UNIVERSITI PUTRA MALAYSIA

FACILE SYNTHESIS, CHARACTERIZATION AND BIOCATALYTIC APPLICATION OF IMIDAZOLIUM-BASED CHIRAL IONIC LIQUIDS

NG SHIE LING

FP 2008 25

FACILE SYNTHESIS, CHARACTERIZATION AND BIOCATALYTIC

APPLICATION OF IMIDAZOLIUM-BASED CHIRAL IONIC LIQUIDS

NG SHIE LING

MASTER OF SCIENCE

UNIVERSITI PUTRA MALAYSIA

2008

FACILE SYNTHESIS, CHARACTERIZATION AND BIOCATALYTIC

APPLICATION OF IMIDAZOLIUM-BASED CHIRAL IONIC LIQUIDS

By

NG SHIE LING

Thesis submitted to the School of Graduate Studies, Universiti Putra Malaysia, in fulfillment of the Requirements for the Degree of Master of Science

MARCH 2008

Abstract of thesis presented to the Senate of Universiti Putra Malaysia in fulfillment of the requirement for the degree of Master of Science.

FACILE SYNTHESIS, CHARACTERIZATION AND BIOCATALYTIC APPLICATION OF IMIDAZOLIUM-BASED CHIRAL IONIC LIQUIDS

By

NG SHIE LING

MARCH 2008

Chairperson: Mohd. Basyaruddin Abdul Rahman, PhD.

Faculty: Science

In view of the emerging importance of ionic liquids as reaction media in organic

synthesis, researchers have recently focused on the synthesis of chiral ionic liquids

(CILs) for their particularly potential applications to chiral discrimination. The study

of the application of CILs in asymmetric synthesis is not only an opportunity but

also a challenge for researchers. Herein, the synthesis of new CILs based on alkyl-

imidazole as the cation and four different chiral acids as the anion were reported.

Eighteen chiral ionic liquids were synthesized and characterized by a variety of

physico-chemical techniques. Four different chiral acids chosen were L-lactic acid,

L-tartaric acid, (R)-(-)-camphor-10-sulfonic acid and L-malic acid. Imidazole was

chosen because they are easier to prepare and less toxic compared to thiazole and

pyrrolidine which contain sulfur and nitrogen compounds respectively. These salts

were prepared using simple ion-exchange reaction which gave good overall yield (>

95 %) at room temperature. All the CILs synthesized are hygroscopic. Their

enantiomeric purity was analyzed using 1H NMR spectroscopy. The effect of alkyl

ii

substituents bonded to the nitrogen on imidazolium cation on the physical properties

especially its melting point was also examined and observed. The melting points for

bulkier ionic liquids are higher as compared to those of small ionic liquids. For the

solid CILs, their solubility in organic solvents were tested and followed by

recrystallization. Their three dimensional network of cation-anion and hydrogen

bonding were analyzed by single-crystal X-ray diffraction analysis. Each CILs

optical polarity was measured using polarimeter.

An example of the application of CILs is in biocatalysis. Chiral ionic liquid coated-

enzyme (CILCE) was prepared by coating Candida rugosa lipase with 1-hydrogen-

3-hexylimidazolium hydrogen-tartrate. CILCE was then used to catalyze some non-

chiral and chiral esterification reactions. For non-chiral esterification, we found that

CILCE gave higher percentage of conversion compared to native enzyme for short

and medium chain acids, where all acids were reacted with oleyl alcohol. For chiral

esterification, enantioselective esterification of (±)-menthol with butyric anhydride

was studied. Percentage conversion of menthyl butyrate in CILCE (81.91 %) was

better than in CRL (28.19 %). However, its enantiomeric excess (ee) from CILCE

was low compared to CRL with 1.1 and 3.3, respectively calculated from its

enantiomeric value, E.

iii

Abstrak tesis yang dikemukakan kepada Senat Universiti Putra Malaysia bagi memenuhi keperluan Ijazah Master Sains.

FASIL SINTESIS, PENCIRIAN DAN APLIKASI DALAM BIOMANGKIN BAGI CECAIR IONIK KIRAL YANG BERDASARKAN IMIDAZOLIUM.

