves as 2D nanosheets are pro-
posed to act as a planar substituent of a-amino acid ligand
in improving the enantioselectivity probably through either
steric resistance or multiple interactions. This work investi-
gates theoretically the validity of LDH nanosheet as an effi-
cient planar substituent to enhance enantioselectivity first in
the vanadium-catalyzed asymmetric epoxidation of allylic al-
cohols, and then in the zinc-catalyzed direct asymmetric
aldol addition between unmodified ketones and aldehydes, a
reaction which is considered to be difficult to achieve satis-
factory enantioselectivity.[25–27] The computational prediction
is further confirmed experimentally in zinc-catalyzed direct
asymmetric aldol addition by controlling the location of cat-
alytic sites. This work provides valuable insight into the
strategy, as well as the applicability and practicability, of de-
signing efficient catalysts in enantioselective catalysis and
asymmetric synthesis.
Heterogeneous asymmetric catalysis is considered as an en-
vironmentally friendly chemical process to produce chiral
compounds, and has been greatly stimulated by the growing
demand for optically pure compounds in chemical and phar-
maceutical industries.[1–3] But binding a homogeneous cata-
lyst to solid surfaces usually leads to deteriorated activity[4]
and enantioselectivity,[5–8] or even complete elimination of
enantioselectivity.[9,10] A lot of attempts have been reported
to improve the enantioselectivity of heterogeneous catalysis.
Confinement of metal complexes[11–15] and/or metal-free or-
ganocatalyst[16–18] in the channels or mesopores was found to
be able to enhance the enantiomer excess (ee) or at least
retain the enantioselective level of homogeneous counter-
parts. Intercalation of active centers into the interlayer re-
gions of layered compounds, layered double hydroxides
(LDHs)[19] or laponite,[20,21] for example, was also reported
to be able to retain or improve the enantioselectivity. A
moderate ee value has been achieved by this approach even
in the case that the homogeneous counterpart could only
afford racemic products.[22]
In our recent research,[23] it was revealed in the vanadium-
catalyzed asymmetric epoxidation of allylic alcohols by
using nanosheet-attached a-amino acid anions as chiral li-
gands that the enantioselectivity improvement was retained
after elimination of interlayer confinement by delamination
of ligand-intercalated LDHs. Further investigation[24] indi-
cated that the increment of enantioselectivity displayed a
Results and Discussion
Theoretical prediction of the validity of inorganic nanosheet
as an efficient planar substituent: In the intercalate struc-
ture,[24] the carboxylic protons of a-amino acids are replaced
by positively charged LDH layers. Then, the interlayer a-
amino acid anions bear “huge” and “rigid” nanosheets, in-
stead of single atoms. Especially when the vanadium centers
[a] L.-W. Zhao, H.-M. Shi, Z. An, J.-Z. Wang, Prof. J. He
State Key Laboratory of Chemical Resource Engineering
Beijing University of Chemical Technology
Box 98, 15 Beisanhuan Dong Lu
Beijing 100029 (P.R. China)
Fax : (+86)10-64425385
E-mail: jinghe@263.net.cn
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Chem. Eur. J. 2013, 19, 12350 – 12355

FULL PAPER
are coordinated with the a-amino acid anions situated at the
inner interlayer regions (Figure 1), the LDH layer as the
substituent of a-amino acid ligand displays plane-symmetry.
Qualitatively, the uniform chiral environment provided by
Figure 1. Schematic illustration of the LDH layer as a substituent display-
ing plane-symmetry.
nanosheet-modified a-amino acid is able to favor the forma-
tion of one transition state, thereby enhancing chiral induc-
tion. In addition to the electrostatic interactions between
positively charged layers and interlayer a-amino acid anions,
À
À
two H-bonds (C2 O1···H1 and C2 O2···H2) are formed be-
tween the hydroxyl groups of LDH layers and the attached
a-amino acid anions, which were calculated to be 1.77 and
1.68 ꢁ (Figure 2a). The existence of the H-bonds, a kind of
short-range and orientation interaction,[28] facilitates LDH
layers as the substituent of attached a-amino acid anions.
