Synthesis and characterisation of novel cationic imidazolium derivatives [Elektronische Ressource] : on the route to possible drugs = Synthese und Charakterisierung neuer kationischer Imidazol-Derivate auf dem Weg zu möglichen Wirkstoffen / vorgelegt von Eyad Mazin Mallah

Synthesis and Characterisation of Novel Cationic Imidazolium
Derivatives - on the Route to Possible Drugs
♦♦♦♦♦♦♦♦♦♦♦♦
Synthese und Charakterisierung neuer kationischer Imidazol -
Derivate auf dem Weg zu möglichen Wirkstoffen



DISSERTATION


der Fakultät für Chemie und Pharmazie
der Eberhard-Karls-Universität Tübingen

zur Erlangung des Grades eines Doktors
der Naturwissenschaften



2009

Vorgelegt von

Eyad Mazin Mallah

























Tag der mündlichen Prüfung: 09.06.2009

Dekan: Prof. Dr. L. Wesemann
1. Berichterstatter: Prof. N. Kuhn
2. Dr. H. A. Mayer






Dedication



To my

Parents, wife, brothers, sister and my lovely kid















This doctoral thesis was carried out from March 2007 to June 2009 at the Institut für
Anorganische Chemie, Fakultät für Chemie und Pharmazie der Eberhard-Karls-Universität
Tübingen, Germany, under the guidance of Prof. Dr. Norbert Kuhn.








I would like to express my deep and sincere gratitude to my supervisor



Prof. Dr. Norbert Kuhn




For providing the opportunity to study in perfect working conditions. Heartfelt appreciation is
also expressed for his kind assistance, fruitful suggestions, excellent instructions and limitless
encouragement throughout the entire research project of my doctoral dissertation.





Acknowledgments

I am greatly thankful to ALLAH for assistance and protection.

I would like to express my faithful appreciation and thanks to my supervisor Prof. Dr.
Norbert Kuhn for his unconditional support, encouragement, useful suggestions and technical
guidance, special thanks to Prof. Dr. Klaus-Peter Zeller for great assistance. I am also grateful to
the members of the examination committee: Prof. Dr. H. A. Mayer, Prof. Dr. Wolfgang Voelter,
Prof. Dr. Reiner Anwander, and Prof. Dr. Martin E. Maier for their valuable discussions.

All the thanks to Dr. Cäcilia Maichle-Mößmer, Mrs. Elke Niquet, Dr. Markus. Ströbele,
and Mr. Manfred Steimann for the X-ray structural determinations included in this thesis. I am
also thankful to Mr. W. Bock for the elemental analysis, to Mrs. Angelika Ehmann for the
assistance in the NMR measurements, and to Mrs. Barbara Saller for all efforts and help.

In addition, I am deeply thankful all my working group members for valuable discussions
and their friendship in the normal life. I would like to specially thank Dr. Qutaiba Abu-Salem,
Dr. Ahmed Abu-Rayyan, Dr. Annette Kuhn, Dr. Isabel Walker, Dr. Ahmad Al-Sheikh, and Dr.
Kamal Sweidan for the nice working atmosphere in the laboratory.

I wish to express my deepest reverence to Prof. Dr. Tawfiq Arafat for much encouragement
and advice, and I also express my cordial gratitude to Prof. Dr. Khalid Matalka for his endless
help and cooperation.

I am grateful to my friends Salah Al- Sabbareeny, Mohammed Khaleel, Isa Al-Yassury,
Hani Al- khateeb, Akram Al-Azeh, Ezz Hassan,Mohammed Saleh, Jafar Haider, Dr. Mohammed
Fayez, Dr. Jafar Alawneh, and Walid Abu-Rayyan for friendly assistance and support.

