A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification

Article abstract of DOI:10.1016/j.chempr.2017.07.004

We show that CMOM-3S, a previously unreported porous crystalline metal-organic material that exhibits intrinsic homochirality, serves as a general-purpose chiral crystalline sponge (CCS) and a chiral stationary phase (CSP) for gas chromatography (GC). The properties of CMOM-3S are enabled by nano-sized channels connected to adaptable molecular recognition sites that mimic enzyme-binding sites. Further, CMOM-3S is composed of inexpensive components, facile to prepare, and requires only trace amounts of analyte. When coupled with the thermal and hydrolytic stability of CMOM-3S, these features mean that a coated fused silica capillary column in which CMOM-3S serves as a CSP is both more versatile and more robust than three benchmark commercial columns. That the enantiomer with the longer GC retention time is consistently captured in CCS experiments enables CMOM-3S to serve as a powerful tool to enable both chiral purification and enantiomer identification.

Full text of DOI:10.1016/j.chempr.2017.07.004

Article
A Chiral Metal-Organic Material that Enables
Enantiomeric Identification and Purification
Shi-Yuan Zhang, Cheng-Xiong
Yang, Wei Shi, Xiu-Ping Yan,
Peng Cheng, Lukasz Wojtas,
Michael J. Zaworotko
shiwei@nankai.edu.cn (W.S.)
xpyan@nankai.edu.cn (X.-P.Y.)
xtal@ul.ie (M.J.Z.)
HIGHLIGHTS
Crystal engineering enables the
design of a new chiral porous
material, CMOM-3S
CMOM-3S functions as both a
chiral crystalline sponge and a
chiral stationary phase
Practical enantiomer separation
and identification are achieved by
CMOM-3S
Enantiomeric separation and purification of new chemical entities is an ongoing
challenge for synthetic, process, and analytical chemists. The chiral porous
material CMOM-3S functions as a chiral crystalline sponge (CCS) for structural
determination of either chiral or achiral molecules. Further, CMOM-3S is robust
enough to serve as a chiral stationary phase (CSP) for chromatographic separation
of enantiomers. A new tool for chiral separation and identification, the CSP-CCS
method, is thereby enabled.
Zhang et al., Chem 3, 1–9
August 10, 2017 ª 2017 Elsevier Inc.
http://dx.doi.org/10.1016/j.chempr.2017.07.004

Please cite this article in press as: Zhang et al., A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification, Chem
2017), http://dx.doi.org/10.1016/j.chempr.2017.07.004
(
Article
A Chiral Metal-Organic Material
that Enables Enantiomeric
Identification and Purification
Shi-Yuan Zhang,1,8 Cheng-Xiong Yang,2,8 Wei Shi,2,3,4,5,* Xiu-Ping Yan,2,4,6,* Peng Cheng,2,3,4,5
Lukasz Wojtas, and Michael J. Zaworotko1,9,
7
*
SUMMARY
The Bigger Picture
We show that CMOM-3S, a previously unreported porous crystalline metal-
organic material that exhibits intrinsic homochirality, serves as a general-
purpose chiral crystalline sponge (CCS) and a chiral stationary phase (CSP) for
gas chromatography (GC). The properties of CMOM-3S are enabled by nano-
sized channels connected to adaptable molecular recognition sites that mimic
enzyme-binding sites. Further, CMOM-3S is composed of inexpensive compo-
nents, facile to prepare, and requires only trace amounts of analyte. When
coupled with the thermal and hydrolytic stability of CMOM-3S, these features
mean that a coated fused silica capillary column in which CMOM-3S serves as
a CSP is both more versatile and more robust than three benchmark commercial
columns. That the enantiomer with the longer GC retention time is consistently
captured in CCS experiments enables CMOM-3S to serve as a powerful tool to
enable both chiral purification and enantiomer identification.
Enantiomeric identification of new
chemical entities (NCEs) and
natural products represents an
analytical challenge that has an
impact on technologies as diverse
as pharmaceuticals,
agrochemicals, flavorings, and
fragrances. Currently, assays to
identify enantiomers involve
comparison with reference
standards, which are unavailable
for NCEs. Here, we detail a
protocol for chiral discrimination
that eliminates the need for
enantiomerically pure reference
standards and requires only trace
amounts of analyte. A thermally
and hydrolytically robust
INTRODUCTION
Whereas natural processes can exhibit exquisite discrimination over chirality, the
same cannot be said in general about synthetic, process, and analytical chemistry.
1
In 1848, Pasteur kick-started the field of stereochemistry when he reported that
homochiral metal-organic
crystallization of racemic compounds can afford spontaneous resolution (racemic
conglomerates), but this remains the exception rather than the norm. Today,
enantiomeric separation and identification matters to technologies as diverse as
pharmaceuticals, agrochemicals, flavorings, fragrances, and asymmetric synthesis.
