HPLC enantioseparation on a homochiral MOF-silica composite as a novel chiral stationary phase

Article abstract of DOI:10.1039/c5ra26520g

The last frontier in the development of chiral stationary phases for chromatographic enantioseparation involves homochiral metal-organic frameworks (MOFs). Using enantiopure (R)-2,2′-dihydroxy-1,1′-binaphthalene-6,6′-dicarboxylic acid as a starting material, we prepared three homochiral MOFs that were further used as chiral stationary phases for high-performance liquid chromatography to separate the enantiomers of various kinds of racemic sulfoxides, sec-alcohols, β-lactams, benzoins, flavanones and epoxides. The experimental results showed excellent performances for enantioseparation, and highlighted that enantioseparation on homochiral MOF columns is practical.

Full text of DOI:10.1039/c5ra26520g

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ARTICLE
HPLC Enantioseparation on Homochiral
MOF-Silica Composite as a Novel Chiral
Stationary Phase
Cite this: DOI: 10.1039/x0xx00000x
Koichi Tanaka*a, Toshihide Muraokaa, Yasuhiro Otuboa, Hiroki Takahashib
and Atsushi Ohnishic
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
The last frontier in the development of chiral stationary phases for chromatographic
enantioseparation involves homochiral metalꢀorganic frameworks (MOFs). Using enantiopure
www.rsc.org/
(
R
)ꢀ2,2’ꢀdihydroxyꢀ1,1’ꢀbinaphthaleneꢀ6,6’ꢀdicarboxylic acid as a starting material, we prepared
three homochiral MOFs that were further used as chiral stationary phases for highꢀperformance
liquid chromatography to separate the enantiomers of various kinds of racemic sulfoxides, sec
alcohols, ꢀlactams, benzoins, flavanones and epoxides. The experimental results showed
ꢀ
β
excellent performances for enantioseparation, and highlighted that enantioseparation on
homochiral MOF columns is practicable.
UMCMꢀ1 analogues into HPLC columns.6b The Chiralꢀ
UMCMꢀ1 was selective for 1ꢀphenylꢀ1ꢀethanol enantiomers in
Introduction
Metalꢀorganic frameworks (MOFs) are a novel class of porous
materials that are built using metal ions and organic linkers.1
They are promising materials for many applications, such as
gas storage and separation,2 catalysis,3 and sensors.4 This is
because of their advantageous characteristics, such as high
surface area, large pore size, high thermal and chemical
stability, uniformly structured cavities and availability for
modification. Recently, MOFs have attracted increased
attention as new stationary phases for chromatography.5 In
particular, homochiral MOFs have attracted considerable
attention because of their applications in enantioselective
separations and catalysis. Microporous MOFs with good
solvent stability are attractive stationary phases for highꢀ
performance liquid chromatography (HPLC) and some achiral
MOFs have been successfully used as stationary phases for
HPLC separation of small achiral molecules. However,
examples of chromatographic separations of enantiomers using
homochiral MOFs are rare and only a few chiral MOFs have
been studied as chiral stationary phases (CSPs).6
The first attempt to use chiral MOFs as CSPs in preparative
column chromatography was reported by Fedin et al.6a In their
work, a column was prepared by loading a glass tube with a
suspension of 3D porous chiral MOF [Zn2ꢀ(bdc)(lꢀ
lac)(dmf)]·DMF. Resulting chromatograms showed that
PhSOMe enantiomers were completely separated using the
column, while other sulfoxide enantiomers with electronꢀ
withdrawing substituents showed reduced enantioselectivity.
Kaskel et al. then synthesized and packed two new Chiralꢀ
n
ꢀheptane, but the resolution was too low and strong tailing
occurred. Yuan and coworkers reported another chiral MOF
([(CH3)2NH2][Cd(bpdc)1.5
2DMA) as a CSP.6d This MOF
successfully separated some different enantiomers: 1,1ꢀbiꢀ2ꢀ
naphthol, 1,2ꢀdiphenylꢀ1,2ꢀethanediol, 1ꢀ(4ꢀ
chlorophenyl)ethanol, furoin, benzoin, flavanone, Troger’s base,
3ꢀbenzyloxyꢀ1,2ꢀpropanediol, 3,5ꢀdinitroꢀ ꢀ(1ꢀphenylethyl)ꢀ
]
·
N
benzamide and warfarin sodium. Hydrogen bonding
interactions played a vital role in the chiral separation because
of the poorer resolution obtained using hexane–isopropanol
than hexaneꢀdichloromethane as the mobile phase. Tang and
coworkers reported separation for racemic ibuprofen,
phenylethylamine and benzoin using MOFs ({[ZnLBr]·H2O}n)
synthesized using the chiral organic linker Nꢀ(4ꢀpyridylmethyl)ꢀ
lꢀleucine·HBr.6e Recently, Cui et al. reported a 1,1’ꢀbiphenolꢀ
based chiral MOF containing oneꢀdimensional nanosized
channels decorated with chiral dihydroxy group for the
separation of racemic aromatic amines and amides.6f It should
be noted that almost all of the MOFs reported previously
featured narrow ranges of chiral enantioselectivity.
