Application of homochiral alkylated organic cages as chiral stationary phases for molecular separations by capillary gas chromatography

Article abstract of DOI:10.3390/molecules21111466

Molecular organic cage compounds have attracted considerable attention due to their potential applications in gas storage, catalysis, chemical sensing, molecular separations, etc. In this study, a homochiral pentyl cage compound was synthesized from a condensation reaction of (S,S)-1,2-pentyl-1,2-diaminoethane and 1,3,5-triformylbenzene. The imine-linked pentyl cage diluted with a polysiloxane (OV-1701) was explored as a novel stationary phase for high-resolution gas chromatographic separation of organic compounds. Some positional isomers were baseline separated on the pentyl cage-coated capillary column. In particular, various types of enantiomers including chiral alcohols, esters, ethers and epoxides can be resolved without derivatization on the pentyl cage-coated capillary column. The reproducibility of the pentyl cage-coated capillary column for separation was investigated using nitrochlorobenzene and styrene oxide as analytes. The results indicate that the column has good stability and separation reproducibility after being repeatedly used. This work demonstrates that molecular organic cage compounds could become a novel class of chiral separation media in the near future.

Full text of DOI:10.3390/molecules21111466

molecules
Article
Application of Homochiral Alkylated Organic Cages
as Chiral Stationary Phases for Molecular Separations
by Capillary Gas Chromatography
Shengming Xie, Junhui Zhang, Nan Fu, Bangjin Wang, Cong Hu and Liming Yuan *
Department of Chemistry, Yunnan Normal University, Kunming 650500, China;
xieshengming_2006@163.com (S.X.); zjh19861202@126.com (J.Z.); funan123@163.com (N.F.);
wangbangjin711@163.com (B.W.); hucong657312@163.com (C.H.)
* Correspondence: yuan_limingpd@126.com or yuan_liming@hotmail.com; Tel./Fax: +86-871-6594-1088
Academic Editor: Yoshio Okamoto
Received: 16 September 2016; Accepted: 28 October 2016; Published: 8 November 2016
Abstract: Molecular organic cage compounds have attracted considerable attention due to their
potential applications in gas storage, catalysis, chemical sensing, molecular separations, etc. In this
study, a homochiral pentyl cage compound was synthesized from a condensation reaction of
(S,S)-1,2-pentyl-1,2-diaminoethane and 1,3,5-triformylbenzene. The imine-linked pentyl cage diluted
with a polysiloxane (OV-1701) was explored as a novel stationary phase for high-resolution gas
chromatographic separation of organic compounds. Some positional isomers were baseline separated
on the pentyl cage-coated capillary column. In particular, various types of enantiomers including
chiral alcohols, esters, ethers and epoxides can be resolved without derivatization on the pentyl
cage-coated capillary column. The reproducibility of the pentyl cage-coated capillary column for
separation was investigated using nitrochlorobenzene and styrene oxide as analytes. The results
indicate that the column has good stability and separation reproducibility after being repeatedly
used. This work demonstrates that molecular organic cage compounds could become a novel class of
chiral separation media in the near future.
Keywords: porous organic cage; capillary column; chiral stationary phase; chiral separation; gas
chromatography
1. Introduction
The separation of chiral compounds is one of the most interesting and challenging tasks
in the field of separation science [1], because enantiomers show identical chemical and physical
properties in an achiral environment. Chromatographic techniques such as high performance liquid
chromatography (HPLC), gas chromatography (GC), supercritical fluid chromatography (SFC),
thin layer chromatography (TLC), and capillary electrochromatography (CEC) are still the most
convenient and cost-effective approaches to obtain optically pure compounds [
HPLC and capillary GC are the most reliable and commonly employed analytical techniques for
the separation of enantiomers [ ]. Compared to other chromatographic techniques, capillary GC
2]. Among them,
3,4
possesses the advantages of high-resolution, high-efficiency, sensitivity, fast analysis and absence of
liquid mobile phases. Therefore, it is very necessary to continue developing novel chiral materials as
stationary phases with high resolution and excellent enantioselectivity capable of separating a wide
variety of chiral compounds in GC.
