Kinetics and Mechanism of Acylation of Amines with 2-Naphthoyl Azide

Western Michigan University ScholarWorks at WMU Dissertations Graduate College 4-1983 Kinetics and Mechanism of Acylation of Amines with 2-Naphthoyl Azide Abraham L. Faburada Western Michigan University Follow this and additional works at: https://scholarworks.wmich.edu/dissertations Part of the Organic Chemistry Commons Recommended Citation Faburada, Abraham L., "Kinetics and Mechanism of Acylation of Amines with 2-Naphthoyl Azide" (1983). Dissertations. 2423. https://scholarworks.wmich.edu/dissertations/2423 This Dissertation-Open Access is brought to you for free and open access by the Graduate College at ScholarWorks at WMU. It has been accepted for inclusion in Dissertations by an authorized administrator of ScholarWorks at WMU. For more information, please contact [email protected]. KINETICS AND MECHANISM OF ACYLATION OF AMINES WITH 2-NAPHTHOYL AZIDE by Abraham L . Faburada A Dissertation Submitted to the Faculty of The Graduate College in partial fulfillment of the Requirements for the Degree of Doctor of Philosophy Department of Chemistry Western Michigan University Kalamazoo, Michigan April, 1983 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. KINETICS AND MECHANISM OF ACYLATION OF AMINES WITH 2-NAPHTHOYL AZIDE Abraham L. Faburada, Ph. D. Western Michigan University, 1983 The reaction of 2-naphthoyl azide with primary and secondary amines in protic and aprotic solvents follows second-order kinetics. The effect of increasing solvent polarity is shown to increase the rate of reaction. For amines of similar basicity, the rate of reaction decreases with increasing steric hindrance on the amine. The changes in free energy and entropy of activation for n-butylamine and cyclohexylamine are in accord with steric requirements of amines. For amines of similar steric hindrance, the rate of reaction increases with increasing amine basicity. The mechanism of addit ion-elimination involving the for mation of a tetrahedral intermediate is consistent with the data obtained. The rate-determining step in this re action is postulated on the basis of amine and azide ion basicities, and the possibility of anchimeric-type as sistance by the azide group in the expulsion of the amine from the tetrahedral intermediate. The absence of general base catalysis in this reaction is explained in terms of a fast proton transfer from the protonated amide inter mediate to a solvent or an amine molecule which occurs after the rate-determining step. Qualitative evaluation Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. of the total steric and electronic effects on the rate this reaction indicates that the former factor is pre dominant. The combination of high basicity and small steric hindrance on the amine results in a dramatic en hancement in rate of reaction as demonstrated by pyrrol dine. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. INFORMATION TO USERS This reproduction was made from a copy of a document sent to us for microfilming. While the most advanced technology has been used to photograph and reproduce this document, the quality of the reproduction is heavily dependent upon the quality of the material submitted. The following explanation of techniques is provided to help clarify markings or notations 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. 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For illustrations that cannot be satisfactorily reproduced by xerographic means, photographic prints can be purchased at additional cost and inserted into your xerographic copy. These prints are available upon request from the Dissertations Customer Services Department. 5. Some pages in any document may have indistinct print. In all cases the best available copy has been filmed. University M icrtxilm s International 300N.Zeeb Road Ann Arbor, Ml 48106 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8314208 Faburada, Abraham L. KINETICS AND MECHANISM OF ACYLATION OF AMINES WITH 2- NAPHTHOYL AZIDE Western Michigan University Ph.D. 1983 University Microfilms International 300 N . Zeeb Road, Ann Arbor, M I 48106 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS I wish to take this opportunity to express my sincere thanks of gratitude to Dr. Donald C. Berndt, my research advisor, for his guidance, understanding, and constructive criticisms in the course of this research project; to the members of my dissertation committee, Dr. Stephen Friedman, Dr. Robert Harmon, Dr. Robert Nagler, and Dr. Jochanan Stenesh, for their kind attention and careful evaluation of the work accomplished; to the Department of Chemistry and The Graduate College for the much needed monetary support in the form of assistantship and fellowship awards which both have provided me through the years; to all the people who, in one way or another, have extended me their help unselfishly to make this undertaking•possible; and to my dear wife, Yolanda, for her unyielding patience, en couragement, and understanding in bearing with me through. Abraham L . Faburada ii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Kerwln and Kathleen iii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS ACKNOWLEDGEMENTS..................................... ii DEDICATION........................................... iii LIST OF TABLES....................................... v LIST OF FIGURES............................... '..... vi Chapter I. INTRODUCTION.................................. 1 II. REVIEW OF LITERATURE.......................... 3 III. RESULTS AND OBSERVATIONS..................... 14 IV. DISCUSSION OF RESULTS........................ 29 V. EXPERIMENTAL METHODS AND PROCEDURES.......... 44 Chemicals and Equipment...................... 44 Purification of Solvents.................. 45 Purification of Amines....................... 46 Preparation of 2-Naphthoyl Azide............. 46 Preparation of Amide Derivatives............. 49 Purification by Column Chromatography........ 50 Determination of Yield by Gas Chromatography.. 51 Kinetic Measurements ............ 52 Physical Data of Amide Products.............. 53 BIBLIOGRAPHY......................................... 56 iv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES TABLE 1. pKa of Ammonium Ions of Amines in Aqueous Solution........................................ 15 2. Per Cent Yield of N-Substituted-2-Naphthamides.. 17 3. Absorbance-Time Data for the Acylation of n-Butylamine in Acetonitrile............ ....... 19 4. Observed Pseudo First-Order Rate Constants for n-Butylamine in Acetonitrile............... 21 5. Second-Order Rate Constants for the Acylation of Amines....................................... 25 6. Activation Parameters in Ethanol............... 26 7. Steric Substituent Constants, Es, for Aliphatic Substituents in the Series, R'COOR, at 25 °C.... 33 8. pK of Ammonium Ion of Amines in Ethanol and Acetonitrile.................................... 34 9. pKg of Hydrazoic Acid and Substituted Phenols... 38 10. Physical Properties of Purified Amines......... 47 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES FIGURE 1. Plot of At versus + 20 2. Plot of kobs versus [Amine]................... 23 3. Plot of ln(k/T) versus 1/T......... 27 vi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. C H A P T E R I INTRODUCTION The reaction of acyl azides with amines was first introduced by Curtius in 1902.^ Since then, the reaction 2 3 has been utilized in the synthesis of peptides. ’ 0 0 t t ti R-C-N3 + R"R'NH ■> R-CNR'R" + HN3 In peptide systhesis a common problem often en countered is the tendency of reactants to undergo racemization during the process. Although such racemization has been observed in the azide method of peptide synthesi the extent is

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