DEVELOPMENT OF NOVEL CHIRAL STATIONARY PHASES FOR HPLC BASED ON COVALENTLY BONDED POLYSACCHARIDE DERIVATIVES ZHANG SHENG NATIONAL UNIVERSITY OF SINGAPORE 2009 DEVELOPMENT OF NOVEL CHIRAL STATIONARY PHASES FOR HPLC BASED ON COVALENTLY BONDED POLYSACCHARIDE DERIVATIVES ZHANG SHENG (B.Sc., Peking University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2009 Acknowledgements I would like to express my immense gratitude to my supervisor, Prof. Hardy Chan, for his invaluable guidance and supervision throughout these years of my project. He has devoted his valuable time to help me in the project and thesis, not only with his knowledge but also with his zealous encouragement and constant concern. Special thanks to Prof. Ng Siu Choon and Dr. Ong Teng Teng for their advice and help during the research project and the preparation of my thesis. I wish to express my sincere thanks to all postdoctoral fellows, postgraduates and undergraduates in the Functional Polymer Laboratory. In particular, I wish to thank Dr. Lai Xianghua, Dr. Zhang Weiguang, Dr. Tang Weihua, Lee Teck Chia, Xu Changhua, Sylvia Tan and Soh Wanqin for the exchange of knowledge and opinion on organic synthesis and HPLC analysis; Dr. Xia Haibin, Dr. Chen Daming, Dr. Tang Jiecong, Liu Xiao, Che Huijuan, Lu Xiaomei, Fan Dongmei, Wen Tao for their advice and friendship. I also want to thank National University of Singapore for the award of the Research Scholarship and Department of Chemistry for the facilities to carry out my research work. Last but not least, I am very thankful to my parents for their warmest advice and constant encouragement during my studies. i Table of Contents Acknowledgements Table of Contents Summary List of Tables List of Figures List of Schemes List of Structures Abbreviations and Symbols i ii vi viii xi xiii xiv xv Chapter Introduction 1.1 Chirality and need of chiral separation 1.2 Chiral separation techniques 1.3 High performance liquid chromatography in chiral separation 1.3.1 1.3.2 1.3.3 Type I CSPs in HPLC: Pirkle-type CSPs Type II CSPs in HPLC: polysaccharide-derived CSPs Type III CSPs in HPLC: inclusion-type CSPs 8 1.3.3.1 1.3.3.2 1.3.3.3 Cyclodextrin-derived CSPs in HPLC Crown ether-derived CSPs in HPLC Optically active synthetic polymer derived CSPs in HPLC 11 11 1.3.4 1.3.5 Type IV CSPs in HPLC: chiral complex CSPs Type V CSPs in HPLC: protein-derived CSPs and antibioticsderived CSPs 11 12 1.4 Polysaccharide-derived CSPs in HPLC 13 1.4.1 1.4.2 1.4.3 Early development of polysaccharide-derived CSPs Development of coated polysaccharide-derived CSPs Development of immobilized polysaccharide-derived CSPs 14 14 18 1.4.3.1 1.4.3.2 1.4.3.3 19 19 20 1.4.3.4 Immobilized polysaccharide-derived CSPs by direct covalent linkage Immobilized polysaccharide-derived CSPs by reticulation Immobilized polysaccharide-derived CSPs by a combination of covalent linkage and reticulation Commercially available immobilized polysaccharide-derived CSPs 1.4.4 Other polysaccharide-derived CSPs 21 1.4.4.1 Polysaccharide-derived CSPs based on other chromatographic supports Polysaccharide-derived CSPs with no chromatographic support 22 1.4.4.2 21 23 ii 1.4.5 1.5 Mechanism study of polysaccharide-derived CSPs Research objectives and scope 24 26 Chapter Synthesis of azido cellulose phenylcarbamate, its immobilization onto aminopropyl silica gel via the Staudinger reaction and its application as CSP for HPLC 28 2.1 Introduction 29 2.2 Synthesis 30 2.2.1 30 2.2.2 Synthesis of azido cellulose phenylcarbamate (AzCPC) via the “protection-deprotection” route Immobilization of AzCPC via the Staudinger reaction 2.2.2.1 2.2.2.2 Immobilization via the “bonding-with-pre-coating” approach Immobilization via the “bonding-without-pre-coating” approach 40 42 2.3 2.4 37 Comparison of enantioseparation of CSP AzCPC-I and AzCPC-II 