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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
xi
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