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Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48106 73- 26,796 INFORMATION TO USERS This material was produced from a microfilm copy of the original document. While the most advanced technological means to photograph and reproduce this document have been used, the quality is heavily dependent upon the quality of the original submitted. The following explanation of techniques is provided to help you understand markings or patterns which may appear on this reproduction. 1.The sign or "target" for pages apparently lacking from the document photographed is "Missing Page(s)". If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting thru an image and duplicating adjacent pages to insure you complete continuity. 2. When an image on the film is obliterated with a large round black mark, it is an indication that the photographer suspected that the copy may have moved during exposure and thus cause a blurred image. You will find a good image of the page in the adjacent frame. 3. When a map, drawing or chart, etc., was part of the material being photographed the photographer followed a definite method in "sectioning" the material. It is customary to begin photoing at the upper left hand corner of a large sheet and to continue photoing from left to right in equal sections w ith a small overlap. If necessary, sectioning is continued again — beginning below the first row and continuing on until complete. 4. The majority of users indicate that the textual content is of greatest value, however, a somewhat higher quality reproduction could be made from "photographs" if essential to the understanding of the dissertation. Silver prints of "photographs" may be ordered at additional charge by writing the Order Department, giving the catalog number, title, author and specific pages you wish reproduced. 5. PLEASE NOTE: Some pages may have indistinct print. Filmed as received. Xerox University Microfilms 300 North Zeeb Road Ann Arbor, Michigan 48106 73- 26,796 DeNEALE, Richard Jay, 1942- A STUDY ON THE CONFIGURATION AND HYDROLYSIS OF SOME OXAZOLIDINES DERIVED FROM THE EPHEDRINES. The Ohio State University, Ph.D., 1973 Health Sciences, pharmacy University Microfilms, A XEROX Company , Ann Arbor, Michigan THIS DISSERTATION HAS BEEN MICROFILMED EXACTLY AS RECEIVED. A STUDY ON THE CONFIGURATION AND HYDROLYSIS OF SOIVIE OXAZOLIDINES DERIVED FROM THE EPHEDRINES DISSERATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Richard Jay DeNeale, B.S. ***** The Ohio State University 1973 Reading Committee Louis Mals£ei_s Approved By Jules B, LaPidus Robert_E_î_ Notari__ Lester Mitscher Ai^isey Department of Pharmacy ACKNOWLEDGMENTS I would like to express my gratitude toward the many friends, colleagues, and acquaintances who have generously contributed their criticira, support, and encouragement during my tenure at Ohio State, Especially, I am grateful for the efforts of my adviser, Dr, Louis Malspeis, in providing his concern for and interest in his students, I am appreciative of the financial support given me by the National Institutes of Health in the form of a Medicinal Chemistry Trainee Grant (GMl9^9-03) under which most of the present work was accomplished. Finally, and most important, I cannot acknowledge adequately in any manner the self- sacrificing efforts of my wife. Leanna, in bringing the efforts of the past years to fruition. ii VITA September 20, 1942........ Born - Washington, D. C. 1967 ......... ......... B.S. in Pharmacy, The University of Maryland, Baltimore, Maryland 1967-1969 ............ Teaching Assistant, College of Pharmacy, The Ohio State University, Columbus, Ohio 1969 -1973» ...... NSF-NIH Trainee, College of Pharmacy, The Ohio State University, Columbus, Ohio FIELDS OF STUDY Major Fieldj Pharmaceutical Chemistry Studies in Organic Chemistry. Professors Harold Shechter, Paul Gassman, and Derek Horton Studies in Pharmaceutics. Professors Louis Malspeis, Robert Notari, and Theodore Sokoloski Studies in Separation Techniques. Professor Raymond Doskotch Studies in Biopharmaceutics. Professors Robert Notari and Richard Reuning Studies in Surface Chemistry. Professor Quentin Van Winkle Studies in Chemical Kinetics. Professor Frank Verhoek Studies in Chemical Thermodynamics. Professor George MacWood Studies in Radioisotopes. Professor Louis Malspeis Studies in Statistics. Professor Russell Skavaril ill TABLE OF CONTENTS Page ACKNOWLEDGMENTS............................. ü VITA....................................... iii LIST OF TABLES............ ... .............. vii LIST OF FIGURES............................. % LIST OF COMPOUNDS........................... xiii INTRODUCTION AND STATEMENT OF PROBLEM........ 1 Chapter I. BACKGROUND........ '... ............... 