44 2.3.1 2.3.2 Theoretical plate number and surface concentration Enantioseparation in normal phase mode 44 46 2.3.2.1 2.3.2.2 Enantioseparation in standard normal phases Enantioseparation in chloroform-containing normal phases 46 49 2.3.3 2.3.4 Enantioseparation in reverse phase mode Loading capacity of the HPLC columns 50 52 Summary 56 Chapter Azido cellulose phenylcarbamates with different amount of azido group and their application as CSPs for HPLC 57 3.1 Introduction 58 3.2 Synthesis 61 3.2.1 62 3.2.2 Synthesis of azido cellulose phenylcarbamates (AzCPCs) via the homogenous synthetic route Immobilization of AzCPC onto aminopropyl silica gel via the “bonding-with-pre-coating” approach 65 iii 3.3 3.4 Characterization of “iodine-ratio” AzCPC and CSP series 66 3.3.1 3.3.2 66 74 Enantioseparation results of the “iodine-ratio” CSP series 76 3.4.1 3.4.2 77 78 3.4.3 3.4.4 3.4.5 3.5 Characterization of “iodine-ratio” AzCPC series Characterization of “iodine-ratio” CSP series Theoretical plate numbers of the “iodine-ratio” CSP series Enantioseparation results of “iodine-ratio” CSP series in the standard IPA-hexane solvent system Enantioseparation results of CSP AzCPC-1.5I2 in chloroformIPA-hexane solvent system Enantioseparation results of CSP AzCPC-1.5I2 in dichloromethane-IPA-hexane solvent system Enantioseparation results of CSP AzCPC-1.5I2 in EA-IPAhexane and THF-IPA-hexane solvent systems Summary 83 90 94 96 Chapter Substituted azido cellulose phenylcarbamates and their application as CSPs for HPLC 98 4.1 Introduction 99 4.2 Synthesis of CSPs based on substituted azido cellulose phenylcarbamate 101 4.3 Enantioseparation results of substituted azido cellulose phenylcarbamate in standard IPA-hexane solvent systems 103 4.4 Enantioseparation results of substituted azido cellulose phenylcarbamate in non-standard solvent systems 113 4.4.1 115 4.4.2 4.5 Enantioseparation of flavanone and flavanone derivatives in non-standard mobile phases Enantioseparation of benzoin and benzoin derivatives in nonstandard mobile phases Summary 126 136 iv Chapter Experimental 138 5.1 139 General 5.1.1 5.1.2 5.1.3 5.1.4 5.2 Materials Characterization instrumentation HPLC instrumentation Basic chromatographic parameters 139 140 140 140 Synthesis of azido phenyl carbamate (AzCPC) 142 5.2.1 Synthesis of AzCPC by the “protection-deprotection” route 142 5.2.1.1 5.2.1.2 142 143 5.2.1.3 5.2.1.4 Dissolution of cellulose in DMAc/LiCl Synthesis of 6-O-(4-methoxytrityl)-2,3-diphenylcarbamoylcellulose III Synthesis of 2,3-diphenylcarbamoylcellulose - IV Synthesis of azido cellulose phenylcarbamate (AzCPC) - V 5.2.2 Synthesis of AzCPC by homogeneous route 145 5.2.2.1 5.2.2.2 5.2.2.3 5.2.2.4 Synthesis of azido cellulose Synthesis of AzCPC by perfunctionalization of azido cellulose Synthesis of substituted azido cellulose phenylcarbamate Synthesis of diisopropylureido cellulose phenylcarbamate (DIPUCPC) 145 145 146 146 5.3 Preparation and packing of CSPs 5.3.1 5.3.2 5.3.3 Preparation of CSP via the “bonding with pre-coating” approach Preparation of CSP via the “bonding-without-pre-coating” approach HPLC column packing 143 144 146 146 147 148 Chapter Conclusions and suggestions for future work 149 6.1 Conclusion 150 6.2 Suggestions for future work 152 Reference 154 v Summary Chirality is of more and more concern in modern chemistry and related areas. The importance of single enantiomer of high value-added chemicals, especially pharmaceuticals, has greatly stimulated research and application in both asymmetric synthesis and chiral separation. High performance liquid chromatography (HPLC) with chiral stationary phase (CSP) is one of the most successful approaches towards chiral analysis and separation, in both analytical scale and preparative scale. In this work, new classes of chiral stationary phases have