In recent years, porous materials containing some unusual properties such as diverse compositions
and structures, high surface areas, ordered porosity, good chemical stability, tunable pore size and so on,
have attracted significant attention in many areas, including gas adsorption and storage, catalysis,
Molecules 2016, 21, 1466; doi:10.3390/molecules21111466
www.mdpi.com/journal/molecules

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separation, etc. In general, porous materials can be designed and synthesized by using two main
synthetic strategies: extended networks and discrete organic cage molecules. To date, there are various
kinds of chiral porous network materials, such as metal-organic frameworks (MOFs) [
5–14], porous
organic frameworks (POFs) [15 16] and inorganic mesoporous materials [17 18], which have been
,
,
used as chiral chromatographic stationary phases for separation of enantiomers. Unlike network
materials, porous organic cages (POCs) are composed of discrete molecules with intermolecular
forces rather than covalent or coordination bonds [19]. In past few years, many shape-persistent
POCs have been designed and explored for various areas (e.g., gas adsorption, molecular separation,
heterogeneous catalysis, and sensing) by several research groups [20–24]. In 2008, an imine-linked
[4+6] tetrahedral cage has been synthesized through imine condensation of 1,3,5-triformylbenzene
and (R,R)-1,2-cyclohexanediamine by Gawronski et al. [25], but the crystal structure of the tetrahedral
cage was not studied. Subsequently, Cooper and co-workers reported a series of new POCs obtained
through the condensation of 1,3,5-triformylbenzene or tris(4-formylphenyl)amine with various
diamines [26
permanent porosity through weak intermolecular forces and separate rare gases and some organic
molecules [30 31]. An important advantage of POCs is their good solubility in common organic
–29]. Surprisingly, these cage molecules can self-assemble into crystalline materials with
,
solvents, which makes them suitable for use as separation media in capillary GC. In February 2015, our
group first proved useful commercially of a homochiral POC in GC enantioseparations and applied
China’s patent [32]. Subsequently, the application of POCs in GC chiral separation has been further
developed. Recently, several homochiral POCs (e.g., CC3-R [33,34], CC9 [35] and CC10 [36]) useful
as capillary GC stationary phases for enantioselective separation of enantiomers have been reported
by the Cooper group and our group. These POCs-based stationary phases exhibited excellent chiral
recognition ability toward a wide range of chiral compounds.
Cooper and co-workers reported the syntheses of homochiral alkylated organic cages functionalised
with twelve n-hexyl, n-pentyl, isohexyl or n-octyl tails by a one-step [6+4] condensation of the
corresponding (S,S)-1,2-functionalised-1,2-diamines with 1,3,5-triformylbenzene in chloroform for 72 h
at 60 or 65 ◦C using trifluoroacetic acid as the catalyst [37]. Herein we report the use of a homochiral
pentyl cage diluted with polysiloxane (OV-1701) as chiral stationary phase for high-resolution capillary
GC separation. The pentyl cage-coated capillary column exhibits good selectivity and chiral recognition
ability towards a wide variety of racemates belonging to different classes such as chiral alcohols, esters,
ethers and epoxides, especially for chiral alcohols. Besides, the pentyl cage-based capillary column
also offers good performance for the separation of positional isomers.
2. Results and Discussion
2.1. Characterization of the Synthesized Pentyl Cage and the Pentyl Cage-Coated Capillary Column
NMR data analysis (Figures S1 and S2, Supplementary Materials) demonstrates that the pentyl
cage was successfully synthesized. The corresponding TGA curve reveals that the pentyl cage is at
least stable up to 290 ◦C, indicating its suitability for use in GC (Figure 1a). The inner surface of the
pentyl cage-coated capillary column was characterized by SEM. Figure 1b shows the SEM image of the
inner wall on the fabricated column. As can be seen from SEM image, a thin and uniform coating with
about 260 nm thickness was formed on the inner wall of the capillary column.
Column efficiency of the pentyl cage-coated capillary column was measured by using n-dodecane
as analyte at 120 ◦C. The number of theoretical plates of the capillary column was 3510 plates
further indicating the good coating performance of the pentyl cage.
·
m−1
,
McReynolds constants are used to evaluate the polarity of a stationary phase. The polarity
of pentyl cage-coated capillary column was determined using benzene, 1-butanol, 2-pentanone,
1-nitropropane, and pyridine as probe compounds (Table 1). The McReynolds constants of the
five selected analytes represent various stationary phase characteristics (e.g., dispersion forces,
hydrogen-bonding ability, electron donor and acceptor ability, dipolar and acidic character, etc.)
interacting with the analytes. Squalane was used as a standard nonpolar stationary phase, and the
McReynolds constants of pentyl cage-coated capillary column were compared to those of squalane.

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The average of the five McReynolds constants is 130.6, revealing a moderate polarity of the pentyl
cage-coated capillary column.
Figure 1.
(a) TGA of pentyl cage; (b) SEM image of the thickness of stationary phase coating in part of
the pentyl cage-coated capillary column.
◦
Table 1. McReynolds constants of the pentyl cage-coated capillary column at 120 C.
0
0
0
0
0
S
X
Y
Z
U
Av.
37
185 102
203 126 130.6
X0, Y0, Z0, U0 and S0 refer to benzene, 1-butanol, 2-pentanone, 1-nitropropane, and pyridine, respectively.