After the coordination of vanadium centers to a-amino acid
anions, the LDH layer affords a more H-bond with O=V
moiety (Figure 2b), which is calculated as 1.80 ꢁ when V
centers are located at the inner interlayer regions and
1.70 ꢁ when V centers are located at the edges. The V=
O···layer OH bond weakens the H-bonds between LDH
Figure 2. The primary H-bonding distances between a) LDH layer and at-
tached a-amino acid anion; b) LDH layer, attached a-amino acid anion,
and vanadium centers coordinated (left) at the inner interlayer region or
(right) at edge of interlayer region; c) LDH layer, attached a-amino acid
anion, and zinc centers coordinated (left) at the inner interlayer region
or (right) at edge of interlayer region (light blue=Zn, pink=Al, dark
blue=N, gray=C, white=H).
À
layer and a-amino acid anions from 1.77/1.68 ꢁ (C2
À
O1···H1/C2 O2···H2) to 1.90/1.70 ꢁ and 2.07/1.87 ꢁ, respec-
tively. In accordance, the linkage rigidity between brucite-
like layer and attached a-amino acid anions is stronger
when V centers are coordinated at the inner interlayer re-
gions.
In the vanadium-catalyzed epoxidation of 2-methyl-cin-
namyl alcohol, our previous work[24] has revealed that when
the vanadium centers are coordinated at the inner interlayer
regions, the access of 2-methyl-cinnamyl alcohol in its
convex conformation to form the (2S,3S) transition state has
À
to weaken the C2 O1···H1 from 1.90 to 1.95 ꢁ, whereas the
access in its concave conformation to form (2R,3R) well pre-
À
serves the C2 O1···H1 (from 1.90 to 1.85 ꢁ). That means,
Figure 3. The calculated energies and primary bonding distances for the
optimized transition states in the epoxidation of 2-methyl cinnamyl alco-
hol when the catalytic centers are located at the edges of the interlayer
regions.
the (2R,3R) transition state is favored whereas (2S,3S) is in-
hibited. When the vanadium centers are coordinated at the
edges of LDH interlayer regions (Figure 3), the access of 2-
methyl-cinnamyl alcohol in its convex conformation weak-
À
ens C2 O1···H1 from 2.07 to 2.10 ꢁ, whereas concave
À
access strengthens C2 O1···H1 from 2.07 to 2.05 ꢁ. As a
O2···H2 bonds is strengthened, from 1.70 to 1.61 ꢁ (access
in concave conformation) or 1.67 ꢁ (access in convex con-
formation) when the catalytic centers are located at the
inner interlayer regions, and from 1.87 to 1.84 or 1.82 ꢁ
when the catalytic centers are located at the edges.
result, either the catalytic centers are located at the inner in-
terlayer regions or at the edges, it is easier for (2R,3R) tran-
sition state to be formed, accounting for the ee increment in
À
comparison to homogeneous counterpart. In each case C2
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J. He et al.
On the other hand, in the (2R,3R) transition state, the
C3-O3···H3 that is preserved in (2S,1’R) transition state.
Meanwhile, the aldehyde moiety (O6) and nitro moiety
(O8) in 4-nitrobenzaldehyde also form H-bonds with LDH
layer, which are 2.31 and 2.19 ꢁ in (2S,1’R) transition state,
whereas they are 2.32 and 2.25 ꢁ in (2R,1’S) transition state.
It can be predicted from either the alteration of H-bonds in
the substrate access and the difference between the H-
bonds in the transition states that LDH layers are to pro-
mote ee values with (2S,1’R) as the excess enantiomer.