been developed based on azido cellulose phenylcarbamate derivatives. Azido cellulose phenylcarbamate (AzCPC) is first synthesized by the “protectiondeprotection” route in four steps. It is then immobilized onto aminopropyl silica gel via the Staudinger reaction. Two CSPs are prepared via the “bonding-with-pre-coating” approach (CSP AzCPC-I) and the “bonding-without-pre-coating” approach (CSP AzCPC-II). Since these two CSPs are prepared from the same chiral selector and substrate, the effect of immobilization approach is studied. Enantioseparation results show that CSP AzCPC-I has a better performance because of its larger surface concentration of the AzCPC chiral selector. Based on this successful “bonding-with-pre-coating” immobilization approach, another five AzCPCs are immobilized to afford a series of “iodine-ratio” CSPs. In the preparation of these five AzCPCs from the homogeneous synthetic route, different amount of iodine is used to react with cellulose in the LiCl/DMAc solvent system. Different AzCPC synthesized from different iodine-cellulose ratio has different degree of vi substitution value of azido and phenylcarbamoyl group, as characterized by elemental analysis, 1H NMR and 13 C NMR. By comparison of the enantioseparation results of 25 racemic analytes in standard IPA-hexane mobile phases, CSP AzCPC-1.5I2 is considered the best CSP in the “iodine-ratio” series. Further study in non-standard mobile phases shows that addition of chloroform or dichloromethane generally improves the resolution of tested racemic analytes. On the other hand, addition of tetrahydrofuran is only able to improve the resolution of a few analytes, while addition of ethyl acetate does not show any improvement. Ten substituted azido cellulose phenylcarbamates are synthesized by reaction of azido cellulose and corresponding substituted phenyl isocyanates. Optimum ratio of iodine : cellulose = 1.5:1 is used. The immobilized CSPs are compared in both standard and non-standard mobile phases. CSP AzCPC-3,5-(CH3)2 has the best overall performance while CSP AzCPC-4-CH3, AzCPC-3-Cl, AzCPC-4-Cl and AzCPC-4-I also resolve certain racemic analytes well. Because of the bonded nature of the current CSPs, they are resistant to non-standard mobile phases containing chloroform, dichloromethane or tetrahydrofuran. Optimization of selected racemic analytes is realized on various CSPs in chloroform-containing, dichloromethane-containing, tetrahydrofurancontaining mobile phases, as well as standard IPA-hexane mobile phases. vii List of Tables Table 2.1 Surface concentration of CSP AzCPC-I and CSP AzCPC-II. 45 Table 2.2 HPLC enantioseparation results for CSP AzCPC-I and CSP AzCPC-II in IPA-hexane mobile phases. 47 Table 2.3 HPLC enantioseparation results of CSP AzCPC-I in CHCl3-IPAhexane mobile phases. 49 Table 2.4 Enantioselectivity α of CSP AzCPC-I in reverse phase. 50 Table 2.5 Separation of different amount of trans stilbene oxide on CSP AzCPC-I in 10% IPA-90% hexane mobile phase. 53 Table 2.6 Separation of different amount of benzoin methyl ether on CSP AzCPC-I in 10% IPA-90% hexane mobile phase. 54 Table 2.7 Separation of different amount of trans stilbene oxide on CSP AzCPC-I in 10% CHCl3-90% hexane mobile phase. 55 Table 3.1 Molar ratios of cellulose to iodine in the synthesis of the “iodineratio” AzCPC series. 64 Table 3.2 DS of the “iodine-ratio” AzCPC series determined by elemental analysis. 67 13 70 Table 3.3 C NMR chemical shifts (ppm) of CTPC and AzCPC samples. Table 3.4 DS of the “iodine-ratio” AzCPC series by 13C-NMR and 1HNMR. 71 Table 3.5 Surface concentration of the “iodine-ratio” series CSPs. 76 Table 3.6 Theoretical plate numbers of the “iodine-ratio” series CSPs. 78 Table 3.7 Enantioseparation results of the “iodine-ratio” series CSPs in standard IPA-hexane solvent system. 