Boosting Enantioselectivity of Chiral Organocatalysts with Ultrathin Two-Dimensional Metal-Organic Framework Nanosheets

Article abstract of DOI:10.1021/jacs.9b07633

The development of methodologies for inducing and tailoring enantioselectivities of catalysts is an important issue in asymmetric catalysis. In this work, we demonstrate for the first time that chiral molecular catalysts can be boosted from completely nonselective to highly enantioselective when installed in nanostructured metal-organic frameworks (MOFs). Exfoliation of layered crystals is one of the most direct synthetic routes to unltrathin nanosheets, but its use in MOFs is limited by the availability of layered MOFs. We illustrate that layered MOFs can be designed using ligand-capped metal clusters and angular organic linkers. This leads to the synthesis of two three-dimensional (3D) layered porous MOFs from Zn₄-p-tert-butylsulfonyl calix[4]arene and chiral angular 1,1′-binaphthol/-biphenol dicarboxylic acids, which can be ultrasonic exfoliated into one- and two-layer nanosheets. The obtained MOF materials are efficient catalysts for asymmetric cascade condensation and cyclization of 2-aminobenzamide and aldehydes to produce 2,3-dihyroquinazolinones. While both binaphthol and biphenol display no enantioselectivity, restriction of their freedom in the MOFs leads to 56-90% and 46-72% ee, respectively, which are increased to 72-94% and 64-82% ee after exposure to external surfaces of the flexible nanosheets. Moreover, the MOF crystals and nanosheets exhibit highly sensitive fluorescent enhancement in the presence of chiral amino alcohols with enantioselectivity factors being, respectively, increased up to 1.4 and 2.3 times of the values of the diols, allowing them to be utilized in chiral sensing. Therefore, the observed enantioselectivities increase in the order organocatalyst < MOF crystals < MOF nanosheets in both catalysis and sensing. This work not only provides a strategy to make 3D layered MOFs and their untrathin nanosheets but also paves the way to utilize nanostructured MOFs to manipulate enantioselectivities of molecular catalysts.

Full text of DOI:10.1021/jacs.9b07633

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Article
Boosting Enantioselectivity of Chiral Organocatalysts
with Ultrathin 2D Metal–Organic Framework Nanosheets
Chunxia Tan, Kuiwei Yang, Jinqiao Dong, Yuhao Liu, Yan Liu, Jianwen Jiang, and Yong Cui
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07633 • Publication Date (Web): 13 Oct 2019
Downloaded from pubs.acs.org on October 13, 2019
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Boosting Enantioselectivity of Chiral Organocatalysts with Ultrathin
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Chunxia Tan,† Kuiwei Yang,‡ Jinqiao Dong,† Yuhao Liu,† Yan Liu,*,† Jianwen Jiang*,‡ and Yong Cui*,†
†School of Chemistry and Chemical Engineering and State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University,
Shanghai 200240, China
‡Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, 117576 Singapore
Supporting Information
ABSTRACT: The development of methodologies for inducing and tailoring enantioselectivities of catalysts is an important issue in asymmetric
catalysis. In this work, we demonstrate for the first time that chiral molecular catalysts can be boosted from completely non-selective to highly
enantioselective when installed in nanostructured metal-organic frameworks (MOFs). Exfoliation of layered crystals is one of the most
direct synthetic routes to unltrathin nanosheets, but its use in MOFs is limited by the availability of layered MOFs. We illustrate that
layered MOFs can be designed using ligand-capped metal clusters and angular organic linkers. This leads to the synthesis of two 3D
layered porous MOFs from Zn4-p-tert-butylsulfonyl calix[4]arene and chiral angular 1,1’-binaphthol/-biphenol dicarboxylic acids, which
can be ultrasonic exfoliated into one- and two-layer nanosheets. The obtained MOF materials are efficient catalysts for asymmetric cascade
condensation and cyclization of 2-aminobenzamide and aldehydes to produce 2,3-dihyroquinazolinones. While both binaphthol and
biphenol display no enantioselectivity, restriction of their freedom in the MOFs leads to 56-90% and 46-72% ee, respectively, which are
increased to 72-94% and 64-82% ee after exposure to external surfaces of the flexible nanosheets. Moreover, the MOF crystals and
nanosheets exhibit highly sensitive fluorescent enhancement in the presence of chiral amino alcohols with enantioselectivity factors being
respectively increased up to 1.4 and 2.3 times of the values of the diols, allowing them to be utilized in chiral sensing. Therefore, the
observed enantioselectivities increase in the order organocatalyst < MOF crystals < MOF nanosheets in both catalysis and sensing. This
work not only provides a strategy to make 3D layered MOFs and their untrathin nanosheets, but also paves the way to utilize
nanostructured MOFs to manipulate enantioselectivities of molecular catalysts.
enantioselectivity enhancement was observed relative to
monomeric models due to confinement effects within the
INTRODUCTION
frameworks facilitating host-guest interactions and/or synergistic
interactions with substrates.9c,10b,11c However, none of the
materials yet reported is capable of inducing enantioselectivity
from non-selective catalysts. By reducing one dimension of MOFs
to single or few layers, 2D MOF nanosheets (MONs) have
emerged as a new class of functional 2D materials.12 Compared
with the 3D MOF bulk crystals, the merits of combining more
accessible active sites, super flexibility, faster diffusion, and
improved host-guest affinity of substrates/products within 2D
MONs make them ideal candidates as highly active catalysts13 and
sensors.14 Nonetheless, chiral MONs remains a virgin land waiting
for exploration,15 and there is no report of MONs for
enantioselective catalysis and sensing. Among various known
methods for fabrication of MONs, exfoliation of 3D layered MOF
crystals into their 2D constituents is one of the most direct
approaches, in which various driving forces are used to break
weak van der Waals interactions between the stacked layers.16
Unfortunately, the types of 3D layered MOFs are still limited,
preventing its wide use.15,16a,17 This limitation represents a major
challenge in preparing 2D MONs.12f To address this issue, here we
illustrate a new strategy for preparing layered MOFs by using
bulky hydrophobic ligand-capped metal clusters as building
blocks. Such weak hydrophobic interactions between interlayers
would benefit the fabrication of ultrathin 2D anisotropic MONs
via ultrasonic liquid exfoliation.