2.2. Separation of Positional Isomers on the Pentyl Cage-Coated Capillary Column
High-resolution separation of positional isomers is of significant importance in the chemical
industry and environmental analysis [38]. However, it is a challenging task to separate some positional
isomers owing to their similar physical and chemical properties. So far, capillary GC is one of the
most efficient methods for the separation of various positional isomers. To investigate the separation
properties of the pentyl cage-coated capillary column, some positional isomers were selected as test
solutes. The pentyl cage-coated capillary column offered good separation of some isomer mixtures,
including dichlorobenzene, dibromobenzene, nitrochlorobenzene, and nitrobromobenzene. Molecular

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structures of these isomers are shown in Figure S3 (Supplementary Materials). The chromatograms and
results of separation of isomer mixtures on pentyl cage-coated capillary column are shown in Figure 2
and Table 2, respectively. As can be seen from Figure 2, baseline separation of all isomers were achieved
on the pentyl cage-coated capillary column. Interestingly, the elution sequence of all isomers followed
an increasing order of para-isomer < ortho-isomer < meta-isomer, rather than the order of their boiling
point◦s (e.g., meta-dibromobenzene (218 ◦C) < para-dibromobenzene (219 ◦C) < ortho-dibromobenzene
(225 C)). All the meta-isomers eluted much later than the ortho- and para-isomers on the pentyl
cage-coated capillary column, indicating higher selectivity and stronger retention behavior toward
meta-isomers than the ortho- and para-isomers. This experimental result is in agreement with previously
reported data for POCs-based chiral stationary phases such as CC3-R, CC9 and CC10 when used
for GC separation of positional isomers [34–36]. The main reason for this can probably be attributed
to the meta-substituted aryl face geometry of the building unit (1,3,5-triformylbenzene) which was
employed for the synthesis of the pentyl cage and the abovementioned POCs (CC3-R, CC9 and CC10).
In other words, the molecular geometry of meta-substituted isomers will better match with pentyl cage
molecules, resulting in longer retention times for meta-isomers than those of ortho- and para-isomers on
the pentyl cage-coated capillary column.
Figure 2. GC chromatograms using the pentyl cage-coated capillary column for separation of positional
−1 ◦
isomers: (
a
) o-, m-, and p-dibromobenzene under a N2 flow rate of 13.8 cm
·
s
at 90 C; (b) o-, m-, and
−1
◦
p-dibromobenzene under a N2 flow rate of 13.8 cm·s at 110 C; (c) o-, m-, and p-nitrochlorobenzene
under a N2 flow−r1ate of 14.9 cm
·
s−1 at 115 ◦C; (
d) o-, m-, and p-nitrobromobenzene under a N2 flow
◦
rate of 14.9 cm·s at 120 C.
Table 2. Separation factor (α) and resolution (Rs) for separation of positional isomers on the pentyl
cage-coated capillary column.
Separation Factor (α)
Resolution (Rs)
◦
T ( C)
Isomers
α
1
α
2
Rs1
Rs2
Dichlorobenzene
Dibromobenzene
Nitrochlorobenzene 115
Nitrobromobenzene 120
90
110
1.24
1.23
1.14
1.08
1.10
1.12
1.67
1.60
2.51
2.83
2.91
1.99
1.51
1.57
9.59
10.30

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2.3. Separation of Enantiomers on the Pentyl Cage-Coated Capillary Column
As a new class of chiral materials, homochiral POCs have been attracting attention because of
their potential applications in enantioselective separation [33 36]. To investigate the chiral resolution
–
ability of the pentyl cage, a great deal of enantiomers were analyzed without derivatization on the
pentyl cage-coated capillary column. We found that this column exhibited good chiral separation
performance toward various types of enantiomers, including alcohols, esters, ethers and epoxides,
especially for chiral alcohols. Figure S4 (Supplementary Materials) shows the molecular structures
of the enantiomers. The retention factor (k1) for the first eluted enantiomers, separation factor (α)
and resolution (Rs) are listed in Table 3. The resolution chromatograms of enantiomers are given in
Figure 3. The chromatograms show baseline or at least 80% valley separation for all enantiomers
except for 2-phenyl-1-propanol, 1-(2-naphthyl)ethanol, ethyl 3-hydroxybutyrate and γ-valerolactone.
Notably, a high-resolution gas chromatographic enantioseparation of trans-stilbene oxide (Rs = 4.94)
was achieved on the pentyl cage-coated capillary column.
Figure 3. GC chromatograms on the pentyl cage-coated capillary column for separation of racemates:
(
a
) styrene oxide; (
epoxypropane; ( ) n-butyl glycidyl ether; (
) 3-butyn-2-ol; ( ) 1-phenylethanol; ( ) 1-phenyl-1-propanol; (
) 1-(2-naphthyl)ethanol; (
b
) trans-stilbene oxide; (
c
) 1,2-epoxybutane; (
) 1-methoxy-2-hydroxypropane; (
) 4-chlorophenethylalcohol; (
) methyl 3-hydroxybutyrate, (q
d
) 1,2-epoxyhexane; (
) 1-methoxy-2-butanol;
) 2-phenyl-
) ethyl
e) 1-bromo-2,3-
f
j
g
h
(i
k
o
l
m
1-propanol; (
n
) 1-naphthylethanol; (
p
3-hydroxybutyrate; (r) γ-valerolactone. The separation conditions are shown in Table 3.

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Table 3. Separation of racemates on the pentyl cage-coated capillary column.