79 Table 3.8 Enantioseparation results of CSP AzCPC-1.5I2 in different standard IPA-hexane mobile phases. 82 Table 3.9 Enantioseparation results of CSP AzCPC-1.5I2 in CHCl3-IPAhexane solvent system I (hexane volume ratio = 90%). 84 viii 5.3.3 HPLC column packing The immobilized CSPs were packed by the slurry method. The slurry solvent was p-dioxane/tetrachloromethane and the packing solvent was methanol. 3.5 g of CSP was packed into a stainless steel column (∅4.6×250 mm) at a pressure of 7800 psi for 20 before the pressure was gradually released. The column was conditioned with mobile phase before use. 148 Chapter Conclusions and suggestions for future work 149 6.1 Conclusion A new class of chiral stationary phases has been developed based on immobilization of azido cellulose derivatives. Seventeen CSPs have been prepared in the following three series. (i) “Immobilization approach” series: CSP AzCPC-I and CSP AzCPC-II. These two CSPs were prepared from the same chiral selector AzCPC (from the “protection-deprotection” synthetic route). CSP AzCPC-I was prepared via the “bond-with-pre-coating” approach and CSP AzCPC-II was via the “bonding-withoutpre-coating” approach. The influence of pre-coating step was investigated by using the same chiral selector, substrate and chemical linkage. The CSPs showed satisfactory enantioselectivities towards a variety of racemic compounds in standard normal phase, chloroform-containing normal phase and reverse phase. The CSP AzCPC-I immobilized via the “bonding-with-pre-coating” approach has a larger surface concentration and thus larger loading capacity, which is essential for semipreparative and preparative scale chromatography. By comparison of the two CSPs, the “bonding-with-pre-coating” approach has been proven a better immobilization approach and utilized in the subsequent work. (ii) “Iodine-ratio” series: the azido cellulose phenylcarbamates in this series were synthesized by the homogenous synthetic route in DMAc/LiCl solvent system. Five AzCPCs have been synthesized by adjusting the iodine-cellulose ratio in order to control the amount of azido spacer. The structures of these AzCPCs were characterized by elemental analysis, FT-IR, 1H and 13 C NMR. The AzCPCs were immobilized via the “bonding-with-pre-coating” approach to afford the “iodine-ratio” series CSPs. Enantioseparation results show that CSP AzCPC-1.5I2 (iodine : cellulose = 1.5:1) is the best among the five CSPs. In addition, a comparison between the non- 150 standard and standard mobile phases was made using CSP AzCPC-1.5I2. It is found that chloroform-containing, dichloromethane-containing and tetrahydrofuran- containing mobile phases can improve the enantioseparation results of some racemates such as trans stilbene oxide, flavanone, 5-methoxyflavanone, benzoin ethyl ether, benzoin isopropyl ether and benzoin, whereas ethyl-acetate-containing mobile phases show no improvement to any of the tested racemates. (iii) “Substituted AzCPC” series: ten substituted AzCPCs were synthesized by reaction of azido cellulose with ten different substituted phenyl isocyanates. In the synthesis, the iodine-cellulose ratio was kept at constant 1.5:1 and the phenyl isocyanates had different electron-donating or electron-withdrawing groups on the phenyl ring. The substituted AzCPCs were immobilized via the “bonding-with-precoating” approach and the resulted CSPs were compared. Similar to previously reported results in the literature, CSPs with substituents on the 3- and 4-position of the phenyl rings generally showed improved enantioselectivity than the un-substituted CSPs, while the CSPs with substituents on the 2-position of the phenyl ring showed poorer performance. In addition, CSP AzCPC-4-CH3O and AzCPC-4-CF3O performed poorly because the polar methoxy or trifluoromethoxy groups are far from the