OXIDATIVE KINETIC STUDY OF FLUOROQUINOLONE PHARMACEUTICALS IN ACIDIC/BASIC AQUEOUS SOLUTIONS A THESIS Submitted to the University of Kota, Kota for the Degree Of Doctor of Philosophy In Chemistry (Faculty of Science) Submitted by: ANKITA JAIN Under the Supervision of Dr. (Mrs.) Vijay Devra Department of Chemistry J. D. B. Govt. P.G. Girls College Kota (Rajasthan) 2017 Dedicated to My Parents, My Husband Amit & My Daughter Aarna University of Kota, Kota M. B. S. Marg, Near Kabir Circle, Rawatbhata Road, Kota (Raj.) Certificate It is to certify that, (i) The thesis entitled “Oxidative Kinetic Study of Fluoroquinolone Pharmaceuticals in Acidic/Basic Aqueous Solutions” submitted by Ankita Jain is an original piece of research work carried out by the candidate under my supervision. (ii) Literary presentation is satisfactory and the thesis is in a form suitable for publication. (iii) Work evidences the capacity of the candidate for critical examination and independent judgment. (iv) Fulfills the requirement of the ordinance relating to the Ph.D. degree of the university. (v) Candidate has put in at least 200 days of attendance every year. Dr. (Mrs.) Vijay Devra Department of Chemistry, J. D. B. Govt. P. G. Girls College, Kota (Raj.) A Word of Gratitude “Words are powerless to express my gratitude.” I take this opportunity to express my deep sense of gratitude to my adored mentor and supervisor Dr. (Mrs.) Vijay Devra, Senior Lecturer, J. D. B. Govt. Girls College, Kota, (Raj.) for her constant guidance, cooperation, motivation and support. Without her kind and patient instruction, it is impossible for me to finish this thesis. This is the right moment to thank her from bottom of my heart for her support in changing my dreams into reality. I owe a lot of gratitude to her for always being there for me and I feel privileged to be associated with a person like her during my life. She has taught me another aspect of life, that, “goodness can never be defied and good human beings can never be denied”. Ankita Jain Acknowledgement I take this opportunity to extend my sincere gratitude and appreciation to all those who made this Ph.D. thesis possible. I believe that my work is blessing to me from lord Mahavira. I would like to bow to Lord Mahavira, for blessing me so abundantly, far beyond what I deserve. First and foremost, I offer my sincerest gratitude to my supervisor, Dr. (Mrs.) Vijay Devra, Senior Lecturer, Department of Chemistry, J. D. B. Govt. Girls College, Kota, who has supported me throughout my research and thesis with his patience and knowledge whilst allowing me the room to work in my own way. I attribute the level of my supervisor’s encouragement and effort, without her this research and thesis, too, would not have been completed or written. One simply could not wish for such a better or friendlier supervisor. I would like to expand my thanks to Dr. (Mrs.) Reeta Gulati, Principal; Dr. (Mrs.) Uma Sharma, Vice-Principal and Dr. (Mrs.) Kalpna Sharma, Head, Department of Chemistry, J. D. B. Govt. Girls College, Kota, for their inspiring guidance and generous support. I express my heart-felt gratitude to Dr. Naveen Mittal, Dr. Manju Bala Yadav, Dr. Shweta Saxena and all faculty members of J. D. B. Govt. Girls College, Kota, who have been very kind enough to extend their help at various phases of this research. My special words of thanks should also go to Prof. Ashu Rani (Professor, Department of Pure and Applied Chemistry, University of Kota, Kota) for her guidance and support throughout the research work. It is an honor for me to convey my special regards to Dr. Pankaj Kachhawah, for his genuine interest, continuous encouragement and optimistic support. I would also like to extend my love and thanks to Pranav for his scientific inputs and friendly nature. My heartfelt thanks to my seniors Dr. Shanu Mathur, Dr. Khushboo Shrivastava, and Dr. Renu Hada for their guidance and moral support. In my daily work I have been blessed with a friendly and cheerful group of fellow students. My fellow researchers Shikha Jain, Niharika Nagar, Gajala Tazwar, Priya Vijayvergiya, Rajesh Meena, Nisha Ambwani and Dhanraj Meena, always helped me out when I got any difficulties or queries regarding experiments. I owe my deepest gratitude towards my better half “Amit” and my daughter “Aarna”, who ungrudgingly tolerated my persistent absence from their lives while I was working. They are my Inspiration, my life and my very breath. His patience and sacrifice will remain my inspiration throughout my life. Without his help, I would not have been able to complete much of what I have done and become who I am. These past years have not been an easy ride, both academically and personally. I truly thank Amit for sticking by my side, and for understanding my goals and aspirations. Finally, I would like to acknowledge the people who mean