À
À
C2 O1···H1 and C2 O2···H2 bonds are calculated to be 1.85
and 1.61 ꢁ when catalytic centers are located at the inner
interlayer regions, which are both stronger than those in the
(2S,3S) transition state (1.95 and 1.67 ꢁ). Moreover, a new
H-bond is formed between the alcoholic moiety (O4) in 2-
methyl-cinnamyl alcohol and the LDH layer, which is also
stronger in the (2R,3R) transition state than in the (2S,3S)
transition state (1.72 versus 1.81 ꢁ). When the catalytic cen-
ters are located at the edges of interlayer regions (Figure 3),
For the catalytic system in which the catalytic centers are
located at the edges of interlayer regions, the Si face attack
of aldehyde to the syn-enolate to form the (2R,1’S) transi-
À
although the C2 O1···H1 is stronger in the (2R,3R) transi-
tion state than in (2S,3S) transition state (2.05 vs. 2.10 ꢁ),
À
À
À
the C2 O2···H2 is weaker than in (2S,3S) transition state
tion state strengthens the C2 O1···H1 and C3 O3···H4 from
1.78 and 1.99 ꢁ to 1.74 and 1.91 ꢁ, whereas the Re face
attack of aldehyde to anti-enolate to form the (2S,1’R) tran-
(1.84 vs. 1.82 ꢁ). In addition, the 2-methyl-cinnamyl alcohol
molecules that attack in either concave or convex conforma-
tion form no new H-bond with the LDH layer, which de-
creases the difference in the H-bonding interaction between
(2R,3R) and (2S,3S) transition states. As a result, the energy
difference between (2R,3R) and (2S,3S) transition states is
2.94 kJmolÀ1 kJmolÀ1 lower when vanadium centers are lo-
cated at edge than at inner interlayer region, accounting for
less increment of the ee value when the catalytic centers are
located at edge than at inner interlayer region (80 vs.
91% ee for trans isomers). According to the calculation re-
sults based on experimental observations, it is apparent that
the efficient enhancement of enantioselective induction orig-
inates from the location of catalytic centers at the inner in-
terlayer regions, which supports the rational presumption
(Figure 1) of the significance of the plane-symmetry of inor-
ganic nanosheet as the substituent.
À
sition state preserves the C3 O3···H4 but has to weaken
À
C2 O1···H1 to 2.22 ꢁ (Figure 4). That means, it is easier for
Figure 4. The calculated energies and primary bonding distances for the
optimized transition states in the direct asymmetric aldol reaction when
the catalytic centers are located at the edges of the interlayer regions.
On the basis of the results for the vanadium-catalyzed ep-
oxidation, further theoretical prediction is performed on the
zinc-catalyzed direct asymmetric aldol addition of cyclohex-
anone to 4-nitrobenzaldehyde using l-glutamate as chiral
ligand. According to the optimized configuration (Fig-
ure 2c), both carboxylates of a-amino acid anion afford co-
ordination to Zn, facilitating the formation of an eight-
member ring to orient the carboxyl groups to the LDH
layer. The H-bonds between LDH layers and attached a-
(2R,1’S) to be formed than (2S,1’R) transition state. On the
À
À
other hand, although, the C2 O1···H1 and C3 O3···H4 are
weaker in (2S,1’R) transition state than in (2R,1’S) transition
state (2.22 and 1.99 ꢁ vs. 1.74 and 1.91 ꢁ), the H-bonds be-
tween the nitro moiety (O7 and O8) in 4-nitrobenzaldehyde
and LDH layer are calculated to be both stronger in
(2S,1’R) transition state than in (2R,1’S) transition state
(1.75 and 1.88 ꢁ vs. 1.96 and 2.00 ꢁ). That means, (2S,1’R)
is more stable than (2R,1’S) transition state. The difference
between the H-bonds in the transition states is conflict to
the alteration of H-bonds in the substrate access, making
neither (2S,1’R) nor (2R,1’S) isomer favored.