However, chiral identification remains a scientific and technological challenge,
particularly for new chemical entities (NCEs). The state of the art for separation of
enantiomers, chiral chromatography, is based upon the use of chiral stationary
phases (CSPs), which require enantiomerically pure reference standards for enan-
material, CMOM-3S, enables
chromatographic separations and
single-crystal X-ray diffraction to
work synergistically because it is
stable enough to serve as a chiral
stationary phase and its
recognition sites are specific
enough to act as a homochiral
crystalline sponge.
2
tiomer identification. Other techniques such as mass spectrometry and infrared/
UV-visible spectroscopy are likewise limited. Here, we reveal that CMOM-3S, a
3
–5
porous crystalline metal-organic material (MOM),
is the first homochiral MOM
6
that serves as both a general-purpose chiral crystalline sponge (CCS) and a CSP
for gas chromatography (GC). CMOM-3S thereby enables CSP and CCS to work syn-
ergistically to enable enantiomer purification and identification. This CSP-CCS
method requires no reference standard and only trace amounts of analyte (Figure 1).
Chiral separations represent one of the most difficult of preparative and analytical
separations because enantiomers have identical physical and chemical properties
and most separation methods tend to rely on differences in boiling points or
Chem 3, 1–9, August 10, 2017 ª 2017 Elsevier Inc.
1

Please cite this article in press as: Zhang et al., A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification, Chem
2017), http://dx.doi.org/10.1016/j.chempr.2017.07.004
(
Figure 1. Chiral Separation and Identification by the CSP-CCS Method
Enantiomers can be routinely separated by chromatography, but identification of the absolute
configuration of each enantiomer requires an enantiopure reference standard in an additional
experiment (method 1). In method 2, a homochiral metal-organic material, CMOM-3S, is used as
both a chiral stationary phase for separation and a chiral crystalline sponge for structure
determination, eliminating the need for a reference standard.
7
solubilities. Commercial CSPs are typically based upon polymer composites that
incorporate component(s) with chiral recognition features such as polysaccharide,
2
,8,9
b-cyclodextrin, and homochiral amino acids.
tion of CSPs are expensive to manufacture, lack versatility across all types of chiral
Unfortunately, the current genera-
1
0–17
1Department of Chemical Science, Bernal
Institute, University of Limerick, Limerick,
Republic of Ireland
analytes, and tend to exhibit poor robustness. Chiral MOMs (CMOMs),
porous
1
8,19
20,21
organic cages,
and chiral covalent organic frameworks
have also been re-
26,27
2
1–25
searched for their potential utility as CSPs
and membranes
but have not
2Department of Chemistry, College of Chemistry,
yet been adapted for commercial use. None of these existing classes of CSPs enable
enantiomer identification without access to enantiopure reference standards. This is
a considerable drawback with respect to natural products or NCEs that are often only
Nankai University, Tianjin 300071, People’s
Republic of China
3Key Laboratory of Advanced Energy Materials
Chemistry (MOE), Nankai University, Tianjin
300071, People’s Republic of China
6
available in trace quantities. The concept of ‘‘crystalline sponges,’’ pioneered and
2
8
29–31
developed by the group of Fujita and others,
exploits the crystallinity and
4
Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin), Nankai
University, Tianjin 300071, People’s Republic of
China
porosity of MOMs to offer a new approach to structurally characterize NCEs, espe-
cially those hard to crystallize or only available in trace quantities. However, whereas
determination of the absolute configuration of an enantiomer included in a crystal-
5State Key Laboratory of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
1
0–17,32
line sponge is feasible and homochiral MOMs are long known,
the current
31
6
,28–30
generation of crystalline sponges are achiral
or heterochiral (conglomerate)
6Research Center for Analytical Sciences, State
Key Laboratory of Medicinal Chemical Biology,
Tianjin Key Laboratory of Molecular Recognition
and Biosensing, Nankai University, Tianjin
and unsuited for enantiomeric purification. Consequently, there are not yet any
materials that facilitate both separation and structural identification of the compo-
nents of racemates. This matter is addressed herein.
300071, People’s Republic of China
7Department of Chemistry, University of South
Florida, 4202 East Fowler Avenue, CHE205,
Tampa, FL 33620, USA
RESULT AND DISCUSSION
CMOM-3S is a variant of [Co
2
(man)
2
(bpy)
3
](NO
3
)
2
] (man = S-mandelate [CMOM-1S]
8These authors contributed equally
9Lead Contact
0
or R-mandelate [CMOM-1R]; bpy = 4,4 -bipyridine), an enantiomeric pair of cationic
coordination networks that provide insight into the binding sites of chiral guests such
*
Correspondence: shiwei@nankai.edu.cn (W.S.),
3
3
as 1-phenyl-1-propanol. That CMOM-1 is inherently modular makes it amenable to
xpyan@nankai.edu.cn (X.Y.), xtal@ul.ie (M.J.Z.)