Oleh

NG SHIE LING

MARCH 2008

Pengerusi: Mohd. Basyaruddin Abdul Rahman, PhD.

Fakulti: Sains

Dewasa ini, kepentingan cecair ionik sebagai media tindak balas dalam sintesis

organik semakin berkembang. Kini, para penyelidik mula memfokuskan kepada

sintesis cecair ionik kiral (CILs) yang berpotensi dalam aplikasi diskriminasi kiral.

Kajian aplikasi CILs dalam sintesis asimetri bukan hanyalah satu peluang malah

juga adalah satu cabaran bagi para penyelidik. Dalam kajian ini, sintesis CILs baru

yang berasaskan alkil-imidazol sebagai kation dan pelbagai asid kiral sebagai anion

dilaporkan.

Lapan belas CILs telah disintesis dan dicirikan menggunakan pelbagai teknik kimia-

fizikal. Empat asid kiral berlainan yang dipilih adalah L-asid laktik, L-asid tartarik,

(R)-(-)-asid camphor-10-sulfonik dan L-asid malik. Imidazol telah dipilih kerana ia

mudah disediakan dan kurang toksik jika dibandingkan dengan thiazol dan

piroldinium yang mengandungi sulfur dan nitrogen. Kesemua garam ini telah

disediakan menggunakan kaedah tindak balas penukargantian-ion mudah yang

memberikan hasil yang tinggi (> 95 %) pada suhu bilik. Kesemua cecair ionik kiral

iv

yang disintesis adalah higroskopik. Ketulenan enantiomerik CILs dicirikan

menggunakan 1H spektroskopi magnetik resonan nuklear (NMR). Kesan

penukargantian alkil dalam ciri-ciri fizikal khususnya terhadap takat leburnya juga

telah diuji dan diperhatikan. Takat lebur bagi cecair ionik yang lebih besar saiznya

adalah lebih tinggi jika dibandingkan dengan cecair ionik yang lebih kecil. Bagi

cecair ionik pepejal, keterlarutan dalam pelarut organik diuji, diikuti oleh

penghabluran semula. Rangkaian tiga dimensi antara kation-anion dan ikatan

hidrogen dianalisis menggunakan X-ray serakan kristal tunggal. Polariti optik bagi

setiap cecair ionik diukur dengan menggunakan polarimeter.

Salah satu contoh aplikasi CILs adalah dalam biopemangkinan. Enzim bersalut

cecair ionik kiral (CILCE) disediakan dengan menyalut lipase Candida rugosa

dengan 1-hidrogen-3-heksilimidazolium hidrogen-tartrat. CILCE kemudiannya

digunakan untuk memangkin beberapa tindak balas pengesteran mudah tak-kiral dan

kiral. Bagi pengesteran tak-kiral, CILCE memberikan peratusan penukaran yang

lebih tinggi berbanding enzim asli bagi asid berantai pendek dan sederhana, di mana

semua asid ditindak balaskan dengan olil alkohol. Bagi pengesteran kiral,

pengesteran enantioselektif bagi (±)-menthol dengan butirik anhidrida telah dikaji.

Peratus penukaran menthil butirat dalam CILCE (81.41 %) adalah lebih bagus

daripada dalam CRL (28.19 %). Walau bagaimanapun, lebihan enantiomerik, (ee)

daripada CILCE adalah rendah berbanding CRL dan masing-masing memberikan

1.1 dan 3.3 bagi nilai enantiomeriknya, E.

v

ACKNOWLEDGEMENTS

First and foremost, I would like to extend my heartfelt thanks to both of my

supervisors, Associate Professor Dr. Mohd. Basyaruddin Abd Rahman from

Universiti Putra Malaysia and Professor Kenneth Richard Seddon from Queen's

University of Belfast, for their help, advice and tireless encouragement throughout

this period of study. I would also like to thank them for giving me the opportunity to

come to Belfast; a small city with cold weather, but very warm people.

