SELF-ASSEMBLY OF PERFUNCTIONALIZED -CYCLODEXTRINS AND CHIRAL DISCRIMINATION BY QUARTZ CRYSTAL MICROBALANCE XU CHANGHUA NATIONAL UNIVERSITY OF SINGAPORE 2010 SELF-ASSEMBLY OF PERFUNCTIONALIZED -CYCLODEXTRINS AND CHIRAL DISCRIMINATION BY QUARTZ CRYSTAL MICROBALANCE XU CHANGHUA (B.Sc. (Hons.), Tsinghua University) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2010 Acknowledgements I would like to express my immense gratitude to my supervisors, Prof. Chan Sze On, Hardy and Prof. Ng Siu Choon for their invaluable guidance and advice, constant encouragement and inspiring discussions throughout this project and during the preparation of my thesis. I deeply appreciate the kind assistance from Dr. Cheng Jinting, Dr. Ong Teng Teng, Dr. Ye Enyi, Dr. Yi Jiabao, Dr. Shi Jiahua and Dr. Kiew Shih Tak. My acknowledgement also goes to my peers at the Functional Polymer Laboratory, Department of Chemistry, NUS. In particular, I wish to thank Dr Tang Jiecong who has rendered meritorious help in organic synthesis, Zhang Sheng, Che Huijuan, Fan Dongmei, Fu Caili, Xu Jia and Wen Tao for their advices and friendship. Last but not least, I also want to thank National University of Singapore for awarding the research scholarship and for providing the facilities to carry out the research work reported herein. i Table of Content Acknowledgements . i  Table of Content .ii  Summary .vii  List of Tables . x  List of Figures . xiii  Abbreviations and Symbols xx  Current Publication .xxii  Chapter Introduction  1.1 Introduction 2  1.1.1 Stereoisomers and chirality 2  1.1.2 Why are chiral discrimination and separation important? . 3  1.2 Approaches for chiral separation . 5  1.2.1 Techniques for chiral separation . 5  1.2.2 Chiral sensors . 9  1.3 Functionalized cyclodextrins . 12  1.3.1 Characteristics of cyclodextrins . 12  1.3.2 Modification of cyclodextrins 17  1.3.3 Applications of cyclodextrins in chiral discrimination and separation 19  1.3.4 Mechanisms of chiral recognition 21  ii 1.4 Quartz crystal microbalance 27  1.4.1 Theory of QCM 28  1.4.2 Applications of QCM . 31  1.5 Self-assembled technique 33  1.5.1 Overview 34  1.5.2 Applications of self-assembled technique . 35  1.5.3 Self-assembly of thiolated cyclodextrins . 37  1.6 Objectives 38  Chapter 2    Perfunctionalization of -cyclodextrins and Their Self-Assembled Monolayers on Gold Surface  2.1 Introduction 41  2.2 Modification of -Cyclodextrins . 43  2.2.1 Synthesis of heptakis-(6A-azido-6A-deoxy)--CDs derivatives . 43  2.2.2 Synthesis of sulfide pendants . 45  2.2.3 Synthesis of mercaptyl perfunctionalized -CDs . 45  2.3 Fabrication and Characterizations of Monolayers . 48  2.3.1 Immobilization processes . 48  2.3.2 Characterization of monolayer structures by AFM 52  2.3.3 Characterization of monolayer structures by XPS . 54  2.3.4 Surface monolayer concentration and coating reproducibility . 56  2.3.5 Characterization of monolayer structures by Spectroscopic ellipsometry60  iii 2.4 Summary 63 Chapter 3    Gas Phase Chiral Discrimination by Chiral Sensors Coated with Mercaptyl Perfunctionalized -Cyclodextrins based on Quartz Crystal Microbalance  3.1 Introduction 66  3.2 Stability of Chiral Receptors 68  3.3 Reproducibility of Chiral Discrimination 68  3.4 Analyte Concentration Study . 70  3.5 Determination of Enantiomeric Composition/Purity 72  3.6 Gas Phase Chiral Discrimination toward Selected Enantiomers . 74  3.6.1 Sensor responses and chiral discrimination by MP--CD . 76  3.6.2 Chiral discrimination by chiral selectors with distinct cavity sizes 86  3.6.3 Chiral discrimination by similar sizes of chiral selectors with different substituent on phenyl groups . 90  3.7   Thermodynamic Study of Chiral Discrimination in Gas Phase 93  3.7.1   Thermodynamic of enantiomeric recognition 93  3.7.2   Enthalpy-entropy compensation of chiral recognition . 98  3.8   Summary . 100 Chapter 4    Liquid Phase Chiral Discrimination by Chiral Sensors Coated with Mercaptyl Perfunctionalized -Cyclodextrins based on Quartz Crystal iv Microbalance  4.1   Introduction . 104  4.2 Chiral Discrimination in Liquid Phase 107  4.2.1 Interpretation of chiral discrimination results in the dynamic mode . 110  4.2.2 Response to histidine . 