3
4
crystal engineering. A hydrophobic variant, CMOM-3S, was prepared by layering
http://dx.doi.org/10.1016/j.chempr.2017.07.004
2
Chem 3, 1–9, August 10, 2017

Please cite this article in press as: Zhang et al., A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification, Chem
2017), http://dx.doi.org/10.1016/j.chempr.2017.07.004
(
Figure 2. The CSP-CCS Method Enabled by CMOM-3S
A) The crystal structure of CMOM-3S exhibits 1D channels (C, gray; O, red; N, blue; F, green; S,
yellow; H, white; Co, pink; solvent guest molecules are omitted for clarity).
B) A capillary column is coated by CMOM-3S. Shown are SEM images of the CMOM-3S-coated
(
(
capillary column, the thickness of the CMOM-3S film, and a chromatogram of separated
enantiomers.
(
C) The process used for determining the molecular structure of the analyte: a single crystal of
CMOM-3S is submerged in racemic analyte to facilitate guest inclusion, the crystal is mounted on a
diffractometer, SCXRD data are collected on a conventional diffractometer, and the favorable
binding site and the absolute structure of the analyte are determined.
(
D) CSP and CCS synergistically afford chiral separation and identification.
Co(OTf)
dichlorobenzene (DCB) buffer layered over a 1,2-DCB solution of bpy. CMOM-3S
crystallizes in chiral space group P2 with bnn topology (Table S1). Pore chemistry,
2 2
,6H O and enantiopure (S)-mandelic acid in MeOH above a 1:1 MeOH/1,2-
1
size, and shape are adaptable to a variety of guests (Table S2) thanks to the mande-
ꢀ
late linker and the orientation of the OTf counterion. The maximum pore size of the
1
D channel, ca. 0.8 3 0.8 nm after subtracting van der Waals radii, is controlled
3
5,36
by the length of the bpy linkers (Figure 2A). CMOM-3S, unlike most MOMs,
is
stable to solvent exchange (Figure S1), heat (Figures S2 and S3), and humidity (Fig-
ure S1), prompting us to investigate its utility as a both a CSP (Figure 2B) and a CCS
(
Figure 2C).
CMOM-3S as a CSP
CMOM-3S can be prepared in an efficient one-step method that affords cuboid
nanocrystals dimensions of ꢁ500 nm, as revealed by scanning electron microscopy
(
SEM) (Figure S4). The powder X-ray diffraction (PXRD) pattern of the as-synthesized
nanocrystals matches that calculated and measured for single crystals of CMOM-3S.
CMOM-3S nanocrystals were loaded onto a capillary column through a dynamic
coating process. Figure 2B illustrates an SEM image of the CMOM-3S coating on
Chem 3, 1–9, August 10, 2017
3

Please cite this article in press as: Zhang et al., A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification, Chem
2017), http://dx.doi.org/10.1016/j.chempr.2017.07.004
(
Figure 3. GC Separation of Ten Racemates by a CMOM-3S-Coated Capillary Column (30 m long 3
.32 mm inner diameter)
0
The following analytes were studied: (A) 1-phenylethanol, (B) 1-phenyl-1-propanol, (C) 1-phenyl-2-
propanol, (D) a-vinylbenzyl alcohol, (E) 2-phenylpropanenitrile, (F) 1-phenyl-1-butanol, (G)
1
2
-phenyl-1-pentanol, (H) 1-phenyl-2-butanol, (I) a-cyclopropylbenzyl alcohol, and (J)
-phenylbutyronitrile. Additional peaks in the chromatograms are attributed to impurities in the
as-received samples. Separation conditions are given in Table 1. The absolute configuration of
separated enantiomers is confirmed by single-enantiomer reference injection (black) and/or
analysis by the CCS method (green). See also Figures S5–S7 for the separation performance of
commercial b-DEX 225, Cyclosil B, and Chirasil-L-Val.
