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Design, Synthesis and Studies of Radical and Radical Ion Probes: from Enzyme Investigations to Electroactive Surfactants

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Design, Synthesis and Studies of Radical and Radical Ion Probes: From Enzyme Investigations to Electroactive Surfactants DISSERTATION zur Erlangung des Grades eines Doktors der Naturwissenschaften vorgelegt von Mukul Lal M.Sc. geb. am 28.Mai 1973 in Hyderabad, Indien. eingereicht beim Fachbereich 8 der Universität Siegen Siegen 2004 Gutachter: Prof. Dr. M. Schmittel Prof. Dr. H. Ihmels Tag der mündlichen Prüfung: 21-01-2005 urn:nbn:de:hbz:467-1954 Ph. D. Thesis of Mukul Lal Design, Synthesis and Studies of Radical and Radical Ion Probes: From Enzyme Investigations to Electroactive Surfactants Abstract The present work is centered at understanding the mechanistic details of the coenzyme B12 dependent enzymes such as diol and glycerol dehydratase that are known to involve radical and radical ionic intermediates in transforming vicinal diols to carbonyl compounds. The work aims on translating such reactive intermediates to relatively long lived ones (making use of beta cleavage leading to persistent radical or electron transfer processes) thereby enabling their spectroscopic detection. A number of modified enzyme substrates attached with groups such as ferrocene, quinone and 2,2,6,6-tetramethylpiperidinoxy were synthesised and were investigated. The efficacies of electrophores to probe radical ions at the active site of the enzyme inherently rely on the electron transfer process. Modulation of the oxidising/reducing property of radical cation/radical anion formed at the active site invariably effects the trapping efficiency of the electrophore. Cyclic voltammetry investigations on the model compounds based on Fuson enols revealed that hydrogen bonding can indeed alter oxidation potentials of enols by up to 500 mVFc cathodically. The concept was also tested in solution by generating and trapping radical cations in solution via inter as well as intramolecular electron transfer from ferrocene as a donor to enol/enol ether radical cation. Use of stable and reversible redox systems can set a precedent to the development of not only radical ion clocks, they can additionally prove pivotal in areas of nano-technology requiring transfer of small volumes (nano litre range) of solutes in a well defined manner. Thus a couple of redox active compounds were synthesised and investigated for their surfactant property, electrochemical and chemical stability. Zusammenfassung Die vorliegende Arbeit beschäftigt sich mit mechanistischen Details der Coenzym B12- abhängigen Enzyme, z.B. Diol- und Glyceroldehydratase. Im Verlauf der Umwandlung vicinaler Diole in Carbonylverbindungen treten Radikale und Radikalionen als Zwischenstufen auf. Es wurde versucht diese reaktiven Zwischenstufen in langlebigere Modelle zu übersetzen, um so spektroskopische Untersuchungen zu ermöglichen. Dabei wurden ß-Spaltungs- und Elektronentransferreaktionen eingesetzt. Zahlreiche modifizierte Enzymsubstrate (mit zusätzlichen Ferrocen-, Chinon- und 2,2,6,6-Tetramethylpiperidinoxy- Substituenten) wurden synthetisiert und untersucht.. Die Wirksamkeit der Elektrophore bei der Untersuchung von Radikalionen im aktiven Zentrum des Enzyms hängt wesentlich vom Elektronentransferprozeß ab. Veränderungen der Oxidations-/Reduktionseigenschaften der gebildeten Radikalkationen/-anionen beeinflussen die Effizienz des Elektroneneinfangs der Elektrophore. CV-Messungen an Modellverbindungen, die auf Fuson Enolen basierten, zeigten, daß Wasserstoffbrückenbindungen die Oxidationspotentiale der Enole bis zu 500 mVFc kathodisch verschieben. Dieses Konzept wurde auch in Lösung getestet, indem sowohl inter- als auch intramolekularer Elektronentransfer von Ferrocen zu Enol- bzw. Enolether-Radikalkationen untersucht wurde. Die Verwendung von stabilen reversiblen Redoxsystemen kann eine Schlüsselfunktion in der Nanotechnologie einnehmen, wenn es um den Transfer kleinster Flüssigkeitsvolumina (Nanoliter-Maßstab) geht. Daher wurden einige redoxaktive Verbindungen hergestellt und ihre Oberflächeneigenschaften sowie ihre elektrochemische und chemische Stabilität untersucht. For Ritika The Present work was carried out under the guidance of Prof. Dr. Michael Schmittel I take the present opportunity to extend my sincere and deepest gratitude to Prof. Dr. M. Schmittel for providing me an opportunity to carry out the present work under his expertise. I would also like to thank him for the constant encouragement that I had received from him all throughout this work. I would also like to thank Dr. Demuth, Ms. Hatzig and Mr. Bodenstedt for providing technical assistance throughout this work. I would also like to thank Prof. B. Schink, Britta Müller from University of Konstanz (phenoxyethanol dehydratase) and