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Nov 8, 2016 - Department of Chemistry, Yunnan Normal University, Kunming 650500, China; ... Abstract: Molecular organic cage compounds have attracted ...... Jones, J.T.A.; Hasell, T.; Wu, X.; Bacsa, J.; Jelfs, K.E.; Schmidtmann, M.; Chong ...
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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; [email protected] (S.X.); [email protected] (J.Z.); [email protected] (N.F.); [email protected] (B.W.); [email protected] (C.H.) * Correspondence: [email protected] or [email protected]; 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 [2]. Among them, HPLC and capillary GC are the most reliable and commonly employed analytical techniques for the separation of enantiomers [3,4]. Compared to other chromatographic techniques, capillary GC 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,

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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 [26–29]. Surprisingly, these cage molecules can self-assemble into crystalline materials with 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 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·m−1 , further indicating the good coating performance of the pentyl cage. 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 column. Moleculescapillary 2016, 21, 1466 3 of 11

Figure 1. (a) TGA of pentyl cage; (b) SEM image of the thickness of stationary phase coating in part

Figure 1. (a) TGA of pentyl cage; (b) SEM image of the thickness of stationary phase coating in part of of the pentyl cage-coated capillary column. the pentyl cage-coated capillary column. Table 1. McReynolds constants of the pentyl cage-coated capillary column at 120 °C.

Table 1. McReynolds constants of the pentyl cage-coated capillary column at 120 ◦ C. Av. X’ Y’ Z’ U’ S’ 37 185 102 203 126 130.6 X0 Y0 Z0 U0 S0 Av.

X’, Y’, Z’, U’ and S’ refer to benzene, 1-butanol, 2-pentanone, 1-nitropropane, and pyridine, respectively.

37 0 , Y0 , Z0 , U0 2.2.XSeparation

185

102

203

126

130.6

of Positional on1-butanol, the Pentyl2-pentanone, Cage-Coated1-nitropropane, Capillary Column and S0 refer toIsomers benzene, and

pyridine, respectively.

High-resolution separation of positional isomers is of significant importance in the chemical industry environmental analysis [38]. However, it is a challenging to separate some positional 2.2. Separationand of Positional Isomers on the Pentyl Cage-Coated Capillarytask Column isomers owing to their similar physical and chemical properties. So far, capillary GC is one of the most High-resolution of positional isomers is ofisomers. significant importance the chemical efficient methods separation for the separation of various positional To investigate the in separation properties of the pentyl cage-coated capillary column, positional isomers were selected aspositional test industry and environmental analysis [38]. However, it issome a challenging task to separate some solutes. Thetopentyl capillary column offered good separation of capillary some isomer isomers owing their cage-coated similar physical and chemical properties. So far, GCmixtures, is one of the including dichlorobenzene, dibromobenzene, nitrochlorobenzene, and nitrobromobenzene. Molecular most efficient methods for the separation of various positional isomers. To investigate the separation structures of these isomers are shown in Figure S3 (Supplementary Materials). The chromatograms properties of the pentyl cage-coated capillary column, some positional isomers were selected as test and results of separation of isomer mixtures on pentyl cage-coated capillary column are shown in