111  4.2.3 Response to leucine 118  4.2.4 Response to mandelic acid . 121  4.2.5 Response to menthol 125  4.3 Summary 129  Chapter 5    Experimental  5.1 General . 132  5.1.1 Chemicals . 132  5.1.2 Solvents 132  5.1.3 Instrumentation 133  5.2   Synthesis 134  5.2.1 Thiol spacers 134  5.2.2 Mercaptyl perfunctionalized -CD . 138  5.3 Fabrication of chiral sensors with QCM 150  5.3.1 QCM . 150  5.3.2 Preparation of monolayer solution 151  5.3.3 Preparation of self-assembled monolayers . 152  v 5.4 QCM measuring systems . 153  5.4.1 Gas phase detection 153  5.4.2 Liquid phase detection 159 Chapter 6    Conclusion and Recommendations for Future Work  6.1 Conclusion . 165  6.1.1 Synthesis of new perfunctionalized -cyclodextrins . 165  6.1.2 Characterizations of SAMs 165  6.1.3 Gas phase chiral discrimination . 166  6.1.4 Aqueous phase chiral discrimination . 167  6.2 Recommendations for future work . 169  6.2.1 Gas phase chiral discrimination . 169  6.2.2 Liquid phase chiral discrimination and HPLC . 170  6.2.3 Functionalized -CD derivatives with multiple thiol linkers 170  6.2.4 Molecular modeling . 171  References . 173  vi Summary Chirality is an intrinsic property of many building blocks of life found in nature. Since enantiomers have identical physical and chemical properties except for the rotation of the plane of polarized light, chiral separation has been considered as one of the most challenging tasks in chemistry from both an analytical and a preparative viewpoint. Despite still in an early stage of development, chiral sensors represent a most promising alternative to the traditional enantio-separation assays for high-throughput screening. In this work, new quartz crystal microbalance (QCM) chiral sensors incorporated with perfunctionalized -cyclodextrins (-CDs) were developed and their performance was evaluated in the gas and liquid phase, respectively. The mechanisms of chiral discrimination in the gas and liquid phase were also investigated. Seven pairs of mercaptyl-perfunctionalized -CDs were successfully synthesized coded as Ph--CDX [X = S (short thio-linker) & L (long thio-linker)], MP--CDX, CP--CDX, BP--CDX, IP--CDX, MtP--CDX, MdP--CDX. The new perfunctionalized -CDs were immobilized onto gold surface of QCM crystals employing self-assembled technique. The monolayer structures were characterized by surface-sensitive techniques including XPS, in-situ QCM measurement, spectroscopic ellipsometry, and atomic force microscopy. vii Good reproducibility of self-assembled monolayer (SAM) fabrication were achieved by our self-assembly techniques. All L-type SAMs were thicker and possessed higher surface concentration than their S-type counterparts. This suggests that the S-type SAMs were formed in a monolayer structure while the L-type counterparts were arranged in a quasi-two-layer arrangement. The surface concentration of the mercaptyl functionalized -cyclodextrin followed the order Me>Pe>By>Ph>CP>BP>IP>MP>MtP>MdP, which reflected the bulkiness of the group and the effect of steric hindrance. Enhanced chiral discrimination in the gas phase was achieved on most of the QCM sensors in comparison with the reported separation results obtained in GC separation. Among the candidates, MP--CD arrays performed the best. The results were discussed on the basis of gas phase host-guest interactions. Generally, L-type sensors were found to exhibit better chiral discrimination ability than their S-type counterparts. Effective cooperative weak interactions, which depend on the molecular structures of the -CDs and analytes (lock and key principle and extensive three-point rule), are mainly responsible for improved chiral discrimination. The ability to determine compositions of the enantiomers in a mixture was also demonstrated by the limonene/MP--CDS system. The fourteen QCM sensors also showed chiral discrimination towards four pairs of enantiomeric analytes in the liquid phase under a new dynamic environment. 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Barbiric, Current Organic Chemistry 2006, 10, 715. 196 [...]