À
amino acid anions are calculated to be 2.22 (C2 O1···H1),
À
À
1.69 (C2 O2···H2), and 1.82 ꢁ (C3 O3···H3) when the Zn
centers are coordinated at the inner interlayer regions,
À
whereas they are calculated as 1.78 (C2 O1···H1) and 1.99
À
(C3 O3···H4) when the Zn centers are coordinated at the
edge interlayer regions. Our previous work[29] has revealed
that in the direct aldol addition of cyclohexanone to 4-nitro-
benzaldehyde, the Si face attack of aldehyde to syn-enolate
Experimental verification of LDH nanosheets as a valid
plane-symmetric substituent to enhance enantioselectivity in
zinc-catalyzed direct asymmetric aldol addition: According
to the theoretical prediction, the locations of catalytic cen-
ters are altered experimentally, and the relationship between
the ee value and locations of active centers have then been
explored (Figure 5). The dispersion of Zn centers along the
2D interlayer region has been probed by line-scanning
energy dispersive spectroscopy (EDS; Figure 5a). The Zn
centers are mainly located at the edges of interlayer regions
À
to form the (2R,1’S) transition state has to break C2
À
O2···H2 and C3 O3···H3 bonds when the catalytic centers
are located at the inner interlayer regions, whereas the Re
face attack of aldehyde to anti-enolate to form the (2S,1’R)
À
transition state well preserves C3 O3···H3 (1.83 vs. 1.82 ꢁ)
À
and only weakens C2 O2···H2 from 1.69 to 2.08 ꢁ. That
means, the formation of (2S,1’R) transition state is favored,
whereas (2R,1’S) is inhibited. In the (2R,1’S) transition state,
À
À
the H-bond C3 O3···H4 is formed instead of C3 O3···H3.
(Figure 5b) using Zn
to the l-glutamate-intercalated Zn/Al-LDH. With the Zn
ACHTUNGRTEN(NUNG OAc)2 as the precursor to coordinate
À
C3 O3···H4 is calculated to be 2.00 ꢁ, which is weaker than
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Inorganic Nanosheets
FULL PAPER
cence under the laser excitation.[30] As can be seen from
Figure 5, the fluorescent images of the location in which 8-
hydroxyquinoline coordinated with zinc centers, for the cat-
alyst affording no enantioselectivity, the fluorescent light
was much stronger at the edge than the inner interlayer
region (Figure 6a), indicating that the catalysis occurred
Figure 5. Images of zinc distribution visualized by energy dispersive spec-
troscopy (EDS) energy profiles and the ee values observed with the cor-
responding catalysts: a) Zn/Al-LDHs intercalated with l-glutamate; the
inset indicates the scanning line through the 2D plane for (a)–(d); b) Zn-
ACHTUNGTRENNUNG
Figure 6. Fluorescent images using 8-hydroxyquinoline as a tracing mole-
cule to monitor the location of catalytic reactions using the catalysts
AHCTUNGTRENNUNG
based on a) Zn
calated LDHs; b) Zn
attached to exfoliated LDH layers; c) ZnACHTUNGTRENNNUG
ACHTUNGTRENNUNG
coordinated with the l-glutamate attached to exfoliated LDH layers. In
each case, the uncoordinated zinc moieties were excluded by thorough
washing prior to the characterizations.
AHCTUNGTRENNUNG
nated with l-glutamate intercalated LDHs. The catalytic results are also
provided to present a clear image of the substituent role of LDH layers.
The excess enantiomer is (2S,1’R).
centers coordinated at the edges as catalytic sites, only race-
mic products are obtained. By using ZnACTHNUGTRNEUNG(CH2CH3)2 as the
precursor, the Zn centers are mainly located at the inner in-
terlayer regions (Figure 5c). With the Zn centers coordinat-
ed at the inner region, 61% ee is afforded for anti-isomers
with 83% conversion. Exfoliating l-glutamate-intercalated
Zn/Al-LDH to make the interlayer ligand more accessible,
the Zn centers are coordinated homogeneously with the l-
glutamate (Figure 5d) even using Zn (OAc)2 as the precur-
sor of catalytic site. As a result, 72% ee was afforded for
anti-isomers with 99% conversion. The crucial role of the
LDH layer as a planar substituent of attached a-amino acid
ligand in the enantioselective improvement has been clearly
revealed.
To further confirm the role of LDH layers in the enantio-
selective boost, the site of catalytic reaction was monitored
by using 8-hydroxyquinoline as a tracing molecule. 8-Hy-
droxyquinoline is similar in size to 4-nitrobenzaldehyde, one
of the catalyzed substrate in this work. 8-Hydroxyquinoline
can coordinate with the Zn centers that are introduced as
catalytic sites and in unsaturated coordination, rather than
with the hexa-coordinated Zn in the brucite-like layers. The
complex between Zn and 8-hydroxyquinoline emits fluores-
mainly at the edges of interlayer region or at the gallery en-
trances. For the catalysts giving visible enantioselective pro-
motion, the fluorescent light was homogeneous throughout
the hexagonal crystallite (Figure 6b and c), indicating that
the catalysis took place homogeneously in the interlayer
region. The observations further demonstrate the role of
LDH layers in the enantioselectivity enhancement as huge
and rigid planar substituent of attached chiral a-amino acid
ligand.