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. Molecules 2016, 21, 1466 As can be seen from Figure 2, baseline separation of all isomers were 4 ofachieved 11 on the pentyl cage-coated capillary column. Interestingly, the elution sequence of all isomers followed Figure 2 order and Table 2, respectively. As can be seen Figure 2, rather baselinethan separation of all an increasing of para-isomer < ortho-isomer < from meta-isomer, the order ofisomers their boiling were achieved on the pentyl cage-coated capillary column. Interestingly, the elution sequence of all ◦ ◦ points (e.g., meta-dibromobenzene (218 C) < para-dibromobenzene (219 C) < ortho-dibromobenzene isomers followed an increasing order of para-isomer < ortho-isomer < meta-isomer, rather than the (225 ◦ order C)). All the meta-isomers eluted much later than the ortho- and para-isomers on the pentyl of their boiling points (e.g., meta-dibromobenzene (218 °C) < para-dibromobenzene (219 °C) cage-coated capillary column, indicating selectivityeluted and stronger retention toward < ortho-dibromobenzene (225 °C)). All higher the meta-isomers much later than thebehavior ortho- and meta-isomers than on thethe orthoandcage-coated para-isomers. Thiscolumn, experimental result is inselectivity agreement with previously para-isomers pentyl capillary indicating higher and stronger retention toward meta-isomers than thephases ortho- and para-isomers. result used reported data behavior for POCs-based chiral stationary such as CC3-R, This CC9experimental and CC10 when is in agreement with previously reported data for POCs-based chiral stationary phases such as for GC separation of positional isomers [34–36]. The main reason for this can probably be attributed CC3-R, CC9 and CC10 when used for GC separation of positional isomers [34–36]. The main reason to the meta-substituted aryl face geometry of the building unit (1,3,5-triformylbenzene) which was for this can probably be attributed to the meta-substituted aryl face geometry of the building unit employed for the synthesis of the pentyl cage and the abovementioned POCs (CC3-R, CC9 and CC10). (1,3,5-triformylbenzene) which was employed for the synthesis of the pentyl cage and the In other words, the molecular geometry of meta-substituted isomers will better match with pentyl cage abovementioned POCs (CC3-R, CC9 and CC10). In other words, the molecular geometry of molecules, resulting in longerwill retention timeswith for meta-isomers than those of orthoand para-isomers on meta-substituted isomers better match pentyl cage molecules, resulting in longer retention the pentyl capillary column. timescage-coated 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

Figure 2. GC chromatograms using the pentyl cage-coated capillary column for −1 separation of positional positional isomers: (a) o-, m-, and p-dibromobenzene under a N2 flow rate of 13.8 cm∙s at 90 °C; (b) o-, m-, −1 at 90 ◦ C; (b) o-, m-, and isomers: (a) o-, m-, and p-dibromobenzene under a N flow rate of 13.8 cm · s 2 −1 at 110 °C; (c) o-, m-, and p-nitrochlorobenzene and p-dibromobenzene under a N2 flow rate of 13.8 cm∙s 1 at 110 ◦ C; (c) o-, m-, and p-nitrochlorobenzene p-dibromobenzene under aN of 13.8 cmo-, ·s−m-, 2 flow under a N2 flow rate of 14.9 cm∙s−1rate at 115 °C; (d) and p-nitrobromobenzene under a N2 flow − 1 ◦ −1 underrate a Nof rate of 14.9°C. cm·s at 115 C; (d) o-, m-, and p-nitrobromobenzene under a N2 flow 14.9 cm∙s at 120 2 flow rate of 14.9 cm·s−1 at 120 ◦ C. Table 2. Separation factor (α) and resolution (Rs) for separation of positional isomers on the pentyl cage-coated capillary column.

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) Isomers T (°C) α1 α2 Rs1 Rs2 Separation Factor (α) 1.10 Resolution (Rs)1.51 Dichlorobenzene 90 1.24 2.51 T (◦ C) Isomers Dibromobenzene 110 1.12 Rs1 2.83 Rs21.57 α1 1.23 α2 Nitrochlorobenzene 115 1.14 1.67 2.91 9.59 Dichlorobenzene 90 1.24 1.10 2.51 1.51 Nitrobromobenzene 120 1.08 1.60 1.99 10.30 Dibromobenzene 110 1.23 1.12 2.83 1.57 Nitrochlorobenzene 115 Nitrobromobenzene 120