... chapter, approaches for chiral discrimination and separation, working mechanism of quartz crystal microbalance, preparation of perfunctionalized  -cyclodextrins and self- assembly technique are reviewed Finally, the scope and objectives of this research are presented 1.2 Approaches for chiral separation 1.2.1 Techniques for chiral separation Since enantiomers have identical physical and chemical properties... representation of possible substituents of -CD 18  Figure 1.8 The “three-point” interaction model for chiral separation (C* denotes the chiral carbon) 24  Figure 1.9 Common configuration/view of quartz crystal microbalances with a holder and connector 28  Figure 1.10 AT-cut of a quartz crystal from which the metal coated QCM quartz crystals are produced and an end on crystal view of the... to mandelic acid (plotted by -fR in Table 4.3) 122  Figure 4.12 Chiral discrimination factor (R/S) upon exposure to mandelic acid in aqueous media 123  Figure 4.13 Chiral discrimination factor (R/S) of all chiral sensors with a short sulfide pendent upon exposure to mandelic acid in aqueous media 124  Figure 4.14 Liquid phase chiral discrimination of (+) and (-)-menthol by. .. of inclusion complexation process of 4 pairs of enantiomers by MP--CDS and MP--CDL 80  Figure 3.10 Chiral discrimination factors in gas phase by MP--CDS and MP--CDL towards four pairs of enantiomers: methyl lactate, ethyl lactate, 2-butanol, and 2-octanol 81  Figure 3.11 Schematic view of the complexation and interactions between methyl lactate and MP--CD (Left) (+)-methyl D-lactate;... xxi Current Publication C.H Xu, S.C Ng, H.S.O Chan, Self- Assembly of Perfunctionalized  -Cyclodextrins on a Quartz Crystal Microbalance for Real-Time Chiral Recognition Langmuir 24(2008), 9118-9124 xxii Chapter 1 Introduction 1 1.1 Introduction 1.1.1 Stereoisomers and chirality Stereoisomers are those molecules which possess the same constitutions and structural formulas but only differ from each other...previously by our group, but also offered the advantage of simpler experimental procedure and shorter analysis time Unlike in the gas phase, S-type sensors displayed better chiral discriminating ability than their L-type counterparts in the liquid phase Among the candidates, MP--CD arrays performed the best Generally, the chiral discrimination depends on the shape and size of the host and guest molecules and. .. 83  Table 3.4 Discrimination factors and their determining forces of MP--CDS and MP--CDL exposure to four pairs of enantiomers 86  Table 3.5 The chiral discrimination factor (R/S) of QCM sensors with different functional groups in gas phase 93  Table 3.6 Differences of enantioselective enthalpies R/S(H0) and entropies R/S(S0) for the complexation of analytes with modified... and white in colour, respectively 88  Figure 3.14 Chiral discrimination factors of the chiral sensors with different substituent on phenyl groups for the three enantiomers: 2-octanol, methyl lactate, and ethyl lactate 90  Figure 3.15 Plot of ln R/S vs (1/T)×103 between 288.15 K (15 C) and 313.15 K (40 C) for methyl lactate, ethyl lactate, 2-butanol and 2-octanol depicted by MP--CDS and. .. enlarge image of the adsorption process 110  Figure 4.3 Liquid phase chiral discrimination of D- and L-histidine by MP--CDS (a) and MP--CDL (b) monolayers in aqueous solution (10-4 M) 112  Figure 4.4 Signal responses of QCM sensors immobilized with mercaptyl functionalized -CDs upon exposure to histidine (plotted by -fR in Table 4.3) 114  Figure 4.5 Chiral discrimination. .. 116  Figure 4.6 Chiral discrimination factor (R/S) of all chiral sensors with a short sulfide pendent upon exposure to histidine in aqueous media * results from our previous work[249] 117  Figure 4.7 Liquid phase chiral discrimination of D- and L-leucine by MP--CDS (a) and MP--CDL (b) monolayers in aqueous solution (10-4 M) 118  Figure 4.8 Signal responses of QCM sensors immobilized . SELF- ASSEMBLY OF PERFUNCTIONALIZED  -CYCLODEXTRINS AND CHIRAL DISCRIMINATION BY QUARTZ CRYSTAL MICROBALANCE XU CHANGHUA NATIONAL UNIVERSITY OF SINGAPORE. NATIONAL UNIVERSITY OF SINGAPORE 2010 SELF- ASSEMBLY OF PERFUNCTIONALIZED  -CYCLODEXTRINS AND CHIRAL DISCRIMINATION BY QUARTZ CRYSTAL MICROBALANCE XU CHANGHUA (B.Sc. (Hons.),. 4Liquid Phase Chiral Discrimination by Chiral Sensors Coated with Mercaptyl Perfunctionalized  -Cyclodextrins based on Quartz Crystal v Microbalance 4.1  Introduction 104 4.2 Chiral Discrimination