Efficient HPLC enantiomer separation using a pillared homochiral metal-organic framework as a novel chiral stationary phase

Article abstract of DOI:10.1039/c6nj00090h

HPLC enantioseparation of racemates using novel pillared homochiral metal-organic framework-silica composite as chiral stationary phase has been successfully demonstrated.

Full text of DOI:10.1039/c6nj00090h

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Efficient HPLC enantiomer separation using a
pillared homochiral metal–organic framework
Cite this:DOI: 10.1039/c6nj00090h
as a novel chiral stationary phase†
Koichi Tanaka,*a Naoki Hotta,a Shohei Nagasea and Kenji Yozab
Received (in Montpellier, France)
9th January 2016,
Accepted 25th April 2016
DOI: 10.1039/c6nj00090h
www.rsc.org/njc
HPLC enantioseparation of racemates using novel pillared homochiral N-donor linkers, trans-bis(4-pyridyl)ethylene (2, bpe) and trans-
metal–organic framework–silica composite as chiral stationary phase bis(4-pyridyl)ethane (3, bpa). Heating a mixture of (R)-1 (50 mg,
has been successfully demonstrated.
0.13 mmol), trans-bis(4-pyridyl)ethylene (2, 24 mg, 0.13 mmol),
and ZnO (11 mg, 0.13 mmol) in a mixture of dimethylacetamide
Porous metal–organic frameworks (MOFs) have attracted much (DMA, 2 mL) and H2O (0.5 mL) at 60 1C for 24 h afforded yellow
attention in the last decade because they have can be used for prisms of (R)-MOF-4 {[Zn(BDA)(bpe)]ꢀ2DMA}(68 mg). Similarly,
various potential applications such as gas storage,1 separation,2 colorless prisms of (R)-MOF-5 {[Zn(BDA)(bpa)]ꢀ2DMA} were
sensing,3 and catalysis.4 Recently, MOFs have been considered prepared from a mixture of (R)-1, trans-bis(4-pyridyl)ethane (3)
as separation materials for chromatography owing to their high and ZnO under the same reaction conditions. The successful
surface area, uniform structural cavities, outstanding thermal syntheses of (R)-MOF-4 and (R)-MOF-5 were confirmed by X-ray
and chemical stability, and selective adsorption phenomena.5 analyses (Fig. 1 and 2).‡
To date, a number of chiral MOFs have been developed and
For HPLC CSPs, we prepared (R)-MOF-4-silica and (R)-MOF-
synthesized.6 Chiral MOFs have great potential as chiral stationary 5-silica composites from a mixture of (R)-H2BDA (1), ZnO,
phases (CSPs) for HPLC enantioseparation of racemic compounds. monodisperse spherical silica gel (Daisogel SP-120-7P; particle
However, there are only a few attempts of chiral MOFs being used size, 7 mm), and bpe (2) or bpa (3) in DMF under solvothermal
in liquid chromatographic enantioseparation; most of which conditions. A suspension of (R)-MOF-4–silica or (R)-MOF-5–
exhibited a relatively narrow range of chiral enantioselectivity.7 silica composites in hexane/i-PrOH (90 : 10) was slurry-packed
Herein, we report novel homochiral pillared MOFs with excellent into a stainless steel column (10 cm long ꢁ 4.6 mm i.d.). We
selectivity for HPLC enantiomeric separation of various racemates also prepared (R)-MOF-68–silica composites from a mixture of
such as sulfoxides, sec-alcohols and flavanones.
(R)-H2BDA 1, Cu(NO3)2 and monodisperse spherical silica gel
In the present work, we built two novel homochiral pillared
MOFs (4 and 5) from zinc oxide, (R)-1,10-binaphthyl-2,20-
dihydroxy-5,50-dicarboxylic acid (H2BDA, 18), and rigid linear
a Department of Chemistry and Materials Engineering, Faculty of Chemistry,
Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan.
E-mail: ktanaka@kansai-u.ac.jp
b Bruker AXS K.K., 3-9, Moriya-cho, Kanagawa-ku, Yokohama, 221-0022, Japan
† Electronic supplementary information (ESI) available: IR, TG, CD spectra and HPLC
chromatographic data. CCDC 1444396 and 1444397. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c6nj00090h
Fig. 1 Crystal structure of (R)-MOF-4; two DMA molecules of crystallization
were omitted for clarity.
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Fig. 2 Crystal structure of (R)-MOF-5; two DMA molecules of crystallization
were omitted for clarity.
(Daisogel SP-120-7P; particle size, 7 mm) without using pillar
linkers under the same reaction condition.