1.14 1.08

1.67 1.60

2.91 1.99

9.59 10.30

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2.3. Separation of Enantiomers on the Pentyl Cage-Coated Capillary Column 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 As a new class of chiral materials, homochiral POCs[33–36]. have been attracting attention because of their potential applications in enantioselective separation To investigate the chiral resolution 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 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 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, performance toward various types of enantiomers, including alcohols, esters, ethers and epoxides, especially for chiral alcohols. Figure S4 (Supplementary Materials) shows the molecular structures especially for chiral alcohols. Figure S4 (Supplementary Materials) shows the molecular structures of the enantiomers. The retention factor (k ) for the first eluted enantiomers, separation factor (α) of the enantiomers. The retention factor (k11) for the first eluted enantiomers, separation factor (α) andand resolution (Rs) areare listed enantiomers given resolution (Rs) listedininTable Table3.3.The Theresolution resolution chromatograms chromatograms ofofenantiomers areare given in in Figure 3. 3. The showbaseline baseline orleast at least separation for all enantiomers Figure Thechromatograms chromatograms show or at 80% 80% valleyvalley separation for all enantiomers except except for 2-phenyl-1-propanol, 1-(2-naphthyl)ethanol, ethyl 3-hydroxybutyrate and γ-valerolactone. for 2-phenyl-1-propanol, 1-(2-naphthyl)ethanol, ethyl 3-hydroxybutyrate and γ-valerolactone. Notably, Notably, a high-resolution gas chromatographic enantioseparation of trans-stilbene oxide (Rs = 4.94) a high-resolution gas chromatographic enantioseparation of trans-stilbene oxide (Rs = 4.94) was wasachieved achievedonon the pentyl cage-coated capillary column. the pentyl cage-coated capillary column.

Figure 3. GC chromatogramson onthe thepentyl pentylcage-coated cage-coated capillary of of racemates: Figure 3. GC chromatograms capillarycolumn columnfor forseparation separation racemates: (a) styrene oxide; (b) trans-stilbene oxide, (c) 1,2-epoxybutane; (d) 1,2-epoxyhexane; (e) 1-bromo-2,3(a) styrene oxide; (b) trans-stilbene oxide; (c) 1,2-epoxybutane; (d) 1,2-epoxyhexane; (e) 1-bromo-2,3epoxypropane; (f) n-butyl glycidyl ether; (g) 1-methoxy-2-hydroxypropane; (h) 1-methoxy-2-butanol, epoxypropane; (f) n-butyl glycidyl ether; (g) 1-methoxy-2-hydroxypropane; (h) 1-methoxy-2-butanol; (i) 3-butyn-2-ol; (j) 1-phenylethanol; (k) 1-phenyl-1-propanol; (l) 4-chlorophenethylalcohol; (m) (i) 3-butyn-2-ol; (j) 1-phenylethanol; (k) 1-phenyl-1-propanol; (l) 4-chlorophenethylalcohol; (m) 2-phenyl2-phenyl-1-propanol; (n) 1-naphthylethanol; (o) 1-(2-naphthyl)ethanol; (p) methyl 3-hydroxybutyrate, (q) 1-propanol; (n) 1-naphthylethanol; (o) 1-(2-naphthyl)ethanol; (p) methyl 3-hydroxybutyrate, (q) ethyl ethyl 3-hydroxybutyrate; (r) γ-valerolactone. The separation conditions are shown in Table 3. 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. Racemates

T (◦ C)

k1

α

Rs

v [a] (cm·s−1 )

Styrene oxide trans-Stilbene oxide 1,2-Epoxybutane 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

110 178 50 110 85 95 78 82 67 120 125 135 130 175 175 90 100 115

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 3.42 3.04

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

[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-1,2diamino-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 π-π interactions between enantiomers and pentyl cage, are most responsible for chiral recognition. 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 chromatogramson onthe thepentyl pentyl cage-coated cage-coated capillary column for for the the separation Figure 4. Reproducible chromatograms capillary column separation (b) styrene oxide of (a) o-, m-, and p-nitrochlorobenzene at 115 °C under a N2 flow rate of 14.9 cm∙s−1 − ◦ 1 of (a) o-, m-, and p-nitrochlorobenzene at 115 C−1under a N2 flow rate of 14.9 cm·s ; (b) styrene oxide at 110 °C under a N2 linear velocity of 10.8 cm∙s (1) Chromatograms obtained before the column were at 110 ◦ C under a N2 linear velocity of 10.8 cm·s−1 (1) Chromatograms obtained before the column repeatedly used; (2), (3) and (4) chromatograms obtained after the columns have been subjected to 100, were repeatedly used; (2), (3) and (4) chromatograms obtained after the columns have been subjected 300, and more than 500 injections, respectively. to 100, 300, and more than 500 injections, respectively.