To my research group, CREAM in UPM, thank you all especially to Professor Abu

Bakar Salleh and Professor Mahiran Basri for your valuable advice and suggestions

you gave during our weekly meeting. I would also like to express my deepest

gratitude to Professor Jim Swindall OBE and Dr. Sarah Thompson for all the

paperwork that they had to deal with in order to get me there to Belfast. I really

appreciate it. And of course, thanks too, to both super-secretaries, Deborah Poland

and Louis Porter.

To all my friends in Malaysia, thanks for always being there for me. I want to thank

all of you for the good time we shared together. Your names alone would fill the rest

of this thesis, and more importantly, would put me in very difficult position of

having to decide on an order of preference. And to Nora, I could never thank you

enough for extending a helping hand with all my leftover work during the period

when I was in Belfast. Without you, I would not have made it this far.

Special thanks go to Isaac Nyambiya for all his guidance, patience and fruitful

chemistry discussions. None of this could have happened without you. To all the

vi

QUILL labmates; Alina, Natasha, Gosia, Geetha, Lynsey, Zheng Xi, Jamie, Laurent,

Kris, Marcus, Manuella, Tayeb, Martin, Martyn Earle and Angela, thank you for all

your help, support and also the lovely coffee breaks we had together at 12 noon

everyday. They were the best! And also to the many people who has already left

QUILL, especially Alberto, José Santiago, Marianna and my Scottish buddy, Craig,

thank you so much for making my stay at QUILL so enjoyable.

To my Belfast best friend and labmate, Monica Sanches, you will always have a

special place in my heart. I will always remember our 3 hours lunch break that

ended up in the city centre and all the traveling we did together these past few

months. And because of you, I got to meet some of the coolest people on Earth, the

IAESTE bunch. To all my IAESTE buddies; Jacobo, Katherina, Stephanie, Anna,

Sylvia, Athula, Robin, Diana, Sabrina, Anna, Ewa, Monica (Poland), Qasha, Tom,

Sebastian, Manuel, Jørgen, Manuel, Karun, Maria (Austria), Maria (Malta) and Ben,

thank you for the lovely times we have had together, for being my friends, for all the

trips that we made together and most importantly, for the many experiences that

have taught me to be a better person. You are really a wonderful group of people. A

million thanks also go out to all my flat-mates and friends in Guthrie House for their

food sharing and the party.

Last but definitely not least, to my family, especially my mom, there is no way I can

adequately express my gratitude in words, for the support, love and encouragement

you have shown me throughout the years and for the many sacrifices that you have

made for me. I will always cherish it in my heart and soul.

I love you all.

vii

I certify that an Examination Committee met on 24 March 2008 to conduct the final

examination of Ng Shie Ling on her Master of Science thesis entitled “Facile

Synthesis, Characterization and Biocatalysis Application of Imidazolium-Based

Ionic Liquids” in accordance with Universiti Pertanian Malaysia (Higher Degree)

Act 1980 and Universiti Pertanian Malaysia (Higher Degree) Regulation 1981. The

Committee recommends that the candidate be awarded the degree of Master of

Science, MSc.

Members of the Examination Committee are as follows:

Dr. Nor Azah, Ph.D. Lecturer, Faculty of Science, Universiti Putra Malaysia (Chairman) Dr. Mohamed Ibrahim Mohamed Tahir, D. Phil. Lecturer, Faculty of Science, Universiti Putra Malaysia (Internal examiner) Dr. Tan Yen Ping, Ph.D. Lecturer, Faculty of Science, Universiti Putra Malaysia (Internal examiner) Dr.(forget his name), Ph.D. Associate Professor, Faculty of Science, Universiti Teknologi Malaysia (External examiner)

HASANAH MOHD. GHAZALI, Ph.D.

Professor and Deputy Dean

School of Graduate Studies

Universiti Putra Malaysia

Date:

viii

The thesis was submitted to the Senate of Universiti Putra Malaysia has been

accepted as fulfillment of the requirement for the degree of Master of Science. The

members of the Supervisory Committee are as follows:

Mohd. Basyaruddin Abdul Rahman, PhD.

Associate Professor

Faculty of Science

Universiti Putra Malaysia

(Chairperson)

Mahiran Basri, PhD.

Professor

Faculty of Science

Universiti Putra Malaysia

(Member)

Abu Bakar Salleh, PhD.