To investigate the chiral recognition ability of these stationary
phases, racemates of sulfoxides, sec-alcohols, and flavanones were
selected as test solutes. As shown in Table 1 and Table S1 (ESI†),
14 (7, 8, 9, 10, 11, 12, 14, 15, 17, 18, 19, 20, 21, and 22) out of 16
sulfoxides were separated using the MOF-5 column, while only
three sulfoxides (15, 18, and 20) were partially separated using the
MOF-4 column. In contrast, the MOF-6 column showed no chiral
recognition ability except for p-nitrophenyl methyl sulfoxide 19. In
many cases, the separation factors (a) were larger for unsubstituted
and p-substituted phenyl methyl sulfoxides (1, 2, 10, 12, 15, and 18)
than for their o- and m-substituted counterparts (9, 11, 13, 14, 16,
and 17). The best chiral recognition performance was obtained
from naphthyl methyl sulfoxide (20) on the MOF-5 column that
had an a value of 3.03 as shown in Fig. 3. To investigate the solvent
effect on the enantioselectivity of MOF-5, we checked the seconde
eluent (hexane/EtOH) to improve the separation results. However,
this eluent system did not work as shown in Table S2 (ESI†). The
most probable reason was that most of the analytes had weak
hydrogen bonding force on MOF-5 with alcohols.
Fig. 3 Enantiomer resolution of sulfoxide (20) on MOF-5 using hexane/
2-PrOH (90/10) as mobile phase. Flow rate: 1.0 mL minꢂ1; detection:
UV 254 nm.
The racemates of sec-alcohols (23–33) were well separated on
both the MOF-4 and MOF-5 columns, although they failed to
separate on the MOF-6 column (Table 2 and Table S3, ESI†).
The separation factors (a) were also larger for p-substituted
derivatives (30, 32, and 33) than for their o- and m-substituted
counterparts (28, 29, and 31), which is most likely because of
steric constraints. Interestingly, the introduction of electron-
withdrawing substituents on the aromatic ring, such as compound
32, gave rise to a prominent base-line separation of enantiomers
as shown in Fig. 4. The p–p interactions between the N-donor
Table 1 Chromatographic data for the resolution of sulfoxides
MOF-4
MOF-5
MOF-6
Compound
a
Rs
a
Rs
a
Rs
Table 2 Chromatographic data for the resolution of sec-alcohols
7
8
9
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.10
1.00
1.00
1.34
1.00
1.84
1.00
1.00
—
—
—
—
—
—
—
—
0.08
—
—
0.11
—
0.20
—
1.33
1.52
1.18
1.46
1.62
1.87
1.00
1.34
1.90
1.00
1.19
2.40
1.23
3.03
1.83
1.57
0.12
0.26
0.10
0.25
0.30
0.23
—
0.17
0.57
—
0.13
1.06
0.17
1.30
0.32
0.19
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.62
1.00
1.00
1.00
—
—
—
—
—
—
—
—
—
—
—
—
MOF-4
MOF-5
MOF-6
10
11
12
13
14
15
16
17
18
19
20
21
22
Compound
a
Rs
a
Rs
a
Rs
23
24
25
26
27
28
29
1.57
1.00
1.00
1.69
2.99
1.00
1.00
1.71
1.81
4.07
2.56
0.59
—
—
0.37
0.74
—
1.43
1.42
1.29
1.81
1.87
1.35
1.24
1.75
1.23
1.93
1.52
0.76
0.21
0.25
1.03
1.32
0.30
0.24
1.03
0.25
0.97
0.38
1.00
1.00
1.00
1.00
1.00
1.00
1.00
2.24
1.00
1.00
1.00
—
—
—
—
—
—
—
0.33
—
—
—
—
0.14 30
0.50
0.39
1.03
0.53
—
—
—
31
32
33
—
Eluent: hexane/2-PrOH = 90/10.
Eluent: hexane/2-PrOH = 99/1.
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The crystal structure of (R)-MOF-4 possessed a large 13.7 Å by
15.0 Å pore (Fig. 1), while that of (R)-MOF-5 was a smaller
hexagonal nanotube with a diameter of 7 Å (Fig. 2). In contrast,
(R)-MOF-68 had a two dimensional staggered structure and
no channel for the analyte to travel into the crystals. Therefore,
the stereoselectivity was mostly caused by the interaction of
the racemates with the inner pore space of (R)-MOF-4 and
(R)-MOF-5, and (R)-MOF-5 had the most appropriate size and
steric fit for weak interactions such as dispersion, dipole–
dipole, and hydrogen-bonding.
In conclusion, we present the syntheses of novel homochiral
pillared MOFs and successful HPLC chromatographic resolution
of many types of enantiomers using the homochiral MOFs as
CSPs. However, the large peak separations result in limited
analyte resolutions. Therefore, chiral recognition mostly depends
on the interaction of the analytes with the homochiral cylindrical
channels in which the best steric fit is the main interactive forces.
The design and development of a wide variety of this type of novel
cylindrical homochiral MOFs as chiral stationary phases in HPLC
enantiomer separation are underway.
Fig. 4 Enantiomer resolution of 1-(4-fluorophenyl)ethanol (32) on
MOF-4 column using hexane/2-PrOH (99/1) as mobile phase. Flow rate:
1.0 mL minꢂ1; detection: UV 254 nm.
