Microchim Acta DOI 10.1007/s00604-017-2095-5

ORIGINAL PAPER

In situ synthesis of the imine-based covalent organic framework LZU1 on the inner walls of capillaries for electrochromatographic separation of nonsteroidal drugs and amino acids Deying Kong 1,2 & Tao Bao 1,2 & Zilin Chen 1,2

Received: 9 October 2016 / Accepted: 20 January 2017 # Springer-Verlag Wien 2017

Abstract The covalent organic framework LZU1 (Lan Zhou University-1) is one of the imine-based covalent organic frameworks (COFs) that possesses attractive properties such as structural regularity, stability and good porosity. This work reports on the in-situ synthesis of COFLZU1 on the inner walls of capillary column for opentubular capillary electrochromatography (OT-CEC). The fused-silica capillary was first modified with 3aminopropyltriethoxysilane and glutaraldehyde. Epitaxial growth of COF-LZU1 on the inner walls was accomplished by Schiff base reaction. The formation of COF-LZU1 was confirmed by SEM and FT-IR. The COF-LZU1 coating increases the interactions between analytes and coating, which remarkably improves the CEC separation selectivity of neutral analytes, amino acids and nonsteroidal antiinflammatory drugs. The COF-LZU1-modified column exhibits good stability and repeatability. The precisions (relative standard deviations) for intra-day, inter-day and column-to column are <1.6%, 5.6% and 6.8%, respectively. Hence, the imine-based COFs represent attractive stationary phase for application in CEC separations.

Deying Kong and Tao Bao contributed equally to this work. Electronic supplementary material The online version of this article (doi:10.1007/s00604-017-2095-5) contains supplementary material, which is available to authorized users. * Zilin Chen [email protected] 1

Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, and Wuhan University School of Pharmaceutical Sciences, Wuhan 430071, China

2

State Key Laboratory of Transducer Technology, Chinese Academy of Sciences, Beijing 10080, China

Keywords COF-LZU1 . Drug analysis . Capillary electrochromatography . In situ synthesis . Amino acids and NSAIDs . Schiff base . Open tubular column

Introduction Covalent organic frameworks (COFs) are a class of porous crystalline polymers that can be obtained by linking the organic building blocks via covalent bond into twodimensional(2D) layered eclipsed structure or threedimensional (3D) networks [1–3]. Since COFs were reported by Yaghi’s group in 2005 [4], they have been shown to possess great potential for further application. As these materials entirely consist of light weight elements (C, Si, B, O and N), they possess low mass densities, high thermal stabilities, tunable pore size and structure and large surface area. Besides, COFs have some unique advantages that are different from metal-organic frameworks (MOFs), such as structural regularity, atomic connectivity and porosity [5]. These properties make the COFs useful in gas storage [6], photoelectric applications [7], adsorption [8] and catalysis [9]. The application of COFs gradually extended to analytical fields. Yang et al. reported a simple and facile room-temperature solutionphase synthesis to fabricate a spherical covalent organic framework for chromatographic separation [10]. In the solid-phase microextraction, Wu et al. made use of a polydopamine method to immobilize COF on a stainless steel fiber [11]. These works inspire us to explore the novel strategy and COFs material to act as stationary phase, which is important to promote the development of capillary electrochromatography. Capillary electrochromatography (CEC) is a powerful separation technique that combines the high selectivity of high