◦
−1
v [a] (cm·s
)
Racemates
T ( C)
k1
α
Rs
Styrene oxide
trans-Stilbene oxide
1,2-Epoxybutane
110
178
50
110
85
95
78
82
67
120
125
135
130
175
175
90
3.24
5.76
3.15
3.28
4.24
1.63
2.01
3.30
3.01
5.06
4.95
5.89
5.77
6.57
6.50
3.6
1.07
1.15
1.10
1.07
1.03
1.05
1.09
1.14
1.11
1.06
1.09
1.03
1.03
1.08
1.03
1.09
1.06
1.03
1.59
4.94
0.86
1.69
0.94
0.84
1.01
1.57
1.30
1.56
1.69
1.18
0.57
2.20
0.58
1.01
0.71
0.15
10.8
11.9
11.0
10.7
10.8
12.5
12.0
12.3
11.9
11.8
13.6
12.3
13.0
10.2
11.4
11.2
10.3
12.4
1,2-Epoxyhexane
1-Bromo-2,3-epoxypropane
n-Butyl glycidyl ether
1-Methoxy-2-hydroxypropane
1-Methoxy-2-butanol
3-Butyn-2-ol
1-Phenylethanol
1-Phenyl-1-propanol
1-(4-Chlorophenyl)ethanol
2-Phenyl-1-propanol
1-Naphthylethanol
1-(2-Naphthyl)ethanol
Methyl 3-hydroxybutyrate
Ethyl 3-hydroxybutyrate
γ-Valerolactone
100
115
3.42
3.04
[a]
v is the linear velocity of the N2 carrier gas.
The pentyl cage has a tetrahedral cage structure with twelve n-pentyl tails formed by
imine condensation between four 1,3,5-triformylbenzene molecules and six (S,S)-1,2-pentyl-1,2-
diamino-ethanes (Figure S5, Supplementary Materials). It is very difficult to completely understand the
chiral recognition mechanisms for enantioseparation on a chiral stationary phase because the influence
of the chiral microenvironment on the chiral properties of chromatographic systems is complicated [39].
Many different classes of enantiomers can be separated on the pentyl cage-coated capillary column.
There is no doubt that only one retention mechanism cannot explain all these chiral chromatographic
resolution results. Therefore, chiral recognition may depend on multimodal enantioselective retention
mechanisms existing in the pentyl cage, which may involve chiral steric fits, van der Waals forces,
hydrogen-bondings, dispersion forces, dipole-dipole interactions and π-π interactions, etc. For instance,
the pentyl cage-coated capillary column offered good resolution for chiral alcohols, suggesting chiral
discrimination mainly ascribable to a specific interaction between the hydroxyl group of chiral
alcohols and the nitrogen atom in the imine of pentyl cage, and other interactions also affect the
chiral recognition. In addition, other enantiomers such as esters, ethers and epoxides, which either
contain no hydrogen bonding groups or contain only hydrogen bonding acceptor groups and/or have
permanent dipole moments, were also resolved [34]. Consequently, dipole-dipole interactions as well
as other interactions, including van der Waals forces, dispersion forces and
enantiomers and pentyl cage, are most responsible for chiral recognition.
π-π interactions between
2.4. The Reproducibility of the Pentyl Cage-Coated Capillary Column for Separation
Separation reproducibility of the pentyl cage-coated capillary column was investigated
using nitrochlorobenzene and styrene oxide as examples. The reproducible chromatograms of
nitrochlorobenzene and styrene oxide, separated before and after the columns have been subjected to
100, 300, and more than 500 injections (Figure 4). From Figure 4, no significant changes in retention
time and recognition ability were observed, indicating good stability and reproducibility of the pentyl
cage-coated capillary column for GC separation.

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Figure 4. Reproducible chromatograms on the pentyl cage-coated capillary column for the separation
◦
of (
a
) o-, m-, and p-nitrochlorobenzene at 115 C under a N2 flow rate of 14.9 cm
·
s b) styrene oxide
−1; (
at 110 ◦C under a N2 linear velocity of 10.8 cm
were repeatedly used; (2), (3) and (4) chromatograms obtained after the columns have been subjected
to 100, 300, and more than 500 injections, respectively.
·
s−1 (1) Chromatograms obtained before the column
3. Experimental Section
3.1. Reagents and Materials
All chemicals and reagents used were at least of analytical grade. All racemates were purchased
from Sigma-Aldrich (St. Louis, MO, USA), Adamas-beta (Shanghai, China) or TCI (Tokyo, Japan).
The positional isomers (dichlorobenzenes, dibromobenzenes, nitrochlorobenzene, and nitrobromo-
benzenes) were obtained from Aladdin Chemistry Co. Ltd. (Shanghai, China). Hexanal, (R,R)-1,2-bis(2-
hydroxyphenyl)-1,2-diaminoethane and 1,3,5-triformylbenzene were acquired from Acros (Geel,
Belgium) and Sigma-Aldrich. Chloroform, dichloromethane, toluene, methanol, diethyl ether and
acetone were from Tianjin Fengchuan Fine Chemical Research Institute (Tianjin, China). Trifluoroacetic
acid was purchased from Alfa Aesar (Shanghai, China). The untreated fused-silica capillary column
(0.25 mm inner diameter) was purchased from Yongnian Chromatogram Apparatus Co. Ltd. (Yongnian
County, Hebei, China).
