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INFORM ATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. Each original is also photographed in one exposure and is included in reduced form at the back of the book. Photographs included in the original manuscript have been reproduced xerographically in this copy. Higher quality 6 " x 9 " black and white photographic prints are available for any photographs or illustrations appearing in this copy for an additional charge. Contact UMI directly to order. A Bell & Howell Information Company 300 North Z eeb Road. Ann Arbor. M l 48106-1346 USA 313/761-4700 800/521-0600 THE MECHANISM AND STEREOCHEMISTRY OF CARBON-HYDROGEN BOND ACTIVATION VIA CYCLOMETALLATION OF 8-(R)-(-)-a-DEUTERO- ETHYLQUINOLINE WITH PALLADIUM(II) SALTS by Harald Louis Holcomb A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (Chemistry) August 1995 Copyright © 1995 Harald Louis Holcomb UMI Number: 9617102 UMI Microform 9617102 Copyright 1996, by UMI Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. UMI 300 North Zeeb Road Ann Arbor, MI 48103 UNIVERSITY OF SOUTHERN CALIFORNIA THE GRADUATE SCHOOL UNIVERSITY PARK LOS ANGELES, CALIFORNIA 90007 This dissertation, written by Harald #Loui s,. Ho1comb.................. under the direction of If..-? :? ...... Dissertation Committee, and approved by all its members, has been presented to and accepted by The Graduate School, in partial fulfillment of re quirements for the degree of DOCTOR OF PHILOSOPHY Dean of Graduate Studies D a te # k . I h j m DISSERTATION COMMITTEE Chairperson In loving memory o f my mother, Eleonore R. Holcomb (1934-1992). Acknowledgments I would like to thank Dr. Flood for his patience, guidance and intellectual stimulation, all o f which have allowed me to grow into a better person. During my graduate studies I have faced intellectual challenges and personal ones as well. If it had not been for the understanding and the willingness of Dr. Flood to support me, I would not have seen this stage o f my life to completion. Dr. Flood has been, above all other things, not only a mentor of chemistry but one of life as well; thanks, Dr. Flood. I will always appreciate what you have done for me. If there is one person that I could only thank, it would be my wife, Michelle. She has shown the patience of a saint during a process which, to her, must have seemed endless. She has been thoughtful, loving and above all supportive. I love you Michelle, with all my soul and with each new day that love only grows stronger. O f the remaining people that I thank, if there is anyone whom I have forgotten, I apologize now. Dr. Robert Reed (Rob) has been a friend of unmentionable magnitude. He has suffered with me and for me during the writing o f this thesis. Rob has pushed me and has shown me the importance of doing a good job, always. Thanks, Rob; you will always have my deepest appreciation and gratitude. Mark Kozak has been in the thick of it with me. I am proud to call him a friend and most of all I will never forget our trip to Cabo San Lucas. I have known Masanori Iimura since his sophomore year at USC and since then he has become a good friend. He has also become a good chemist, who will some day do great things; good luck Mas, my thoughts are with you. Furthermore, I would like to thank Tim La, Ginette Struck, Lin Wang, Gumming Wang, John Lim and Mark Deming for the help they have given me over the years and there friendship. To the newest members of the Flood group, Renjie Zhou and Hong Shi Zhen, good luck on the adventure you are about to begin. Others in the department who must be thanked are Michelle Dea for her help with everything. Allan Kershaw who has been a valuable resource and a good friend. Jim Merritt for always coming through when I needed him. Dr. James Ellem for his helpful discussions about my research and Dr. Bau for his patience during my attempts at solving the x-ray structure of my compounds. Also, I want to thank Michael Sims for his helpful discussions and good friendship. I would also like to express my thanks to my newest friends Barry Dennen and James McGachy for their support during the finishing of this thesis and with the difficulties of life as well. Thanks to Mohammed Sarki Abba who has supported me in all my endeavors since I was very young. To my great aunt Erna Rapp I want to say thank you and I am glad you have motivated me to finish my studies and get on with life. Finally, I want to thank Tasha, for staying up with me on those late nights while I finished my thesis. She is a wonderful friend and companion. Table of Contents Dedication Acknowledgments List of Tables List of Figures Abstract Preface Chapter I: The First Synthesis of Optically Active 8-(i?)-(-)-a- deuteroethylquinoline. 1.1 Introduction 1.2 Results and Discussions 1.2.1 Total Synthesis of 8-(7?)-(-)-a-deuteroethylquinoline. 1.2.2 Determination of the Optical Purity o f 8-(7?)-(-)- a-deuteroethylquinoline. 1.2.3 Following the Deuterium Loss During the Synthesis of 8-(R)- (-)-a-deuteroethylquinoline. 1.2.4 Chemical Shifts of the Ring Protons in 8-(R)- (-)-a-deuteroethylquinoline. 1.3 Summary 1.4 Experimental Chapter II: The Stereochemical Consequences of C-H Activation via Cyclometallation of 8-(i?)-(-)-a-deuteroethylquinoline. 2.1 Introduction 2.2 Results and Discussions 2.2.1 Formation of Palladium 8-(/?/5)-a-deuteroethylquinoline Dimer. 2.2.2 Determination of the Isotope Effect. 77 2.2.3 Synthesis and Resolution of the Diastereomers. 81 2.2.4 X-ray Determination of Compound 3. 89 2.2.5 Reactivity of Compound 3. 97 2.3 Summary 102 2.4 Experimental 103 Appendix: X-ray data for the cyclometallated ethylquinoline-a-phenethyl- 111 amine palladium(II) derivative. vi List of Tables Chapter I. Page 1. Optical rotations o f chiral compounds. 22 2. Percent diastereomeric excess of racemic 8-a-deuteroethylquinoline. 29 3. Percent enantiomeric excess o f 8-(/?)-(-)-a-deuteroethylquinoline. 32 Chapter II. 1. The reaction of K2PdCl4 with 8-ethylquinoline. 71 2. The reaction of PdCl2 with 8-ethylquinoline. 73 3. The reaction of Pd(OAc)2 with 8-ethylquinoline. 74 4. The reaction of 8-(/?)-(-)-a-deuteroethylquinoline with palladium(II). 91 vii List of Figures Chapter I. Fig. 1 Synthetic strategy for the formation of the quinoline derivative. Fig. 2 Retrosynthetic strategy for the production o f S-(R)-(-)-a- deuteroethylquinoline from (/?)