Our laboratory has reported chiral HPLC enantiomer
separation using (R)ꢀCuMOFꢀ1ꢀsilica composite as a CSP that
was synthesized from a mixture of (
binaphthaleneꢀ6,6’ꢀdicarboxylic acid
DMF.6c The packed column (10 cm length, 4.6 mm id)
successfully separated 15 sulfoxide enantiomers with hexaneꢀ
EtOH (50/50) and 16 enantiomers with hexaneꢀiꢀPrOH (90/10)
as mobile phases. Exploration of chiral MOFs as stationary
R
1
)ꢀ2,2’ꢀdihydroxyꢀ1,1’ꢀ
and Cu(NO3)2 in
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phases for diverse chiral compound separation is still required
because chiral separations are extremely important. Here we
Single crystal Xꢀray analysis revealed that (
R)ꢀCuMOFꢀ2
report the investigation of some homochiral MOF–silica was formulated as [Cu2[(
composites prepared from )ꢀ2,2’ꢀdihydroxyꢀ1,1’ꢀ crystallized in the space group
binaphthaleneꢀ6,6’ꢀdicarboxylic acid and ( )ꢀ2,2’ꢀdimethoxyꢀ contains one Cu(II), half of a (
1,1’ꢀbinaphthaleneꢀ6,6’ꢀdicarboxylic acid
enantiomeric HPLC separation of a wide range of racemates, consists of dinuclear Cu units and is typical of dinuclear
R
)ꢀ2]4(H2O)2]·DMA, which
(
R
C
2. The asymmetric unit
1
R
R)ꢀ2 moiety, one coordinated
2
as CSPs for water molecule and a DMA molecule as a guest. The structure
such as sulfoxides, secꢀalcohols,
βꢀlactams, benzoins, [M2(carboxylate)4L2] complexes, with (R)ꢀ2 ligands providing
flavanones and epoxides.
the four metalꢀbridging bidendate caboxylate groups (Cu1ꢀ
Cu1*, 2.625 Å; Cu1ꢀO3RCOO, 1.976 Å; Cu1*ꢀO4RCOO, 2.016 Å;
symmetry code*, 1 – x, y, – z) and two oxygen atoms (Cuꢀ
CO2H
CO2H
O8w, 2.217 Å). A 1D chain structure is constructed from (R)ꢀ2ꢀ
HO
HO
MeO
bridged –[Cu2–[(
R
)ꢀ2]2]– along the
a
ꢀaxis (Fig. 2).
(R)-
(R)-
MeO
CO2H
CO2H
1
2
Results and discussion
Synthesis and characterization of chiral MOFs. Crystalline
)ꢀCuMOFꢀ was prepared using a slightly modified version
of the method previously reported by Lin et al.7 by heating a
DMF solution containing )ꢀ2,2’ꢀdihydroxyꢀ1,1’ꢀ
binaphthaleneꢀ6,6’ꢀdicarboxylic acid and Cu(NO3)2•3H2O at
80°C for 18 h. Crystals of ( )ꢀZnMOFꢀ were obtained by
heating a mixture of ( )ꢀ2,2’ꢀdihydroxyꢀ1,1’ꢀbinaphthaleneꢀ
6,6’ꢀdicarboxylic acid and Zn(NO3)2•6H2O in a mixture of N-
methylformamide (NMF) and EtOH at 80°C for 24 h. ( )ꢀ
CuMOFꢀ was prepared by heating a mixture of ( )ꢀ2,2’ꢀ
dimethoxyꢀ1,1’ꢀbinaphthaleneꢀ6,6’ꢀdicarboxylic acid and
(
R
1
(
1
R
R
1
R
1
R
Figure 2 1D chain structure of (
]4(H2O)2 along the
(bottom). DMA molecules and Hꢀatoms are omitted for clarity.
R
)ꢀCuMOFꢀ2 composed of Cu2[(R)ꢀ
2
R
2
2
a axis (top). A spaceꢀfilling model of the 1D chain
Cu(NO3)2•3H2O in a solvent mixture of N,Nꢀdimethylacetamide
(DMA) and H2O at 60°C for 48 h.
Single crystal Xꢀray analysis revealed that (
existed as [Zn[( )ꢀ ]2(NMF)2]·NMF, which crystallized in the
space group 2221. The asymmetric unit contains one Zn(II),
NMF and half of a molecule of ( )ꢀ , and a guest NMF
molecule in which the methyl group was disordered over two
positions with an occupancy factor of 0.68/0.32. The Zn atom
R)ꢀZnMOFꢀ1
In the crystal of (R
)ꢀCuMOFꢀ17, 1D chain structures stack
indirectly on each other (red and blue molecules in Fig. 8,
bottom) to form hourglassꢀshaped channels with diameters of
approximately 6.2 Å along the aꢀaxis. For the (R)ꢀCuMOFꢀ2
crystal, the chain structures lie directly on top of each other (red
and blue molecules in Fig. 3, top) and the chain structure is
tilted at 69.2° relative to the stacking direction (cꢀaxis, Fig. 3)
so that the channels adopt almost cylindrical shapes. On this
basis we speculate that chiral guest molecules are able to enter
R
1
C
R
1
in mononuclear (R)ꢀZnMOFꢀ1 is sixꢀcoordinated in a geometry
best described as a skewedꢀtrapezoidal bipyramid, in which
four oxygen atoms are from the asymmetric bidentate
carboxylate groups (Zn1ꢀO2, 2.093 Å; Zn1ꢀO3, 2.243 Å) of
and readily pass through the chiral channels of (
in Fig. 3 (bottom). ( )ꢀCuMOFꢀ crystals have channels
running along the ꢀaxis in Fig. 3 (top). The volume and
R)ꢀCuMOFꢀ1
(
R
)ꢀ
zigzag 1D chain is formed by –[Zn–(
extends along the ꢀaxis (Fig. 1).