3.2. Instrumentations
A Shimadzu GC-2014C system (Kyoto, Japan) equipped with a flame ionization detector (FID),
split injection port and capillary control unit was employed for all GC separations. The data acquisition
was performed on a N-2000 chromatography data system (Zhida Information Engineering Co. Ltd.,
1
Zhejiang University, China). High purity N2 (99.999%) was used as the carrier gas. H- and 13C-NMR
spectra were recorded on a Bruker DRX 500 NMR ultrashield spectrometer (Karlsruhe, Germany).
Scanning electron microscopy (SEM) images were carried out on a FEI Quanta FEG 650 scanning
electron microscope (Hillsboro, OR, USA). Thermogravimetric analysis (TGA) was performed on
◦
a ZRY-1P simultaneous thermal analyzer (Shanghai, China) from room temperature to 800 C at a ramp
rate of 10 ◦C·min−1
.
3.3. Synthesis of (S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane
(S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane was synthesized according to a
previous literature report [37] (Scheme 1). Hexanal (2.46 mL, 20.50 mmol) was added to a solution
of (R,R)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (2.0 g, 8.2 mmol) in toluene (50 mL) at room
temperature. Subsequently, the resulting solution was refluxed overnight with a Dean-Stark trap.
After removal of the solvent under reduced pressure, the resulting viscous yellow oil was purified
1
by precipitation using methanol. Finally, a yellow solid (1.98 g, yield 59%) was obtained. H-NMR
(CDCl3):
δ
13.48 (br s, 2H), 8.28 (s, 2H), 7.29 (ddd, 3JHH = 9 Hz, 4JHH = 1 Hz 2H), 7.23 (dd, 3JHH = 9 Hz,
4JHH = 1 Hz, 2H), 6.98 (d, 3JHH = 6 Hz, 2H), 6.85 (ddd, 3JHH = 6 Hz, 4JHH = 1 Hz, 2H), 3.32–3.28 (m,
2H), 1.69 (m, 4H), 1.29 (m, 12H), 0.88 (t, 3JHH = 6 Hz, 6H). 13C-NMR (CDCl3):
δ 164.8, 161.3, 132.2,
131.3, 118.5, 118.5, 117.1, 73.7, 32.5, 31.6, 25.9, 22.6, 14.0.

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Scheme 1. Synthesis of (S,S)-N,N’-bis(salicylidene)-1,2-pentyl-1,2-diaminoethane. Reagents and Conditions:
(i) Toluene, Dean-Stark apparatus.
3.4. Synthesis of (S,S)-1,2-Pentyl-1,2-diaminoethane
(S,S)-1,2-pentyl-1,2-diaminoethane was synthesized according to a previous literature
procedure [37] (Scheme 2). (S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane (2.6 mmol) was
dissolved in 12 mL of THF, then a mixture of 0.78 mL of 37% HCl solution and 12 mL of THF was
added and stirred at ambient temperature for 24 h. Subsequently, the mixture was diluted with
50 mL of diethyl ether and extracted three times with 15 mL of water. The water phase was basified
using NaOH 1.0 M, extracted three times with 30 mL of dichloromethane and dried over dry Na2SO4.
(S,S)-1,2-Pentyl-1,2-diaminoethane (0.31g, yield 57.9%) was obtained as a red liquid and used without
further purification. 1H-NMR (CDCl3):
δ 2.59 (bs, 2H), 1.47–1.32 (m, 16H), 1.12 (bs, 4H), 0.93 (t,
3JHH = 7 Hz, 6H). 13C-NMR (CDCl3): δ 55.2, 34.8, 32.0, 26.2, 22.7, 14.1.
Scheme 2. Synthesis of (S,S)-1,2-pentyl-1,2-diaminoethane. Reagents and Conditions: (i) THF/HCl 37%
solution, ambient temperature for 24 h; (ii) NaOH 1M.
3.5. Synthesis of Homochiral Pentyl Cage
The pentyl cage was synthesized according to a previous reference [37] (Scheme 3). Typically,
a mixture of (S,S)-1,2-pentyl-1,2-diaminoethane (0.145 g, 0.73 mmol) dissolved in 3.3 mL of CHCl3 and
1,3,5-triformylbenzene (0.06 g, 0.40 mmol) dissolved in 2.3 mL CHCl3 was prepared, and trifluoroacetic
◦
acid (0.01 mL, 0.13 mmol) was added. The reaction mixture was stirred at 60 C for 72 h. Then,
the solvent was removed under reduced pressure and the crude purified by precipitation from acetone.