-(-)-a-deuteroethylbenzene. Fig. 3 ' h NMR of a one-to-one mixture of 2 and 4-ethylnitrobenzene. Fig. 3.1 'id NMR of 2-a-deuteroethylnitrobenzene. Fig. 3.2 'id NMR showing an increased concentration of 4- ethylnitrobenzene. Fig. 3.3 'id NMR showing the final fraction taken during the separation of 2 and 4-ethylnitrobenzene. Fig. 4 ' h NMR of 8-(R)-(-)-a-deuteroethylquinoline. Fig. 5 'id NMR of the shifted spectra o f the racemic 8-a-deuteroethyl- quinoline utilizing Yb(hfc)3. Fig. 5.1 JH NMR of the a proton of the racemic 8-a-deuteroethyl- quinoline showing 3.6% ee. Fig. 5.2 'h NMR of the a proton of the racemic 8-a-deuteroethyl- quinoline showing 1.5% ee. Fig 5.3 *H NMR of the a proton of the racemic 8-a-deuteroethyl- quinoline showing 3.6% ee. Fig. 6 'id NMR of the shifted spectra of the racemic 8-a-deuteroethyl- quinoline utilizing Yb(hfc)3 at different temperatures. Fig. 7 'l4 NMR of the shifted spectra of 8-(7?)-(-)-a-deuteroethyl- quinoline utilizing Yb(hfc)3. Fig. 7.1 'id NMR of the a proton of 8-(7?)-(-)-a-deuteroethylquinoline showing 32% ee. Page 2 5 17 18 19 20 21 26 27 27 27 28 30 31 viii Fig. 7.2 'h NMR of the a proton of 8-(R)-(-)-a-deuteroethylquinoline showing 40% ee. Fig. 7.3 lH NMR of the a proton of 8-(/?)-(-)-a-deuteroethylquinoline showing 36% ee. Fig. 8 *H NMR of the shifted spectra of 2 and 4-(-)-a-deuteroethyl- aniline utilizing Yb(hfc)3. Fig. 8.1 'l4 NMR of the a proton of 2-(-)-a-deuteroethylaniline showing a 54% ee. Fig. 8.2 !H NMR of the a proton of 4-(-)-a-deuteroethylaniline showing a 64% ee. Fig. 9 'id NMR illustrating the relative peak areas of the ring protons to the a proton of 8-(/?)-(-)-a-deuteroethylquinoline. Fig. 10 The chemical shift assignments in ppm of 8-(R)-(-)-a- deuteroethylquinoline. Fig. 11 2D ' h NMR of 8-ethylquinoline. Fig. 11.1 2D 'H NMR of the aromatic region of 8-ethylquinoline. Chapter II. Fig. 1 Illustrates the orientation of the isopropyl group with respect to palladium of the coordinated 8-isopropylquinoline. Fig. 2 Illustrates the two possible mechanistic paths of cyclometallation. Fig. 3 Depicts the lack of rotation of coordinated 2,8-dimethyl- quinoline. Fig. 4 Orientation of the chiral center after cyclometallation. Fig. 5 Showing the reaction sequence of cyclometallation and diastereomeric formation. 31 31 36 37 38 41 42 43 44 63 64 65 67 68 ix Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 Fig. 16 Fig. 17 Fig. 18 Fig. 19 'FI NMR of the cyclometallated 8-ethylquinoline chloro-bridged palladium(II) dimer. *H NMR of the cyclometallated 8-ethylquinoline acetate-bridged palladium(II) dimer. 'h NMR of the cyclometallated racemic 8-a-deuteroethyl- quinoline chloro-bridged palladium(II) dimer. Diagram illustrating the possible orientations of the chiral center after cyclometallation. ' h NMR of the cyclometallated 8-ethylquinoline a-phenethyl- amine palladium(II) complex. !H NMR of the cyclometallated 8-ethylquinoline bornylamine palladium(II) complex. 1 FI NMR of 3. 1 H NMR of 3, after a quick fractional crystallization at -23°C resulting in >90% de. X-ray structure of the 8-ethylquinoline a-phenethylamine palladium(II) derivative. X-ray structure of the 8-ethylquinoline bornylamine palladium(II) derivative. 'FI NMR of 3 at 20% de, obtained from the reaction of PdCl2 with 8-(R)-(-)-a-deuteroethylquinoline (36% ee). 'id NMR of 3 at 26% de, obtained from the reaction of K2PdCl4 with 8-(/?)-(-)-a-deuteroethylquinoline (36% ee). 'H NMR of 3 at 35% de, obtained from the reaction of Pd(OAc)2 with 8-(/?)-(-)-a-deuteroethylquinoline (36% ee). 'FI NMR of the cyclometallated ethylquinoline palladium(II) a - phenethylamine derivative at 26% de obtained from 3 at 59% de. Fig. 20 *H NMR of 6. 100 Fig. 21 I9F N M R o f6 101 xi A bstract The characterization, including 'il NMR, 2D NMR, optical rotation and percent enantiomeric excess o f the newly synthesized 8-(7?)-(-)-a-deuteroethylquinoline are described. The optical rotation was determined to be -0.36° at [a]589. The percent enantiomeric excess was calculated to be 36%, utilizing the chiral lanthanide shift reagent tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]ytterbium(III) in conjunction with 'H NMR. The mechanism of cyclometallation of 8-(/?)-(-)-oc-deuteroethylquinoline when subjected to reaction with palladium(II) salts and their eventual conversion to diastereomeric complexes, has been examined by 'H NMR, isotope effects and x-ray crystallography. The result of this process, retention of configuration, suggests that the reaction proceeds by means of a traditional three-centered transition state. Preface Oil; every day we use this precious substance at an ever increasing rate. Whether to fuel our automobiles or for the production o f synthetic fibers for clothing, oil has become an integral part of our lives. However, the world supply of this “black gold” is being reduced to zero, see Table. Oil Supply1 Billion Barrels of Oil Total proven world oil reserves. 1,000 Total annual world production. 22 Estimated number of years of oil remaining at current rate of production. 45.5 In order to slow the impending doom that will result once all o f the world’s oil supplies have been depleted, scientists are developing new methods to convert the more abundant fossil fuels such as methane into methanol for example, which would prove to be more useful (i.e., methanol would be easier to transport than methane). The process of carbon- hydrogen bond activation (i.e., C-H activation) was developed to convert methane into a more useful substance. Another process, aside from the conversion of methane into methanol that has developed from C-H activation is the cyclometallation of alkanes by means of C-H activation.3 Over the past two decades there has been an increase of interest in cyclometallations, especially in the stereochemical outcome of this process.4 1 US Geological Survey; Oil and Gas Journal. 2 a) Schwarz, H. Angew. Chem. Int. Ed. Engl. 1991, 30(7), 820. b) Crabtree, H. R. Chem. Rev. 1985, 85, 245. c) Shilov, E. A., Shteinman, A. A. Coord. Chem. Rev. 1977, 24, 97. 