the inner wall of the column, which has a thickness of ca. 0.7 mm. The fabricated
CMOM-3S-coated capillary column described above was evaluated for its ability
to separate racemic mixtures of ten chiral alcohols or nitriles. All ten racemates
were separated on the column within 5 min (Figure 3). The chiral separation ability
of three benchmark commercial columns was tested against the same racemates:
b-DEX 225, Cyclosil B, and Chirasil-L-Val (Figures S5–S7). The optimal separation
conditions, separation times of two eluted enantiomers, and resolutions are pro-
vided in Table 1. The enantioselectivity of the CMOM-3S-coated column was found
to be superior to that of Chirasil-L-Val, with which most of the racemates could not be
easily resolved. The resolution values of the racemates were observed to be compa-
rable or better for the CMOM-3S column versus b-DEX 225 and Cyclosil B. Further,
the separation time of the racemates on the CMOM-3S-coated column was shorter
than with b-DEX 225 and Cyclosil B (e.g., 1.7 versus 13 min for 1-phenyl-2-propanol
on b-DEX 225; 4 versus 30 min for 2-phenylpropanenitrile on Cyclosil B). These re-
sults demonstrate that CMOM-3S serves as an effective CSP for GC separation of
a range of enantiomers. In addition, the durability of the CMOM-3S-coated column
was evaluated by studying its performance after 10 months of shelf-life and 1,000
multiple injections. In both instances, there was no loss of performance (Figure S8).
CMOM-3S as a CCS
The supramolecular interactions between the ten analytes and the pores of
CMOM-3S were studied by single-crystal X-ray diffraction (SCXRD) after
exposing crystals of CMOM-3S to each of the ten racemates. Existing CSPs
4
Chem 3, 1–9, August 10, 2017

Please cite this article in press as: Zhang et al., A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification, Chem
2017), http://dx.doi.org/10.1016/j.chempr.2017.07.004
(
Table 1. A Comparison of the Separation Performance of Ten Racemates by a CMOM-3S-Coated Column versus Commercial b-DEX 225, Cyclosil B,
and Chirasil L-Val Columns
CMOM-3S
b-DEX 225
Cyclosil B
Chirasil L-Val
a
b
c
d
a
b
c
d
a
b
c
d
a
b
c
d
Analyte
T
P
t
R
T
P
t
R
T
P
t
R
T
P
t
R
A
B
C
D
E
F
G
H
I
130
150
150
140
150
135
150
130
150
150
150
150
150
150
150
100
100
150
150
150
2.1
1.7
1.7
2.1
2.4
4.0
3.0
5.0
3.5
2.5
1.54
1.53
1.52
1.47
1.45
1.51
1.42
1.52
1.57
1.42
130
120
110
120
115
110
150
150
130
120
150
150
150
150
150
150
150
150
150
150
5.5
9.7
1.56
1.55
1.76
1.92
1.53
1.61
130
150
130
140
150
110
150
130
150
150
150
150
150
150
150
150
100
150
150
150
6.5
1.56
80
100
125
150
150
150
150
150
150
150
150
9.0
1.19
1.10
e
4.6
7.2
7.5
4.2
–
100
150
100
150
135
100
80
6.0
1.7
5.0
1.5
4.5
e
13.0
11.0
13.5
20.0
8.0
1.55
1.26
2.28
1.31
1.75
1.51
–
0.56
e
–
e
30.0
13.5
11.0
9.0
–
e
–
12.0
12.0
12.0
2.0
0.87
1.08
0.35
e
6.0
–
e
15.5
14.7
1.73
0.45
–
100
150
e
J
5.4
2.22
–
a
ꢂ
Separation temperature ( C).
b
2
N pressure (kPa).
c
Total separation time (min).
d
Resolution.
e
Could not be separated. All the separations were performed with optimized conditions.
2
(
e.g., polysaccharides and cyclodextrins) are not amenable to diffraction studies so
the precise nature of preferred binding sites in a CSP has not yet been directly
observed. That CMOM-3S has an extra-framework cation enables its cavities to
adapt to the guest. When coupled with its low-symmetry space group, this adapt-
ability allowed us to directly observe the binding sites of CMOM-3S in high resolu-
tion by using a conventional X-ray diffractometer. The absolute configurations of the
preferred chiral guest molecules were unambiguously determined and validated for
all ten racemates thanks to the anomalous scattering effects of heavy atoms (Co and
S). The absolute configuration of the chiral analytes corresponds with the longest
retention time, as confirmed by an enantiopure reference standard (Figure 2). The
binding preference between CSP and CCS can also be determined without a refer-
ence standard. Crystals of CMOM-3S were submerged in racemates as described for
the CCS studies, and enantiomer-enriched CMOM-3S crystals were harvested and
analyzed with the CMOM-3S column. Figure S9 reveals that the slowest eluent
exhibited the higher enantiomeric excess (ee) ratio for all ten racemates. Figure 4 re-
veals the tight nature of the binding sites for two of the analytes: (R, S)-1-phenyl-1-
propanol ((R, S)-1P1P) and (R, S)-1-phenyl-2-propanol ((R, S)-1P2P). The analytes are
located in the channel of CMOM-3S in a similar fashion except for one disordered
3
molecule of 1P2P (Figure 4I), in which the phenyl group and terminal –CH moiety
of the analyte interacts with the host framework through p/p and C–H/p interac-
tions. Triflate counterions are involved in the formation of C–H/F and O–H/O
hydrogen bonding interactions with the analytes, which is presumably a key factor
3
7,38
in the observed enantioselectivity. Hirshfeld surface analysis
of each analyte in-
dicates that the analytes are tightly encapsulated in the chiral channel. A plethora of
weak but directional intermolecular forces are therefore responsible for the enantio-
selectivity toward (S)-1P1P and (R)-1P2P.