Because of the importance of chirality in pharmaceutical and
biological chemistry, the development of methodologies for preparing
and detecting enantiopure compounds is an important issue.1 The use
of chiral metal and organic complexes as homogeneous catalysts
is a well-established and efficient strategy for the synthesis of
optically active compounds.2,3 Varying steric and electronic
properties of catalysts have a significant effect on substrate activation
and structures of transition states and intermediates, and have been
widely used to control stereoselectivity in asymmetric catalysis.4 In this
work, a new method of manipulating enantioselectivities of
molecular catalysts is presented. We demonstrate that
nanostructured metal-organic frameworks (MOFs) can be used as a
promising platform to induce and tailor enantioselectivitie of
organocatalysts in both catalysis and sensing. Furthermore, this method
can also facilitate separation and recycling of homogeneous
catalysts. It should be noted that the multiplicity and intractability
of the active sites in conventional chiral solids often complicate
structure/performance-based
control
over
regio-
and
stereoselectivity.5
MOFs are a highly versatile class of porous crystalline hybrid
materials with many applications.6 By taking advantage of their
permanent porosity and tunable structures, MOFs provide a
powerful platform to integrate chiral building blocks into robust
structures for enantioselective processes.7-11 A number of chiral
MOF-based catalysts and sensors with modest to high
enantioselectivity have been designed, including binol-, biphenol-
and metallosalen-based MOFs.9-11 In a relative few cases,
Sulfonylcalix[4]arenes can react with metal ions to form a
shuttlecock-like tetrametallic clusters, which are capable of
serving as four-connected nodes to make discrete coordination
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cages by treating with linear rigid organic linkers.18 With the
hydrophobic TBSC-capped Zn4 clusters (H4TBSC
However, when diols are used as organocatalysts, they generally
display low enantioselectivities.4a We describe here that both the
1
=
p-tert-butylsulfonyl calix[4]arenes), we show that 3D porous
layered MOFs can be synthesized from semi-rigid and angular
organic linkers (Figure 1). The desired MOFs constructed from
enantiopure
2,2’-dihydroxyl-1,1’-binol(biphenol)-3,3’-dicarboxylic acids can
be easily ultrasonic exfoliated into ultrathin 2D MONs. Axially
chiral diols such as 1,1’-binaphthol (binol) and 1,1′-biphenol are
well established in the organic community as beneficial chiral
auxiliaries for asymmetric catalysis and chiral recognition.3,4
3D MOF bulk crystals and 2D MONs can be used as efficient
catalysts for asymmetric cascade condensation and cyclization of
anthranilamide and aromatic aldehydes and as fluorescent sensors
for discriminating chiral amino alcohols. In both cases, the
enantioselectivities increased in the order binol/biphenol < MOF
bulk crystals < MONs, likely due to framework confinement
effects and/or flexibility of the ultrathin framework layers with
high surface utilization.
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O
O
O
O
S
S
O
O
a)
HO
OH
O
O
O
O
O
Zn
O
Zn
HO
HO
OH
OH
O
Zn
O
O
S
Zn
O
S
O
O
O
HO
OH
O
O
O
O
O
O
c)
b)
e)
d)
Figure 1. (a) Construction of MOFs 1 and 2 from H2L and the Zn4 cluster. (b, d) View of the 2D structure of MOF 1 along the c-axis and
b-axis. (c, e) View of the 2D structure of MOF 2 along the c-axis and b-axis (Zn, blue; S, orange; O, red; C, grey).
[Zn4(µ4-H2O)(TBSC)][L2]2∙DMF∙CH3CN∙7H2O (2). The products
RESULTS AND DISCUSSION
1 and 2 have an average size of 38 and 48 m, respectively
(Figures 2b and S3). Both of them were stable in air and insoluble
in water and common organic solvents. They were formulated
based on single-crystal X-ray diffraction, IR spectra, elemental
analysis and thermogravimetric analysis (TGA).
Single-crystal X-ray diffraction showed that MOF 1 crystallizes
in the chiral space group P4, with one fourth of the formula in the
asymmetric unit. As shown in Figure 1, in the shuttlecock-like
[Zn4(µ4-H2O)(TBSC)] cluster, each Zn ion is octahedrally
coordinated by two phenoxo oxygen and one sulfonyl atom from
Synthesis and Characterization. The ligand H2L1 was
prepared from (R)- or (S)-2,2’-diethoxy-1,1′-binaphthalene in two
steps in 80% overall yields, and H2L2 was prepared from (R)- or
(S)-5,5',6,6'-tetramethyl-3,3'-dibromo-1,1’-biphenyl-2,2'-diol
in
two steps in 39% overall yields. As shown in Figure 1, heating
Zn(NO3)2∙6H2O, H4TBSC and H2L1/H2L2 in a mixed solvent of
dimethylformamide (DMF) and CH3OH or CH3CN at 100 °C
afforded
colorless
crystals
of
[Zn4(µ4-H2O)(TBSC)][L1]2∙3DMF∙CH3OH∙6H2O
(1)
and
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the deprotonated TBSC4- anion, one µ4-H2O atom and two
to give a 2D neutral framework in the ab plane, with the
1
2
3
4
carboxylate oxygen atoms from two L1 ligands. Each L1 ligand
contains two bidentate carboxylate groups and the dihedral angle
between the two binaphthyl subunits is 77.2°. Each Zn4 cluster is
linked by four exo-bidentate L1 ligands to four adjacent Zn4 cores
maximum thickness of 14.8 Å. A space-filling representation of
MOF 1 (Figure S1d) clearly demonstrates the formation of chiral
cavities.