Prof. J. Rétey, C. Weber (diol and glycerol dehydratase) for their help in enzymatic investigations. I would like to thank Prof. G. Bucher from University of Bochum for LFP investigations. It gives me a pleasure to thank Dr. T. Mukherjee and Dr. S. Adhikari from BARC (India) for pulse radiolysis investigations. I thank the group members, W. Henn, V. Kalsani, R. Kishore, Atul Mahajan, H. Lin, B. He and V. Chandrasekhar for all the help that they have extended during this work. I would also like to thank Ms. U. Ulrike for the help that she had extended to me throughout this work. I would also like to thank Hisham and Deena for correcting the manuscript. I would like to thank my parents, Dr. Mani Lal and Dr. Asha Rani. I am very much obliged to my parents-in-law, Mr. Anil Marathe and Mrs. Vrishali Marathe for their constant support in all ways. Finally I would like to thank my wife Rupali Lal for her constant support and encouragement during the research. Publications 1) M. Lal, A. Langels, H.-J. Deiseroth, J. Schlirf, M. Schmittel, The Role of Hydrogen Bonding in the Oxidation Potential of Enols, J. Phys. Org. Chem. 2003, 16, 373-379. 2) M. Schmittel, M. Lal, M. Schlosser, H.-J. Deiseroth, Unusual ladder like supramolecular arrangement by cooperative effect of bifurcated O-H…O hydrogen bonding in crystals of racemic 4-ferrocenylbutan-1,2-diol, CrystEngComm. 2003, 5, 294-299. 3) M. Schmittel, M. Lal, W. A. Schenk, M. Hagel, N. Burzlaff, A. Langels, Synthesis and One-Electron Oxidation Chemistry of Stable ß,ß-Dimesityl Enols with Heteroaryl Substituents, Z. Naturforschg. B 2003, 58b, 877-884. 4) M. Schmittel, M. Lal, M. Schlosser, H.-J. Deiseroth, A Supramolecular Ladder Motif in 2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)propane-1,3-diol, Acta Cryst. C 2004, C60, o589-o591. 5) M. Schmittel, M. Lal, K.-H. Graf, I. Suske, N,N’-Dimethyl-2,3-dialkylpyrazinium Salts as Redox-Switchable Surfactants? Redox, Spectral, EPR and Surfactant Properties, Chem. Commun. 2005, 45, 5650-5652. Manuscript in Preparation 6) M. Schmittel, M. Lal, R. Lal, M. Röck, A. Langels, Z. Rappoport, J. Schlirf, H.-J. Deiseroth, M. Keller, G. Gescheidt, U. Flörke, A Comprehensive picture of the one- electron oxidation chemistry of enols, enolates and α-carbonyl radicals-Oxidation potentials and characterisation of radical intermediates. 7) M. Schmittel, M. Lal, G. Bucher, Ferrocene as reporter molecule of enol radical cations in solution. 8) M. Schmittel, M. Lal, J. Schlirf, H.-J. Deiseroth, Non-covalent interaction motifs in the crystal structure of β,β-dimesitylenols with heterocylic substituents. 9) M. Schmittel, M. Lal, M. Schlosser, H.-J. Deiseroth, Crystal structure of diethyl-2- methyl-2-(2,2,6,6-tetramethyl-piperidin-1-yloxy)malonate. Poster presentations 1) "Design and synthesis of substrates to probe radical and radical ionic intermediates in coenzyme B12 dependent enzymes such as diol and glycerol dehydratase"- Postgraduate Winter School on Organic Reactivity-WISOR, Bressanone, Jan., 2003. 2) "Design and synthesis of substrates to probe radical and radical ionic intermediates in coenzyme B12 dependent enzymes such as diol and glycerol dehydratase"-Gordon Research Conference on "Free Radical Reactions", New-Hampshire, July, 2003. 3) "Design and synthesis of substrates to probe radical and radical ionic intermediates in coenzyme B12 dependent enzymes such as diol and glycerol dehydratase"-6th International Symposium of the Volkswagen-Stiftung on Intra- and Intermolecular Electron Transfer, Köln, Oct. 29-Nov. 1, 2003. 4) "Design and synthesis and studies of 2,3-disubstituted pyrazinium tetrafluoroborates-towards redox modulated surfactants"-6th International Symposium of the Volkswagen-Stiftung on Intra- and Intermolecular Electron Transfer, Köln, Oct. 29-Nov. 1, 2003. Abbreviations Used Abs Absorbance Ad Adenosyl B3LYP Becke Lee Yang Parr BuLi t-Butyl lithium BP Boiling Point CIDNP Chemically Induced Dynamic Nuclear Polarisation DABCO 1,4-Diazbicyclo[2,2,2]octan DCM Dichloromethane DFT Density Functional Theory DMAP 4-N,N-Dimethylaminopyridine DME Dimethoxyethane DMF Dimethyl formamide DMSO Dimethyl sulfoxide E. coli Escherichia coli Eq. Equivalents EPR Electron Pair Resonance Spectroscopy ESI-MS ElectroSpray Ionisation Mass Spectroscopy ESR Electron Spin Resonance Spectroscopy Fc Ferrocene HOMO Highest Occupied Molecular Orbital HPLC High Performance Liquid Chromatography HRMS High Resolution Mass Spectrometry IR Infrared Spectrometry KIE Kinetic Isotope Effects LAH Lithium aluminium hydride LDA Lithium diisopropylamide LFP Laser Flash Photolysis LUMO Lowest Occupied Molecular Orbital MCPBA m-Chloroperoxybenzoic acid MO Molecular Orbital MP Melting Point Pd-C Palladium-Carbon PTOC Pyridine-thione carboxylic acid RNR Ribonucleotide Reductases SN2 Nucleophilic Substitution SOMO Singly Occupied Molecular Orbital SPh Thiophenyl TBAP
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