3 Bruce I. M. Angew. Chem. Int. Ed. Engl. 1977, 16, 73-86. A a) Evans W. D., Newkome R. G., Baker G. G. Coord. Chem. Rev. 1989, 93, 155. b) Deeming J. A., Rothwell P. I. J. Organomet. Chem. 1981, 205, 117. c) Sokolov 1. V., Bashilov V. V., Musaev A. A., Reutov A. O. J. Organomet. Chem. 1982, 225, 57. d) Pfeffer M„ Spencer J., Maassarani F. Tetrahedron: Asymmetry, 1994, 5(3), 321. xiii However, aside from a few examples, no one to date has adequately demonstrated the stereochemical course of cyclometallation resulting from the C-H activation of an alkyl group. Stille5 has shown that oxidative addition of benzyl halides to palladium complexes occurs with inversion of configuration. This result, however, does not address the issue concerning the stereochemical orientation as a result of C-H activation under the conditions of cyclometallation. To address this issue it was necessary to design a model system. In order to determine the stereochemical course of cyclometallation certain criteria must be met. The beginning substrate must be of known chiral configuration. This can be determined by either synthesizing the chiral compound via a known route or through separation of a racemic substrate to give one enantiomer. Furthermore, the racemic cyclometallated product must be able to react with another chiral ligand of known configuration, so that the separation of the now newly formed diastereomers may be achieved. Finally, determination of the absolute configuration of the newly produced chiral center must be accomplished, in order to determine whether cyclometallation occurs via inversion or retention o f configuration. Our model system will take advantage of the properties of the ligand 8-ethylquinoline, for the following reasons. First, it is known that this substrate reacts with palladium(II) salts to form stable cyclometallated compounds. Second, it has been demonstrated by Deeming and Rothwell that 8-methylquinoline and 8-ethylquinoline react readily with palladium(II) salts to yield cyclometalated compounds, however, 8-isopropylquinoline 5 Stille K. J., Lau Y. S. K„ Wong K. P. J. Am. Chem. Soc. 1976, 98(19), 5832. xiv does not. 6 This result seems odd, since one would expect the isopropylquinoline to be ideally set up for cyclometallation. Due to the steric constraints o f the isopropyl derivative, the methyl groups point away from the metal center, Scheme 1, path A. Scheme 1 3-Centered T.S. Retention o f Configuration Stereochemistry ? Back-Side Electrophilic Metal Assisted T.S. Inversion o f Configuration As depicted in Scheme 1, path A is set up ideally for cyclometalation to occur by means of a traditional three-centered transition state. Path B on the other hand, would also allow cyclometallation to occur; but utilizing a back-side metal assisted transition state. Nevertheless, cyclometallation does not occur for 8-isopropylquinoline for either steric or electronic reasons. Therefore, our substrate must be similar to 8-ethylquinoline, but 6 Deeming J. A., Rothwell P. I. J. Organomet. Chem. 1981, 205, 117. xv stereochemically different, so that upon cyclometallation we are able to differentiate which mechanistic pathway A or B was followed, Scheme 1. To achieve this we chose to synthesize 8-(i?)-(-)-a-deuteroethylquinoline, which is chemically the same as 8-ethylquinoline and therefore able to cyclometallate, but chiral; so that we can follow whether inversion or retention of configuration occurs upon cyclometallation with palladium(II) salts. However, it is important to note that the conditions o f cyclometallation for this ligand are for the chelated case and may not necessarily apply to the non-chelated substrate. Chapter 1 The First Synthesis of Optically Active -Deuteroethylquinoline 1.1 Introduction The production of optically active 8-(/?)-(-)-a-deuteroethylquinoline would offer opportunities to carry out interesting mechanistic studies in the area of C-H activation. Although 8-ethylquinoline1 is a known compound, the optically active 8- (7?)-(-)-a-deuteroethylquinoline derivative has not been synthesized. Most researchers rely on halides or heavy atoms as a method of introducing chirality into a compound; however, by using a deuterium that has similar properties to that of a hydrogen, we can study the stereochemistry of C-H activation without the additional complications (i.e., oxidative addition) of a halide or other substituent.2 A retrosynthetic look at the formation of 8-(/?)-(-)-a-deuteroethylquinoline 1, illustrates that a variety of possibilities exist when considering the synthesis of this compound, Figure 1. O f these possibilities, the use of enantiomers as the starting material or as an intermediate during the synthesis and their eventual separation will be essential during the production of the target molecule. The separation of enantiomers will be made possible by converting them into diastereomers, which is 1 Evans, D. W ., N ew k om e, G. R., Baker, G. R. C oord. Chem. Rev., 1989, 93, 155-183. 2 Sok olov, V. I. In organ ica C him ica A cta , 1976, 18, L9. 1 required because enantiomers possess the same chemical properties (i.e., melting points, boiling points, solubilities, etc.), but diastereomers do not. CH3 Single Enantiomer NH2 c h 3 Single Enantiomer CH3 Single Enantiomer CH3 Single Enantiomer C H 3 Racemic Figure 1, synthetic strategy for the formation of the quinoline derivative. 2 In order to successfully construct 8-(/?)-(-)-a-deuteroethylquinoline several methods were investigated (see Figure 1). One publication3 has claimed that 8-a- bromoethylquinoline 2 had been resolved. Since this compound is easily converted via inversion of configuration4 in to the target molecule by reaction with lithium aluminum deuteride it seemed to be an attractive point from which to synthesize 8- (/?)-(-)-a-deuteroethylquinoline 1. 2 Another synthetic possibility would be to form 8-a-hydroxyethylquinoline 3, transform .this into a chiral acid ester, and then separate the enantiomers by means of fractional crystallization utilizing an optically pure base. 3 3 So k o lo v , V . I. In organ ica C him ica A cta , 1976, 18, L9. 4 E liel, E. L. J. Am. Chem . Soc., 1949, 71 , 3 9 7 0 -3 9 7 2 . And references therein. 3 Reduction of the enantiomerically pure acid ester to the alcohol followed by reaction with thionyl chloride and lithium aluminum deuteride would furnish the desired product 8-(7?)-(-)-a-deuteroethylquinoline. As an additional effort, to utilize compounds that posses the quinoline skeleton, a stereoselective reduction could be performed on 8-acetylquinoline 4. 4 The product of this reduction, optically enriched 8-cc-hydroxyethylquinoline 3, could be reduced by means of thionyl chloride or />toluenesulfonyl chloride followed by reaction with lithium aluminum deuteride, affording the optically active target compound, 8-a-deuteroethylquinoline. The most tedious synthetic option, and ultimately the most useful for this work, would be to implant synthetically the chirality of the alpha carbon into the ethyl group before formation of the quinoline ring. A retrosynthetic look at the formation of the quinoline ring shows that this could be accomplished by using R-a- deuteroethylbenzene 5, as the starting material, Figure 2. 4 'NH- CH Figure 2 The disadvantage of this method is in the difficult preparation and purification of enantiomericlly enriched /?