Professor

Faculty of Biotechnology and Biomolecular Sciences

Universiti Putra Malaysia

(Member)

AINI IDERIS, PhD.

Professor and Dean

School of Graduate Studies

Universiti Putra Malaysia

Date:

ix

DECLARATION

I declare that the thesis is my original work except for quotations and citations

which have been acknowledged. I also declare that is has not been previously and is

not concurrently, submitted for any other degree at Universiti Putra Malaysia or at

any other institution.

NG SHIE LING

Date:

x

TABLE OF CONTENTS ABSTRACT ii ABSTRAK iv ACKNOWLEDGEMENTS vii APPROVAL viii PENGESAHAN ix DECLARATION x LIST OF TABLES xiv LIST OF FIGURES xv LIST OF SCHEMES xviii LIST OF ABBREVIATIONS xix LIST OF APPENDICES xxi CHAPTER PAGE

1. INTRODUCTION 1 1.1 Research Objectives 4

2. LITERATURE REVIEW 5 2.1 The Prehistory 5 2.2 Introduction to Ionic Liquids 6 2.3 Bulk Physical and Chemical Properties 11

2.3.1 Melting point 12 2.3.2 Thermal stability 14 2.3.3 Viscosity 14 2.3.4 Density 15 2.3.5 Miscibility with water 15 2.3.6 Polarity 17

2.4 Ionic Liquids and Its Application 18 2.4.1 ILs as Solvents for Extraction 18 2.4.2 ILs in Biocatalysis 19

2.5 Chiral Ionic Liquid 21 2.6 Synthesis and Applications 23 2.7 Ionic Liquid-Coated Enzyme (ILCE) 26

3. MATERIALS AND METHODS 27 3.1 Materials 27

3.1.1 Solvents 27 3.1.2 Chemicals 28 3.1.3 Enzymes 29 3.1.4 Equipments/ Instruments 29 3.1.5 Other Materials 30

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3.2 Methods 31 3.2.1 Recrystallization of Imidazole 31 3.2.2 Distillation of N-alkylImidazole 31 3.2.3 Synthesis of N-hexylimidazole 31 3.2.4 Synthesis of Chiral Ionic Liquids via Ion-exchange

Reaction 32 3.2.5 Preparation of Chiral Ionic Liquid-Coated Enzyme

(CILCE) 34 3.2.6 Esterification of Non-Chiral Esters 34 3.2.7 Preparation of Standard Menthyl Esters 35 3.2.8 Esterification of (±)-Menthyl butyrate 36

3.3 Analytical Methods 38 3.3.1 Nuclear Magnetic Resonance (NMR) Spectroscopy 38 3.3.2 CHN – Element Analysis 38 3.3.3 Differential Scanning Calorimetry (DSC) 39 3.3.4 X-Ray Crystallography 39 3.3.5 Optical Rotation 40 3.3.6 Thin Layer Chromatography (TLC) 40 3.3.7 Gas Chromatography (GC) Analysis 41

4. RESULTS AND DISCUSSIONS 42

4.1 Synthesis and Characterization of Chiral Ionic Liquids (CILs) 42 4.2 Properties of Synthesized Chiral Ionic Liquids 43 4.2.1 N-Alkylimidazole with L-lactic acid 43

1, 3-dihydrogenimidazolium lactate, [H2-im] [lac] 43 1-hydrogen-3-methylimidazolium lactate,

[H-mim] [lac] 44 1-hydrogen-3-butylimidazolium lactate,

[H-bim] [lac] 45 1-hydrogen-3-hexylimidazolium lactate,

[H-him] [lac] 46

4.2.2 N-Alkylimidazole with L-tartaric acid 48 1, 3-dihydrogenimidazolium hydrogen-tartrate, 48

[H2-im] [H-tar] 1-hydrogen-3-methylimidazolium hydrogen-tartrate, 49

[H-mim] [H-tar] 1-hydrogen-3-butylimidazolium hydrogen-tartrate, 50

[H-bim] [H-tar] 1-hydrogen-3-hexylimidazolium hydrogen-tartrate, 51

[H-him] [H-tar] 1, 3-dihydrogenimidazolium tartrate, [H2-im] [tar] 52

xii

4.2.3 N-Alkylimidazole with camphor-10-sulfonic acid 54 1, 3-dihydrogenimidazolium camphor-10-sulfonate, 54

[H2-im] [sulf]