Finally, crystals were grown by diffusing acetone in a solution of the pentyl cage in dichloromethane
1
(0.060 g, yield 60%). H-NMR (CDCl3):
δ
8.08 (s, 12H), 7.90 (s, 12H), 3.36–3.35 (d, 3JHH = 8 Hz, 12H),
1.80–1.64 (m, 24H), 1.27–1.10 (m, 72H), 0.87 (t, 3JHH = 6 Hz, 36H). 13C-NMR (CDCl3): δ 159.35, 136.62,
129.57, 75.41, 31.80, 26.10, 22.58, 14.12.
◦
Scheme 3. Synthesis of pentyl cage. Reagents and Condition: (i) TFA, CHCl3, 60 C, 72 h.

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3.6. Capillary Pretreatment and Preparation of the Pentyl Cage-Coated Capillary Column
A fused-silica capillary column (15 m long
×
0.25 mm i.d.) was pretreated according to the
following method prior to coating: the column was firstly rinsed with 1.0 M NaOH for 3 h, deionized
water for 1 h, 0.1 M HCl for 1 h and again using deionized water for a period of time to ensure the
washing was neutral. Finally, the capillary was dried via a nitrogen purge for 6 h at 120 ◦C. Pentyl
cage-coated capillary column was fabricated by a static method [34]. A mixture of a 1 mL solution−o1f
)
pentyl cage (3 mg
·
mL−1) in dichloromethane and 1 mL solution of polysiloxane OV-1701 (4.5 mg
·
mL
in dichloromethane was used to produce a pentyl cage-coated capillary column. The coating process
was as follows: after the column was filled up with the stationary phase solution, one end of capillary
column was sealed and the other end was connected to a vacuum system to gradually remove the
solvent at 36 ◦C under vacuum to form a uniform film of the stationary phase on the inner surface of
the capillary column. Finally, the pentyl cage-coated column was conditioned from 30 ◦C to 200 ◦C at
a heating rate of 2 ◦C·min−1 and held at 200 ◦C for 3 h under a flow of nitrogen.
4. Conclusions
A homochiral pentyl cage with a tetrahedral cage structure was obtained by an imine condensation
reaction of (S,S)-1,2-pentyl-1,2-diaminoethane and 1,3,5-triformylbenzene. We have then fabricated
a pentyl cage-coated capillary GC column via a static method. The pentyl cage-coated capillary column
exhibited good selectivity and recognition ability for the GC separation of positional isomers and
racemates. This results demonstrate that POCs-based chiral stationary phase are promising chiral
selectors for enantioseparation in GC.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
11/1466/s1.
Acknowledgments: This research was supported by the National Natural Science Foundation (No. 21275126,
21365024) and the Yunnan Province’s Basic Research Program (No. 2013FB035) of China.
Author Contributions: Shengming Xie performed the preparation of the chiral stationary phase and drafted
the manuscript; Junhui Zhang and Nan Fu synthesized the pentyl cage; Bangjin Wang characterized the pentyl
cage and chiral stationary phase; Cong Hu performed the chromatographic data collection and the data analysis;
Liming Yuan designed and supervised the research work.
Conflicts of Interest: The authors have declared no conflict of interest.
Abbreviations
HPLC
GC
high performance liquid chromatography
gas chromatography
SFC
supercritical fluid chromatography
thin layer chromatography
capillary electrochromatography
metal-organic frameworks
porous organic frameworks
porous organic cages
TLC
CEC
MOFs
POFs
POCs
FID
flame ionization detector
SEM
TGA
scanning electron microscopy
thermogravimetric analysis
References
1.
2.
3.
Kumar, A.P.; Park, J.H. Zirconia-based stationary phases for chiral separation: Mini review. Anal. Lett. 2012
45, 15–42. [CrossRef]
,
Francotte, E.R. Enantioselective chromatography as a powerful alternative for the preparation of drug
enantiomers. J. Chromatogr. A 2001, 906, 379–397. [CrossRef]
Lee, G.R.; Hyun, M.H. Liquid chromatographic resolution of fendiline and its analogues on a chiral stationary
phase based on (+)-(18-Crown-6)-2,3,11,12-tetracarboxylic Acid. Molecules 2014, 19, 21386–21397. [CrossRef]
[PubMed]

Molecules 2016, 21, 1466
10 of 11
4.
Zhang, X.L.; Wang, L.T.; Dong, S.Q.; Zhang, X.; Wu, Q.; Zhao, L.; Shi, Y.P. Nanocellulose derivative/silica
hybrid core-shell chiral stationary phase: Preparation and enantioseparation performance. Molecules 2016
21, 561. [CrossRef] [PubMed]
,
5.
6.
7.
Xie, S.M.; Zhang, Z.J.; Wang, Z.Y.; Yuan, L.M. Chiral metal-organic frameworks for high-resolution gas
chromatographic separations. J. Am. Chem. Soc. 2011, 133, 11892–11895. [CrossRef] [PubMed]
Xie, S.M.; Zhang, M.; Fei, Z.X.; Yuan, L.M. Experimental comparison of chiral metal-organic framework used
as stationary phase in chromatography. J. Chromatogr. A 2014, 1363, 137–143. [CrossRef] [PubMed]
Liu, H.; Xie, S.M.; Ai, P.; Zhang, J.H.; Zhang, M.; Yuan, L.M. Metal-organic framework Co(D-Cam)1/2
(bdc)1/2(tmdpy) for improved enantioseparations on a chiral cyclodextrin stationary phase in gas
chromatography. ChemPlusChem 2014, 79, 1103–1108. [CrossRef]
8.