-(-)-a-deuteroethylbenzene. Enantiomerically enriched R- (-)-a-deuteroethylbenzene can be obtained by reacting optically pure a-methylbenzyl alcohol 6, with thionyl chloride and subsequent reduction with lithium aluminum deuteride. 6 The two optimum methods for obtaining a single enantiomer of a-methylbenzyl alcohol are either by resolving the enantiomers with a chiral reagent or by forming the chiral center through an asymmetric synthesis. Both methods are reliable for obtaining enantiomericaly pure a-methylbenzyl alcohol, and as will be discussed later, these methods were investigated fully. After i?-(-)-a-deuteroethylbenzene has 5 been formed, the production of 8-(i?)-(-)-a-deuteroethylquinoline will be reasonably straight forward. Once 8-(7?)-(-)-a-deuteroethylquinoline has been synthesized, it will be necessary to fully characterize this new compound. One of the properties of 8-(7?)-(-)-a-deuteroethylquinoline that will be measured is its optical purity, which is required in order to enable the study of the stereochemistry of C-H activation via cyclometallation. Several techniques were used to fully characterize enantiomerically enriched 8-a-deuteroethylquinoline. Polarimetry, diastereomeric fractional crystallization, NMR in conjugation with a chiral lanthanide shift reagent, and two-dimensional NMR: these techniques were all instrumental in the assignment of the absolute configuration of 8-(/?)-(-)-a- deuteroethylquinoline. The usefulness of NMR in distinguishing the enantiomers of 8-ot- deuteroethylquinoline is tremendous. Two approaches have been investigated in order to determine the optical purity of 8-a-deuteroethylquinoline. The first, was to react chiral 8-a-deuteroethylquinoline with a chiral acid and measure the diastereomeric ratio using proton NMR. From the relative peak area of each diastereomer the amount of each enantiomer can be determined. Also, a chiral lanthanide shift reagent was used to form diastereomers and a measurement of their peak area using proton NMR allowed the amount of each enantiomer to be calculated. As will be seen, (vide infra) the latter method proved the most useful. 6 Also, determination of the deuterium content will be necessary to assure in the measurement of the kinetic isotope effect o f C-H activation. This is possible by using proton NMR and comparing the proton peak areas of the alpha carbon and ring protons. As will be discussed later, by comparing these areas and by looking at the difference, it will be possible to determine the amount of deuterium present. Finally, a two-dimensional spectrum will be taken in order to assign the protons of the newly synthesized 8-(7?)-(-)-a-deuteroethylquinoline. This will be valuable for determining which proton chemical shifts change by C-H activation and diastereomeric formation. The formation of 8-(7?)-(-)-a-deuteroethylquinoline will serve as a powerful tool in the on-going investigation o f C-H activation via cyclometallation. Furthermore, the development of chiral reagents based on isotopic labeling will also enhance our ability to investigate mechanisms that involve stereoselective reactions. 7 1.2 Results and Discussion 1.2.1 Total Synthesis of Optically Active 8-(/?)-(-)-a-Deuteroethylquinoline The preparation of enantiomerically pure 8-a-deuteroethylquinoline turned out to be less than trivial. The first attempt at the formation of 8-(/?)-(-)-a- deuteroethylquinoline was to utilize enantiomericlly enhanced 8-a- bromoethylquinoline prepared as previously described by Solkolv.5 Scheme 3 outlines Solkolv’s methodology using 8-a-bromoethylquinoline. Once synthesized, 8-a-bromoethylquinoline was reacted with cZ-camphorsulfonic acid in an attempt to resolve the enantiomers by means of fractional crystallization. Contrary to Solkolv’s report, however, this method proved unreliable and we, as well as others,6 were not able to obtain the optically enriched diastereomeric salt; therefore, this method was abandoned. Scheme 3 1) Chiral Acid 2) Fractional Crystallization csr* enantiomers RB H •"/' C lV " .S-diastereomer "Hr / c h 3 7 /?-diastereomer H 5 Sok olov, V . I. ln o rg a n ica C h im ica A cta , 1976, 18, L9 6 Pfeffer, M ., Spencer, J., M aassarani, F., Fischer, J., D eC ian, A. T etrahedron: A sym m etry, 1994, 5(3), 3 2 1 -3 2 4 , also report reproducibility problem s with S o lk o lv ’s procedure. 8 The subsequent method was to synthesize the previously reported 8-a- hydroxyethylquinoline7 and react this with phthalic anhydride to produce a chiral acid ester 7. Once the chiral acid ester was formed, it was reacted with the chiral base 5’ -(-)-a-methylbenzylamine, yielding a diastereomeric salt 8 , which was subjected to a potpourri of fractional crystallization techniques in an attempt to give one diastereomer, as outlined in Scheme 4. Scheme 4 P hthalic anhydride 2 ) Fractional C rystallizaation H3C O O O C H O O C If resolved, the alcohol would have been easily converted to 8-(R)-(-)-a- deuteroethylquinoline through the reaction of thionyl chloride and subsequent treatment with lithium aluminum deuteride. However, after exhausting a variety of methods to resolve the chiral amine complex 8 , (for example, low temperature fractional crystallization and vapor diffusion with various solvents: chloroform, dichloromethane, ether, tetrahydrofuran, acetone, pentane and hexane) this method was discarded and another synthetic route was investigated to produce 8-(/?)-(-)-a- deuteroethylquinoline. 7 Suggs, J. W „ Pearson, G. N. D. J. Org. Chem. 1980, 45, 1514-1515. 9 The next approach, and slightly more difficult than the proceeding attempts, was to synthesize 8-(7?)-(-)-a-deuteroethylquinoline by an asymmetric reduction of 8- g acetylquinoline to the corresponding optically enriched 8-a- deuterohydroxyethylquinoline. This was accomplished by means of lithium aluminum deuteride and chirald 9 ([(2S1 , 3/?)-(+)-4-dimethylamino-l,2-diphenyl-3- methy 1-2-butanol]), as depicted in Scheme 5. Scheme 5 Ph CH3 ? T PhCH2- C —C—CH2NMe2 OH ft UAID4 Et20, (PC 12 hr. o A c h 3 v"OH c h 3 Once a reasonably enantiomericly pure alcohol was obtained, it would be converted to 8-(i?)-(-)-a-deuteroethylquinoline in a straight-forward fashion by reaction with p- toluenesulfonyl chloride or thionyl chloride followed by reduction with lithium aluminum hydride. The enantiomeric excess of 8-a-deuterhydroxyethylquinoline obtained was 70 % via NMR utilizing a chiral lanthanide shift reagent; however, the conversion o f the alcohol by means of thionyl chloride or by p-toluenesulfonyl chloride yielded either an unidentifiable product or in the case of the latter no 8 C am pbell, K. N ., K erwin, J. F., L aForge R. A ., C am pbell B., K. J. Am. Chem . Soc., 1946, 68 , 1844- 1846. 