3. Experimental Section

3. Experimental Section 3.1. Reagents and Materials

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,were USA), (Shanghai, China) or TCI (Tokyo, All chemicals and reagents used at Adamas-beta least of analytical grade. All racemates wereJapan). purchased The positional isomers (dichlorobenzenes, dibromobenzenes, nitrochlorobenzene, and from Sigma-Aldrich (St. Louis, MO, USA), Adamas-beta (Shanghai, China) or TCInitrobromo(Tokyo, Japan). benzenes) were obtained from Aladdin Chemistry Co. Ltd. (Shanghai, China). Hexanal, (R,R)-1,2-bis(2The positional isomers (dichlorobenzenes, dibromobenzenes, nitrochlorobenzene, and nitrobromohydroxyphenyl)-1,2-diaminoethane and 1,3,5-triformylbenzene were acquired from Acros (Geel, benzenes) were obtained from Aladdin Chemistry Co. Ltd. (Shanghai, China). Hexanal, (R,R)-1,2-bis(2Belgium) and Sigma-Aldrich. Chloroform, dichloromethane, toluene, methanol, diethyl ether and hydroxyphenyl)-1,2-diaminoethane and were acquired Acros (Geel, acetone were from Tianjin Fengchuan Fine1,3,5-triformylbenzene Chemical Research Institute (Tianjin, China).from Trifluoroacetic Belgium) andpurchased Sigma-Aldrich. Chloroform, dichloromethane, toluene, methanol, diethyl ether and acid was from Alfa Aesar (Shanghai, China). The untreated fused-silica capillary column acetone were Fengchuan Fine from Chemical Research InstituteApparatus (Tianjin, China). (0.25 mmfrom innerTianjin diameter) was purchased Yongnian Chromatogram Co. Ltd. Trifluoroacetic (Yongnian County, Hebei, China). 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 3.2.Hebei, Instrumentations County, China). A Shimadzu GC-2014C system (Kyoto, Japan) equipped with a flame ionization detector (FID),

3.2. Instrumentations 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.,

A Shimadzu GC-2014C system (Kyoto, Japan) equipped with a flame ionization detector (FID), Zhejiang University, China). High purity N2 (99.999%) was used as the carrier gas. 1H- and 13C-NMR split injection port and capillary control unit was employed for all GC separations. The data acquisition spectra were recorded on a Bruker DRX 500 NMR ultrashield spectrometer (Karlsruhe, Germany). was performed on a N-2000 chromatography Co. Ltd., Scanning electron microscopy (SEM) imagesdata weresystem carried (Zhida out on aInformation FEI Quanta Engineering FEG 650 scanning 1 H- and 13 C-NMR Zhejiang University, China). High purity N (99.999%) was used as the carrier gas. 2 electron microscope (Hillsboro, OR, USA). Thermogravimetric analysis (TGA) was performed on a spectra weresimultaneous recorded onthermal a Bruker DRX(Shanghai, 500 NMRChina) ultrashield spectrometer ZRY-1P analyzer from room temperature(Karlsruhe, to 800 °C at aGermany). ramp −1 Scanning microscopy (SEM) images were carried out on a FEI Quanta FEG 650 scanning rate ofelectron 10 °C∙min . electron microscope (Hillsboro, OR, USA). Thermogravimetric analysis (TGA) was performed on 3.3. Synthesis of (S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane a ZRY-1P simultaneous thermal analyzer (Shanghai, China) from room temperature to 800 ◦ C at a ramp ◦ − 1 rate of 10 (S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane C·min . was synthesized according to a previous literature report [37] (Scheme 1). Hexanal (2.46 mL, 20.50 mmol) was added to a solution

3.3. Synthesis of (S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane 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.

