UNIVERSITY OF CINCINNATI Date:___________________ I, _________________________________________________________, hereby submit this work as part of the requirements for the degree of: in: It is entitled: This work and its defense approved by: Chair: _______________________________ _______________________________ _______________________________ _______________________________ _______________________________ SYNTHESIS OF ORGANOARSENIC COMPOUNDS FOR ELEMENTAL SPECIATION A Dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY (Ph.D.) in the Department of Chemistry of the College of Arts and Sciences 2004 by Michael Fricke B.S., The Ohio State University, 1997 B.A., The Ohio State University, 1998 Committee: Professor John Thayer, Co-Chair Professor Joseph Caruso, Co-Chair Professor Anna Gudmundsdottir ABSTRACT Ongoing toxicokinetic and biogenesis investigations require gram quantities of naturally occurring arsenobetaines and dimethylribofuranosides. The principal synthetic routes to these compounds are hazardous; at least one laboratory explosion has occurred. New routes to these compounds are now reported that eliminate dangerous procedures and materials inherent in these syntheses. Previously reported syntheses of arsenobetaines have all involved trimethylarsine as a synthetic precursor. Due to the high vapor pressure (BP 52oC), extreme toxicity and pyrophoric nature of this compound it is both difficult and expensive to handle in a laboratory. In seeking to avoid this trimethylarsine as a precursor in the synthesis of arsenobetaines, the novel arsines ethoxycarbonylmethyldimethylarsine and 2-ethoxycarbonylethyl(dimethyl)arsine have been synthesized and isolated. The higher vapor pressure of these arsines permits purification by vacuum distillation and allows for safer handling. Subsequent conversion to arsenobetaines is simple and this route is preferred to those previously reported on the basis of material costs, operator time and safety. The synthesis of the desired dimethylribofuranoside has involved the hydrogen peroxide oxidation in ether of a parent arsine to provide the desired arsine oxide moiety. This reaction is hazardous. New routes to arsine oxides have been explored including the reduction of novel arsinoyl imidazolides and rearrangements involving Meyer chemistry that dates from the year 1883. Finally, the oxidation of arsines using the mild oxidant dimethyldioxirane was attempted. I The dimethyldioxirane oxidation of triphenylarsine provided the desired triphenylarsine oxide quickly and quantitatively. After demonstrating this reaction on the small scale oxidation of triphenylarsine, the dimethyldioxirane oxidation was employed to replace the oxidation step in the synthesis of the required dimethylribofuranoside. This alternative oxidation worked well and the hazardous oxidation of arsines with hydrogen peroxide in ether can be abandoned. II III Dedicated To Mom and Dad Without their love and patience none of this would have been possible. IV ACKNOWLEDGEMENTS I would like to thank a number of people who have contributed to my graduate school experience. First I would like to thank Professor John Alexander. Unfortunately, I was one of the last individuals to have the opportunity to learn on a graduate level from this accomplished chemist. With his untimely passing, we lost a patient man who went out of his way to teach those that others considered to be lost causes. He leaves a legacy of excellence and generosity that I hope to emulate in some small part in my future endeavors. JJA is missed but can never be forgotten. I would like to thank Professor John Thayer for doing his best to fill some very big shoes in his capacity as my replacement advisor. Dr. Thayer was an easy choice because of his close friendship to Dr. Alexander and my own experience assisting him in the teaching of freshman chemistry. He brought a fresh perspective to my research and valuable experience with organoarsenic chemistry. Professor Joseph Caruso or “Doc” has been a pillar since my childhood. His example in no small part contributed to my early interest in chemistry and his guidance played an even larger part in my opportunity to pursue this interest. Doc’s chemistry is an enlightened network of the world’s top analytical scientists coupled with a laboratory ethos that emphasizes individual creativity and performance. Doc has cultured a workspace where he never has need to speak a harsh word to any of his students. He has been close to the ideal advisor. Professor Anna Gudmundsdottir and I both started our work at the University of Cincinnati in 1998 and she has been a continual presence for me throughout graduate school - teaching my 8:00 AM class on