10 reasonable reaction. Therefore, this method was also abandoned and another route to 8-(7?)-(-)-a-deuteroethylquinoline was selected. The successful and most challenging method was to design a synthetic sequence that would permit the formation of the optically enriched site before completion of the quinoline ring. As discussed in the introduction, chiral a-deuteroethylbenzene would serve as a good starting material, especially since there are proven examples in the literature where 7?-(-)-a-deuteroethylbenzene has been synthesized.9 As outlined in Scheme 6 , /?-(-)-a-deuteroethylbenzene was synthesized by resolving a-methylbenzyl alcohol and then reducing it to R-(-)-a- deuteroethylbenzene 5. Scheme 6 Phthalic anhydride H ' ' ' O H H3C O H '" /n No c h 3c 1)RH2N 2) Fractional Crystallization 3) Reduction HOOC D - r h 3c 5 'H From ^-(-)-a-deuteroethylbenzene the desired quinoline product 8-(/?)-(-)-a- deuteroethylquinoline would finally be obtained after the series of manipulations outlined in Scheme 7. 9 M osher, H. S., Elsenbaum er, R. L ../ Org. Chem ., 1979, 4 4 (4 ), 6 0 0 -6 0 4 . And references therein. Scheme 7 Reduction Nitration Skraup Reduction h " 7 ^ d h 3c Our first attempt at the isolation of optically active a-methylbenzyl alcohol was by resolving it by fractional crystallization utilizing brucine 1 0, a strychnine derivative. 10 Reacting a-methylbenzyl alcohol with phthalic anhydride produced the chiral dl-a- methylbenzylhydrogen phthalic ester. Stirring brucine with the acid ester resulted in formation of a diastereomeric salt that resolved to give an enriched enantiomer. The 12 salt was then decomposed and the ester was hydrolized to yield enantiomericly enriched a-methylbenzyl alcohol in 50% yield, 95% enantiomeric excess as determined by polarimetry. This proved to be tedious, however, requiring several weeks for fractional crystallization and large quantities of the extremely toxic brucine. Therefore, a method less hazardous to the researcher was pursued. The best method was to proceed with a-methylbenzyl alcohol as the starting material, but obtained from a different source. /(’ -(-)-Mandelic acid (a- hydroxyphenylacetic acid) can be reduced to 5'-(-)-a-methylbenzyl alcohol and then converted to /?-(-)-a-deuteroethylbenzene, thereby forming the chiral center before synthesis of the quinoline ring. /?-(-)-a-deuteroethybenzene may then be converted to the quinoline derivative through the same transformations as outlined in Figure 2 (vide supra), which ultimately takes advantage of the Skraup synthesis to form 8-(/?)- (-)-a-deuteroethylquinoline. As illustrated in Scheme 8, the synthesis of /?-(-)-a-deuteroethylbenzene is accomplished by a series of six steps starting with /?-(-)-mandelic acid. 13 Scheme 8 P h o OH N : DMP, H2 SO4 Ph 4 o h LAH, DME p h ." , 0 H ► c Ao o h MeOH, Reflux 4hr AoOM e 12hr RT ' Ah 2o h 100% ee 80% yield 87% yield Ph 4 c TsCl, Py P h ." OH v r LAH, Et20 P h O / 0 H Ah 2o h 0OC-RT, 4hr * V_/ Ah 2o t s 78% yield 0OC-RT, 3hr A h 3 75% yield P h o , 0H v c A h 3 SOCI2 , RT H pi P1V / A h 3 D 1 ph LAD/LiD, THF u ^ p ' Reflux 24hr * 1 c h 3 79% yield 61% yield 92% ee /?-(-)-Mandelic acid, methanol and sulfuric acid were dissolved in 2,2- dimethoxypropane (DMP) and refluxed. Removal of the solvent and crystallization of the oil in hexanes resulted in the formation of the white solid methyl (/?)-(-)- mandelate. Methyl (7?)-(-)-mandelate was then treated with lithium aluminum hydride in 1,2-dimethoxyethane (DME) at room temperature. After work up, /?-(-)- 1 -phenyl-1,2-ethanediol was obtained as a white waxy solid. The diol was then reacted with p-toluenesulfonyl chloride in pyridine to give R-{-)-1 -phenyl-1,2 - ethanediol 2-tosylate. Reaction of the tosylate with lithium aluminum hydride in ether gave optically active £'-(-)-a-methylbenzyl alcohol. Treatment of the alcohol 14 with thionyl chloride according to the procedure of Mckenzie and Clough1 0 gave optically active .S'-(-)-a-methylbenzyl chloride. The chloride was then reduced by the method of Eliel1 1 to give ^-(-)-a-deuteroethylbenzene. In order to form the quinoline ring, the Skraup synthesis as modified by Bailey 12 and Glenn was utilized, (Scheme 9). Scheme 9 H2 SO3/HNO3 Separation of Isomers C H NO Skraup Li, Liquid NH3 synthesis 19% yield 53% yield 3% overall /?-(-)-a-Deuteroethylbenzene was reacted with a mixture of sulfuric and nitric acids to give ortho and para /?-(-)-a-deuteroethylnitrobenzene in approximately 100% yield. Separation of these isomers was possible via a spinning-band column operating at 2000 rpm and 16 mm of mercury. As depicted in Figure 3, the ortho 1 0 M cK en zie, A ., C lough, G. W. 1913, 6 8 7 -6 9 9 . " Eliel, E. L. J. Am. Chem . Soc., 1949, 71, 3 9 7 0 -3 9 7 2 . 1 2 B ailey, J. R., G lenn, R. A . J. Am. Chem . Soc., 1941, 6 3 , 63 9 -6 4 1 . 15 and para components exist in a one-to-one ratio upon completion of nitration. Utilizing the spinning-band column, however, the ortho isomer was initially obtained in 19% yield, but as the distillation proceeded the amount of the para isomer increased, Figures 3.1 through 3.3. After isolation, reduction of the ortho isomer was possible with lithium and liquid ammonia, according to the method of Krapcho1 3 depicted in Figure 9. The product of the reduction, 2 -(/?)-(-)-a-deuteroethylaniline was used without purification in the Skraup synthesis. The Skraup synthesis proceeds violently at first and after initiation, the resulting black tar-like mixture was refluxed for twenty-four hours. Completion of the reaction and work up gave 8-(7?)-(-)-a- deuteroethylquinoline in 53% yield (Figure 4). The overall yield of the synthesis starting from /?-(-)-mandelic acid through 8-(/?)-(-)-a-deuteroethylquinoline was 3%. 1.2.2 Determination of the Optical Purity of 8-(/?)-(-)-a-Deuteroethylquinoline As mentioned in the introduction, it is necessary to determine the optical purity of 8-(/?)-(-)-a-deuteroethylquinoline so that a proper mechanistic examination of the cyclometallation process can be achieved. As will be discussed in Chapter 2, by knowing the optical purity of 8-(/?)-(-)-a-deuteroethylquinoline it will now be possible to unequivocally determine whether cyclometallation proceeds by way of inversion or retention of configuration. 1 3 K rapcho, A. P., C ollin s, T. A . S ynth etic C om m u nications, 1982, 12(4), 2 9 3 -2 9 8 . 16 b JuWt q ;b l l j l V y ' 0 7 1 5 7! 0 els E! 0 s ' s 5.0 * 15 <<!o 3.5 3 0 3 'j 3 0 : .5 Tf.