9.
Nuzhdin, A.L.; Dybtsev, D.N.; Bryliakov, K.P.; Talsi, E.P.; Fedin, V.P. Enantioselective chromatographic
resolution and one-pot synthesis of enantiomerically pure sulfoxides over a homochiral Zn-organic
framework. J. Am. Chem. Soc. 2007, 129, 12958–12959. [CrossRef] [PubMed]
Tanaka, K.; Muraoka, T.; Hirayama, D.; Ohnish, A. Highly efficient chromatographic resolution of sulfoxides
using a new homochiral MOF-silica composite. Chem. Commun. 2012, 48, 8577–8579. [CrossRef] [PubMed]
10. Zhang, M.; Pu, Z.J.; Chen, X.L.; Gong, X.L.; Zhu, A.X.; Yuan, L.M. Chiral recognition of a 3D chiral nanoporous
metal-organic framework. Chem. Commun. 2013, 49, 5201–5203. [CrossRef] [PubMed]
11. Kuang, X.; Ma, Y.; Su, H.; Zhang, J.; Dong, Y.B.; Tang, B. High-performance liquid chromatographic
enantioseparation of racemic drugs based on homochiral metal-organic framework. Anal. Chem. 2014, 86,
1277–1281. [CrossRef] [PubMed]
12. Zhang, M.; Zhang, J.H.; Zhang, Y.; Wang, B.J.; Xie, S.M.; Yuan, L.M. Chromatographic study on the high
0
performance separation ability of a homochiral [Cu2(D-Cam)2(4,4 -bpy)]n based-column by using racemates
and positional isomers as test probes. J. Chromatogr. A 2014, 1325, 163–170. [CrossRef] [PubMed]
13. Fei, Z.X.; Zhang, M.; Zhang, J.H.; Yuan, L.M. Chiral metal-organic framework used as stationary phases for
capillary electrochromatography. Anal. Chim. Acta 2014, 830, 49–55. [CrossRef] [PubMed]
14. Fei, Z.X.; Zhang, M.; Xie, S.M.; Yuan, L.M. Capillary electrochromatographic fast enantioseparation based on
a chiral metal-organic framework. Electrophoresis 2014, 35, 3541–3548. [CrossRef] [PubMed]
15. Qian, H.L.; Yang, C.X.; Yan, X.P. Bottom-up synthesis of chiral covalent organic frameworks and their bound
capillaries for chiral separation. Nat. Commun. 2016. [CrossRef] [PubMed]
16. Dong, J.Q.; Liu, Y.; Cui, Y. Chiral porous organic frameworks for asymmetric heterogeneous catalysis and
gas chromatographic separation. Chem. Commun. 2014, 50, 14949–14952. [CrossRef] [PubMed]
17. Zhang, J.H.; Xie, S.M.; Zhang, M.; Zi, M.; He, P.G.; Yuan, L.M. Novel inorganic mesoporous material with
chiral nematic structure derived from nanocrystalline cellulose for high-resolution gas chromatographic
separations. Anal. Chem. 2014, 86, 9595–9602. [CrossRef] [PubMed]
18. Zhang, J.H.; Zhang, M.; Xie, S.M.; He, P.G.; Yuan, L.M. A novel inorganic mesoporous material with
a nematic structure derived from nanocrystalline cellulose as the stationary phase for high performance
liquid chromatography. Anal. Methods 2015, 7, 3448–3453. [CrossRef]
19. Xie, S.M.; Yuan, L.M. Recent progress of chiral stationary phases for separation of enantiomers in gas
chromatography. J. Sep. Sci. 2016. [CrossRef] [PubMed]
20. Acharyya, K.; Mukherjee, S.; Mukherjee, P.S. Molecular marriage through partner preferences in covalent
cage formation and cage-to-cage transformation. J. Am. Chem. Soc. 2013, 135, 554–557. [CrossRef] [PubMed]
21. Zhang, G.; Mastalerz, M. Organic cage compounds-from shape-persistency to function. Chem. Soc. Rev. 2014
,
43, 1934–1947. [CrossRef] [PubMed]
22. Jin, Y.H.; Wang, Q.; Taynton, P.; Zhang, W. Dynamic covalent chemistry approaches toward macrocycles,
molecular cages, and polymers. Acc. Chem. Res. 2014, 47, 1575–1586. [CrossRef] [PubMed]
23. Klotzbach, S.; Beuerle, F. Shape-controlled synthesis and self-sorting of covalent organic cage compounds.
Angew. Chem. Int. Ed. 2015, 54, 10356–10360. [CrossRef] [PubMed]