1
and two from NMF molecules (Zn1ꢀO4, 2.020 Å). A
R
2
R
)ꢀ1]– coordination and
c
c
diameter of the channel in the crystal lattice were 197 Å3 and
4.4 Å, respectively. There were no guest molecules in the
channels of the
(
R
)ꢀCuMOFꢀ
2
crystal. The poor
enantioselectivity on (
R
)ꢀCuMOFꢀ
2
may be because of the
small entrance to the channel of (
)ꢀZnMOFꢀ
, twelve discrete voids of 18–25 Å3 are present in
the unit cell (Fig. 4).
R)ꢀCuMOFꢀ2. In the crystal of
(
R
1
Figure 1 1D chain structure of (
]2(NMF)2 along the axis. Guest NMF molecules and Hꢀatoms are
omitted for clarity.
R)ꢀZnMOFꢀ1 composed of Zn[(R)ꢀ
1
c
2 | J. Name., 2012, 00, 1-3
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Daisogel (SPꢀ120ꢀ7P) in a mixture of DMA and H2O at 80°C
for 18 h. The resulting green precipitate was filtered and
washed with MeOH, and dried in vacuo at 80°C. The successful
preparation of a series of (
R
)ꢀCuMOFꢀ
1
ꢀsilica composite, (
R)ꢀ
ZnMOFꢀ ꢀsilica composite and (
1
R
)ꢀCuMOFꢀ2
ꢀsilica composite
was confirmed by scanning electron microscopy (SEM) (Fig.
S7ꢀS9), powder Xꢀray diffraction (PXRD) (Fig. S10), and N2
physisorption data (Fig. S11) in Supplementary Information.
The packed columns for HPLC were prepared by loading the
suspension of MOFꢀsilica composite in hexane/iꢀPrOH (90 :
10) into a stainless steel column (10 cm length × 4.6 mm i.d.).
Chromatographic enantiomer separation on (R)-CuMOF-1.
To investigate the chiral recognition ability of the (
ꢀsilica composite packed column, various sulfoxide racemates
(Fig. 5) were first selected as test solutes. Table 1 shows the
separation ( ) and retention ( s) factors for the resolution
efficiency. As can be seen from the Table 1, fourteen (
10 15 19 20 22 and 25) out of 23 sulfoxides were resolved
with goodꢀtoꢀexcellent selectivity using hexane/EtOH (50/50)
as the mobile phase. For the resolution of sulfoxides 11
16 17 18 21 23 and 24, separation factors were improved
when the mobile phase was changed from hexane/EtOH (50/50)
to hexane/ ꢀPrOH (90/10). The chromatograms showed clear
R)ꢀCuMOFꢀ
1
α
R
3, 6, 7, 8,
9
,
,
,
,
,
4
,
5
,
,
,
,
,
,
i
Figure 3 The channel structures in (
R
)ꢀCuMOFꢀ
2
crystal (top) and (
R)ꢀ
baseline separation.
CuMOFꢀ crystal (bottom, from reference 7) viewed along the
1
b
ꢀaxis.
The lattice channels in both crystals are depicted as yellow Connolly
surface visualized with Mercury. Hꢀatoms are omitted for clarity.
O
S
O
O
S
O
S
S
Me
Me
Et
Me
5
4
3
6
O
S
O
S
O
S
O
S
Me
Me
Me
Me
O2N
OMe MeO
Me
7
10
9
8
O
O
O
O
S
S
S
S
Me
Me
Me
Me
Me
HO
11
Cl
12
Cl
14
13
Cl
O
O
O
S
S
S
S
Me
Me
Me
O
Br
Br
Figure 4 Crystal structure of (R)ꢀZnMOFꢀ1. The lattice voids are
18
17
Br
16
15
depicted as yellow Connolly surface visualized with Mercury. Guest
NMF molecules and Hꢀatoms are omitted for clarity.
O
S
O
S
Me
S
Me
Me
S
O
O
(
R
)ꢀCuMOFꢀ
the previously reported method.6c
composite was prepared by heating a mixture of (
1
ꢀsilica composite was prepared according to
)ꢀZnMOFꢀ ꢀsilica
)ꢀ1,
21
22
19
20
(
R
1
R
O
S
O
O
S
Zn(NO3)2•6H2O and Daisogel (SPꢀ120ꢀ7P) in a mixture of
NMF and EtOH at 80°C for 24 h. The resulting green
precipitate was filtered and washed with MeOH, and dried in
S
Me
Me
Me
OH
24
23
25
vacuo at 80°C. (
prepared by heating a mixture of (
R
)ꢀCuMOFꢀ
2
ꢀsilica composite was also
)ꢀ , Cu(NO3)2•3H2O and
Figure 5 Chemical structures of selected sulfoxides.