-v Figure 3, *H NMR of a one-to-one m ixture of 2 (a) and 4-ethylnitrobenzene (b) in CDCU Figure 3.1, lH NMR of the first fraction taken during the separation of 2 (a) and 4-ethyInitrobenzene (b) showing mostiy 2-cthylnitrobcnzene present in CDC13. F ig u re 3.2, *H N M R sh o w in g an in crease o f 4 -cth y ln itro b en zc n c (a) as co m p a re d to 2 -eth y ln itro b en ze n e (b) in C D C I3. v O F igu re 3.3, *H N M R o f the final fraction taken d u r in g the sep aration o f 2 (a) an d 4 -eth y ln itro b en ze n e (b) in C D C l3. to o Figure 4, 'h NMR of 8-(R)-(-)-a-dcutcrocthvIquinoIinc in CDC13. Several techniques were investigated in order to measure the optical purity of the newly synthesized 8-(7?)-(-)-a-deuteroethylquinoline. For the known compounds that were produced during the synthesis of 8-(i?)-(-)-a-deuteroethylquinoline, polarimetry was performed and compared to the literature values, Table 1. Compound Experimental Rotation1 4 Literature Rotation Percent enantiomeric excess1 5 5'-(-)-a-methyl- benzyl alcohol -44.4° -45.5016 97% S'-(-)-a-chloroethyl- benzene -45.4° -50.30 1 7 90% /?-(-)-a-deutero- ethylbenzene -.648° l o o o 00 92% Table 1 However, for 8-(/s’ )-(-)-a-deuteroethylquinoline that has no literature value, it was necessary to use alternative methods for the optical assay. O f the methods investigated, two techniques seem to dominate the literature. First, by the formation of diastereomeric salts, and by comparing the proton peak area of integration of the two diastereomers via 'H NMR, it is possible to determine the amount of each diastereomer present. Equation 1 shows the method used to calculate the percent diastereomeric excess (% de.). 1 4 V alues w ere taken on a Rudelph Research A utopol III Autom atic polarim eter at 25° C at [ a ] 589, C is concentration in M, L is the cell length 1dm. 1 5 Percent ee w as determ ined by dividing the experim ental value by the literature value and m ultiplying by one hundred. 1 6 M cK enzie, A ., C lough, G. W. 1913, 6 8 7 -6 9 9 . ,7Ott. Ber., 1 9 2 8 ,6 1 ,2 1 2 4 . 1 8 M osher, H. S., Elsenbaum er, R. L. J. Org. Chem ., 1979, 4 4 (4 ), 6 0 0 -6 0 4 . A nd references therein. 22 Area of Peak A- Area of Peak B % D.E. = ----------------------------------------------- * 100 __________ Area o f Peak A + Area of Peak B________ equation 1 The second method is to use a chiral lanthanide shift reagent, in the hopes that the diastereomers formed will show different chemical shifts in the proton NMR. Comparing the proton peak areas of these diastereomers and using equation 1 will also allow determination of their relative amounts. Our first attempt at determining the optical purity was to use the chiral acid (1R)- (-)-lO-camphorsulfonic acid to form the diastereomeric salt 11. After resolving it by means of fractional crystallization, the peak area ratio of the proton NMR of the diastereomers could be compared to yield the relative amounts of each diastereomer (i.e., optical purity). However, after successive attempts at fractionally separating the diastereomers through the use of various solvents and low temperature techniques, the relative proportions of the diastereomers remained unchanged. CH c h 3 ' 11 23 Our second and successful choice was to use a chiral lanthanide shift reagent. 1 9 Since 8-(/?)-(-)-a-deuteroethylquinoline contains a nitrogen that can serve as a weak base, it is possible that it can form an equilibrium with a chiral lanthanide shift reagent. Once a rapid equilibrium is established between the enantiomers and the chiral shift reagent, diastereomers are formed. Now that these complexes are diastereomeric, they will have different chemical shifts resulting from two probable factors. First, the equilibrium constant for each diastereomeric complex may be different, resulting in larger shifts for the complex having the larger binding constant.20 Second, is that the two diastereomeric complexes formed may have a different geometry, thereby causing a difference in the induced shift by the chiral lanthanide reagent on one of the complexes. In order to determine the optical purity, the chiral shift reagent tris[3- (heptafluoropropylhydroxymethylene)-(+)-camphorato]ytterbium(III) 12 was chosen. Yb O ' 12 l9a) Fraser, R., R. A sym m etric Synth esis, 1983, 1, 173-196. b) G oering, H., L., et. al. J. Am. Chem . Soc., 1974, 96, 1493-1501. 20 W hitesides, G. M ., et al. J. Am. Chem . Soc., 1974, 96, 1038. 24 This reagent was selected because various publications in the literature indicate that tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]ytterbium(III) induces 2 1 larger shifts down field between diastereomers. Other chiral shift reagents either give only small down field separation of diastereomers or up field shifts that would not be useful in this case. The selected chiral shift reagent was able to separate the racemic mixture, as depicted in Figure 5. In order to determine the correct amount of shift reagent to use and to establish the reliability of this technique, a control experiment was performed on a racemic mixture of 8-a-deuteroethylquinoline. Figure 5 illustrates the effect of adding 50 microliter aliquots to the mixture over time. In an effort to maximize the peak separation of the racemate, the temperature of the probe of the NMR was varied. However, this only decreased the peak separation upon raising the temperature, or broadened the peaks upon lowering the temperature of the racemate, as illustrated in Figure 6 . Therefore, the temperature of the probe was maintained at 298 K (i.e., the optimized temperature), in order to maintain the maximum separation, of the peaks of the diastereomers. Once obtaining maximum peak separation the relative amounts of each diastereomer were determined by the use of line fitting software,22 as illustrated in Figures 5.1-5.3. 2 1 Parker, D. Chem . Rev., 1991, 91, 1441 -1 4 5 7 and references therein. 22 N U T S N M R data processing softw are obtained from Acorn N M R , used at the U SC N M R facility. 