(S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane was synthesized according to a After removal of the solvent under reduced pressure, the resulting viscous yellow oil was purified previous literature report [37] (Scheme 1). Hexanal (2.46 mL, 20.50 mmol) was added to a solution by precipitation using methanol. Finally, a yellow solid (1.98 g, yield 59%) was obtained. 1H-NMR of (R,R)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane g, 8.2 in toluene mL) 4JHH mmol) 3JHH (CDCl3): δ 13.48 (br s, 2H), 8.28 (s, 2H), 7.29 (ddd, 3JHH =(2.0 9 Hz, = 1 Hz 2H), 7.23 (dd,(50 = 9 at Hz,room 4JHH = 1 Hz, 3JHH refluxed temperature. Subsequently, overnight with a Dean-Stark 2H), 6.98 (d, 3Jthe HH = resulting 6 Hz, 2H), solution 6.85 (ddd,was = 6 Hz, 4JHH = 1 Hz, 2H), 3.32–3.28 (m, 2H), trap. 3JHH = 6 pressure, After 1.69 removal of the under reduced resulting yellow was131.3, purified (m, 4H), 1.29solvent (m, 12H), 0.88 (t, Hz, 6H). 13the C-NMR (CDClviscous 3): δ 164.8, 161.3, oil 132.2, 118.5, 118.5, 117.1, 32.5, 31.6, 25.9, 22.6, 14.0. solid (1.98 g, yield 59%) was obtained. 1 H-NMR by precipitation using73.7, methanol. Finally, a yellow (CDCl3 ): δ 13.48 (br s, 2H), 8.28 (s, 2H), 7.29 (ddd, 3 JHH = 9 Hz, 4 JHH = 1 Hz 2H), 7.23 (dd, 3 JHH = 9 Hz, 4J 3 3 4 HH = 1 Hz, 2H), 6.98 (d, J HH = 6 Hz, 2H), 6.85 (ddd, J HH = 6 Hz, J HH = 1 Hz, 2H), 3.32–3.28 (m, 2H), 1.69 (m, 4H), 1.29 (m, 12H), 0.88 (t, 3 JHH = 6 Hz, 6H). 13 C-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:

Scheme 1. Synthesis of (S,S)-N,N’-bis(salicylidene)-1,2-pentyl-1,2-diaminoethane. Reagents and Conditions: (i) Toluene, Dean-Stark apparatus. (i) Toluene, Dean-Stark apparatus. Schemeof1.(S,S)-1,2-Pentyl-1,2-diaminoethane Synthesis of (S,S)-N,N’-bis(salicylidene)-1,2-pentyl-1,2-diaminoethane. Reagents and Conditions: 3.4. Synthesis Toluene, Dean-Stark apparatus. 3.4. Synthesis(i)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]3.4. (Scheme (S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane was dissolved in (S,S)-1,2-pentyl-1,2-diaminoethane was synthesized according(2.6 tommol) aandprevious literature Scheme2). 1.ofSynthesis of (S,S)-N,N’-bis(salicylidene)-1,2-pentyl-1,2-diaminoethane. Reagents Conditions: Synthesis (S,S)-1,2-Pentyl-1,2-diaminoethane 12 mL of THF, then a mixture of 0.78 mL of 37% HCl solution and 12 mL of THF was added and (i) Toluene, Dean-Stark apparatus. procedure [37] (Scheme 2). (S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane (2.6 mmol) was (S,S)-1,2-pentyl-1,2-diaminoethane was synthesized according to a previous literature procedure stirredinat12 ambient