R
2
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5RA26520G
O
S
Me
Table 1 Chromatographic data for the resolution of sulfoxides. 6c
Cl
Eluent Ia
αc
Eluent IIb
12
Compound
Rsd
α
Rs
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4.40
1.92
1.63
1.93
5.71
1.33
2.59
2.31
1.32
1.24
1.99
2.11
1.90
1.67
2.94
1.00
2.38
1.24
1.00
1.25
1.00
1.00
1.28
1.50
1.03
0.92
0.75
1.53
0.35
1.08
1.20
0.15
0.33
0.93
1.06
0.52
0.57
1.07
ꢀꢀꢀ
3.99
2.80
2.39
1.47
2.16
1.31
1.43
1.63
1.40
1.09
1.95
1.90
1.00
2.49
3.03
2.01
1.77
1.00
2.23
1.20
1.05
1.27
1.00
1.33
0.84
0.87
0.65
1.01
0.36
0.78
1.07
0.33
0.06
1.04
0.79
ꢀꢀꢀ
0.68
0.94
0.84
0.93
ꢀꢀꢀ
1.36
0.39
0.18
0.31
ꢀꢀꢀ
0
5
10
15
Time [min]
O
S
Me
13
Cl
0
10
Time [min]
20
O
S
Me
Cl
14
1.14
0.17
ꢀꢀꢀ
0.49
ꢀꢀꢀ
0
10
20
Time [min]
30
40
Figure 6 HPLC chromatogram for the resolution of methyl chlorophenyl
sulfoxide isomers (12ꢀ14) using eluent I as the mobile phase at a flow rate of
1.0 mL minꢀ1 with a UV detector at 254 nm.
ꢀꢀꢀ
0.71
a Hexane/EtOH (50/50)
OH
Me
OH
OH
28
OH
b Hexane/iꢀPrOH (90/10)
c
29
27
26
Calculated from k2′/k1′, where k1′ = (t1 − t0)/t0 and k2′ = (t2 − t0)/t0. The
retention times for the faster and slower moving enantiomers are designated
as t1 and t2, respectively, and that for 1,3,5ꢀtri-tertꢀbutylbenzene used as a
void volume marker is designated as t0.
OH
Me
OH
Me
OH
Me
OH
Me
Me
Et
F
MeO
Br
33
OH
Me
d Calculated from 2(t2ꢀt1)/ω1ꢀω2, where ω is peak width.
31
OH
Me
32
OH
Me
30
OH
Me
Sulfoxides 18 and 21, for example, which were not resolved
when hexane/EtOH (50/50) was used, had excellent resolution
using less polar hexane/iꢀPrOH (90/10) as the mobile phase. It
is interesting to note that the chiral recognition of substituted
sulfoxides occurred more efficiently for the paraꢀsubstituted
derivatives than the metaꢀ and orthoꢀsubstituted derivatives
Cl
35
OH
F
34
36
Cl 37
OH
Me
OH
OH Me
40
OH
Cl
Me
41
39
38
may be due to the steric reasons. For example,
chlorophenyl methyl sulfoxide 12 ꢀchlorophenyl methyl
sulfoxide 13 and ꢀchlorophenyl methyl sulfoxide 14 were
1.24, 1.99 and 2.11, respectively, as shown in Fig. 6.
Interestingly, the ( )ꢀisomer of the sulfoxides eluted before the
)ꢀisomer in all cases tested, suggesting stronger retention of
the ( )ꢀenantiomer in the cavity of ( )ꢀCuMOFꢀ . This was
likely because of intermolecular hydrogen bond interactions
α values for oꢀ
OH
OH Cl
OH
,
m
Cl
p
44
Cl
43
42
S
HO
OH
(
R
N
R
R
1
H
OH
47
45
46
between the phenolic OH group of (
group of the sulfoxide.
R)ꢀCuMOFꢀ1 and the O=S
Figure 7 Chemical structures of selected secꢀalcohols.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA26520G
34
35
36
37
38
39
40
41
42
43
44
45
46
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.21
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.17
1.15
1.00
1.00
1.27
1.00
1.60
2.09
1.28
1.22
1.29
1.42
1.00
1.00
1.00
0.31
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.56
ꢀꢀꢀꢀꢀ
0.59
0.70
0.55
0.33
0.44
0.78
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
1.00
1.14
1.34
1.00
1.86
1.89
1.00
1.81
1.00
1.37
2.44
2.44
1.74
1.77
ꢀꢀꢀꢀꢀ
0.26
0.36
ꢀꢀꢀꢀꢀ
0.93
0.98
ꢀꢀꢀꢀꢀ
0.47
ꢀꢀꢀꢀꢀ
0.28
0.62
0.70
0.83
0.44
S+R
OH
Hexane/EtOH=50/50
27
0
5
10
Hexane/IPA=99/1
0
5
10
15
20
47
a Hexane/EtOH = 50/50
Figure 8 Chromatogram for the resolution of 1ꢀphenylꢀ1ꢀpropanol 27.
b Hexane/iꢀPrOH = 99/1
c Hexane/CH2Cl2 = 10/90
In the HPLC resolution of secꢀalcohols 26–47, the composition of
the mobile phase played a significant role in retention and resolution.