25 Figure 5, !H NMR of the shifted spectra of racemic 8-a-deutcroethyiquinoline with an increase in concentration of Yb(hfc)3 with in CDCI3. R a c e m ic m e t h y le n e p r o to n w ith a p e a k s e p e r a tio n o f 0 .0 7 pp m a n d 3 .6 % e e . Figure 5.1 H NMR showing the racemic 8-a-deuterocthylquinoline. R a c e m ic m e t h y le n e p r o to n w ith a p e a k s e p e r a tio n o f 0 .0 6 6 ppm a n d 1 .5% e e . \ ' / \ / Figure 5.2 *H NMR showing the racemic 8-a-deuteroethylquinoline. Racemic methylene proton with a peak seperation of 0.078 ppm and 3.6% ee. // //I , 10 5 103 10.4 ppm Figure 5.3 *H NMR showing the racemic 8-a-deuteroethylquinoline. T=300 S'- T=295 T=290 T=285 j ; T=273 11 10 9 8 7 ppm Figure 6 , 'h NMR of the shifted spectra of the racemic 8-a-deuteroethylquinoline utilizing Yb(hfc)3 at different tem peratures in CDCI3. to C O Table 2 shows the peak separation of the diastereomers (labeled A and B); and that the percent diastereomeric excess is only 2.9%. Since this should be a racemic mixture, the percent diastereomeric excess must be the error of the method used to calculate the peak area and will therefore be appropriately applied when calculating the enantiomeric excess of the optically active compound. Spectrum No. Chemical Shift2 3 of A Chemical Shift2 4 of B Relative Area of A Relative Area of B Percent de 12.1 9.799 9.729 1.00 0.93 3.6% 12.2 9.444 9.378 1.00 0.97 1.5% 12.3 10.501 10.423 1.00 0.93 3.6% Avg. % ee = 2.9% Table 2 The same method was then utilized to determine the amount of each enantiomer present in the optically enriched 8-a-deuteroethylquinoline sample. Figure 7 illustrates the effects of adding 50 microliter aliquots to the optically enriched sample and Figures 7.1-7.3 depict the relative amounts of each enantiomer (labeled A and B in Table 3) via the line fit analysis software. From the line fitted spectra (Figures 7.1-7.3) it was possible to determine the optical purity of 8-a-deuteroethylquinoline by using equation 1 above. Taking the averages of the three spectra of one sample, a value of 36% (±3%) enantiomeric excess was determined as shown in Table 3. 23 C hem ical shifts are in PPM. 24 C hem ical shifts are in PPM. 25 The starting 8-(R )-(-)-a-deuteroethylqu inolin e w as 91% dx and the integral ratio o f the Y b (h fc)3- shifted a -C H D + a -C H 2 w as 1.99/1, so the optical purity o f the dx portion w as 36% ee. 29 11 10 9 8 7 ppm Figure 7, *H NMR of the shifted spectra of 8-(R)-(-)-a-deuteroethylquinoline utilizing Yb(hfc)3 in CDC13 . o Optically active methylene proton with a peak separation of 0.073 ppm and 32% ee. 10.3 Figure 7.1 Determination of the optical purity of 8-(R)-(-)-a- deutcroethylquinoline. , . y - 1 0 6 Optically active methylene proton with a peak separation of 0.078 ppm and 40% ee. Figure 7.2 Determination of the optical purity of 8-(R)-(-)-a- deuterocthylquinoline. Optically active methylene proton with a peak separation of 0.079 ppm and 36% ee. 11.1_____________1U )____________ 1 0 9 ____________ 1 0 8 ____________ 1 07____________ 1 0 6 ____________ 10.5 10.4__________ 10.3 ppm Figure 7.3 Determination of the optical purity of 8-(R)- (-)-a- deuteroethylquinoline. 31 Spectrum No. Chemical Shift of A Chemical Shift of B Relative Area of A Relative Area of B Percent ee 14.1 10.086 10.159 1.00 0.55 32% 14.2 10.506 10.584 1.00 0.46 40% 14.3 10.689 10.768 1.00 0.50 36% Avg. % ee = 36% ± 3% Table 3 Since this value is considerably less than that of /?-(-)-a-deuteroethylbenzene (92%, vide infra), 2-(-)-a-deuteroethylaniline was examined using the chiral lanthanide shift reagent to determine if loss of optical activity had occurred following the nitration and subsequent reduction of /^-(-)-a-deuteroethylbenzene. As Figures 8 and 8.1 illustrate, the methylene proton of the optically active alpha carbon is easily shifted, resulting in a 54% (±3%) enantiomeric excess for 2-(-)-a- deuteroethylaniline. Since the examination of 2-(-)-a-deuteroethylaniline was an afterthought, the synthesis of this compound was done on a small scale compared to that of the original production of 2-(-)-a-deuteroethylaniline and hence, a much shorter reaction time. As a result of this, it is suggested that the discrepancy in values arises from the original mixture being exposed to lithium and liquid ammonia longer than the latter material. This is significant because it is known that under basic conditions isoracemization may occur, as seen in Scheme 10.26 27 26 M arch, J. In A d v a n c ed O rg a n ic C h em istry; John W iley & Sons, Inc.: N ew York, U S A , 1985; Chapter 12, pp. 51 8 -5 1 9 . 27 Low ry, H. T., Richardson, S. K. In M echanism a n d T heory in O rgan ic C hem istry, Harper & R ow , Publishers: N ew York, U S A , 1987; Chapter 6, pp. 5 3 4 -5 3 5 , and references therein. 32 Scheme 10 y ^ C -D + iNRj C- ENR, \ / © C-ENR? z ^ C -D + = N R ? / x This phenomenon allows the carbanion and the conjugate acid of the amine to remain associated as an ion pair. Periodically the ion pair dissociates allowing the carbanion to flip over and recapture the proton, thereby causing racemization to occur, however, extensive exchange of the deuterium (which is not seen) may occur. Another possibility that may explain the loss of optical activity of /?-(-)-a- deuteroethylbenzene to /?-(-)-a-deuteroethylaniline, is that upon separation of the ortho and para nitrobenzene derivatives an intramolecular shift (or a [1,5] sigmatropic shift) of the proton/deuteron to the nitro group may occur in the ortho derivative. This may happen during the separation o f the two derivatives via the spinning band column when the pot temperature reaches 135°C, as depicted in Scheme 11. Scheme 11 135°C 33 Furthermore, analysis of the para aniline derivative by means of the chiral shift reagent revealed that the optical purity of this derivative was reduced to 64% (±3%) enantiomeric excess, which suggests that an intermolecular exchange (or a [1,7] sigmatropic shift) occurs (perhaps more slowly than the intramolecular exchange) during the distillation, as illustrated in Scheme 12. Scheme 12 D— B OD Considering the ortho (54% ee, Figure 8.1) and the para (64% ee, Figure 8.2) derivatives both show a reduced optical purity from the starting material R-(-)-a- deuteroethylbenzene (92% ee) and that the loss of deuterium of the aniline derivative is minimal (100% deuterium for /?-a-deuteroethylbenzene to 91% for /?-(-)-a- deuteroethylaniline vide infra), strengthens the plausibility of the intramolecular or intermolecular mechanism as a means of optical activity loss. The configuration of 8-(-)-a-deuteroethylquinoline was established as follows. Knowing that the specific rotation of /Ca-deuteroethylbenzene is negative at [a ]589 34 28 and that it has a configurational assignment of R, the configurational assignment of 8-a-deuteroethylquinoline was achieved as follows. Upon formation of 8-a- deuteroethylquinoline, the rotation was determined to be -0.36° at [a ]5g9 and since it is known that the chiral center undergoes no chemical changes after being synthesized (see outlined synthetic routes, Schemes 8 and 9), one can conclude that the configuration of the quinoline species is 8-/?