CMOM-3S can serve as a CCS for natural products and biologically active molecules
with minute quality. Geraniol and nerol are monoterpenoid isomers present in oils
that are used in biosynthesis and as flavors. We exposed a single crystal of
CMOM-3S to 20 mL of dichloromethane (DCM) solutions (0.1%, v/v) containing
Chem 3, 1–9, August 10, 2017
5

Please cite this article in press as: Zhang et al., A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification, Chem
2017), http://dx.doi.org/10.1016/j.chempr.2017.07.004
(
Figure 4. Chiral Binding Sites in CMOM-3S as Determined by SCXRD
The binding sites for 1-phenyl-1-propanol (1P1P, A–D in the blue box) and 1-phenyl-2-propanol
(
1P2P, E–J in the green box) are sustained by a plethora of intermolecular interactions. Shown are
interactions of position-disordered 1P1P molecules (colored magenta and green; A and C) and
P2P molecules (colored magenta, green, and orange; E, G, and I) in the cavity of CMOM-3S, as well
as absolute configuration and corresponding Hirshfeld surface of 1P1P molecules (B and D) and
P2P molecules (F, H, and J).
1
1
1
7 mg of geraniol or nerol in a 0.3 mL microvial. The screw cap was loosened to
enable slow evaporation of CH Cl over 2 days. The molecular structures of geraniol
2
2
and nerol were determined by SCXRD with a conventional X-ray diffractometer as
revealed in Figure S10.
The CSP-CCS Method
Whereas CCSs are established for structure identification and MOMs that serve as
CSPs are known, the type of synergy between CSPs and CCSs observed here has
not been reported previously. CMOM-3S is therefore the first porous material that
enables the CSP-CCS method (Figure 2). We attribute its performance to a
combination of distinct properties and structural features: (1) CMOM-3S exhibits
homochirality with exceptional thermal and hydrolytic stability, which enables fabri-
cation of a robust chiral GC column; (2) the nature of the multiple and directional
intermolecular interactions in CMOM-3S creates enzymatic-like binding sites for
the accommodation of a range of chiral and achiral guest molecules. The tight ste-
reospecific binding sites are the driving force for chiral recognition and separation;
(
3) the highly crystalline nature and low-symmetry space group of CMOM-3S enables
determination of the absolute configuration of chiral guest molecules and assign-
ment of chirality in the CSP experiments without the need for a reference standard.
To conclude, CMOM-3S is to our knowledge the first porous material that can serve
as both a CCS and a CSP. A new reference standard-free method for chiral identifi-
cation of trace analytes, the CSP-CCS method, is thereby enabled. CMOM-3S dem-
onstrates how CMOMs can address chiral separation challenges that were hitherto
6
Chem 3, 1–9, August 10, 2017

Please cite this article in press as: Zhang et al., A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification, Chem
2017), http://dx.doi.org/10.1016/j.chempr.2017.07.004
(
difficult or intractable. We envisage that the CSP-CCS method could be applied to
natural product separation, asymmetric synthesis, and drug discovery in future
developments.
EXPERIMENTAL PROCEDURES
Synthesis of CMOM-3S Single Crystals
The compound CMOM-3S was synthesized by
that reported recently. Specifically, a 5 mL methanol solution of 0.4 mmol
Co(CF SO ,6H O (180 mg) and 0.4 mmol enantiopure (S)-mandelic acid
60.8 mg) was layered above a 5 mL 1,2-DCB solution of 0.3 mmol bpy (46.8 mg).
a procedure analogous to
3
3
)
2
2
(
The buffer solution of 5 mL 1:1 methanol/DCB was layered between the top and
the bottom layers to allow slow diffusion for 7 days. Red rectangular prismatic crys-
tals were obtained in ꢁ60% yield. The as-synthesized crystals were exchanged with
DCM daily for 5 days to remove DCB. The resultant crystalline samples were stored
in neat DCM for all further experiments.