24. Lee, S.; Yang, A.; Moneypenny, T.P., II; Moore, J.S. Kinetically trapped tetrahedral cages via alkyne metathesis.
J. Am. Chem. Soc. 2016, 138, 2182–2185. [CrossRef] [PubMed]
25. Skowronek, P.; Gawronski, J. Chiral iminospherand of a tetrahedral symmetry spontaneously assembled in
a [6+4] cyclocondensation. Org. Lett. 2008, 10, 4755–4758. [CrossRef] [PubMed]

Molecules 2016, 21, 1466
11 of 11
26. Jones, J.T.A.; Hasell, T.; Wu, X.; Bacsa, J.; Jelfs, K.E.; Schmidtmann, M.; Chong, S.Y.; Adams, D.J.; Trewin, A.;
Schiffman, F.; et al. Modular and predictable assembly of porous organic molecular crystals. Nature 2011
474, 367–371. [CrossRef] [PubMed]
,
27. Jelfs, K.E.; Wu, X.; Schmidtmann, M.; Jones, J.T.A.; Warren, J.E.; Adams, D.J.; Cooper, A.I. Large
self-assembled chiral organic cages: Synthesis, structure, and shape persistence. Angew. Chem. Int. Ed. 2011
50, 10653–10656. [CrossRef] [PubMed]
,
28. Jelfs, K.E.; Eden, E.G.B.; Culshaw, J.L.; Shakespeare, S.; Pyzer-Knapp, E.O.; Thompson, H.P.G.; Bacsa, J.;
Day, G.M.; Adams, D.J.; Cooper, A.I. In silico design of supramolecules from their precursors: Odd-even
effects in cage-forming reactions. J. Am. Chem. Soc. 2013, 135, 9307–9310. [CrossRef] [PubMed]
29. Hasell, T.; Culshaw, J.L.; Chong, S.Y.; Schmidtmann, M.; Little, M.A.; Jelfs, K.E.; Pyzer-Knapp, E.O.;
Shepherd, H.; Adams, D.J.; Day, G.M.; et al. Controlling the crystallization of porous organic cages:
Molecular analogs of isoreticular frameworks using shape-specific directing solvents. J. Am. Chem. Soc. 2014
,
136, 1438–1448. [CrossRef] [PubMed]
30. Mitra, T.; Jelfs, K.E.; Schmidtmann, M.; Ahmed, A.; Chong, S.Y.; Adams, D.J.; Cooper, A.I. Molecular shape
sorting using molecular organic cages. Nat. Chem. 2013, 5, 276–281. [CrossRef] [PubMed]
31. Chen, L.J.; 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. Separation of rare gases and chiral molecules by selective binding in porous organic
cages. Nat. Mater. 2014, 13, 954–960. [CrossRef] [PubMed]
32. Yuan, L.M.; Zhang, J.H. A capillary Column Based on Chiral Porous Organic Cage for Separation of Optical
Isomers. China Patent 201510050956.7, 2 February 2015.
33. Kewley, A.; Stephenson, A.; Chen, L.J.; Briggs, M.E.; Hasell, T.; Cooper, A.I. Porous organic cages for gas
chromatography separations. Chem. Mater. 2015, 27, 3207–3210. [CrossRef]
34. Zhang, J.H.; Xie, S.M.; Chen, L.; Wang, B.J.; He, P.C.; Yuan, L.M. Homochiral porous organic cage with
high selectivity for the separation of racemates in gas chromatography. Anal. Chem. 2015, 87, 7817–7824.
[CrossRef] [PubMed]
35. Xie, S.M.; Zhang, J.H.; Fu, N.; Wang, B.J.; Chen, L.; Yuan, L.M. A chiral porous organic cage for molecular
recognition using gas chromatography. Anal. Chim. Acta 2016, 903, 156–163. [CrossRef] [PubMed]
36. Zhang, J.H.; Xie, S.M.; Wang, B.J.; He, P.G.; Yuan, L.M. Highly selective separation of enantiomers using
a chiral porous organic cage. J. Chromatogr. A 2015, 1426, 174–182. [CrossRef] [PubMed]
37. Giri, N.; Davidson, C.E.; Melaugh, G.; Del Popolo, M.G.; Jones, J.T.A.; Hasell, T.; Cooper, A.I.; Horton, P.N.;
Hursthouse, M.B.; James, S.L. Alkylated organic cages: From porous crystals to neat liquids. Chem. Sci. 2012
3, 2153–2157. [CrossRef]
,
38. Peng, J.L.; Zhang, Y.; Yang, X.H.; Qi, M.L. High-resolution separation performance of poly(caprolactone)diol
for challenging isomers of xylenes, phenols and anilines by capillary gas chromatography. J. Chromatogr. A
2016, 1466, 148–154. [CrossRef] [PubMed]
39. Yamamoto, C.; Yashima, E.; Okamoto, Y. Structural analysis of amylose tris(3, 5-dimethylphenylcarbamate)
by NMR relevant to its chiral recognition mechanism in HPLC. J. Am. Chem. Soc. 2002, 124, 12583–12589.
[CrossRef] [PubMed]
Sample Availability: Samples of the compounds racemates and positional isomers are available from the authors.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
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