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performance liquid chromatography (HPLC) with the high separation efficiency of capillary electrophoresis (CE) [12]. As one of capillary column formats in CEC, open tubular capillary electrochromatography (OT-CEC) has advantages of facile preparation without the fabrication of frits for packed columns or regulating the ration of function monomer and pore forming agent for monolith columns [13]. However, the disadvantages of low phase ratios and sample capacity slow down the development of OT-CEC [14]. The key of an OTCEC system is to choose the appropriate stationary phase materials that can enhance separation selectivity based on their structures and make up the shortcomings of OT-CEC. Therefore, more and more porous materials and nanoparticles have been applied as novel stationary phase [15, 16]. For example, graphene [17], magnetic nanoparticles [18], metal-organic frameworks (MOFs) [19]. As the advantages of porosity, selectivity and stability, COFs are the good candidates to act as novel stationary phase in OTCEC. However, the current method of immobilizing the COFs required an off-line course to synthetize COF materials [20]. Therefore, it is significant to develop a facile and convenient method. COF-LZU1 (Lan Zhou University-1), one of the iminebased COFs [21], was built up by the BSchiff base^ reaction of 1,3,5-triformylbenzene with 1,4-diaminobenzene. COFLZU1 possesses some remarkable properties: regular microporous channels, stability in water and most organic solvents, high surface areas and permanent porosity, which is attractive to apply COF-LZU1 in the field of chromatography. The building units of COF-LZU1 are rich in aldehyde and amino groups, which can serve as active site to realize the in situ synthesis of COF-LZU1 on the inner wall of capillary column. The method of in situ synthesis process was developed to graft COF-LZU1 on the inner wall of capillary. Besides, our group has achieved the immobilization of graphene [22], hydroxyapatite [23], MOFs [24–26] and COFs [27] for extraction and electrochromatographic separation, which lays the foundation for exploring a novel method to realize the situ synthesis of COF-LZU1 in capillary. In this work, we prepared a COF-LZU1 coated opentubular column using 3-aminopropyltriethoxysilane and glutaraldehyde as cross linker for electrochromatographic separation. The capillary columns were evaluated by separation of neutral analytes, amino acids and nonsteroidal antiinflammatory drugs (NSAIDs), the baseline separation of these compounds was achieved. In addition, the COF-LZU1 coated open-tubular column exhibited excellent stability and repeatability. The general morphology and surface properties of COF-LZU1 coated open-tubular column were characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectra (FT-IR). This strategy of fabricating the COF-LZU1 coated open-tubular column provided a novel method to apply the imine-based COFs to analytical fields.

Experimental Chemicals and materials 3-aminopropyltriethoxysilane (APTES), 1,3,5benzenetricarboxaldehyde, p-phenylenediamine, ketoprofen, ibuprofen, flurbiprofen, naphthalene, 4-phenyltoluene and phenanthrene were provided by Sigma-Aldrich (MO, U.S.A., www.sigma-aldrich.com). Chlorobenzene, 1,2dichlorobenzene, 1,2,4-trichlorobenzene, L-phenylalanine, L-tryptophan, L-tyrosine, methylbenzene, ethylbenzene and n-propylbenzene were purchased from Aladdin (Shanghai, China, www.aladdin-e.com). Sodium phosphate dibasic dodecahydrate (Na2HPO4·12H2O), glutaraldehyde solution 25%, ethanol and methanol were bought from Sinopharm Chemical Reagent Co., Ltd. (Shanghai, China, http://en. reagent.com.cn). All reagents in the experiments were analytical grade or chromatographic grade. Bare fused-silica capillaries with 50 μm i.d. × 360 μm o.d. were supplied by Ruifeng Chromatographic Devices (Yongnian, Hebei, China, http://liqingmi.b2b.chemm.cn). Deionized water was purified by a Milli-Q system (MA, USA, http://www.emdmillipore. com/US/en). Instrumentation All CEC separations and data collections were carried out on Agilent 7100 CE system (Waldbronn, Germany, http://cn. agilent.com). The CE system is equipped with an automatic sampler, a diode array detector, a temperature controlled column compartment and a chromatographic workstation (Chemistry Station, USA). A COF-LZUI modified opentubular column (50 μm i.d. × 360 μm o.d.) with a 32 cm total length and 23.5 cm effective length was used for all CEC experiments. The surface morphology of COF-LZU1 modified open-tubular column was observed by a Carl Zeiss Ultra Plus Field Emission scanning electron microscope (FESEM, Carl Zeiss, Germany, www.zeiss.com) at an accelerating voltage of 20 kV. Fourier transform infrared spectra (FT-IR) was achieved by using a Thermo Nexus 470 FT-IR system (MA, USA, http://www.thermonexus.com). Preparation of mobile phase and sample solutions The pH value of the phosphate solution was adjusted to the range of 5.0–9.0 by using phosphoric acid. The mobile phase was prepared by mixing Na2HPO4 at different concentration and pH with a certain amount of methanol. All solutions were stored in a refrigerator at 4 °C and filtered by syringe-driven filter before use. The standard solutions of 1 mg·mL−1 of L-phenylalanine, L-tryptophan and L-tyrosine were prepared by dissolving them in deionized water or 0.1 M NaOH individually. The