advanced organic chemistry during my first V quarter through the final signature approving this thesis. I am indebted to her for the honest advice she provided in the early years and then on experimental setups and finally on what was necessary to finish my thesis. Through her efforts, my science has been invaluably strengthened. Professor William Cullen of the University of British Columbia has been a source of insight since our first contact in Graz at the ICEBAMO meeting of 2000. Our collaboration has involved endless correspondence and the recent privilege of spending one month working in his laboratory. I wish him a long and enjoyable retirement but expect I’ll be hearing of his continued efforts in arsenic chemistry long after the renovation of his laboratory building provides the impetus to finally hang up his lab coat and goggles. Professor David Hart of the Ohio State University has made himself available to me for consultation ever since I enrolled in his undergraduate honors organic laboratory course in the spring of 1994. Although he finds organometallic chemistry a bit inconsistent, his expertise in the synthesis of natural products has provided easy solutions to problems arising in my own research. He will be among my first choices for advice on future research. Professor Andrew Benson at the Scripps Institute of Oceanography has provided considerable perspective on my studies. Since his own Ph.D. defense at the California Institute of Technology in 1941, Dr. Benson has had a distinguished career including the use of radioactive carbon dioxide to discern the path of carbon in photosynthesis and more recently he has been interested in the biochemistry of arsenic species in marine organisms. I am grateful for the opportunity to hear the personal accounts of his VI scientific exploration and am humbled by his kind words regarding my own accomplishments. Dr. Jack Creed has been an able mentor at the U.S. Environmental Protection Agency, where I have spent the last year working across the street from the campus in Cincinnati. I will never be able to repay the opportunity Jack provided me or the patience he showed by permitting me to juggle my post-doctoral research while at the same time working to finish my thesis. The slight correlation between the two does not begin to explain the seemingly infinite freedom Jack allowed me to do what had to be done. It can not be understated that I would not have been able to complete my research after Dr. Alexander died had Jack not provided me with a desk and a bench. Finally, I would like to thank Dr. Maria Montes-Bayón for being an excellent post-doctoral fellow with the Caruso group and several graduate students including Dr. Jason Day, Tyre Grant, Sasi Kannamkumarath and Eric Mack for teaching me practical laboratory skills. I had the opportunity to teach Sasi to drive and I think they all consider this some small repayment for their help. VII 1 TABLE OF CONTENTS Page LIST OF FIGURES 6 LIST OF CHEMICALS 7 CHAPTER 1 SYNTHETIC CHEMISTRY FOR ELEMENTAL SPECIATION 12 1.1 Arsenic 13 1.2 Trace Level Elemental Speciation of Arsenic 17 1.3 Plasma Mass Spectroscopy 20 1.4 Electrospray Ionization Mass Spectroscopy 22 1.5 Organometallic Standards 25 1.6 Structural Configuration 26 1.7 Toxicokinetic, Toxicodynamic and Biogenesis Studies 26 1.8 Research 28 CHAPTER 2 SYNTHESIS OF ARSENOBETAINES VIA SODIUM DIMETHYLARSENIDE 30 2.1 Introduction 31 2.2 Experimental 33 2.2.1 Reagents 33 2.2.2 Instrumentation 33 2.3 Synthetic Procedures 34 2.3.1 Dimethyliodoarsine (2) 34 2 Page 2.3.2 Sodium Dimethylarsenide (3) 35 2.3.3 Ethoxycarbonylmethyl(dimethyl)arsine (4) n=1 36 2.3.4 Ethoxycarbonylmethyl(trimethyl)arsonium iodide (5) n=1 36 2.3.5 Arsenobetaine (trimethylarsoniumacetate) (6) n=1 37 2.3.6 2-Ethoxycarbonylethyl(dimethyl)arsine (4) n=2 38 2.3.7 2-Ethoxycarbonylethyl(trimethyl)arsonium iodide (5) n=2 38 2.3.8 Arsenobetaine-2 (trimethylarsoniumpropionate) (6) n=2 39 2.4 Discussion 39 CHAPTER 3 ARSINE OXIDES REVISITED 41 3.1 Introduction 42 3.2 Cause of Explosion 44 3.3 Dioxirane – An Alternate Oxidant 46 3.4 Meyer Reaction 47 3.5 Arsinoyl imidazolides 48 CHAPTER 4 SYNTHESIS OF TRIPHENYLARSINE OXIDE BY OXIDATION OF TRIPHENYLARSINE WITH DIMETHYLDIOXIRANE 50 4.1 Introduction 51 3 Page 4.2 Experimental 53 4.2.1 Reagents 53 4.2.2 Instrumentation 53 4.3 Synthetic Procedures 54 4.3.1 Dimethyldioxirane (DMD) (9) 54 4.3.2 Determination of Concentration of DMD 55 4.3.3 Triphenylarsine oxide (12) 56 4.4 Discussion 56 CHAPTER 5 SYNTHESIS OF (R)-2,3-DIHYDROXYPROPYL 5-DEOXY- DIMETHYLARSINOYL-β-D-RIBOSIDE (As328) 58 5.1 Introduction 59 5.2 Experimental 62 5.2.1 Reagents 62 5.2.2 Instrumentation 62 5.2.3 Chromatography 63 5.3 Synthetic