temperature 24 h. Subsequently, wassolution diluted with 50 mL dissolved mL2).of(S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane THF, then for a mixture of 0.78 mLthe of mixture 37% HCl and 12dissolved mLofofdiethyl THF was [37]Synthesis (Scheme (2.6 mmol) was in 3.4. of (S,S)-1,2-Pentyl-1,2-diaminoethane ether and extracted three times with 15 mL of water. The water phase was basified using NaOH 1.0 M, added and stirred atthen ambient temperature for37% 24 HCl h. Subsequently, theofmixture diluted 12 mL of THF, a mixture of 0.78 mL of solution and 12 mL THF waswas added and with extracted three times with 30 mL of dichloromethane and driedtoover dry Naliterature 2SO4. (S,S)-1,2-Pentyl(S,S)-1,2-pentyl-1,2-diaminoethane synthesized according a previous stirred at ambient temperature for 24 h.was Subsequently, mixture was diluted 50 phase mLprocedure of diethyl 50 mL of diethyl ether and extracted three times with the 15 mL of water. The with water was basified 1,2-diaminoethane (0.31g, yield 57.9%) was obtained as a red liquid and used without [37] (Scheme 2). (S,S)-N,N’-bis(Salicylidene)-1,2-pentyl-1,2-diaminoethane (2.6 mmol) was dissolved in ether and extracted three times with 15 mL of water. The water phase was basified using NaOH 1.0further M, usingpurification. NaOH 1.0 M, extracted three times with 30 mL of dichloromethane and dried over Na SO . 1H-NMR (CDCl3): δ 2.59 (bs, 2H), 1.47–1.32 (m, 16H), 1.12 (bs, 4H), 0.93 (t, 3JHHdry =and 7 Hz,2 4 12 mL of THF, then a mixture of 0.78 mL of 37% HCl solution and 12 mL of THF was added extracted three times with 30 mL of dichloromethane and dried over dry Na2SO4. (S,S)-1,2-Pentyl(S,S)-1,2-Pentyl-1,2-diaminoethane (0.31g, yield 57.9%) was obtained as a red liquid and used without 13C-NMR stirred at ambient temperature for 57.9%) 24 h. Subsequently, theasmixture diluted with 50 mL of diethyl 6H). (CDCl 3(0.31g, ): δ 55.2, 34.8, 32.0, 26.2, 14.1. 1,2-diaminoethane yield was 22.7, obtained a red was liquid and used without further 1 further ether purification. H-NMR (CDCl3): δ of 2.59 (bs,The 2H), 16H), 1.12 and extracted three times with 15 mL water. water phase1.12 was(m, basified using NaOH M, 0.93 (t, 1H-NMR 3J(bs, purification. (CDCl3): δ 2.59 (bs, 2H), 1.47–1.32 (m,1.47–1.32 16H), (bs, 4H), 0.93 (t, HH =1.0 74H), Hz, 3J 13 C-NMR extracted three times with 30 mL of dichloromethane and dried over dry Na 2 SO 4 . (S,S)-1,2-Pentyl13 = 7 Hz, 6H). (CDCl ): δ 55.2, 34.8, 32.0, 26.2, 22.7, 14.1. 6H). C-NMR (CDCl3): δ 55.2, 34.8, HH 3 32.0, 26.2, 22.7, 14.1. 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.