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standard solutions of ketoprofen, ibuprofen, and flurbiprofen were dissolving in methanol to a concentration of 1 mg·mL−1 respectively. The standard solutions of methylbenzene, ethylbenzene, n-propylbenzene, chlorobenzene, 1,2-dichlorobenzene and 1,2,4-trichlorobenzene were prepared individually in methanol at a concentration of 3 mg·mL−1. The standard solution of naphthalene was prepared by dissolving in methanol at a concentration of 0.2 mg·mL−1, and the concentration of 4-phenyltoluene and phenanthrene was 0.5 mg·mL−1. All standard solutions were all stored at 4 °C until to use. Preparation of aldehyde group-functionalized capillary The process of preparing the COF-LZU1 coated open-tubular column is schematically shown in Fig. 1. To achieve the growth of COF-LZU1 on the inner wall of capillary column, two commercial reagents, 3-aminopropyltriethoxysilane (APTES) and glutaraldehyde were applied to act as cross linker. Firstly, bare fused-silica capillary was rinsed with NaOH solution (1.0 M) for 2 h, deionized water for 10 min, HCl solution (0.5 M) for 10 min and deionized water for 10 min in sequence. Then capillary was flushed with the nitrogen stream and dried in an oven (100 °C) for 1 h. Secondly, pretreated capillary column was rinsed with a solution of APTES (10%, v/v) in ultrapure water for 5 min to fill with APTES solution. The capillary was sealed on both ends with a Teflon tube and kept in an oven (95 °C) for 30 min. This modification procedure needed to repeat once to ensure the full coating of amino group on the inner wall of capillary. A solution of glutaraldehyde (25%) was diluted to 2% (v/v) and adjusted pH to 11 with NaOH solution (0.5 M). Then the APTES-coated capillary was continually flushed with the resultant solution for 1 h at room temperature and sealed on both ends with a Teflon tube. The capillary filled with glutaraldehyde solution was put into the ultrasonic bath for 10 min at 40 °C and repeat this step. Before the growth of COF-LZU1

on the inner wall of capillary, the aldehyde groupfunctionalized capillary was flushing with ultrapure water for 30 min and dried with N2.

Preparation of COF-LZU1 coated open-tubular column For the growth of COF-LZU1 on the inner wall of capillary column, the aldehyde group-functionalized capillary was filled with p-phenylenediamine solution (2 mg·mL−1) prepared in dioxane, sealed on both ends with a Teflon tube, and kept in an oil bath at 150 °C for 1 h. Then 2 mg·mL−1 of 1,3,5-benzenetricarboxaldehyde solution in dioxane was injected into the capillary obtained the above step. Then the capillary filled with 1,3,5-benzenetricarboxaldehyde solution was circled by a Teflon tube and kept in an oil bath at 150 °C for 1 h. In this step, aldehyde group of 1,3,5benzenetricarboxaldehyde can react with amino of pphenylenediamine. Finally, the mixture of 0.05 mg·mL−1 pphenylenediamine and 0.05 mg·mL−1 1,3,5benzenetricarboxaldehyde (v/v 1:1), added 3 mol·L−1 aqueous acetic acid was introduced into the prepared capillary and circled by a Teflon tube and kept in an oil bath at 150 °C for 2 h. Between the different modification steps, the capillary was rinsed with anhydrous ethanol for 10 min to eliminate the residual solvent, dried by the nitrogen stream, and kept it in an oven at 100 °C for 1 h. This procedure of growth COFLZU1 on the aldehyde group-functionalized capillary was needed to repeat twice, so that COF-LZU1 was fully grown on the inner wall of the capillary. The COF-LZU1 coated open-tubular column was rinsed with anhydrous ethanol for 12 h to remove the residual solvent and dried with nitrogen stream before use. All the solutions were put through the capillary by the syringe pump (LongerPump Company, Baoding, China, www.lgpump.com.cn) and flow rate was maintained at 0.05 ml·h−1.