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c)
b)
d)
e)
f)
g)
Figure 2. (a) Schematic diagram for the exfoliation of the bulk MOF 1 to ultrathin 2D nanosheets. (b) SEM image of MOF 1. (c) SEM
image of MON 1. (d) TEM image of MON 1. (e) The Tyndall effect of the MON 1 suspension in i-PrOH. (f) AFM image of MON 1. (g)
Height of AFM image for the selective area.
Interestingly, the hydroxyl groups of the BINOL point outwards
the open cavities. Such 2D layers stack on each other along the
c-axis, giving rise to 1D channels with a diameter of ~10.5 Å, in
which hydroxyl groups point inwards and are accessible for guest
molecules. The adjacent layers have weak van der Waals
interactions between TBSC and L1 ligands. As shown in Figure 2b,
the inherent layered structure can also be clearly seen from
scanning electron microscopy (SEM) image.
MOF 2 crystallizes in the triclinic chiral space group P1, with
the whole formula unit in the asymmetric unit. It has a very
similar crystal structure to MOF 1. Each shuttlecock-like
[Zn4(µ4-H2O)(TBSC)] cluster is quadruplely linked by four L2
ligands to afford a 2D layered structure (Figure 1e). The biphenol
subunits of L2 have a similar dihedral angle to the binol of L1
(77.0o vs 77.2 o), and the maximum layer thickness decreases from
14.8 Å in 1 to 14.6 Å in 2 while the 1D channel size decrease
from 10.5 Å to 10.0 Å (Figure S2). The adjacent layers are also
linked by van der Waals interactions between TBSC and L2
ligands to form a porous framework with open channels that are
periodically decorated with the dihydroxy groups of biphenyl
backbones. Again, the layered structure can also be clearly
revealed by scanning electron microscopy (SEM) image (Figure
S3b).
Calculations using PLATON19 show that MOFs 1 and 2 have
about 43.1% and 42.9% void spaces, respectively, available for
guest inclusion. Phase purity of the MOFs was established by
comparison of their observed and simulated powder X-ray
diffraction (PXRD) patterns (Figures 3a and 3b). Thermal
gravimetric analysis (TGA) revealed that the MOFs started to
o
o
decompose at about 350 C (1) and 450 C (2) (Figure S7). The
permanent porosity was examined by CO2 adsorption
measurement at 195 K. The Brunauer-Emmett-Teller (BET)
surface areas were calculated to be 175.9 and 141.1 m2/g for
MOFs 1 and 2, respectively (Figures 3c and 3d). The enantiomeric
nature of the MOFs was revealed by circular dichroism (CD)
spectra. The R-/S-MOFs exhibited very strong bisignate π − π*
bands at 256, 286, 306 and 361 nm for 1 and 254, 300 and 326 nm
for 2. The CD spectra were similar to those of the corresponding
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enantiomers of ligands (251, 303 and 367 nm for H2L1 and 262,
AFM analyses of the exfoliated MON 1 (Figure 2), and MON 2
1
2
3
4
5
6
7
8
303 and 327 nm for H2L2), indicating the cotton effects of MOFs
derived from the chiral 1,1’-naphthyl or -phenyl skeletons.
Moreover, the Cotton effects are much more intense in MOFs than
in the ligands (Figure S6), indicating chiral amplification occurred
during the framework crystallization. The ability to place such
important chiral diol auxiliaries in layered MOFs represents a
major step towards the controllable synthesis and structural
tailoring of nanostructured porous materials.
Due to the weak van der Waals interactions between adjacent
layers, these MOFs can be easily exfoliated into nanosheets
through solvent-assisted liquid sonication (isopropanol for 1 and
acetonitrile for 2). The exfoliation can be evidenced by the
Tyndall effect upon irradiation of the colloid suspensions of
MONs with a laser beam (Figures 2e and S4). It shows the colloid
suspensions remained stable at room temperature for at least six
months, indicating the monodispersity of nanosheets. TEM and
(Figures S4 and S5) confirm their ultrathin 2D-nanosheet
structural features. TEM images of MON 1 showed ultrathin and
wrinkled nanosheets of 0.4 × 0.9 μm2. AFM measurements gave a
thickness of about 3 ± 0.5 nm for MON 1 (Figure 2g), which is
about twice the theoretical thickness of monolayer (1.5 nm),
indicating that MON 1 consists of double layers. In the same way,
the size and thickness of MON 2 were evaluated as 1.0 × 0.5 μm2
and (1.5~3.0) ± 0.5 nm (Figures S4c and S5b), respectively,
indicative of
a
one- and two-layer nanosheets. More
characterizations including FT-IR, CD and TGA also
demonstrated the successful preparation of 2D nanosheets
(Figures S6-S9). The BET surface areas were examined by CO2
adsorption measurement at 195 K with 178.6 and 173.8 m2/g for
MON 1 and MON 2, respectively (Figures 3c and 3d). This
indicates both nanosheets can retain the porous structures as the
pristine MOFs.
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a)
b)
c)
d)
Figure 3. (a, b) PXRD patterns of the MOFs and MONs. (c, d) CO2 adsorption (filled symbols) and desorption (open symbols) isotherms
for the MOFs and MONs at 195 K.