Table 2 presents α and Rs values for the resolution of secꢀalcohols
(26–47) (Fig.7) using different mobile phases (I: Hexane/EtOH =
Table 3 presents the α and Rs values for the resolution of some
50/50, III: Hexane/i-PrOH = 99/1 and IV: Hexane/CH2Cl2 = 10/90). pharmaceutically important lactams (48–54) (Fig. 9) and amides
In contrast to the binary phase hexane/EtOH (50/50), the less polar (55–56) (Fig. 9) using different mobile phases (I: Hexane/EtOH =
hexane/i-PrOH (99/1) mobile phase produced excellent resolution of 50/50 and II: Hexane/iꢀPrOH = 90/10). As can be seen from Table 3,
secꢀalcohols 26, 27, 28, 34, 37, 40, and 42 (Fig. 8 and Table 2). almost all lactams and amides, except 48 and 54, were resolved very
When the mobile phase was changed from hexane/iꢀPrOH (99/1) to efficiently using hexane/EtOH (50/50) as the mobile phase. In this
hexane/CH2Cl2 (10/90), the resolution efficiencies for sec-alcohols
29, 30, 31, 33, 35, 36, 38, 39, 41, and 43ꢀ47 were substantially
improved (Table 2). The observed mobile phase influence on
enantioseparation most likely occurred because of competition from
solvent adsorption via hydrogen bonding. Since the MOF has
hydrogen bonding forces with EtOH, enantioselectivity decreased
compared to when CH2Cl2 was used as the mobile phase. It should
also be noted that the enantiomeric separation of substituted
benzhydrols (42–44) occurred more efficiently for the para-
substituted derivatives than for the metaꢀ and orthoꢀsubstituted
derivatives.
case, enantiomeric separation of substituted βꢀlactams (50–52)
occurred more efficiently for the paraꢀsubstituted derivatives than
for the metaꢀ and orthoꢀsubstituted derivatives. For example, the α
values for o-chloroꢀβꢀlactam (50), m-chloroꢀβꢀlactam (51) and p-
chloroꢀβꢀlactam (52) were 1.42, 2.03 and 5.01, respectively, as
shown in Fig. 10.
OCOPh
Cl
NH
NH
NH
O
O
O
50
49
48
Table 2 Chromatographic data for the resolution of secꢀalcohols.
Cl
F
compound
Eluent Ia
Eluent IIIb
Eluent IVc
Cl
α
Rs
α
Rs
α
Rs
26
27
28
29
30
31
32
33
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
ꢀꢀꢀꢀꢀ
1.31
1.95
1.44
1.17
1.00
1.36
1.00
1.00
0.72
1.00
1.28
1.30
1.92
1.83
1.57
1.00
2.17
ꢀꢀꢀꢀꢀ
NH
NH
52
NH
O
O
O
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
1.38
0.72
0.31
ꢀꢀꢀꢀꢀ
0.48
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.37
0.32
0.52
0.75
0.53
ꢀꢀꢀꢀꢀ
0.93
51
53
Br
OH
CONH2
NH
O
NH
O
56
54
55
Figure 9 Chemical structures of selected amide compounds.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

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DOI: 10.1039/C5RA26520G
Figure 10 HPLC chromatogram for the resolution of βꢀlactam isomers (50-
52) using eluent I as the mobile phase at a flow rate of 1.0 mL minꢀ1 with a
UV detector at 254 nm.
Table 3 Chromatographic data for the resolution of amide and lactams.
Compound
Eluent Ia
αc
Eluent IIb
Rsd
α
Rs
Some benzoin derivatives (57
using mobile phases I (Hexane/EtOH = 50/50), III (Hexane/
PrOH = 99/1) and IV (Hexane/CH2Cl2 = 10/90) (Table 4). For
example, compounds 57 59 were separated using hexane/EtOH
(50/50) as the mobile phase, while hexane/ ꢀPrOH (99/1) was
considered to be more suitable for compounds 61 and 62. The
hydroxyl group of benzoin (57) may be important for the chiral
recognition because compounds 60 and 61 could not be
resolved under these conditions.
–62) (Fig. 11) were resolved
iꢀ
48
49
50
51
52
53
54
55
56
2.18
1.50
1.42
2.03
5.01
1.51
5.37
1.86
3.38
1.33
2.96
1.11
1.00
1.00
3.54
1.27
5.56
1.00
1.74
1.64
0.88
0.33
0.61
1.39
0.87
1.38
0.99
0.73
0.33
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
1.18
0.28
1.28
ꢀꢀꢀꢀꢀ
0.71
–
i
OMe
Me
O
O
O
a Hexane/EtOH = 50/50
OH
OH
OH
MeO
b Hexane/iꢀPrOH = 90/10
Me
57
58
59
O
S
O
O
S
OH
62
OMe
61
Cl
60
Figure 11 Chemical structures of selected benzoyne.
Cl
NH
O
50
Table 4 Chromatographic data for the resolution of benzoin derivatives.