To make full use of the LDH layer as a planar substituent
of attached a-amino acid ligand, edge interlayer catalytic
sites should be avoided. Our previous work[24] has revealed
that the location of vanadium centers could be controlled by
changing the dosed quantity of vanadium sources. When less
vanadium was dosed, vanadium centers were mainly coordi-
nated to the amino acid ligand at edge interlayer sites
before they diffused to the inner interlayer region. But for
ZnII centers, the alteration of ZnII dosage does not work as
expected probably because their diffusion to inner interlayer
region seems to be inhibited more severely. So the location
of ZnII centers has been altered experimentally through ex-
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J. He et al.
foliating the ligand-intercalated LDHs or changing the ZnII
sources in this work. Exfoliation is able to increase the ac-
cessibility of ligand to ZnII center, and neutral ZnII sources
could avoid the static repulsion between positively charged
metal centers and brucite-like LDH layers.
anol (1 mL) and subject to HPLC (Daciel Chiral AD-H column) for con-
version and ee determinations. The assignment of the HPLC or GC re-
tention time to the configuration of corresponding enantiomers was
made in reference to literature.[32] All data was reproduced at least twice.
Computational details: In this work, the H-bonding interactions between
host layer and the multiple-guests were investigated by density functional
theory (DFT)[33] modeling with periodic boundary conditions of Zn/Al
LDH layer. The Zn/Al molar ratio is taken as 2 in an ideal LDH layer
with an R3m space group. The lattice parameter of the two-dimensional
LDH layer is a=b=3.02 ꢁ according to the X-ray diffraction (XRD)
measurements.[23] All geometries were fully optimized with Gaussian 09
package of programs (Revision B.01),[34] and the basis set LANL2DZ[35]
was used for V, Zn, and Al, whereas 6-31G[36] was used for the other
atoms.
Conclusion
The LDH layer has been revealed to act as an analogue to a
planar substituent of a chiral ligand, for example, a-amino
acid, to improve the enantioselectivity through both steric
synergies and multiple H-bonding interactions when the
active centers are located at the inner interlayer regions; its
efficiency was investigated in the vanadium-catalyzed asym-
metric epoxidation of allylic alcohols and the zinc-catalyzed
direct asymmetric aldol addition between unmodified ke-
tones and aldehydes. The main findings of this work are ex-
pected to highlight an efficient strategy for catalyst design in
heterogeneous asymmetric synthesis. The planar substituent
effect can be further expanded to other nanosheet materials.
Acknowledgements
The authors wish to thank NSFC and 973 Project (2011CBA00504) for fi-
nancial support. J.H. particularly appreciates the financial aid of the
China National Funds for Distinguished Young Scientists from the
NSFC.
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aldol reaction, a catalytic amount of ZnACTHNUTRGNENUG(OAc)2 (0.011 mmol) and ligand
(equivalent to 0.0165 mmol of l-glutamate) was added to cyclohexanone
(4.0 mmol) and 4-nitrobenzaldehyde (0.055 mmol) in formamide
(10 mL). The dosage of ZnII is 20 mol% referring to the moles of 4-nitro-
benzaldehyde, and the molar ratio of amino acid to zinc is 1.5:1 if not
specially indicated. The mixture was stirred at 258C for 12 h. From the
reaction mixture, a sample was taken (200 mL) and poured into an extrac-
tion funnel containing brine (2 mL), diluted with distilled H2O (2 mL),
and EtOAc (2 mL). The aqueous phase was extracted with EtOAc
(2 mL) twice. The combined organic phases were dried with Na2SO4 and
concentrated under reduced pressure. The residue was dissolved in meth-
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Received: March 26, 2013
Published online: July 23, 2013
Chem. Eur. J. 2013, 19, 12350 – 12355
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12355