Asymmetric Catalysis. The 2,3-dihydroquinazolinone (DHQZ)
is a privileged scaffold for its extensive pharmacological activities
such as antibacterial, antitumor, antifungal and analgesic
efficacy.20 Regardless of various methods that are available to
synthesize DHQZs as racemates. Catalytic asymmetric synthesis
of 2,3-DHQZ has been a challenge for a long time since the
aminal stereocenter is sensitive to racemization. In fact, there are
catalysts for condensation and cyclization of 2-aminobenzamide
with aldehydes in CH3CN at 40 oC. Specifically, 3.0 mol%
loading of MOF or MON catalyzed the condensation/amine
addition of 4-fluoro-benzaldehyde to give the targeted product in
91-94% yields and 72-92% ee in 60 h. As shown in Table 1, under
the optimized conditions, other benzylaldehyde derivatives can
also be transformed to the targeted DHQZ in 81~92% yields and
46~94% ee. In general, for a given catalyst, reaction of
benzaldehydes bearing electron-withdrawing groups with
2-aminobenzamide afforded the DHQZ products in higher yields
and ee values than the ones with electron-rich substituents. The
absolute configuration of the product is determined by the
handedness of the catalyst (entry 6 and 26). Despite the similar
polymeric structures, MOF 1 and MON 1 showed much higher
stereoselectivities in catalyzing the above reactions than MOF 2
and MON 2 (56-90% vs 46-72% ee and 72-94% vs 64-82% ee),
respectively, probably arising from the bulky binol backbone of
L1 has stronger enantioselective induction ability than the
biphenol of L2. In addition, it appears that MONs 1 and 2 catalysts
only
several
chiral
Brønsted
acids
(BINOL-
and
SPINOL-phosphoric acids)21,22 and Lewis acids (Sc(III)-inda
-pybox)23 that can catalyze condensation and cyclization of
2-aminobenzamide with aldehydes to produce enantiopure
2,3-DHQZ. Encouraged by the efficiency of Brønsted acids
catalysts, the presence of potential hydroxyl protons active sites in
the framework materials prompted us to evaluate their catalytic
activities in condensation/amine addition cascade sequence to
synthesize DHQZ.
To our delight, after screening various reaction conditions
including catalyst loading, reaction time, solvent and temperature
(Table S3), both MOFs and MONs were found to be active
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gave improved reactivity and enantioselectivity related to the
parent MOFs under similar conditions, as shown in Table 1
(entries 1-4 vs 6-9 and 21-24 vs 26-29). The differences in the
reactivity and selectivity were clearly manifested in the reaction
kinetics, as shown in Figures 4 and S12 (see below).
1
2
3
4
5
6
7
8
9
Table 1. Asymmetric condensation and cyclization of 2-aminobenzamide with aldehydes to synthesize DHQZsa
O
O
3.0 mol% Cat.a
CH3CN, 40 oC, 60 h
NH2
NH
H
R
+
R CHO
NH2
N
H
Entry Cat.
R
Yield (%)b ee (%)c
Entry Cat.
R
Yield (%)b ee (%)c
1
2
3
4
5
6
7
MOF 1
4-FPh
4-ClPh
4-MeOPh
Ph
91
88
21
22
23
24
25
26
27
MOF 2
4-FPh
4-ClPh
4-MeOPh
Ph
92
72
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
85
90
90
62
82
56
81
46
89
75
91
46
d
G1/G2/G3
4-FPh
99/39/~9
37/50/20
92(-94)g
94
G1/G2/G3
4-FPh
4-ClPh
99/26/~2
20/11/20
82 (-83)g
75
MON 1
Me2L1
92
90
MON 2
Me2L2
94
91
4-ClPh
8
9
4-MeOPh
Ph
86
88
72
80
28
29
4-MeOPh
Ph
84
92
64
70
10
11
12
13
14
15
16
17
18
19
20
G1/G2/G3
4-FPh
99/72/59
93
49/52/23
30
31
32
33
34
35
36
37
38
39
40
G1/G2/G3
4-FPh
99/62/72
93
40/16/22
0
0
4-ClPh
4-MeOPh
Ph
88
0
4-ClPh
4-MeOPh
Ph
90
0
88
0
84
0
90
0
92
0
G1/G2/G3
4-FPh
99/83/46
~99
98
0/0/0
G1/G2/G3
4-FPh
99/78/45
~99
95
0/0/0
H2L1
0
0
0
0
0
H2L2
0
0
0
0
0
e
e
H2L1Me2
H2L1+ [Zn4]f
4-FPh
H2L2Me2
4-FPh
4-FPh
98
H2L2+ [Zn4]f
Spinol-Ph
Binol-Pj
4-FPh
97
[Zn4]
Me2L1-Pi
4-FPh
45
4-FPh
98
4-FPh
95
4-FPh
97
a For reaction details see Experimental section. b Isolated yield. c The ee was determined by HPLC analysis. d G1 = biphenyl, G2 =
4-anthracylphenyl, G3 = 3,5-bis(benzyloxy)phenyl; e The two phenolic hydroxyl groups of H2L was protected by methyl groups . f A
g
2:1 mixture of tetramer with (S)-Me2L1/-Me2L2 (6.0 mol% loading) was used as a catalyst. Catalyzed by the (R)-MON.
h(R)-1,1’-spirobiindane-7,7-diol-based
spirocyclic
phosphoric
acid.
iPhosphorylated
Me2L1
j(R)-2,2’-diethoxy-1,1′-binaphthalene-based binol phosphoric acids
b)
a)
Figure 4. Plots of ee values (a) and yields (b) with 3.0 mol% MOF 1 and MON 1 and 6.0 mol% of Me2L1 (the same loading of L as the
heterogeneous reaction ).
To understand the different catalytic performances of MOFs and
their MONs, multiple control reactions were carried out. As
shown in Table 1 (entries 16, 17, 36 and 37), with 3.0 mol%
loading of H2L or the ester H2LMe2 (the same loading of L as the
MOF catalyst), the reaction of anthranilamide with
4-fluoro-benzaldehyde proceeded smoothly, affording the product
in more than 95% yield but with no enantioselectivity. The
tetrameric cluster [Zn4(µ4-H2O)(TBSC)(OAc)4] was also
synthesized18d as a model complex of the Zn4 building block in the
MOF to catalyze the reaction, but only the racemic product was
produced in 45% yield (Table 1, entry 19). Control reactions with
a 2:1 mixture of the model Zn4 complex and H2L showed that they
can promote the transformation smoothly (98% yield) but with no
enantioselectivity (Table 1, entries 18 and 38). In contrast, as
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mentioned above, the targeted DHQZ was produced in both high
because this aldehyde cannot access the catalytic sites in the
1
2
3
4
5
6
yield and enantioselectivity in the presence of catalytic amount of
MOF 1 and MON 1. Therefore, the above result showed that the L
ligand and the Zn4 cluster alone or their mixtures are incapable of
providing efficient stereocontrol on the products. This indicates
that the porous frameworks containing special chiral cavities made
from L and [Zn4(µ4-H2O)(TBSC)] is essential for enantioselective
generation of chiral DHQZ.
channel (10.5 Å) as a result of its large diameters (10.2 × 16.0 Å2).