1-hydrogen-3-methylimidazolium camphor-10- sulfonate, [H-mim] [sulf] 55

1-hydrogen-3-butylimidazolium camphor-10- sulfonate, [H-bim] [sulf] 56

1-hydrogen-3-hexylimidazolium camphor-10- sulfonate, [H-him] [sulf] 57

4.2.4 N-Alkylimidazole with L-malic acid 59 1, 3-dihydrogenimidazolium hydrogen-malate, 59

[H2-im] [H-mal] 1-hydrogen-3-methylimidazolium hydrogen-malate, 60

[H-mim] [H-mal] 1-hydrogen-3-butylimidazolium hydrogen-malate, 61

[H-bim] [H-mal] 1-hydrogen-3-hexylimidazolium hydrogen-malate, 62

[H-him] [H-mal] 1, 3-dihydrogenimidazolium malate, [H2-im] [mal] 63

4.3 Elemental Analysis of Chiral Ionic Liquids 67 4.4 Solubility Test and X-Ray Crystallographic Analysis 69

1, 3-dihydrogenimidazolium lactate, [H2-im] [lac] 69 1, 3-dihydrogenimidazolium hydrogen-tartrate, [H2-im] [H-tar] 71 1, 3-dihydrogenimidazolium camphor-10-sulfonate, [H2-im] [sulf] 73

4.5 Optical Rotation 75 4.6 Chiral Ionic Liquid-Coated Enzyme (CILCE) 79

4.7 Non-Chiral Esterification Reactions 80 4.8 Chiral Esterification of (±)-Menthyl butyrate 83 4.9 Analysis of Standard Menthyl Butyrate 85 4.10 Chiral Esterification Reaction 90

5. CONCLUSION 94 5.1 Recommendation for Further Studies 97 REFERENCES & BIBLIOGRAPHY APPENDICES

BIODATA OF STUDENT

xiii

LIST OF TABLES

Page

Table 1 Starting material for the chiral ionic liquids synthesized using 33

the ion-exchange procedure.

Table 2 Elemental Analysis Data for CILs. 67

Table 3 Optical Rotation Data for CILs. 76

Table 4 Percentage conversion and enantioselectivity value for menthyl 91

butyrate.

xiv

LIST OF FIGURES

Page

Figure 1 The structure of the ‘red oil’, heptachlorodialuminate salt. 6

Figure 2 Simple alkylammonium nitrates; ethylammonium nitrate. 6

Figure 3 Difference between an ionic solution and an ionic liquid. 7

Figure 4 Structures of selected common organic cations. 8

Figure 5 Structures of selected common inorganic anions. 8

Figure 6 Structures of selected simple non-halogenated organic anions. 9

Figure 7 1-ethyl-3-methylimidazolium hexafluorophosphate, [emim][PF6]. 13

Figure 8 Possible routes for asymmetric syntheses in ILs. 22

Figure 9 NMR spectrum for 1, 3-dihydrogenimidazolium lactate. 43

Figure 10 NMR spectrum for 1-hydrogen-3-methylimidazolium lactate. 44

Figure 11 NMR spectrum for 1-hydrogen-3-butylimidazolium lactate. 45

Figure 12 NMR spectrum for 1-hydrogen-3-hexylimidazolium lactate. 46

Figure 13 NMR spectrum for 1, 3-dihydrogenimidazolium hydrogen-tartrate. 48

Figure 14 NMR spectrum for 1-hydrogen-3-methylimidazolium hydrogen- 49

tartrate.

Figure 15 NMR spectrum for 1-hydrogen-3-butylimidazolium hydrogen- 50

tartrate.

Figure 16 NMR spectrum for 1-hydrogen-3-hexylimidazolium hydrogen- 51

tartrate.