chiral AGU. The current study confirms the above results not only in the “standard” mobile phases (IPA-hexane) but also in the “non-standard” mobile phases (CHCl3-IPA-hexane, CH2Cl2-IPA-hexane and THF-IPA-hexane). Because of the bonded nature of the immobilized CSPs in this thesis, they are resistant to “nonstandard” mobile phases of different mix. Optimizations of enantioseparation for several racemates were realized by adjusting mobile phase components on various CSPs. 151 To conclude, a new immobilization method has been developed to synthesize new chiral stationary phases. Azido cellulose phenylcarbamate derivatives were reacted with aminopropyl silica gel to afford stable CSPs with urea linkages. The synthesis of azido cellulose phenylcarbamates, the immobilization of azido cellulose phenylcarbamates on silica, the effect of the amount of azido spacer group and the different substitution groups on the ultimate performance of the CSPs have been investigated and optimized. The obtained CSPs show high stability in all mobile phases and give satisfactory enantioseparation results. Enantioseparations of several racemates have been optimized on various CSPs. 6.2 Suggestions for future work The highly ordered 3-D structure of cellulose phenylcarbamates is essential for successful enantioseparations.3 In cellulose triphenylcarbamate, all the hydroxyl groups have been converted to phenylcarbamates, which help to maintain the helical structure of cellulose polymer chain. On the other hand, in AzCPCs, some hydroxyl groups have been converted to azido groups instead of phenylcarbamate groups. The azido groups would change the highly ordered 3-D structure of AzCPC and the change becomes more significant when more azido groups are present on the cellulose chain. It is therefore expected that a reduction of the amount of azido groups would lead to chiral selectors with better chiral discrimination ability. However, the reduction of azido as the spacer group may result in a smaller amount of AzCPC to be immobilized on the silica gel. In other words, a combination of AzCPC with less azido groups and a more efficient immobilization approach would be an obvious approach in the future work. 152 In the current work, various azido cellulose phenylcarbamates have been used as the chiral selectors. The work can be extended to other polysaccharides and other derivatives. Polysaccharides such as amylose, amylopectin, chitosan, chitin, xylan, curdlan, dextran, inulin, pullulan and guar are some natural occurring chiral polymers and they can be converted to azido polysaccharide derivatives as potential chiral selectors. The free hydroxyl groups of the polysaccharide can be converted to benzoates, aliphatic acid esters, alkyl ethers or cycloalkylcarbamates by reaction with corresponding benzoic chlorides, carboxylic acid anhydrides, alkyl halides or cycloalkyl isocyanates. 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The Journal of Organic Chemistry 2008, 73, 78577870. 163 [...]... suggested for environmental, economical, health, safety and intellectual property reasons.16 For environmental science, the metabolism, degradation, transportation, accumulation and toxicity of chiral pollutants are studied by enantioselective analysis.19 For food science, chirality can be used for identification of adulterated foods and beverages, evaluation of food storage, evaluation of flavor and... advantages, HPLC continues to be one of the best choices for chiral analysis and separation Basically, there are two modes to achieve enantioseparation on HPLC: i) the indirect mode by addition of chiral mobile phase additive (CMPA); and ii) the direct mode by using chiral stationary phase (CSP) While CMPA is more often used in CE and TLC enantioseparations, CSP is the dominant enantioseparation mode in