Besides, the ee values of the sterically products obtained with
MON 1 were also higher than those with MOF 1, as shown in
Table 1 (entries 10 vs 5 and 30 vs 25), but the differences became
smaller with the increase of the substrate diameters. It is thus
likely that the catalytic asymmetric reactions may mainly occur
within the MOFs and at the surfaces of MONs.
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The confinement effect was further demonstrated by the sharp
contrast of catalytic activities of MON 1, MOF 1 and Me2L1 for
condensation/amine addition cascade sequence at low
catalyst/substrate (C/S) ratios (Table S6). At the C/S of 1:400,
Me2L1 afforded 83% conversion of the DHQZ, while MOF 1 and
MON 1 gave 84 and 88% conversions, respectively. When the C/S
ratio decreased from 1:400 to 1:1600 and 1:2400, the conversion
dramatically decreased from 83 to 19 and 1% for Me2L1, and from
84 to 60 and 14% for MOF 1, whereas MON 1 could still achieve
69 and 41% conversions. So, the difference in catalytic activity
became larger as the C/S ratio decreased, and it appeared in the
order MON 1 > MOF 1 > Me2L1. Similar catalytic performances
were observed for Me2L2 (3%), MOF 2 (14%) and MON 2 (46%)
when the C/S ratios were decreased from 1:400 to 1:2400. The
above finding further confirmed that the binol and biphenol units
confined in the frameworks displayed much higher activity than
the homogeneous counterparts, especially at low C/S ratio and
also highlighted the key role of ultrathin nanosheet in improving
catalytic performance.
We also monitored the dynamic process during the catalytic
synthesis of 2-(4-fluorophenyl)-2,3-dihydroquinazolin-4(1H)-one
by MONs, MOFs and Me2L, which exhibited quite different
reaction kinetics. As seen from Figure 4a, the ee values of the
DHQZ product experienced a period of 20 h to reach a stable
value for MON 1 and MOF 1, while they were always 0 for
Me2L1. Moreover, MON 1 gave higher enantioselectivity than
MOF 1 in the whole reaction process. In terms of the kinetic
profile of yield, the reaction rate with MON 1 is comparable with
the homogeneous catalyst Me2L1, but is obviously faster than
MOF 1, consistent with the fast diffusion of substrate and product
within the ultrathin layers. Similar kinetic behaviors were
observed for MON 2, MOF 2 and Me2L2 (Figure S12). These
results further demonstrated the unique advantages of MONs.
Upon completion of the catalytic reaction, both MONs and MOFs
could be recovered by centrifugation and reused at least five times
without any loss of its activity and enantioselectivity (Table S7).
PXRD showed that both MOFs and MONs remained almost the
same as the pristine samples after 5 catalytic recycles (Figures 3a
and 3b). Moreover, filtration test showed no indication of catalysis
by leached homogeneous species and inductively coupled plasma
optical emission spectrometry (ICP-OES) analysis of the solution
indicated almost no loss of Zn ions (0.005%) from the structure.
To probe the role of the pore aperture of MOFs and MONs in
catalysis, several sterically aromatic aldehydes with size ranging
from 10~16 Å were selected and subjected to the reactions. As
expected, both Me2L1 and Me2L2 promoted homogeneous
condensation and cyclization of 2-aminobenzamide with the bulky
aldehydes to produce DHQZ in high yields but with no
enantioselectivity (Table 1, entries 15 and 35). MONs also
showed highly efficient activity to the bulky substrates and in
some cases even better than homogeneous catalysts. In contrast,
the yields of the reaction products catalyzed by the MOFs greatly
depend on the substituent size: as the size of the aldehyde
increases, yields of the final products steadily decreases
(99/39/9%, entry 5 and 99/26/2%, entry 25). Specially, only 9%
yield of the product was detected for the sterically more
demanding 3,5-bis(phenoxy-methyl) benzaldehyde catalyzed by
MOF 1, which was much lower than the 46% and 59% yields
obtained with Me2L1 and MON 1, respectively, presumably
To provide microscopic insight into the high enantioselectivity
of DHQZ in the synthesized MOFs and MONs, we performed
DFT calculations for the reaction catalyzed by MON 1 (Figure
S13). According to previous reports,22, 23 the enantioselectivity of
DHQZ is determined by the intramolecular amidation of imine.
The attack of amine to the imine from the Si or Re face leads to
(S)- or (R)-DHQZ. Thus, the intramolecular amidation of imine
was chosen as the target reaction in our calculations. For
comparison, the reactions with the homogeneous Me2L1 catalyst
and without catalyst were also examined.
The DFT calculations suggest that the intramolecular amidation
of imine to DHQZ is a two-step process. In the first step, the
nucleophilic attack of the N of amide group on imine C leads to a
cyclization intermediate; in the second step, one H atom shifts
from NH2 to N to produce DHQZ. For the intramolecular
amidation of imine to DHQZ without catalyst (Figure S14), the
Gibbs energy profiles are exactly the same, implying the ee is 0.
In the homogeneous system with Me2L1 catalyst, the reactant
interacts with the hydroxyl groups through N-H and O-H
hydrogen bonds (Figures S15 and S16), then it undergoes a
two-step conversion from the Si and Re faces, respectively. To
compare the enantioselectivity of DHQZ, the overall barrier
(Gibbs energy difference between TS2/TS2’ and A/A’, Figure 5)
is computed. For intramolecular amidation of imine on Me2L1, the
overall barriers are predicted to be 51.0 and 52.8 kcal/mol for (S)-
and (R)-DHQZ, respectively, which give a small barrier difference
of 1.8 kcal/mol.