5 II. EXPERIMENTAL PROCEDURES............... 15 A. Synthetic Procedures.......... 15 1. Reagents 2. Instrumentation 3. Methods of Synthesis 4. Isolation of Intermediate in the Hydrolysis of 2-Styryl-3, 4-dimethyl-3-phenyloxazolidines 5. Identification of Products of Hydrolysis B. Reaction of Oxazolidines with Grignard Reagents and Hofmann Degradation of the Resulting Tertiary Amino Alcohols........ 39 1. Reagents 2. Instrumentation 3. Procedures C. Kinetic Procedures......... 41 1. Reagents 2. Instrumentation 3. Methods of Analysis a. General Procedures b. Preparation of Buffers iv c. Preparation of Stock Solutions d. Preparation of Solutions of Hydrogen Chloride e. Preparation of Solutions of Sodium Hydroxide D, Measurement of Equilibrium Values for Ring Closure.,....... 50 III. RESULTS AND DISCUSSION.............. 52 A. Synthesis of Oxazolidines from (-)-Ephedrine and (t)-Pseudoephedrine $2 B. Synthesis of Oxazolidines from (x)-Norephedrine and (+)-Norpseudoephedrine.......... 54 C. Stereochemical Aspects of Ring Closure......... 6o 1. Evidence from Proton Magnetic Resonance Spectral Data and Infrared Spectral Data 2. Evidence from Reaction of Grignard Reagents with Oxazolidines and Subsequent Hofmann Degradation 3. Evidence from X-ray Diffraction Analysis 4. Proposed Mechanism of Ring Formation D. Attempt to Measure Equilibrium Values for Ring Closure of the Styryl- oxazolidines. .......... 93 E. Some Spectral Characteristics of Hydrolysis Intermediates from 2-Styryl-3»4-dimethyl-5-phenyl- oxazolidines (II and XII) and 2,5-Diphenyl-3f4-dimethyloxazolidines (I and XI) and of Styrylidene-N- methyl-N-[2-(erythro-1-hydroxy-1- phenyl)propyl] ammonium perchlorate (XXXIV)..... 93 F. Kinetics of the Hydrolysis of Some Oxazolidines Derived from the Ephedrines and of Some Intermediates and Analogues ..... 99 1. Methods of Assay 2. Kinetics of the Hydrolysis of 2-Styryl-3,4-dimethyl-5- phenyloxazolidines a. Methodology b. Kinetics in Acidic Solutions c. Kinetic Characterization of Solvent Participation in Ring Opening of the Oxazolidines in Acidic Solutions d. Kinetics in Buffer Solutions, pH 3.0 - 7.0 e. Rate Dependency on Temperature - Concentrated Acid Solutions f. Kinetics in Alkaline Solutions g. Solvent Kinetic Isotope Effects in Alkaline Solutions h. Rate Dependency on Temperature - Alkaline Solutions i. Stopped-flow Measurements of the Hydrolysis Reaction in Alkaline Solution 3. Some Oxazolidines from (-)-Ephedrine and Aliphatic Carbonyl Compounds 4. Kinetics of the Hydrolysis of 2,^-Diphenyl-3,4-dimethyloxazolidines 5. Comparative Kinetic Characteristics Defining the Hydrolysis of the 2-Styryl- 3,4-dimethyl-5-phenyloxazolidines 6. Comparative Kinetic Characteristics of Ring Opening of the 2-Styryl-3,4- dimethyl-5-phenyloxazolidines 7. Comparative Kinetic Characteristics of the Hydrolysis of the Intermediates from 2-Styryl-3,4-dimethyl-5- phenyloxazolidines from 6 M HCl to pH 7 SUfmARY. ., 190 REFERENCES, 193 Vi LIST OF TABLES Table Page 1. Selected IR and PMR (6) Spectral Properties for Condensation Products of (Î)-Norephedrine and (+)-Norpseudoephedrine with '/arious Carbonyl Compounds in Chloroform-d 56 2. Infrared Bands Between 2700 and 2800 c m .56 3. Selected PMR ((5 ) Chemical Shifts for Oxazolidines from the Ephedrines and Norephedrines in Chloroform-d 69 4. Mollecular Ellipticities at Selected Wavelengths for the Ephedrines and Selected Analogous Compounds in Methanolic Solutions 83 5 . Absolute Configurations of the Ephedrines and Selected Analogous Compounds 84 6. Torsion Angles for 2-p-Bromophenyl-3»4- dimethyl-5-phenyloxazolidines 86 7. Bond Angles for 2-p-Bromophenyl-3,4- dimethyl-5-phenyloxazolidines 87 8. Proton Magnetic Resonance Spectral Data of 2-Styryl-3.4-dimethyl-5-phenyl- oxazolidines and 2,5-Diphenyl-3,4-dimethyl- oxazolidines in Trifluoroacetic Acid 95 9. Selected Circular Dichroisra Spectral Properties of Some Oxazolidines and Their Hydrolytic Products 98 vii 10, Selected Ultraviolet Spectral Properties of Some Oxazolidines and Their Hydrolytic Products 100 11, Rate Constants for the Hydrolysis of 2-Styryl- 3.4-dimethyl-^-phenyloxazolidines (II and XII) in 6.35 M HCl at 30° 103 12, Rate Constants for the Hydrolysis of 2-Styiyl- 3.4-dimethyl-5-phenyloxazolidines (II and XII) in pH 6,00 Phosphate Buffer 0,05 M at 30° 103 1 3 , Rate Constants for the Hydrolysis of 2-Styryl- 3.4-dimethyl-5-phenyloxazolidines (II and XII) in Hydrochloric Acid Solutions at 30° 104 14, Rate Constants for the Hydrolysis of Styrylidene-N-methyl-N-[2-(1-phenyl)propylJ- ammonium Perchlorate (XXXV) in Hydrochloric Acid Solutions at 30° 111 15* Rates of Ring Opening of 2-Styryl-3,4-dimethyl- 5-phenyloxazolidines (II and XII) in Hydrochloric Acid Solutions
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