Figure 17 NMR spectrum for 1, 3-dihydrogenimidazolium tartrate. 52

Figure 18 NMR spectrum for 1, 3-dihydrogenimidazolium camphor-10- 54

sulfonate.

xv

Figure 19 NMR spectrum for 1-hydrogen-3-methylimidazolium camphor- 55

10-sulfonate.

Figure 20 NMR spectrum for 1-hydrogen-3-butylimidazolium camphor- 56

10-sulfonate.

Figure 21 NMR spectrum for 1-hydrogen-3-hexylimidazolium camphor- 57

10-sulfonate.

Figure 22 NMR spectrum for 1, 3-dihydrogenimidazolium hydrogen-malate. 59

Figure 23 NMR spectrum for 1-hydrogen-3-methylimidazolium hydrogen- 60

malate.

Figure 24 NMR spectrum for 1-hydrogen-3-butylimidazolium hydrogen- 61

malate.

Figure 25 NMR spectrum for 1-hydrogen-3-hexylimidazolium hydrogen- 62

malate

Figure 26 NMR spectrum for 1, 3-dihydrogenimidazolium malate. 63

Figure 27 Single crystal structure of 1, 3-dihydrogenimidazolium lactate 70

with intermolecular hydrogen bonding.

Figure 28 Packing of 1, 3-dihydrogenimidazolium lactate, perspective 70

view from b-axis.

Figure 29 Single crystal structure of 1, 3-dihydrogenimidazolium 72

hydrogen-tartrate with intermolecular hydrogen bonding.

Figure 30 Packing of 1, 3-dihydrogenimidazolium hydrogen- 72

tartrate, perspective view from c-axis.

Figure 31 Single crystal structure of 1, 3-dihydrogenimidazolium 74

camphor-10-sulfonate with intermolecular hydrogen bonding.

xvi

Figure 32 Packing of 1, 3-dihydrogenimidazolium camphor-10- 74

sulfonate, perspective view from the b-axis.

Figure 33 Polarimeter and how it rotates a polarized light. 76

Figure 34 Percentage of conversion of straight chain acids to esters in 80

hexane. Reactions were performed at 50 ºC for 1 hr with the

shaking speed of 150 rpm.

Figure 35 Thin layer chromatography analysis of (±)-menthol, butyric 85

anhydride and (±)-menthyl butyrate.

Figure 36 IR spectrum of (-)-Menthyl butyrate. 86

Figure 37 GC chromatogram of standard (-)-menthyl butyrate. 87

Figure 38 GC chromatogram of standard (+)-menthyl butyrate. 88

Figure 39 Chiral capillary GC chromatogram of enantioselective 88

esterification before reaction.

Figure 40 Chiral capillary GC chromatogram of enantioselective 89

esterification after reaction at 40 °C for 24 hrs with the shaking

speed of 150 rpm..