In the heterogeneous system with MON 1 catalyst, the reactant
interacts with the hydroxyl groups through N-H hydrogen bonds
(Figures S17 and S18), and the 4-FPh group is located in the 1D
chiral channel while another benzene ring points to the large
cavity. The overall barriers for intramolecular amidation of imine
to (S)- and (R)-DHQZ are 46.3 kcal/mol and 49.9 kcal/mol,
respectively, which suggests (S)-DHQZ is more preferentially
produced. The barrier difference of 3.6 kcal/mol for (S)- and
(R)-DHQZ is higher than that (1.8 kcal/mol) on Me2L1. This
reveals MON 1 possesses higher enantioselectivity than Me2L1,
which is consistent with the experimentally observed trend. The
intramolecular amidation of imine via Si face features less steric
hindrance in the framework, which leads to the preferential
production of (S)-DHQZ in MON 1 (Figures S17–S19).
Based on the above experimental studies, DFT calculations and
literature findings,21-24 the possible reaction pathway is proposed
in Figure S20. The first imine formation step may be catalyzed by
hydrogen-bonding between the hydroxyl group of the
immobilized binol and the carbonyl group of aldehyde. The
subsequent intramolecular amidation could be carried out by
hydrogen-bonding between the hydroxyl group of binol and
imino-group of the imino-amide intermediate to afford the final
product. In the MOFs and their MONs, the 1D chiral channel
lined with hydroxyl groups not only provides active protons to
intrigue the condensation/amine addition cascade sequence, but
also exerts specific stereocontrol over the intermediates by the
confined chiral environment, which might offer ‘enzyme-like’
pockets available for stronger interactions between substrates and
catalysts and thus better stereoselectivity. This behavior is,
however, unavailable for the molecular catalyst Me2L due to the
lack of confinement effects, and reduced in the MOF catalysts
owing to the limited flexibility and external surface areas. The
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excellent stereoselective control of MONs may arise from specific
most enantioselective homogeneous systems based on phosphoric
1
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8
interactions between substrate and ultrathin layers where the
imino-amide intemediate diffuses into the chiral channel and gets
access to chiral hydroxyl catalytic sites, while the two pendent
aromatic form stable host-guest interactions with the
binaphthyl/biphenyl skeletons of the ligand on the surfaces.
acids reported to date.3b,22
Enantioselective Sensing. The presence of chiral functional
-OH groups in the present MOFs and MONs makes them good
candidates for enantioselective recognition of chiral molecules.
The MOF materials were tested for fluorescence enhancement by
amino alcohols. Microcrystalline particles of MOFs 1 and 2 with
an average size of 2.8 and 3.2 m, respectively, were fabricated
by vigorous stirring with a magnetic stir bar in acetonitrile (Figure
S3). Both MOF particles and MONs show strong fluorescence in
CH3CN with emission maximum around 500 or 430 nm (Figure
S10). They were dispersed in acetonitrile to prepare a stock
solution with the binol/biphenol unit at a concentration of 10 μM.
Aliquots containing different amounts of the D and L enantiomers
of the amino alcohol were added to the acetonitrile suspensions (3
mL), and then the fluorescence signals of the suspensions in the
presence of different amounts of substrates were measured. As
shown in Figure 6c, when (S)-MON 1 was treated with
2-amino-1-propanol (alaninol), the emission at 430 nm was
enhanced by both the D and L enantiomers, but the increase
caused by D-alaninol was greater than that of L-alaninol, implying
selectivity in the fluorescence recognition. The fluorescence
intensity of MON 1 was maximally increased to 1.70 and 1.28
times that of the original value by D- and L-alaninol, respectively.
Figure 6d shows Benesi-Hildebrand plots for MOF 1 and MON 1
(1.0 × 10-5 M) in the presence of D- or L-alaninol in CH3CN. The
association constants KBH of MON 1 were calculated to be
2871.48 ± 143.19 M-1 with D-alaninol and 757.58 ± 48.75 M-1
with L-alaninol, giving an enantioselectivity (or enantiomeric
resolution) factor [EF = KBH(D-alaninol)/KBH(L-alaninol)] of 3.79. MOF 1
was also enantioselective to alaninol with a KBH(D)/KBH(L) value of
3.27, which was much smaller than that of MON 1. Besides, other
chiral amino alcohols such as leucinol, phenylalaminol and
phenylglycinol can also enantioselectively enhance the
fluorescence of MOF 1 and MON 1 (Figure S10). The
KBH(D)/KBH(L) values were determined to be 1.33, 1.43 and 1.86 for
MOF 1 and 2.27, 1.54 and 2.17 for MON 1, respectively.