2. Synthesis of (S,S)-1,2-pentyl-1,2-diaminoethane. Reagents and Conditions: (i) THF/HCl 37% SchemeScheme 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 solution, ambient temperature for Cage 24 h; (ii) NaOH 1M. Scheme 2.ofSynthesis (S,S)-1,2-pentyl-1,2-diaminoethane. Reagents and Conditions: (i) THF/HCl 37% pentyl cage wasofsynthesized reference [37] (Scheme 3). Typically, a 3.5.The Synthesis Homochiral Pentyl Cageaccording to a previous ambient temperature for 24 h; (ii) NaOH 1M.g, 0.73 mmol) dissolved in 3.3 mL of CHCl3 and 3.5. Synthesis of (S,S)-1,2-pentyl-1,2-diaminoethane Homochiral Pentyl Cage mixturesolution, of (0.145 The pentyl cage was synthesized according to a previous reference [37] (Scheme 3). Typically, a

1,3,5-triformylbenzene (0.06 g, 0.40 mmol) dissolved in 2.3 mL CHCl3 was prepared, and trifluoroacetic

mixture ofcage (S,S)-1,2-pentyl-1,2-diaminoethane (0.145 mmol) reference dissolved in[37] 3.3 mL of CHCl 3 and The pentyl was synthesized to g, a 0.73 previous (Scheme 3). Typically, 3.5. Synthesis of Homochiral Pentyl Cageaccording acid (0.01 mL, 0.13 mmol) was added. The reactioninmixture was stirred at 60 °C for 72 h. Then, the 1,3,5-triformylbenzene (0.06 g, 0.40 mmol) dissolved 2.3 mL CHCl 3 was prepared, and trifluoroacetic a mixture of (S,S)-1,2-pentyl-1,2-diaminoethane (0.145 g, 0.73 mmol) dissolved in 3.3 mL of CHCl cagemmol) was synthesized according to athe previous reference [37] (Scheme Typically, a 3 and solvent waspentyl removed under reduced pressure and crudewas purified from acetone. acid The (0.01 mL, 0.13 was added. The reaction mixture stirredby at precipitation 60 °C for 3). 72 h. Then, the 1,3,5-triformylbenzene (0.06 g, 0.40 mmol) dissolved mL CHCl was prepared, and trifluoroacetic mixture of (S,S)-1,2-pentyl-1,2-diaminoethane (0.145 g, 0.73 mmol) incage 3.3 mL of CHCl 3 and Finally, crystals were grown by diffusing acetone a 2.3 solution of dissolved the3 by pentyl in dichloromethane solvent was removed under reduced pressure andinin the crude purified precipitation from acetone. ◦ C for 72 h. Then, 1H-NMR 3JHH 1,3,5-triformylbenzene (0.06 g, 0.40 mmol) dissolved in 2.3 mL CHCl 3 was prepared, and trifluoroacetic acid (0.01 mL, 0.13 mmol) was added. The reaction mixture was stirred at 60 (0.060 g, yield 60%). (CDCl 3 ): δ 8.08 (s, 12H), 7.90 (s, 12H), 3.36–3.35 (d, = 8 Hz, 12H), Finally, crystals were grown by diffusing acetone in a solution of the pentyl cage in dichloromethane 3 13 acid (0.01 mL, 0.13 mmol) was added. The reaction mixture was stirred at 60 °C for 72 h. Then, the 1 3 1.80–1.64 (m, 24H), 1.27–1.10 (m, 72H), 0.87 (t, J HH = 6 Hz, 36H). C-NMR (CDCl 3 ): δ 159.35, 136.62, the solvent was removed reduced the crude purified by precipitation (0.060 g, yield 60%).under H-NMR (CDCl3):pressure δ 8.08 (s,and 12H), 7.90 (s, 12H), 3.36–3.35 (d, JHH = 8 Hz,from 12H),acetone. solvent was removed under reduced pressure crude purified precipitation from acetone. 3JHH the 13C-NMR 1.80–1.64 (m, 24H), 1.27–1.10 (m, 72H), 0.87 (t, and Hz, 36H). (CDCl 3): δ in 159.35, 136.62, 129.57, 75.41, 31.80, 26.10, 22.58, 14.12. Finally, crystals were grown by diffusing acetone in=a6solution of thebypentyl cage dichloromethane Finally, crystals grown by diffusing acetone in a solution of the pentyl cage in dichloromethane 129.57, 31.80, 26.10, 22.58, 14.12. 1were (0.060 g,(0.060 yieldg,75.41, 60%). H-NMR (CDCl (s, 12H), 7.90 (s, 12H), 3.36–3.35 (d, 3 J Hz,=12H), 8 Hz, 12H), 3 ):3):δδ8.08 yield 60%). 1H-NMR (CDCl 8.08 (s, 12H), 7.90 (s, 12H), 3.36–3.35 (d, 3JHH = 8HH 3 13 1.80–1.64 (m, 24H), 1.27–1.10 (m, (m, 72H), 0.87 (t,(t, J3HH Hz,36H). 36H). C-NMR (CDCl 13C-NMR 3 ): δ 159.35, 1.80–1.64 (m, 24H), 1.27–1.10 72H), 0.87 JHH ==66Hz, (CDCl 3): δ 159.35, 136.62, 136.62, 129.57, 75.41, 26.10,26.10, 22.58, 14.12. 129.57, 31.80, 75.41, 31.80, 22.58, 14.12.

Scheme 3.3.Synthesis andCondition: Condition:(i)(i)TFA, TFA,CHCl CHCl 3, 60 °C, 72 h. Scheme Synthesisofofpentyl pentylcage. cage. Reagents Reagents and 3, 60 °C, 72 h.

Scheme 3. Synthesis of pentyl cage. Reagents and Condition: (i) TFA, CHCl3, 60 °C, 72 ◦h. 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 of pentyl cage (3 mg·mL−1 ) in dichloromethane and 1 mL solution of polysiloxane OV-1701 (4.5 mg·mL−1 ) 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 SFC TLC CEC MOFs POFs POCs FID SEM TGA

high performance liquid chromatography gas chromatography supercritical fluid chromatography thin layer chromatography capillary electrochromatography metal-organic frameworks porous organic frameworks porous organic cages flame ionization detector scanning electron microscopy thermogravimetric analysis

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Sample Availability: Samples of the compounds racemates and positional isomers are available from the authors. © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).