0
10
20
30
compound
Eluent Ia
Eluent IIIb
Eluent IVc
Time [min]
α
Rs
α
Rs
α
Rs
57
58
59
60
61
62
2.06
2.23
2.10
1.00
1.00
1.00
0.67
1.97
2.00
1.00
1.00
1.60
1.36
0.62
1.32
1.00
1.00
1.00
1.00
1.00
0.25
0.34
0.32
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.41
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.32
0.73
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
Cl
NH
O
51
a Hexane/EtOH = 50/50
0
20
40
60
Time [min]
80
100
120
b Hexane/iꢀPrOH = 99/1
c Hexane/CH2Cl2 = 10/90
Cl
Some remarkable substituent effects were observed in the resolution
of flavanone derivatives using hexane/CH2Cl2 = 10/90 as the mobile
phase (Table 5). Interestingly, introduction of electronꢀwithdrawing
substituents on the aromatic ring (65 and 67) improved
enantioselectivity, while the introduction of electronꢀdonating
substituents (64 and 66) reduced enantioselectivity, as shown in Fig.
12.
NH
O
52
0
10
20
30
40
50
60
70
Time [min]
6 | J. Name., 2012, 00, 1-3
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View ArticAle ROnTliInCeLE
DOI: 10.1039/C5RA26520G
Table 5 Chromatographic data for the resolution of flavanone.a
Figure 12 HPLC chromatogram for the resolution of flavanone derivatives
(63-67) using eluent IV as the mobile phase at a flow rate of 1.0 mL minꢀ1
with a UV detector at 254 nm.
Compound
α
Rs
63
1.78
0.70
64
65
66
67
1.39
2.77
1.14
2.38
0.36
0.88
0.11
0.86
The polarity of the mobile phase was found to play a significant role
in the resolution of trans-stilbene oxide 68, as shown in Table 6. The
hexane/EtOH (50:50) mobile phase gave poor resolution. Increased
EtOH content in the mobile phase however, allowed for improved
separation of the enantiomer. The results showed that the use of
EtOH (100%) as the mobile phase produced excellent resolution of
a Eluent: Hexane/CH2Cl2 = 10/90
68, with α value of 2.76 (Fig. 13).
O
Table 6 Chromatographic data for the resolution of transꢀstilbene oxide.
Eluent
α
Rs
O
Hexane/EtOH = 50/50
Hexane/EtOH = 30/70
Hexane/EtOH = 10/90
Hexane/EtOH = 0/100
1.32
1.63
1.85
2.76
0.19
0.31
0.58
1.03
63
0
5
10
Time [min]
15
20
O
MeO
O
O
64
Hexane/EtOH = 50/50
0
10
20
30
68
0
5
O
Cl
O
Hexane/EtOH = 30/70
65
0
2
4
6
8
10
0
5
10
15
20
O
Hexane/EtOH = 10/90
O
66
OMe
0
2
4
6
8
10
0
5
10
15
20
Hexane/EtOH = 0/100
O
O
67
Cl
0
5
10
15
Time [min]
0
10
20
30
40
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

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VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C5RA26520G
Figure 13 HPLC chromatogram for the resolution of transꢀstilbene oxide 68
with different solvent systems as eluent at a flow rate of 1.0 mL minꢀ1 with a
UV detector at 254 nm.
Table 7 Chromatographic data for the resolution of sulfoxides a
Table 8 Chromatographic data for the resolution of secꢀalcohols a
compound (
R
)ꢀCuMOF–
1
(R
)ꢀZnMOF–
1
(R)ꢀCuMOF–2
compound (
R
)ꢀCuMOF–
1
(R
)ꢀZnMOF–
1
(R)ꢀCuMOF–2
α
Rs
1.33
α
Rs
α
Rs
α
Rs
0.72
α
Rs
α
Rs
3
3.99
2.80
2.39
1.47
2.16
1.31
1.43
1.63
1.40
1.09
1.95
1.90
1.00
2.49
3.03
2.01
1.77
1.00
2.23
1.20
1.05
1.27
1.93
1.90
2.19
3.17
2.45
1.00
2.15
1.47
4.13
1.00
1.00
2.48
1.00
1.00
1.91
1.63
1.00
1.00
1.00
1.00
1.00
1.00
0.54
0.64
0.46
0.75
0.77
ꢀꢀꢀꢀꢀ
0.59
0.43
0.54
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.55
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.36
0.59
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
1.00
1.45
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
ꢀꢀꢀꢀꢀ
0.11
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
26
27
28
29
30
31
32
33
34
35
36
37
38
39
1.31
1.95
1.44
1.17
1.00
1.36
1.00
1.00
1.15
1.00
1.00
1.27
1.00
1.60
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
4
0.84
0.87
0.65
1.01
0.36
0.78
1.07
0.33
0.06
1.04
0.79
ꢀꢀꢀꢀꢀ
0.68
0.94
0.84
0.93
ꢀꢀꢀꢀꢀ
1.36
0.39
0.18
0.31
1.38
0.72
0.31
ꢀꢀꢀꢀꢀ
0.48
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.31
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.56
ꢀꢀꢀꢀꢀ
0.59
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
a Hexane/iꢀPrOH = 99/1
Table 9 Chromatographic data for the resolution of lactamsa
compound (
R)ꢀCuMOF–
1
(R)ꢀZnMOF–
1
(R)ꢀCuMOF–2
α
Rs
1.64
α
Rs
α
Rs
48
49
50
51
52
53
54
2.96
1.11
1.00
1.00
3.54
1.27
5.56
1.00
1.24
1.00
1.23
1.00
1.00
1.00
ꢀꢀꢀꢀꢀ
0.15
ꢀꢀꢀꢀꢀ
0.25
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
1.74
1.00
1.00
1.00
1.00
1.00
1.00
0.14
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
0.33
ꢀꢀꢀꢀꢀ
ꢀꢀꢀꢀꢀ
1.18
0.28
1.28
a Hexane/iꢀPrOH = 90/10
Chromatographic enantiomeric separation on (R)-ZnMOF–1 and
(R)-CuMOF–2. Eleven sulfoxides (3–7, 9–11, 14, 17 and 18) were
separated using a (R)ꢀZnMOF–1 column (hexane/i-PrOH = 90/10 as
eluent) and the α values for sulfoxides 6, 7, 9, 11 and 14 were higher
than those obtained using the (R)ꢀCuMOF–1 column, as shown in
Table 7. Conversely, the (R)ꢀCuMOF–2 column did not show any
resolution, except for sulfoxide 4. This may be from the lack of
hydrogen bonding interactions between guest molecules and (R)ꢀ
CuMOF–2, which has no hydroxyl group. For the enantiomeric
separation of secꢀalcohols, unsuccessful results were obtained for the
(R)ꢀZnMOF–1 and (R)ꢀCuMOF–2 columns (Table 8). For the
resolution of lactams (48–54), (R)ꢀZnMOF–1 had higher α values
for compounds 49 and 51 than those for (R)ꢀCuMOF–1. (R)ꢀ
CuMOF–2 showed poor enantioselectivity, except for the βꢀlactam
48.