Synthesis of CMOM-3S Nanocrystals
The nanocrystals of CMOM-3S were obtained by the slurry method. Typically,
0
.8 mmol Co(CF
acid (121.6 mg) were stirred in 5 mL of methanol. A solution of 0.6 mmol bpy
93.6 mg) in 5 mL of DCB was added to that solution for 1 day with continuous stir-
3 3 2 2
SO ) ,6H O (360 mg) and 0.8 mmol enantiopure (S)-mandelic
(
ring. The pink nanocrystalline powder was filtrated from the mother solution and
washed with DCM (20 mL) ten times. The resultant material was stored in neat
DCM for all further experiments.
Fabrication of the CMOM-3S-Coated Capillary Column
A fused silica capillary (30 m long 3 0.32 mm inner diameter; Yongnian Optic Fiber
Plant, Hebei, China) was pretreated according to the following recipe before dy-
namic coating: the capillary was washed with 1 M NaOH for 2 hr, ultrapure water
for 30 min, 0.1 M HCl for 2 hr, and ultrapure water until the outflow reached pH 7.0.
ꢂ
The capillary was then dried with N
2
at 100 C overnight. CMOM-3S was coated onto
the pretreated capillary column via a dynamic coating method. A 3 mL DCM suspen-
sion of CMOM-3S (1 mg/mL) was first filled into the capillary column under gas pres-
sure, and then pushed through the column at a constant N
2
pressure of 20 kPa to
leave a wet coating layer on the inner wall of the capillary column. After coating,
the capillary column was settled for 2 hr for conditioning under N
2
. Further condi-
ꢂ
tioning of the capillary column was carried out with a temperature program: 30 C
ꢂ
ꢂ
ꢂ
ꢀ1
ꢂ
for 10 min, ramp from 30 C to 150 C at a rate of 3 C min , and 150 C for 2 hr.
Inclusion of Racemates and Other Guest Molecules in Single Crystals of
CMOM-3S
Multiple single crystals of CMOM-3S were submerged in 0.5 mL of neat racemates
and other guest molecules at ambient temperature for 5 days. This is the regulated
2
9
optimal condition according to previous reports for the following reason. By
placing multiple crystals in parallel, the probability of selecting a high-quality crystal
for SCXRD examination increases. Neat racemates and other guest molecules are
used for inclusion of sufficient quantity of guest within the crystal. The equilibrium
of preferred enantiomers is reached in guest binding sites after 5 days.
Microgram Scale Inclusion of Geraniol and Nerol
A 20 mL DCM solution of 17 mg of geraniol or nerol was added to a 0.3 mL Qsert low
adsorption vial. A single crystal of CMOM-3S was placed at the bottom of the vial
Chem 3, 1–9, August 10, 2017
7

Please cite this article in press as: Zhang et al., A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification, Chem
2017), http://dx.doi.org/10.1016/j.chempr.2017.07.004
(
and submerged in the solvent. Then the vial was loosely capped to allow DCM evapo-
ration over 2 days. The crystal was coated in immersion oil for transfer and mounting.
Stability Test
ꢂ
The crystalline sample of desolvated CMOM-3S was exposed to 40 C and 75%
relative humidity for 7 days in a desiccator. The condition was achieved with a super-
ꢂ
saturated aqueous solution of NaCl maintained at 40 C. After 7 days, the samples
were removed from the desiccator and characterized by PXRD.
ACCESSION NUMBERS
Crystallographic data for this paper have been deposited at the Cambridge
Crystallographic Data Centre under accession numbers CCDC: 1495053–
1
495064. These data can be obtained free of charge from http://www.ccdc.cam.
ac.uk/data_request/cif.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures,
1
0 figures, 2 tables, and 12 crystallographic data files and can be found with this
article online at http://dx.doi.org/10.1016/j.chempr.2017.07.004.
AUTHOR CONTRIBUTIONS
S.Y.Z. and M.J.Z. conceived and designed the project. S.Y.Z. conducted all synthetic
experiments. S.Y.Z. collected and analyzed experimental data including SCXRD
data, PXRD data, SEM images, and stability tests. C.X.Y. performed the preparation
of the GC column and separation of racemates. C.X.Y., X.P.Y., and S.Y.Z. analyzed
the GC data. L.W. revised the SCXRD data. S.Y.Z., W.S., P.C., and M.J.Z. interpreted
GC and SCXRD data. S.Y.Z. and M.J.Z. wrote the paper, and all authors contributed
to revising the paper.
ACKNOWLEDGMENTS
This publication is supported by Science Foundation Ireland (award 13/RP/B2549).
W.S. and P.C. acknowledge the National Natural Science Foundation of China
(
21622105 and 21331003) and the Ministry of Education of China (B12015 and
IRT-13R30). C.X.Y. and X.P.Y. acknowledge the National Basic Research Program
of China (2015CB932001) and the National Natural Science Foundation of China
(
21435001 and 21305071).