world to me, my parents and my family. I want to recognize the support of my mother Smt. Archana Jain, my father Sh. Lal Chand Jain and my sister Ms. Nikita Jain, whose diligent efforts in taking care of my daughter have made this work possible. I love them so much, and I would not have made it this far without them. My heart felt regard goes to my father-in-law Sh. Mahaveer Chand Gangwal, mother-in-law Smt. Madhu Gangwal, sister-in-law Mrs. Archana Jain and her family, Mrs. Anita Jain and her family for their love and moral support. I am also very much grateful to all my family members for their constant inspiration and encouragement. I gratefully acknowledge the University Grants Commission, New Delhi through a Junior Research Fellowship for financial support. I would also like to thank SAIF/CIL, Panjab University, Chandigarh for sample analysis and characterization. I wish to express my gratitude to those who may have contributed to my work directly or indirectly even though they remain anonymous. Ankita Jain CONTENTS Chapters Title Page No. 1. Introduction 1-32 Abstract 1 1.1 Chemical Kinetics 2 1.2 Fluoroquinolones 3 1.3 Oxidation of Fluoroquinolones 7 1.4 Mn(VII) ‒ An Oxidant 12 1.5 Kinetic Studies with Mn(VII) 14 1.6 Scope of the Work 23 1.7 References 24 2. Experimental 33-42 Abstract 33 2.1 Chemicals 34 2.2 Instruments 37 2.3 References 42 3. Mechanistic and Kinetic Study of 43-78 Oxidation of Ciprofloxacin by Permanganate in Aqueous Sulphuric Acid Medium Abstract 43 3.1 Introduction 44 3.2 Experimental 45 3.3 Results 48 3.4 Discussion 65 3.5 Conclusion 75 Chapters Title Page No. 3.6 References 76 4. Mechanistic and Kinetic Study of 79-115 Oxidation of Ofloxacin by Permanganate in Aqueous Sulphuric Acid Medium Abstract 79 4.1 Introduction 80 4.2 Experimental 81 4.3 Results 84 4.4 Discussion 101 4.5 Conclusion 113 4.6 References 114 5. Mechanistic and Kinetic Study of 116-156 Oxidation of Levofloxacin by Permanganate in Aqueous Sulphuric Acid Medium Abstract 116 5.1 Introduction 117 5.2 Experimental 118 5.3 Results 121 5.4 Discussion 138 5.5 Conclusion 149 5.6 References 154 6. Mechanistic and Kinetic Study of 157-191 Oxidation of Enrofloxacin by Permanganate in Aqueous Alkaline Medium Abstract 157 Chapters Title Page No. 6.1 Introduction 158 6.2 Experimental 159 6.3 Results 161 6.4 Discussion 180 6.5 Conclusion 189 6.6 References 190 Annexures Annexure I Annexure II Publications Chapter – 1 Introduction Chapter 1 ABSTRACT The present chapter describes the introduction of chemical kinetics, potassium permanganate, its oxidizing properties and includes a brief discussion on fluoroquinolones ‒ powerful antibiotics used in human and veterinary medicine. The fate of antibiotic parent and metabolite compounds entering environmental ecosystems through various pathways raise environmental impact concerns. The current investigation was undertaken with the intent of computing reaction kinetics and clarifying the reaction pathways involved in oxidative degradation of the environmentally significant fluoroquinolone antibiotics by potassium permanganate in aqueous acidic/alkaline medium. 1 Chapter 1 1.1. CHEMICAL KINETICS Chemical kinetics is the study of rate of chemical processes, it includes investigation of how different experimental conditions can influence the speed of a chemical reaction and yield information about the reaction’s mechanism and transition states, as well as the construction of mathematical models that can describe the characteristics of a chemical reaction. The mathematical models that describe chemical reaction kinetics provide chemists and chemical engineers with tools to better understand and describe chemical processes and the complex chemistry of biological systems. These models also used in the design or modification of chemical reactors to optimize product yield, more efficiently separate products, and eliminate environmentally harmful by-products. One reason for the importance of kinetics is that it provides evidence for the mechanism of chemical processes. Many reactions of great commercial importance can proceed by more than one reaction path; knowledge of the reaction mechanism involved may make it possible to choose reaction conditions favouring one path over another, thereby giving maximum amounts of desired products and minimum amounts of undesired products. Reaction mechanism describes each reactive intermediate, activated complex, transition states, which bonds are broken, and which are formed. A complete mechanism must also explain the reason for the reactants and catalyst used, the stereochemistry observed in reactants, products and the amount of each. The rate law gives additional information about the individual steps that might be involved in the reaction mechanism. Determining the rate law begins with setting up a kinetics experiment for the chemical reaction.