a Hexane/iꢀPrOH = 90/10
Finally, we tested the reproducibility of the results and the
reuse of the chiral MOF columns. Figure 14 shows the HPLC
chromatograms of sulfoxide
that measured on Jan. 2016 (b) on the same
column, showing both excellent reproducibility and good
reusability of )ꢀCuMOF– for the HPLC chiral stationary
phase. On the other hand, )ꢀZnMOF– column is less stable than
)ꢀCuMOF– column since the structural integrity of )ꢀ
ZnMOF– has been lost in the last 1 and a half year (Fig. 15).
3
measured on Dec. 2011(a) and
(R
)ꢀCuMOF–
1
(
R
1
(R
1
(R
1
(R
1
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

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Journal Name
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View Article Online
ARTICLE
DOI: 10.1039/C5RA26520G
HPLC enantiomeric separation in the future. These species may
also open a gateway to a new area in chiral separation science.
Acknowledgements
a)
This study was supported by a GrantꢀinꢀAid for Scientific
Research (C) (No.26410126) from The Ministry of Education,
Culture, Sports, Science and Technology (MEXT). The authors
are grateful to Prof. H. Tsue at Kyoto University for the BET
measurement.
Notes and references
a
Department of Chemistry and Materials Engineering, Faculty of
Chemistry, Materials and Bioengineering, Kansai University, Suita,
Osaka 564ꢀ8680, Japan
b)
b
Graduate School of Human and Environmental Studies, Kyoto
Univesity, Kyoto 606ꢀ8501, Japan
c
CPI Company, Daicel Corporation, Aboshi, Himeji, Hyogo 671ꢀ1283,
Japan
Electronic supplementary information (ESI) available: General
experimental, synthesis and characterization of ligands and homochiral
MOFs, details for single crystal XRD structure refinement. CCDC
reference numbers 1427406 and 1427405. See DOI: 10.1039/b000000x/
Figure 14 a) HPLC chromatogram of sulfoxide
3
measured on Dec.
)ꢀCuMOF–1
2011 and b) that measured on Jan. 2016 on the same (
R
column.
1
(a) M. Eddaoudi, D. B. Moler, H. Li, B. Chen, T. M. Reineke, M.
O'Keeffe and O. M. Yaghi, Acc. Chem. Res., 2001 34, 319–330; (b)
G. Ferey, C. MellotꢀDraznieks, C. Serre and F. Millange, Acc. Chem.
Res. 2005 38, 217–225; (c) R. J. Hill, D. L. Long, N. R.
Champness, P. Hubberstey, M. Schroder, Acc. Chem. Res., 2005 38
335–348; (d) Z. Wang, G. Chen and K. Ding, Chem. Rev. 2009 109
322–359; (e) J. P. John, J. Perman and M. J. Zaworotko, Chem. Soc.
,
,
,
a)
,
,
,
,
,
Rev., 2009
Rev., 2011
,
38, 1400–1417; (f) W. L. Leong and J. J. Vittal, Chem.
111, 688–764; (g) D. Zhao, D. J. Timmons, D. Yuan, H.
,
Zhou, Acc. Chem. Res., 2011
Zheng, P. J. Stang, Chem. Rev.
(a) K. S. Suslick, P. Bhyrappa, J. H. Chou, M. E. Kosal, S. Nakagaki,
D. W. Smithenry, S. R. Wilson, Acc. Chem. Res. 2005 38, 283–
291; (b) L. J. Murray, M. Dinca, J. R. Long, Chem. Soc. Rev., 2009
38, 1294–1314; (c) A. Phan, C. J. Doonan, F. J. UribeꢀRomo, C. B.
Knobler, M. O'Keeffe, O. M. Yaghi, Acc. Chem. Res. 2010 43, 58–
67; (d) K. Sumida, D. L. Rogow, J. A. Mason, T. M. McDonald, E.