(a)
(S)-DHQZ on Me2L1
(R)-DHQZ on Me2L1
60
50
40
30
20
10
0
TS2 (60.1)
TS2'
(59.1)
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TS1
(34.8)
51.0
B
(32.6)
TS1'
(34.5)
B'
(31.7)
52.8
A
(9.1)
A'
(6.3)
(1.1)
(0.6)
(S)-DHQZ
(R)-DHQZ
0.0
Me2L1+imine(g)
(b)
(S)-DHQZ on MON 1
(R)-DHQZ on MON 1
80
70
60
50
40
30
20
10
0
TS2'
TS2 (79.2)
(79.5)
TS1
(59.3)
B'
(57.1)
TS1'
(57.9)
46.3
B
(55.9)
A
(32.9)
49.9
(29.3)
(24.9)
(R)-DHQZ
(S)-DHQZ
A'
(29.6)
0.0
MON 1+imine(g)
From control experiment, the ester Me2L1 of H2L1 showed
obvious low fluorescence enhancement and selectivity towards
amino alcohols, with KBH(D)/KBH(L) values ranging from 1.12 to
2.44. Therefore, for a given analyte, the enantioselectivity
efficiency was in the order MON 1 > MOF 1 > Me2L1. Although
the KBH(D)/KBH(L) values for these four amino alcohols are close for
MOF 1 and Me2L1, the fluorescence of the MOF is much more
sensitive to the monomer enhancers. The observed change in the
fluorescence intensity of the MOF material is probably caused by
static enhancement via the formation of a hydrogen-bonded
host-guest adduct that may perturb proton-transfer-assisted
charge-transfer excited state. The static nature of the complexation
is suggested by the consistent fluorescence lifetimes of the hosts
before and after titration with alaninol (lifetime, τ0, 1.60 vs 1.24 ns
and 1.48 vs 1.07 ns, respectively). As the non-covalent
interactions of the host with amino alcohol enantiomers afford
different diastereomeric complexes, distinct fluorescence
enhancement is thus observed. This finding is consistent with the
catalytic result, as the MOFs and MONs confer a well-confined
chiral environment for efficient enantiodiscrimination in
comparison with Me2L while the ultrathin nature of MONs
facilitates better analyte diffusion and easier access to more
exposed active sites.
Figure 5. Relative Gibbs energy profiles at 313.15 K for the
intramolecular amidation of imine to (S)- and (R)-DHQZ on (a)
Me2L1 and (b) MON 1. (c) Schematic mechanism for (S)-DHQZ
production on MON 1. A/A’: imine in adsorbed state; TS1/TS1’:
nucleophilic attack of the N of amide group on imine C; B/B’:
cyclization intermediate; TS2/TS2’: H shift from NH2 to N.
Although many heterogeneous asymmetric catalysts based on
MOFs have been reported to display superior catalytic activity and
selectivity to their homogenous analogues due to confinement
effects,9c,10b,11a we demonstrate for the first time that the
homogenous chiral catalyst can be boosted from completely
non-selective to highly enantioselective when installed in MOF
nanostructures. Despite great progresses in asymmetric
organocatalysis,3,21,22,25 there are no chiral diol catalysts reported
for enantioselectively catalyzing acetalization reactions of
2-amino benzamide and aldehydes. The enantioselectivities of the
present MON-based protocol are comparable even to those of the
Under otherwise identical conditions, MOF 2, MON 2 and
Me2L2 also displayed enantioselectively binding with alaninol,
leucinol, phenylalaminol and phenylglycinol (Figure S11). The
KBH(D)/KBH(L) values were determined as 1.72/3.30/1.43,
1.50/1.89/1.45, 1.50/1.80/1.11 and 1.72/2.14/1.31, respectively,
and decreased in the order MON 2 > MOF 2 > Me2L2, also
proving the advantage of ultrathin nature of MONs in the
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recognition of chiral analytes. Consistent with the slightly lower
BINOL core, a variety of enantiopure fluorescence sensors
1
2
3
4
5
6
7
8
chiral induction ability of biphenol relative to binol, these
enantioselective values are smaller than the related values for
MOF 1, MON 1 and Me2L1. Compared to the pristine samples,
MOF 2 and MON 2 after titration exhibited slightly changes in
fluorescence lifetimes (τ0, 2.45 vs 2.44 ns and 1.69 vs 1.64 ns
respectively), supporting the static nature of the host-guest
complexation. In addition, PXRD indicated that all MOFs and
MONs remained crystalline after treatment with L-alaninol,
indicative of the good stability of the hosts 1 and 2 (Figures 3a
and 3b). By taking advantages of the strong fluorescence of the
including organic oligomers, polymers and coordination
assemblies have been prepared for chiral species with amino,
hydroxyl and carboxylate groups that can generate hydrogen
bonds with the binol hydroxyl groups.26,27 Because of the ease of
interfacing nanosheets with solid-state devices, the present chiral
MON-based sensors hold the potential to perform online
enantiomer discrimination, with perspectives in process
monitoring.
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b)
d)
f)
a)
c)
e)
Figure 6. (a-c) Fluorescence emission spectra of (S)-Me2L1, MOF 1 and MON 1 with increasing concentrations of D-2-Alaninol in
solutions. (d) Benesi-Hildebrand plots of the fluorescence emissions of Me2L1, MOF 1 and MON 1 enhanced by D-2- and L-2-Alaninol.
(e,f) The comparative EFs of Me2L, MOFs and MONs for four different amino alcohols.
and MONs can also be sensitive fluorescent sensors for
CONCLUSIONS
discriminating chiral amino alcohols and their enantioselectivity
We have shown that 3D layered porous MOFs and
ratios were up to 1.4 and 2.3 times higher than those of the
corresponding ultrathin 2D MONs can be synthesized from
related diols. Therefore, the chiral diol catalysts can be boosted
ligand-capped metal clusters and semi-rigid angular linkers.
from completely non-selective to highly enantioselective when
Controlled assembly of chiral binol/biphenol into MOF
installed in MOF nanostructures, probably as a result of the
nanoparticles and nanosheets enabled the nonselective diol to
steric hindrance and confinement effect of framework and/or 2D
enantioselectively catalyze condensation/amine addition cascade
external surface of the flexible ultrathin layers. The
sequence
to
afford
2,3-dihyroquinazolinones
with
nanostructured MOFs could be recycled and reused without a
noticeable decrease in activity/sensitivity and selectivity. This
8
56-90/46-72% ee and 72-94/64-82% ee, respectively. The MOF
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Jeong, K. S.; Go, Y. B.; Shin, S.; Lee, S. M.; Kim, J.; Yaghi, O. M.;
Jeong, N. Asymmetric Catalytic Reactions by NbO-Type Chiral
Metal-Organic Frameworks. Chem. Sci. 2011, 2, 877.
work thus provides a new strategy to induce and tailor
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stereoselectivity of organocatalyts and promises to develop a
variety of 2D functional materials for enantioselective
processes.