xvii

LIST OF SCHEMES

Page

Scheme 1 Synthesis of lactate imidazolium IL. 24

Scheme 2 The Baylis-Hillman reaction. 25

Scheme 3 General route for the synthesis of chiral ionic liquids. 42

Scheme 4 Chiral esterification reaction of (±)-Menthol and 90

butyric anhydride

xviii

LIST OF ABBREVIATIONS

ILs Ionic liquids

RTIL Room-temperature ionic liquid

CILs Chiral ionic liquids

[H2-im]+ 1,3 dihydrogenimidazolium

[H-mim]+ 1-hydrogen-3-methylimidazolium

[H-bim]+ 1-hydrogen-3-butylimidazolium

[H-him]+ 1-hydrogen-3-hexylimidazolium

[bmim]+ 1-butyl-3-methylimidazolium

[emim] + 1-ethyl-3-methylimidazolium

[lac]- Lactate

[tar]- Tartrate

[H-tar]- Hydrogen-tartrate

[sulf]- Camphor-10-sulfonate

[mal]- Malate

[H-mal]- Hydrogen-malate

[BF4]- tetrafluoroborate

[PF6]- hexafluorophosphate

[Tf2N]- bis(trifluoromethylsulfonyl)imide

[Ms2N]- bis(methanesulfonyl)imide

DABCO 1,4-diazabicyclo[2.2.2]octane

VOC Volatile organic compounds

ee Enantiomeric excess

E Enantiomeric ratio

xix

ATRP Atom transfer radical polymerization

MMA Methyl methacrylate

DMSO Dimethyl sulphoxide

DABCO 1,4-diazabicyclo[2.2.2]octane

TBAB Tetrabutylammonium bromide

PTFE Polytetrafluoroethylene

CILCE Chiral ionic liquid-coated enzyme

ILCE Ionic liquid-coated enzyme

CRL Candida rugosa lipase

CHNS Carbon hydrogen nitrogen sulphur

DSC Differential scanning calorimetry

TLC Thin layer chromatography

GC Gas chromatography

QUILL Queen’s University Ionic Liquid Laboratory

ASEP The Analytical Services and Environmental Projects Unit

xx

xxi

LIST OF APPENDICES

Appendix A Calculation for Non-Chiral Esterification.

Appendix B Calculation for Chiral Esterification.

Appendix C Crystal data for sample 1, 3-dihydrogenimidazolium lactate, [H2-im]

[lac].

Appendix D Crystal data for sample 1, 3-dihydrogenimidazolium Hydrogen-

tartrate, [H2-im] [H-tar].

Appendix E Crystal data for sample 1, 3-dihydrogenimidazolium camphor-10-

sulfonate, [H2-im] [sulf].

CHAPTER 1

1. INTRODUCTION

As we advanced into the 21st century, it has become more evident that chiral drugs

have become a major focus of most pharmaceutical companies. The increasing

demand for many organic esters and chiral drugs creates the need for developing

highly specific catalyst and for this reason, the application of enzymes as the catalyst

for the synthesis of esters is undergoing rapid development (Garcia et al., 1996;

Gryglewicz, 2003). Enzymatic synthesis offers various advantages over chemical

synthesis such as lower energy requirement and enhanced selectivity and quality of

the product. Moreover, enzymes especially lipases have high specificity towards

ester bond and hence eliminating the presence of undesirable side-reactions and by-

products in esterification reaction (Yadav and Devi, 2003).

Chiral analysis is an important subject in science as well as in technology.

Enantiomeric forms of many compounds are known to have different psychological

and therapeutic effects. Very often, only one form of an enantiomeric pair is

pharmacologically active. The other form of the same enantiomeric pair can reverse

or otherwise limit the effect of the desired enantiomer. Recognizing the importance

of chiral effects, the Food and Drug Administration (FDA) in 1992 issued a mandate

requiring pharmaceutical companies to verify the enantiomeric purity of chiral drugs

that are produced. It is, thus, hardly surprising that the pharmaceutical industry

needs effective methods to determine enantiomeric purity and high enantiomeric

excess (ee) (Tran et al., 2006).

1

Room temperature ionic liquids (ILs) are novel and promising materials for a variety

of chemical applications. They have unique chemical and physical properties;

including possessing a high solubility power and virtually no vapour pressure (Earle

et al., 2000 and Earle and Seddon, 2000). Because of these two properties, they can

serve as an alternative to the volatile organic compounds that are traditionally used

as industrial solvents. In view of the emerging importance of ILs as reaction media

in organic synthesis, researchers have focused on the synthesis of chiral ionic liquids

(CILs) for their particularly potential applications to chiral discrimination, including

asymmetric synthesis and optical resolution of racemates (Wang et al., 2005). Chiral

ionic liquids therefore may offer a solution for determining enantiomeric purity and

high ee in asymmetric reactions.

The popularity stems from the fact that it is possible to use CILs to replace the

organic solvent for the enantiomeric purity determination method. Specifically, the

CILs with its high solubility power should dissolve many different types of analytes

(Zhao and Malhotra, 2002). Its chirality may produce the needed diastereomeric

interactions with both enantiomeric forms of an analyte. Unfortunately, despite their

potentials, CILs have been synthesized and the synthesis of reported CILs required

rather expensive reagents and elaborates synthetic schemes. Because of these

limitations, the study and applications of CILs have been severely hindered (Tran et

al., 2006). Therefore, it is of particular importance to develop a novel synthesis by

which CILs can be simply and easily prepared from commercially available reagents

by researchers.

2