D. Bloch, Z. R. Herm, T. Bae, J. R. Long, Chem. Rev. 2012 112
724ꢀ781; (e) B. Van de Voorde, B. Bueken, J. Denayer, D, De Vos,
Chem. Soc. Rev., 2014 43, 5766ꢀ5788.
(a) J. Y. Lee, O. K. Farha, J. Roberts, K. A. Scheidt, B. T. Nguyen, J.
T. Hupp, Chem. Soc. Rev., 2009 38, 1450ꢀ1459; (b) L. Ma, W. Lin,
Topics in Current Chemistry 2010 293, 175ꢀ205; (c) M. Yoon, R.
Srirambalaji, K. Kim, Chem. Rev. 2012 112, 1196ꢀ1231; (d) J. M.
Falkowski, S. Liu, W. Lin, RSC Catalysis Series 2013 12, 344ꢀ364;
(e) A. Dhakshinamoorthy, M. Opanasenko, J. Cejka, H. Garcia,
Catal. Sci. Technol. 2013 , 2509ꢀ2540; (f) J. Liu, L. Chen, H. Cui,
J. Zhang, L. Zhang, C. Su, Chem. Soc. Rev., 2014 43, 6011ꢀ6061.
(a) L. E. Kreno, K. Leong, O. K. Farha, M. Allendorf, R. P. Van
Duyne, J. T. Hupp, Chem. Rev., 2012 112, 1105ꢀ1125; (b) D. Liu,
K. Lu, C. Poon, W. Lin, Inorg. Chem. 2014 53, 1916ꢀ1924; (c) L.
Heinke, M. Tu, S. Wannapaiboon, R. A. Fischer, C. Woell,
Microporous Mesoporous Mater., 2015 216, 200ꢀ215.
,
44, 123–133; (h) T. R. Cook, Y.
,
2013 113, 734ꢀ777.
,
2
b)
,
,
,
,
,
Figure 15 a) HPLC chromatogram of sulfoxide
3
measured on Sep.
)ꢀZnMOF–1
,
,
,
2014 and b) that measured on Jan. 2016 on the same (
R
column.
,
3
,
,
,
Conclusions
,
,
,
,
We have developed homochiral MOFs as a promising chiral
stationary phase for HPLC enantioseparation. Columns packed
,
, 3
with (
recognition towards many kinds of enantiomers, such as
sulfoxides, secꢀalcohols, ꢀlactams, benzoins, flavanones and
R)ꢀCuMOFꢀ1 and (R)ꢀZnMOF–1 showed excellent chiral
,
4
β
,
epoxides. The results indicated that convenient and selective
enantioseparations using homochiral MOF columns is practical
for HPLC. The results are promising for exploring the potential
of homochiral MOFs as novel chiral stationary phases for
,
,
,
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DOI: 10.1039/C5RA26520G
5
6
(a) Z. Gu, C. Yang, N. Chang, X. Yan, Acc. Chem. Res.
734ꢀ745; (b) P. Peluso, V. Mamane, S. Cossu, J. Chromatogr. A.
2014 1363, 11ꢀ26.
(a) A. L. Nuzhdin, D. N. Dybtsev, K. P. Bryliakov, E. P. Talsi, V. P.
Fedin, J. Am. Chem. Soc., 2007 129, 12958–12959; (b) M.
,
2012
,
45
,
,
,
,
Padmanaban, P. Mueller, C. Lieder, K. Gedrich, R. Gruenker, V.
Bon, I. Senkovska, S. Baumgaertner, S. Opelt, S. Paasch, E. Brunner,
F. Glorius, E. Klemm, S. Kaskel, Chem. Commun.
12089–12091; (c) K. Tanaka, T. Muraoka, D. Hirayama, A. Ohnishi,
Chem. Commun. 2012 48, 8577–8579; (d) M. Zhang, Z. Pu, X.
Chen, X. Gong, A. Zhu, L. Yuan, Chem. Commun. 2013 49, 5201ꢀ
5203; (e) X. Kuang, Y. Ma, H. Su, J. Zhang, Y. Dong, B. Tang,
Anal. Chem., 2014 86, 1277ꢀ1281; (f) Y. Peng, T. Gong, K. Zhang,
X. Lin, Y. Liu, J. Jiang, Y. Cui, Nature Commun.,2014 , 4406.
, 2011, 47,
,
,
,
,
,
,
5
7
Y. Cui, H. L. Ngo, P. S. White and W. Lin, Chem. Commun., 2003,
994–998.
10 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA26520G
Graphical Abstract
HPLC Enantioseparation on Homochiral MOF–Silica Composite as a
Novel Chiral Stationary Phase
Koichi Tanaka*, Toshihide Muraoka, Yasuhiro Otubo, Hiroki Takahashi and
Atsushi Ohnishi
Using enantiopure (R)-2,2’-dihydroxy-1,1’-binaphthalene-6,6’-dicarboxylic acid as a
starting material, we prepared three homochiral MOFs that were further used as chiral
stationary phases for high-performance liquid chromatography to separate the
enantiomers of various kinds of racemic sulfoxides, sec-alcohols, β-lactams, benzoins,
flavanones and epoxides.
homochiral MOF
S
R