(8) (a) Seo, J. S.; Whang, D.; Lee, H.; Jun, S. I.; Oh, J.; Jeon, Y. J.; Kim,
K. A Homochiral Metal-Organic Porous Material for Enantioselective
Separation and Catalysis. Nature 2000, 404, 982. (b) Han, Q.; Qi, B.;
Ren, W.; He, C.; Niu, J.; Duan, C. Polyoxometalate-Based Homochiral
Metal-Organic Frameworks for Tandem Asymmetric Transformation of
Cyclic Carbonates from Olefins. Nat. Commun. 2015, 6, 10007.(c) Liu,
L.; Zhou, T. Y.; Telfer, S. G. Modulating the Performance of an
Asymmetric Organocatalyst by Tuning Its Spatial Environment in a
Metal–Organic Framework. J. Am. Chem. Soc. 2017, 139, 39, 13936. (d)
Gedrich, K.; Heitbaum, M.; Notzon, A.; Senkovska, I.; Froöhlich, R.;
Getzschmann, J.; Mueller, U.; Glorius, F.; Kaskel, S. A Family of Chiral
Metal-Organic Frameworks. Chem. -Eur. J. 2011, 17, 2099. (e) Tanaka,
K.; Sakuragi, K.; Ozaki, H.; Takada, Y. Highly Enantioselective
ASSOCIATED CONTENT
Supporting Information.
Experimental procedures, characterization data and DFT
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
9
AUTHOR INFORMATION
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Corresponding Author
Friedel-Crafts
Trans-ß-nitrostyrene
Alkylation
of
N,
N-dialkylanilines
with
*liuy@sjtu.edu.cn
*chejj@nus.edu.sg
*yongcui@sjtu.edu.cn
Catalyzed
by
a
Homochiral
Metal-OrganicFramework. Chem. Commun. 2018, 54, 6328. (f) Zhang,
Z. X.; Ji, Y. R.; Wojtas, L.; Gao, W. Y.; Ma, S. Q.; Zaworotko, M. J.;
Antilla, J. C. Two Homochiral Organocatalytic Metal Organic Materials
with Nanoscopic Channels. Chem. Commun. 2013, 49, 7693.
(9) (a) Zheng, M.; Liu, Y.; Wang, C.; Liu, S.; Lin, W. Cavity-Induced
Enantioselectivity Reversal in a Chiral Metal–Organic Framework
Brønsted Acid Catalyst. Chem. Sci. 2012, 3, 2623. (b) Falkowski, J. M.;
Sawano, T.; Zhang, T.; Tsun, G.; Chen, Y.; Lockard, J. V.; Lin W.
Privileged Phosphine-Based Metal–Organic Frameworks for
Broad-Scope Asymmetric Catalysis. J. Am. Chem. Soc. 2014, 136, 5213.
(c) Wu, C. D.; Hu, A.; Zhang, L.; Lin, W. A Homochiral Porous
Metal-Organic Framework for Highly Enantioselective Heterogeneous
Asymmetric Catalysis. J. Am. Chem. Soc. 2005, 127, 8940.
(10) (a) Mo, K.; Yang, Y.; Cui, Y. A Homochiral Metal-Organic
Framework as an Effective Asymmetric Catalyst for Cyanohydrin
Synthesis. J. Am. Chem. Soc. 2014, 136, 1746. (b) Chen, X.; Jiang, H.;
Hou, B.; Gong, W.; Liu, Y.; Cui. Y. Boosting Chemical Stability,
Catalytic Activity, and Enantioselectivity of Metal−Organic
Frameworks for Batch and Flow Reactions. J. Am. Chem. Soc. 2017,
139, 13476. (c) Chen, X.; Peng, Y.; Han, X.; Liu, Y.; Lin, X.; Cui, Y.
Sixteen Isostructural Phosphonate Metal-Organic Frameworks with
Controlled Lewis Acidity and Chemical Stability for Asymmetric
Catalysis. Nat. Commun. 2017, 8, 2171. (d) Peng, Y.; Gong, T.; Zhang,
K.; Lin, X.; Liu, Y.; Jiang, J.; Cui, Y. Engineering Chiral Porous
Metal-Organic Frameworks for Enantioselective Adsorption and
Separation. Nat. Commun. 2014, 5, 4406.
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Albrecht-Schmitt, T. E. A Metal-Organic Framework Material that
Functions as an Enantioselective Catalyst for Olefin Epoxidation. Chem.
Commun. 2006, 2563. (b) Zhu, C.; Yuan, G.; Chen, X.; Yang, Z.; Cui,
Y. Chiral Nanoporous Metal-Metallosalen Frameworks for Hydrolytic
Kinetic Resolution of Epoxides. J. Am. Chem. Soc. 2012, 134, 8058. (c)
Xia, Q.; Li, Z.; Tan, C.; Liu, Y.; Gong, W.; Cui, Y. Multivariate
Metal−Organic Frameworks as Multifunctional Heterogeneous
Asymmetric Catalysts for Sequential Reactions. J. Am. Chem. Soc.
2017, 139, 24, 8259. (d), Song, F.; Wang, C.; Falkowski, J. M.; Ma, L.;
Lin, W. Isoreticular Chiral Metal-Organic Frameworks for Asymmetric
Alkene Epoxidation: Tuning Catalytic Activity by Controlling
Framework Catenation and Varying Open Channel Sizes. J. Am. Chem.
Soc. 2010, 132, 15390. (e) Falkowski, J. M.; Wang, C.; Liu, S.; Lin, W.
Actuation of Asymmetric Cyclopropanation Catalysts: Reversible
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Frameworks.Angew. Chem. Int. Ed. 2011, 50, 8674.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the National Science
Foundation of China (Grant Nos. 21431004, 21620102001,
21875136, and 91856204), the National Key Basic Research
Program of China (2016YFA0203400), Key Project of Basic
Research of Shanghai (17JC1403100 and 18JC1413200), and
the Shanghai Rising-Star Program (19QA1404300).
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