Received: March 24, 2017
Revised: June 20, 2017
Accepted: July 6, 2017
Published: July 27, 2017
REFERENCES AND NOTES
1
. Flack, H. (2009). Louis Pasteur’s discovery of
molecular chirality and spontaneous resolution
in 1848, together with a complete review of his
crystallographic and chemical work. Acta
Crystallogr. A 65, 371–389.
4. MacGillivray, L.R. (2010). Metal-Organic
Frameworks: Design and Application (John
Wiley).
nanogram to microgram scale using porous
complexes. Nature 495, 461–466.
7. Stalcup, A.M. (2010). Chiral separations. Annu.
Rev. Anal. Chem. 3, 341–363.
5. Batten, S.R., Neville, S.M., and Turner, D.R.
(
2009). Coordination Polymers: Design,
8
. Okamoto, Y., and Yashima, E. (1998).
Polysaccharide derivatives for
chromatographic separation of enantiomers.
Angew. Chem. Int. Ed. 37, 1020–1043.
2. Subramanian, G. (2008). Chiral Separation
Techniques: A Practical Approach (John Wiley).
Analysis and Application (Royal Society of
Chemistry).
3
. Kitagawa, S., Kitaura, R., and Noro, S. (2004).
Functional porous coordination polymers.
Angew. Chem. Int. Ed. 43, 2334–2375.
6. Inokuma, Y., Yoshioka, S., Ariyoshi, J., Arai, T.,
Hitora, Y., Takada, K., Matsunaga, S., Rissanen,
K., and Fujita, M. (2013). X-ray analysis on the
9
. Bicchi, C., D’Amato, A., and Rubiolo, P. (1999).
Cyclodextrin derivatives as chiral selectors for
8
Chem 3, 1–9, August 10, 2017

Please cite this article in press as: Zhang et al., A Chiral Metal-Organic Material that Enables Enantiomeric Identification and Purification, Chem
2017), http://dx.doi.org/10.1016/j.chempr.2017.07.004
(
direct gas chromatographic separation of
enantiomers in the essential oil, aroma and
flavour fields. J. Chromatogr. A 843, 99–121.
(2009). Porous organic cages. Nat. Mater. 8,
973–978.
29. Ramadhar, T.R., Zheng, S.-L., Chen, Y.-S., and
Clardy, J. (2015). Analysis of rapidly synthesized
guest-filled porous complexes with
1
9. Chen, L., Reiss, P.S., Chong, S.Y., Holden, D.,
Jelfs, K.E., Hasell, T., Little, M.A., Kewley, A.,
Briggs, M.E., Stephenson, A., et al. (2014).
Separation of rare gases and chiral molecules
by selective binding in porous organic cages.
Nat. Mater. 13, 954–960.
synchrotron radiation: practical guidelines for
the crystalline sponge method. Acta
Crystallogr. A 71, 46–58.
1
1
1
0. Seo, J.S., Whang, D., Lee, H., Jun, S.I., Oh, J.,
Jeon, Y.J., and Kim, K. (2000). A homochiral
metal-organic porous material for
enantioselective separation and catalysis.
Nature 404, 982–986.
3
0. Vinogradova, E.V., M u¨ ller, P., and Buchwald,
S.L. (2014). Structural reevaluation of the
electrophilic hypervalent iodine reagent for
trifluoromethylthiolation supported by the
crystalline sponge method for X-ray analysis.
Angew. Chem. Int. Ed. 53, 3125–3128.
1. Liu, Y., Xuan, W., and Cui, Y. (2010).
Engineering homochiral metal-organic
frameworks for heterogeneous asymmetric
catalysis and enantioselective separation. Adv.
Mater. 22, 4112–4135.
20. Huang, N., Wang, P., and Jiang, D. (2016).
Covalent organic frameworks: a materials
platform for structural and functional designs.
Nat. Rev. Mater. 1, 16068.
2
1. Qian, H.-L., Yang, C.-X., and Yan, X.-P. (2016).
Bottom-up synthesis of chiral covalent organic
frameworks and their bound capillaries for
chiral separation. Nat. Commun. 7, 12104.
31. Lee, S., Kapustin, E.A., and Yaghi, O.M. (2016).
Coordinative alignment of molecules in chiral
metal-organic frameworks. Science 353,
808–811.
2. Dybtsev, D.N., Nuzhdin, A.L., Chun, H.,
Bryliakov, K.P., Talsi, E.P., Fedin, V.P., and Kim,
K. (2006). A homochiral metal–organic material
with permanent porosity, enantioselective
sorption properties, and catalytic activity.
Angew. Chem. Int. Ed. 45, 916–920.