Fig. 1 Schematic demonstration for growth of COF-LZU1 on the inner wall of aldehyde group-functionalized capillary

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The preparation process of COF-LZU1 coated on the microscope cover glass was same as above procedure. Then the microscope cover glass modified with COF-LZU1 was used to FT-IR characterization.

Results and discussion Choice of materials The COF-LZU1 has common characterizations of COFs materials, such as high thermal stabilities and low densities. Besides, COF-LZU1 has some remarkable characteristics: high surface areas, stability in water and most organic solvents, and permanent porosity. Among these features, high surface areas and porosity can improve the shortcoming of OT-CEC. Stability can make sure that COF-LZU1 coated column does not affect by buffer solution, solvents. The structure of COF-LZU1 rich in benzene ring and amino groups. The characteristics provide the chemical fundamentals for improving the selectivity. It is good candidate as novel stationary phase for CEC. In addition, as a new class of porous crystalline polymers, it is significant to explore the application of COFs. Characterization of COF-LZU1 coated open-tubular column The morphology of bare column and COF-LZU1 coated open-tubular column were investigated by SEM. The inner wall of bare column is obviously smooth, as shown in Fig. S1. However, the inner surface of COF-LZU1 coated open-tubular column is visibly roughened. It can be seen that a large number of COF-LZU1 crystals are uniform grown on the inner surface of capillary. The SEM images of bare column and COF-LZU1 coated open-tubular column indicate the successful growth of COF-LZU1 on the inner wall of capillary. In addition, we need to confirm the immobilized on the aldehyde group-functionalized capillary is COF-LZU1 by FT-IR. Fourier transform infrared spectra was used to confirm the presence of functional groups and the successful modification of COF-LZU1 further. Respective data are given in the Electronic Supporting Material (Fig. S2), the result of FT-IR demonstrates that COF-LZU1 is successfully modified on the microscope cover glass. Therefore, this result also proves that it is feasible to modify COF-LZU1 on the inner wall of the capillary. Hence, the growth of COF-LZU1 on the inner wall of the capillary has been achieved. EOF mobility In CEC, electroosmotic flow (EOF) is the driving force to realize the transmission of mobile phase through the column.

There are many factors to influence the EOF, such as pH, buffer solution, organic solvent, applied voltage, temperature and so on. In this work, the effects of pH, concentration of buffer solution and organic solvent of buffer solution on EOF were investigated. Thiourea and methanol were chosen as neutral marker and organic modifiers respectively. The EOF was calculated using the formula [18]: μeo ¼ LVtd L0 t . Ld represents the effective length (23.5 cm) and Lt means the total length (32 cm). V is the applied voltage (12 kV) and t0 is the migration time of thiourea. As shown in Fig. S3A, the cathodic EOF of COF-LZU1 capillary column increases with the pH value in the range of 5.0–9.0. The inner wall of COF-LZU1 coated open-tubular column contains the uncovered silanol groups, which contributes to generate the EOF. So, the EOF increases with the increasing of pH value due to the increase of the dissociation of hydroxyl group. In the Fig. S3B, it can be seen that EOF decreases with the increase of methanol content. The thickness of the double layer is mainly affected by the percentage of methanol in buffer solution. In addition, the EOF decreases sharply with the increase of concentration of buffer solution as revealed in Fig. S3C. The concentration of buffer solution impacts on the thickness of the double layer and viscosity of solution. Optimization of method The separation performance of neutral compounds was only determined by its chromatographic retentions. Therefore, three neutral analytes (chlorobenzene, 1,2-dichlorobenzene, 1,2,4-trichlorobenzene) were chosen as analytes. The following parameters were optimized: methanol content, pH and concentration of buffer solution. Respective data and figures are given in the Electronic Supporting Material (Fig. S4). We found the following experimental conditions which offer best separation performance: 10 mM Na2HPO4 at pH 8.0 containing 20% methanol. The retention factors of the analytes were calculated to reflect the interaction between analytes and stationary phase. Respective data and formula are given in the Electronic Supporting Material (Fig. S5). This variation trend of retention factors is consistent with above results. Separation performance of COF-LZU1 @ capillary towards neutral analytes, amino acids and NSAIDs To further study the separation ability of COF-LZU1 coated open-tubular column, the electrochromatograms of separation of neutral analytes, amino acids and NSAIDs are shown in Fig. 2, Fig. 3 and Fig. 4 respectively. It can be seen in Fig. 2a, baseline separation for methylbenzene, ethylbenzene and propylbenzene is obtained. The substituents contain more phenyl ring, logP of alkylbenzenes is greater. The elution orders of alkylbenzenes