Words can not express my feeling toward my lovely family, who made it possible for me
throughout my whole life, and for their endless help, unrestricted support, encouragement,
kindness, patience, special care and infinite love which enabled me to finish this work.
Publications:

• Eyad Mallah, Markus Ströbele, Norbert Kuhn, Cäcilie Maichle-Mößmer, Klaus-Peter
Zeller and Manfred Steimann, Nucleophilic Aromatic Substitution with 2,3-Dihydro-1,3-
diisopropyl-4,5-dimethylimidazol-2-ylidene, Z. Naturforsch. Teil B, in progress.

• Norbert Kuhn, Eyad Mallah, Cäcilie Maichle-Mößmer, and Manfred Steimann,
Imidazolium Phenolates, Z. Naturforsch. 2009; 64b, xxx; received March 20, 2009.

• Ahmed Abu-Rayyan, Qutaiba Abu-Salem, Eyad Mallah, Cäcilia Maichle-Mößmer,
Manfred Steimann, Norbert Kuhn, and Klaus-Peter Zeller, The Acetylacetonate Ion as its
E/Z-Isomer in 1,3-Diisopropyl-4,5-dimethylimidazolium Acetylacetonate, Z.
Naturforsch. 2008, 63b, 1438-1440.

• Ahmed Abu-Rayyan, Qutaiba Abu-Salem, Norbert Kuhn, Cäcilia Maichle-Mößmer,
Eyad Mallah, Manfred Steimann, C-H-O Hydrogen Bonds in Imidazolium Carboxylates,
Z. Naturforsch. 2008, 63b, 1015-1019.

• Qutaiba Abu-Salem, Norbert Kuhn, Eyad Mallah, H.-Jürgen Meyer, Markus Ströbele,
and Klaus-Peter Zeller, Stepwise Aldol Addition and Cyanhydrin Formation with
Acetone and Thallous Cyanide, Z. Naturforsch. 2008, 63b, 1040-1044.





Table of Contents I


Table of Contents I
Glossary of Chemical Abbreviations and Units IV
1. List of abbreviations IV
2. List of units V
Chapter 1 1
1. Introduction 2
1.1 Pharmaceutical applications of fluoroaromatic compounds and imidazolium
salts 2
1.1.1 Fluoroaromatic compounds 2
1.1.2 Imidazolium salts 2
1.2 Carbenes 3
1.2.1 Definition 3
1.2.2 Diaminocarbenes 4
1.2.2.1 Synthesis of diaminocarbenes carbenes 4
1.2.2.2 Reactions of diaminocarbenes carbenes 8
1.2.2.2.1 Reactions with hydrogen compounds 8
1.2.2.2.2 Reactions with fluorine compounds 10
1.3 Aim of Study 12
Chapter 2 14
2. Results and Discussion 15
2.1 Nucleophilic aromatic substitution (S Ar) with 2,3-dihydroimidazole-2- ylidenes 15 N
2.1.1 1,3-Diisopropyl-4,5-dimethyl-2,2-(pentafluorophenylimidazolium) tetrafluoroborate 17
2.1.2 1,3-Diisopropyl-4,5-dimethyl-2-pentafluorophenylimidazolium tetrafluoroborate 20
2.1.3 4-(1,3-Diisopropyl-4,5-dimethylimidazolium)-2,5,6-trifluoro-isophthalonitrile
tetrafluoroborate 23
2.1.4 4-(1,3-Diisopropyl-4,5-dimethylimidazolium)- 2,3,5,6-tetrafluoro-benzonitrile 25
2.1.5 2-(1,3-Diisopropyl-4,5-dimethylimidazolium)-4, 6-difluoro-[1, 3, 5] triazine 27
2.2 Imidazolium aryl oxide adducts of the types of 2,3-dihydroimidazole-2-ylidenes 29
2.2.1 1,3-diisopropyl-4,5-dimethylimidazolium phenolate 31 Table of Contents II

2.2.2 1,3-Diisopropyl-4,5-dimethylimidazolium 2,3,4,5,6-pentachloro phenolate 34
2.2.3 2, 3, 4, 5,6-pentafluoro phenolate