HPLC. .. spontaneously formed and mechanically separated;30,31 ii) formation and separation of diastereomers, in which 5 racemic substrate is converted to a pair of diastereomers by reaction with a chiral resolving reagent and separated by distillation, crystallization or non -chiral chromatography;32,33 and iii) kinetic resolution, in which “partial or complete resolution by virtue of unequal rates of reaction... THF-containing solvent system 115 ix Table 4.10 Enantioseparation of flavanone 10 in different mobile phases on CSP AzCPC-3,5-(CH3)2 116 Table 4.11 Enantioseparation of 5-methoxyflavanone 11 in different mobile phases on CSP AzCPC-3,5-(CH3)2 118 Table 4.12 Enantioseparation of 6-methoxyflavanone 12 in different mobile phases on CSP AzCPC-4-I 123 Table 4.13 Enantioseparation of 7-methoxyflavanone 13... chemically bonded proteins are more often used as CSPs For chemical immobilization, proteins can be bonded either via the amino group by a urea linkage107 or an amine linkage,108 or via the carboxyl group by an amide linkage.109 Once chemically bonded, the chiral recognition properties of a protein may be different from its free form in solution because either its functional groups are blocked or its conformation... inclusion, dipole stacking, steric repulsions and a 12 combination of interactions.113 The chemical properties, chromatographic conditions, mechanisms, limitations and applications of macrocyclic antibiotics in HPLC have been reviewed.112,113 1.4 Polysaccharide- derived CSPs in HPLC According to Wainer’s classification,50 polysaccharide- derived CSPs belong to type II CSPs in HPLC The solute-CSP interaction... and analysis of chiral metabolites of chiral and prochiral food components.21 The great need to synthesize and analyze enantiomerically pure chemicals has led to a blooming development of both chiral synthesis and chiral separation in the past decades 1.2 Chiral separation techniques The increasing demand of enantiomerically pure compounds has stimulated development of asymmetric synthesis on both laboratory-scale... Type IV CSPs in HPLC: chiral complex CSPs Type IV CSPs are based on formation of mixed-ligand ternary diastereomeric complexes between the chiral selector and chiral analytes Chromatography based on 11 type IV CSPs is also called chiral ligand exchange chromatography Complexed with Cu(II) or other divalent metal cations, type IV CSPs are especially effective in separation of derivatives of α-amino acids,... chiral compounds by 2007 as shown by the data from ChirBase.39 Chiral GC is mainly used for the analysis of volatile and thermally stable chiral compounds from environmental, biological, agricultural and food sciences.40 Most GC enantioseparations are realized on GC chiral stationary phases (CSPs), which utilize three types of chiral selectors:40,41 i) amino acid derivatives, which form hydrogen bonding... analytes; ii) chiral metal complexes, which interact with the analytes by coordination or complexation; and iii) cyclodextrin (CD) derivatives, which form inclusion complexes with the analytes Chiral HPLC is widely used in enantioseparation of a large variety of chiral compounds and it is reviewed in Section 1.3 Besides GC and HPLC, there are also other chromatographic chiral separation techniques Chiral . DEVELOPMENT OF NOVEL CHIRAL STATIONARY PHASES FOR HPLC BASED ON COVALENTLY BONDED POLYSACCHARIDE DERIVATIVES ZHANG SHENG NATIONAL UNIVERSITY OF SINGAPORE. NATIONAL UNIVERSITY OF SINGAPORE 2009 DEVELOPMENT OF NOVEL CHIRAL STATIONARY PHASES FOR HPLC BASED ON COVALENTLY BONDED POLYSACCHARIDE DERIVATIVES ZHANG SHENG (B.Sc., Peking. opposite directions. As a result, chiral separation is one of the most difficult separation tasks, which is barely possible in a non -chiral separation environment. Although chiral separation is difficult,