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Fig. 2 Separation behavior of neutral compounds on the COF-LZU1 coated open-tubular column. Temperature: 25 °C; Injection: 10 mbar × 5 s; UV detection at 210 nm; Effective length: 23.5 cm, total length: 32 cm. a Voltage: 8 kV; Buffer: 10 mM phosphate buffer with 10% (v/v) methanol,

pH 5.0; Peak identities: 1, methylbenzene; 2, ethylbenzene; 3, propylbenzene. b Voltage: 10 kV; Buffer: 20 mM phosphate buffer with 20% (v/v) acetonitrile, pH 8.5; Peak identities: 1, naphthalene; 2,4phenyltoluene; 3, phenanthrene

is in accordance with the order of molecular sizes and logP. And the separation performance of naphthalene, 4phenyltoluene and phenanthrene is shown in Fig. 2b. The elution orders of the above analytes are consistent with the ascending order of logP value. So, the possible separation mechanism towards neutral compounds is hydrophobic interaction and π-interaction between neutral analytes and COFLZU1 coated open-tubular column. The analytes with stronger hydrophobicity provide stronger hydrophobic interaction with COF-LZU1 layer. As a result, the migration time of analytes is even longer. The pore size of COF-LZU1 layer might contribute to the separation of neutral compounds. As shown in Fig. 3, baseline separation for L-phenylalanine, L-tryptophan and L-tyrosine is achieved. The pKa1 values of the amino acids are all smaller than 3.0 and the pKa2 values of the amino acids are all greater than 9.0 [28,

29]. When the pH value of buffer solution is 8.5, the amino groups of the amino acids are partially protonated. The carboxylic acid groups of the amino acids are completely deprotonated. So the net charge of the amino acids is negatively charged, which will migrate toward the anode. In CEC, there are three process involved in the separation of the amino acids: electrophoretic migration of anionic solutes, EOF and interactions between the amino acids and COF-LZU1 layer. Owing to the rate of the EOF greater than the rate of electrophoresis, the amino acids would migrate toward the cathode in CEC. Therefore, π-interaction of the amino acids with the COF-LZU1 layer plays an important role in separation of Lphenylalanine, L-tryptophan and L-tyrosine. In addition, imine and primary amino groups of COF-LZU1 may form hydrogen bond with the amino acids. The primary amino groups

Fig. 3 Separation behavior of amino acids on the COF-LZU1 coated open-tubular column. Buffer: 30 mM phosphate buffer with 50% (v/v) methanol, pH 8.5. Other experimental conditions are same as Fig. 2. Peak identities: 1, L-tryptophan; 2, L-tyrosine; 3, L-phenylalanine

Fig. 4 Separation behavior of NSAIDs on the COF-LZU1 coated opentubular column. Buffer: 20 mM phosphate buffer with 45% (v/v) methanol. Injection: 22 mbar × 5 s; Voltage: 15 kV. Other experimental conditions are same as Fig. 2. Peak identities: 1, ketoprofen; 2, flurbiprofen; 3, ibuprofen

Microchim Acta Table 1 column

Repeatability and stability of COF-LZU1coated capillary

Analytes

RSDs Intra-day (n = 5)

Inter-day (n = 5)

Column-to-column (n = 3)