2
2. Peluso, P., Mamane, V., and Cossu, S. (2014).
Homochiral metal–organic frameworks and
their application in chromatography
32. Yoon, M., Srirambalaji, R., and Kim, K. (2012).
Homochiral metal–organic frameworks for
asymmetric heterogeneous catalysis. Chem.
Rev. 112, 1196–1231.
enantioseparations. J. Chromatogr. A 1363,
1
3. Vaidhyanathan, R., Bradshaw, D., Rebilly, J.-N.,
Barrio, J.P., Gould, J.A., Berry, N.G., and
Rosseinsky, M.J. (2006). A family of nanoporous
materials based on an amino acid backbone.
Angew. Chem. Int. Ed. 45, 6495–6499.
11–26.
33. Zhang, S.-Y., Wojtas, L., and Zaworotko, M.J.
(2015). Structural insight into guest binding
sites in a porous homochiral metal–organic
material. J. Am. Chem. Soc. 137, 12045–12049.
2
2
2
3. Duerinck, T., and Denayer, J.F.M. (2015). Metal-
organic frameworks as stationary phases for
chiral chromatographic and membrane
separations. Chem. Ing. Sci. 124, 179–187.
1
1
4. Morris, R.E., and Bu, X. (2010). Induction of
chiral porous solids containing only achiral
building blocks. Nat. Chem. 2, 353–361.
34. Moulton, B., and Zaworotko, M.J. (2001). From
molecules to crystal engineering:
4. Kewley, A., Stephenson, A., Chen, L., Briggs,
M.E., Hasell, T., and Cooper, A.I. (2015). Porous
organic cages for gas chromatography
supramolecular isomerism and polymorphism
in network solids. Chem. Rev. 101, 1629–1658.
5. Li, G., Yu, W., and Cui, Y. (2008). A homochiral
nanotubular crystalline framework of
metallomacrocycles for enantioselective
recognition and separation. J. Am. Chem. Soc.
separations. Chem. Mater. 27, 3207–3210.
5. Zhang, J.-H., Xie, S.-M., Chen, L., Wang, B.-J.,
He, P.-G., and Yuan, L.-M. (2015). Homochiral
porous organic cage with high selectivity for
the separation of racemates in gas
35. Burtch, N.C., Jasuja, H., and Walton, K.S.
(2014). Water stability and adsorption in metal–
organic frameworks. Chem. Rev. 114, 10575–
10612.
130, 4582–4583.
1
6. Xiang, S.-C., Zhang, Z., Zhao, C.-G., Hong, K.,
Zhao, X., Ding, D.-R., Xie, M.-H., Wu, C.-D.,
Das, M.C., Gill, R., et al. (2011). Rationally tuned
micropores within enantiopure metal-organic
frameworks for highly selective separation of
acetylene and ethylene. Nat. Commun. 2, 204.
chromatography. Anal. Chem. 87, 7817–7824.
3
6. Kumar, A., Madden, D.G., Lusi, M., Chen, K.J.,
Daniels, E.A., Curtin, T., Perry, J.J., 4th, and
Zaworotko, M.J. (2015). Direct air capture of
CO2 by physisorbent materials. Angew. Chem.
Int. Ed. 54, 14372–14377.
26. Wang, W., Dong, X., Nan, J., Jin, W., Hu, Z.,
Chen, Y., and Jiang, J. (2012). A homochiral
metal-organic framework membrane for
enantioselective separation. Chem. Commun.
48, 7022–7024.
1
1
7. Zhang, S.-Y., Li, D., Guo, D., Zhang, H., Shi, W.,
Cheng, P., Wojtas, L., and Zaworotko, M.J.
3
7. McKinnon, J.J., Jayatilaka, D., and Spackman,
M.A. (2007). Towards quantitative analysis of
intermolecular interactions with Hirshfeld
surfaces. Chem. Commun. 3814–3816.
27. Huang, K., Dong, X., Ren, R., and Jin, W. (2013).
Fabrication of homochiral metal-organic
framework membrane for enantioseparation of
racemic diols. AIChE 59, 4364–4372.
(2015). Synthesis of a chiral crystal form of
MOF-5, CMOF-5, by chiral induction. J. Am.
Chem. Soc. 137, 15406–15409.
8. Tozawa, T., Jones, J.T.A., Swamy, S.I., Jiang, S.,
Adams, D.J., Shakespeare, S., Clowes, R.,
Bradshaw, D., Hasell, T., Chong, S.Y., et al.
28. Hoshino, M., Khutia, A., Xing, H., Inokuma, Y.,
and Fujita, M. (2016). The crystalline sponge
method updated. IUCrJ 3, 139–151.
38. Rissanen, K. (2017). Crystallography of
encapsulated molecules. Chem. Soc. Rev. 46,
2638–2648.
Chem 3, 1–9, August 10, 2017
9