Experimental
(R)-MOF-4
A mixture of (R)-1,10-binaphthyl-2,20-dihydroxy-5,50-dicarboxylic
acid (H2BDA, 1)8 (50 mg, 0.13 mmol), trans-bis(4-pyridyl)ethylene
(2, 24 mg, 0.13 mmol), and ZnO (11 mg, 0.13 mmol) in a mixture
of dimethylacetamide (DMA, 2 mL) and H2O (0.5 mL) was
heated at 60 1C for 24 h to afford yellow prisms of (R)-MOF-4
{[Zn(BDA)(bpe)]ꢀ2DMA}(68 mg, 63% yield). IR (KBr pellet,
cmꢂ1): 3064, 2934, 1612, 1505, 1393, 1333, 1288, 1218, 1071,
1018, 980, 842, 821, 780, 686, 667, 600, 549.
linker (bpe) of the framework and electron-deficient aromatic
group of compound 32 may be one of the reasons.
Flavanone derivatives were partially resolved on both the
MOF-4 and MOF-5 columns, and the introduction of polar
substituents, such as Cl or OH groups, on the aromatic ring
of flavanone improved the chiral resolution ability (Table 3).
The chromatograms for the resolution of flavanones (34–38) are
shown in Table S4 (ESI†).
(R)-MOF-5
A mixture of (R)-1,10-binaphthyl-2,20-dihydroxy-5,50-dicarboxylic
acid (H2BDA, 1)8 (50 mg, 0.13 mmol), trans-bis(4-pyridyl) ethane
(3, 25 mg, 0.13 mmol), and ZnO (11 mg, 0.13 mmol) in a
mixture of dimethylacetamide (DMA, 2 mL) and H2O (0.5 mL)
was heated at 60 1C for 24 h to afford colorless prisms of
(R)-MOF-5 {[Zn(BDA)(bpa)]ꢀ2DMA} (64 mg, 59% yield). IR (KBr
pellet, cmꢂ1): 3136, 1665, 1617, 1506, 1437, 1385, 1333,
1275, 1218, 1153, 1097, 1070, 1027, 979, 867, 817, 788, 760,
698, 666, 560, 506.
Thus, (R)-MOF-5 exhibited more efficient chiral recognition
for the enantiomer separation of many types of sulfoxides,
sec-alcohols and flavanones than (R)-MOF-4 in all cases tested.
This study was supported by a Grant-in-Aid for Scientific
Research (C) (No. 26410126) from The Ministry of Education,
Culture, Sports, Science and Technology (MEXT).
Table 3 Chromatographic data for the resolution of flavanones
Notes and references
MOF-4
MOF-5
MOF-6
‡ Crystallographic data for [Zn(BDA)(bpe)]ꢀ2DMA((R)-MOF-4): Data collection
was performed on a Bruker AXS APEXII ULTRA diffractometer [CuKa
radiation (l = 1.54178 Å); o scans] at 93 K. The crystal structures
were solved and refined using the Bruker SHELXTL Software Package.
Monoclinic, space group C2, a = 21.9801(10) Å, b = 13.6765(6) Å,
c = 25.5651(11) Å, a = 901, b = 102.217(2)1, g = 901, V = 7511.1(6) Å3,
Z = 4, m = 0.078 mmꢂ1, 26 115 reflections measured, 12 130 independent
reflections (Rint = 0.0306). The final R1 and wR(F2) values were 0.0376
(I 4 2s(I)), 0.0990 (I 4 2s(I)), respectively. The goodness of fit on F2
Compound
a
Rs
a
Rs
a
Rs
34
35
36
37
38
1.00
1.00
1.00
1.47
3.10
—
—
—
0.06
0.29
1.21
1.30
1.90
1.00
1.43
0.08
0.19
0.20
—
1.00
1.00
1.00
1.00
1.00
—
—
—
—
—
0.26
Eluent: hexane/2-PrOH = 99/1.
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was 0.991. Crystallographic data for [Zn(BDA)(bpa)]ꢀ2DMA ((R)-MOF-5):
Data collection was performed on a Bruker AXS VENTURE ULTRA
diffractometer [CuKa radiation (l = 1.54178 Å); o scans] at 93 K. The
crystal structures were solved and refined using the Bruker SHELXTL
Software Package. Hexagonal, space group P6522, a = 11.1967(4) Å,
b = 11.1967(4) Å, c = 44.0828(16) Å, a = 901, b = 901, g = 1201,
V = 4786.1(4) Å3, Z = 6, m = 1.534 mmꢂ1, 35 785 reflections measured,
2840 independent reflections (Rint = 0.0277). The final R1 and wR(F2)
values were 0.0269 (I 4 2s(I)), 0.0730 (I 4 2s(I)), respectively. The
goodness of fit on F2 was 1.106. CCDC: 1444396 and 1444397.
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