chlorobenzene

1.1

1.6

2.4

1,2-dichlorobenzene 1,2,4-trichlorobenzene

1.1 1.6

1.3 5.6

0.6 6.8

of COF-LZU1 can provide a hydrophilic interaction with the amino acid. The combined effects of these actions contribute to the baseline separation of amino acids. As revealed in Fig. 4, ketoprofen, ibuprofen and flurbiprofen are achieved the baseline separation. The pKa value of ketoprofen, ibuprofen and flurbiprofen is 3.7, 4.5 and 4.2 respectively [30, 31]. At the buffer solution of 20 mM Na2HPO4 solution containing 40% methanol, the NSAIDs is negative. The elution order is determined by three elements: EOF, electrophoretic migration, and the interaction with the COF-LZU1. Hence, there are the following aspects involved in the possible separation mechanism: π-interaction, hydrophobic interaction and a certain degree of hydrophilic interaction provided by the primary amino groups of COFLZU1. At the same separation conditions, the COF-LZU1 column shows better separation performance as compared with the electrochromatograms of bare column (Fig. S6 and Fig. S7). So, the coating of COF-LZU1 greatly improves the separation selectivity by enhancing stationary and analytes interaction. All the results show that the capillary column modified with COF-LZU1 improves the separation performance and presents a wide range of applicability. Based on above results, this column is suitable for separation of polar compounds, organic acids and some biological samples, such as polypeptides. Table 2

Stability of COF-LZU1 @ capillary In order to develop a new type of stationary phase capillary column successfully, stability and repeatability is one of the important evaluation indexes. The stability of COF-LZU1 coated column was investigated by the relative standard deviations (RSDs) of intra-day, inter-day and column-to-column. The precision of three neutral analytes (chlorobenzene, 1,2-dichlorobenzene and 1,2,4-trichlorobenzene) in migration time was investigated. As shown in Table 1, the intra-day and inter-day RSDs of chlorobenzene compounds for five times are all below 1.6% and 5.6%. The column-to-column RSDs of chlorobenzene compounds for three columns are below 6.8%. In addition, after flushed by anhydrous ethanol for 20 h or run more than 60 times under CEC, the COF-LZU1 coated open-tubular exhibits certain stability without significant changes in migration time and peak shape. So the above data show that COF-LZU1 coated open-tubular exhibits good stability and repeatability. Comparison with reported methods The COF-LZU1 coated column obtained by in-situ synthesis was compared with other materials-coated columns for CEC. As listed in Table 2, the method of in situ synthesis is facile and easy to operate without the processing of synthesis. In addition, the application of COF-LZU1-coated column was expanded to drug analysis and biological analysis. The COF-LZU1-coated column by in situ synthesis exhibited good stability and wide application. In addition, the method of in situ synthesis can be used to immobilize other imine-based COF materials.

Conclusion In conclusion, we have successfully grown COF-LZU1 on the inner wall of capillary column by in situ synthesis for CEC.

An overview on recently reported material-based coatings for capillary electrochromatography

Materials

Methods

Analytes

Applicability

References

magnetic nanoparticle silica nanoparticles ZIF-90 graphene graphene oxide hydroxyapatite MOF HKUST-1

external magnetic force multilayer-by-multilayer process post-modification electrostatic assembly layer-by-layer assembly polydopamine-assisted immobilization liquid-phase epitaxy process

other separation modes use in proteinic applications carboxylate-based MOFs

[32] [33] [34] [12] [35] [23] [25]

COF-LZU1 COF-5

independent synthesis polydopamine-supported immobilization in situ synthesis

organic acids aromatic hydrocarbons neutral, NSAIDs, basic compounds nitroaniline isomers neutral compounds acid, basic and neutral compounds alkylbenzenes, phenols, and phenolic compounds alkylbenzenes, anilines, PAHs neutral, acidic, basic analytes

versatile substrates

[20] [27]

COF-LZU1

amino acids, NSAIDs, neutral compounds imine-based COFs

This work

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The characterization results of SEM and FT-IR show that COF-LZU1 is modified successfully on the inner wall of capillary column. The COF-LZU1 coated open-tubular column possesses good separation efficiency and exceptional selectivity, which is applied to separate the neutral compounds, amino acids and NSAIDs. The column also exhibits good stability and repeatability. The method of in situ synthesis of COFLZU1 in capillary is facile and simple without the independent process of synthesis. The COF-LZU1-coated column by in situ synthesis can be applied into the fields of drug and biological analysis. This work proves the feasibility for introducing imine-based COFs to OT-CEC as novel stationary phase by the method of in situ synthesis. Acknowledgements This work was supported by the National Natural Science Foundation of China (Grant Nos. 81573384, 21375101 and 91417301), Natural Science Foundation of Hubei Province (No. 2014CFA077). Compliance with ethical standards The authors declare that they have no competing interests.

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