-(-)-a-deuteroethylquinoline, based on the known stereochemistry of i?-(-)-a-deuteroethylbenzene. 28 M osher, H. S., Elsenbaum er, R. L. J. O rg. Chem ., 1979, 4 4 (4 ), 6 0 0 -6 0 4 . A nd references therein. 35 b b ,-J................ ' A ' '— / j ! ir -A 10 ppm Figure 8, 'H NMR of the shifted spectra of 2 (a) and 4-(-)-cx-dcutcroethylaniline (b) utilizing Yb(hfc)3 in CDC13 O n Figure 8.1, H NMR illustrating the peak separation of the enantiomers of 2-(-)-a-deuteroethylaniline utilizing Yb(hfc)3 in CDCI3 with the peak at 6.30 ppm having an area of 0.30 and the peak at 6.49 ppm having an area of 1.00. UJ Figure 8.2, H NMR illustrating the peak separation of the enantiomers of 4-(-)-a-deuteroethylaniline utilizing Yb(hfc)3 in CDCljw ith the peak at 4.08 ppm having an area of 0.22 and the peak at 3.91 ppm having an area of 1.00. O O 1.2.3 Following Deuterium Loss During the Synthesis of 8-{R)- (-)-a- Deuteroethylquinoline. So that an accurate kinetic isotope effect may be measured upon C-H activation, it was necessary to determine the amount of deuterium lost through the conversion of /?-(-)-a-deuteroethylbenzene into 8-(7?)-(-)-a-deuteroethylquinoline. The deuterium content was determined at three stages of the synthesis. Initially, the amount of deuterium present for /?-(-)-a-deuteroethylbenzene was calculated to be 100% .29 However, upon formation of 2-(/?)-(-)-a-deuteroethylnitrobenzene via nitration of R- (-)-a-deuteroethylbenzene the deuterium content dropped to 91%. Subsequently, the deuterium content of 8-(/?)-(-)-a-deuteroethylquinoline remained at 91% following the Skraup synthesis. The calculation of the deuterium content was performed as follows. Comparing the integration area of the alpha (i.e., methylene) proton to that of the ring protons, allows for an adequate comparison of the relative amount of the alpha proton present. Utilizing equations 2 and 3, the deuterium content can be calculated for 8-f/?)-(-)-oc-deuteroethylquinoline (Figure 9). As Figure 9 indicates, the relative peak area of the alpha proton is 2.5 while that of the two selected ring protons is 2.3. From equation 2, a value of 2.1 for the deuterium area was obtained. Area of Deuterium = (Area of Ring Proton * 2) - Area of a Proton equation 2 29 B ased on the integrals o f the m ethylene proton and the m ethyl protons o f R -(-)-a - deuteroethylbenzene. 39 Using 2.1 as the area of deuterium in equation 3 allows for the determination of the percent deuterium remaining in the alpha position of 8-(/?)-(-)-a- deuteroethylquinoline. % Deuterium = Area o f Deuterium/Area of Ring Proton * 100 equation 3 From equation 3, it was determined that there was 91 % deuterium present in the alpha position o f 8-(7?)-(-)-a-deuteroethylquinoline. Applying the same methodology to /?-(-)-a-deuteroethylbenzene and 2-(7?)-(-)-a-deuteroethyl- nitrobenzene resulted in values of 100% and 91%, respectively. Therefore, the loss of deuterium during the synthesis of 8-(/?)-(-)-a-deuteroethylquinoline from R-(-)-a- deuteroethylbenzene was only 9%. 4 0 Figure 9, H NMR illustrating the relative area of the ring protons to that of the a proton of 8-(RV{-)-a- deuteroethylquinoline in CDC13. 1.2.4 Chemical Shifts of the Ring Protons in 8-(/?)-(-)-a-deuteroethylquinoline In order to determine the effect on the protons by C-H activation via cyclometallation, a two-dimensional cozy was performed for the assignment of chemical shifts. 7.7 ppm) 8.3 ppm) 1 H H J y^ppm j 7.5 ppm I 'N H [ 1-2 ppm) ^ 3 j ) p m J 8.9 ppm) Figure 10 As Figure 10 and the two dimensional spectra (Figures 11 and 11.1) illustrate, the protons ortho and para to the nitrogen appear the farthest down field, 8.9 ppm and 8.25 ppm, respectively. The proton meta to the nitrogen appears at 7.3 ppm which is the farthest up field. The para, ortho and meta protons on the ethyl side of the ring appear at 7.7 ppm, 7.6 ppm and 7.5 ppm respectively. This assignment will prove useful after the transformation of the palladium complex into a diastereomer. At that point it will be necessary to determine which protons are diastereomeric and which are not, in order to properly measure the amount of each diastereomer present. 4 2 LLtdd U i _____ 1_L "V a V c < # - n- ■ c *\ ■ t i i i ; i i i 7 t— i i i i i i i i i i i 1'! : » i i i i j i~»' i ~ t » i i i n - r m T r r iT p n ' r i i t t i'i i i i i i f-n~rf-rf'i ~ i • > t t t : ■ n T r r r m ~ i- | Figure 11, 2 D 'l l NMR of 8-ethyIquinoline in CDCI3. 43 uidd ] Figure 11.1, 2D *H NMR of the aromatic region of 8-ethyIquinoiine in CDC13. 1.3 Summary In conclusion, the new compound 8-(/?)-(-)-a-deuteroethylquinoline has been synthesized. In order to ensure that all of the variables affecting the C-H activation of 8-(/?)-(-)-a-deuteroethylquinoline via cyclometallation have been taken into account, 8-(/?)-(-)-a-deuteroethylquinoline has been fully characterized, including verification of the optical purity (36% ee) and percent deuterium incorporation (91%). 45 1.4 Experimental Section 1.4.1 General Methods. Chemical shifts of NMR spectra, recorded on Bruker AC 250-, AM 360-, or AM 500 MHz FT spectrometers, are reported in parts per million (5) down field from tetramethylsilane for 'H and l3C. Plots of the NMR spectra were performed using the NUTS software obtained from Acorn NMR. All reactions involving organometallic compounds, unless otherwise mentioned, were carried out in the air. When protection from oxygen was necessary, reactions were carried out under an atmosphere of nitrogen or argon purified over reduced copper catalyst (BASF R3-11) and Aquasorb, in flamed out glassware using standard vacuum line, and Schlenk techniques. When necessary, the glove box used was a Vacuum Atmospheres Model HE-553-2 equipped with a DriTrain MO 40-2 inert gas purifier. The oxygen content o f the dry box was monitored by Cr(acac)2, a light orange color indicating that it was sufficiently oxygen-free. Benzene, ether, hexanes, pentane, and THF were distilled from purple solutions of sodium benzophenone when necessary. CH2C12 was distilled twice from CaH2. Transfers of ammonia were performed on a vacuum line, using standard gas transfer techniques. Elemental analyses were performed by Microanalytical Laboratory, University of California Berkeley. 4 6 1.4.2 Ligand Preparation 1.4.3 Synthesis of Optically Active 8-a-hydroxyethy(quinoline 8-bromoquinoline. 2-Bromoaniline 10 g (58 mmol), glycerol 15.0 g (163 mmol) and iodine 0.5 g (2.0 mmol) were placed in a 300-mL three-neck round- bottom flask equipped with a stir bar, a thermometer in one port and a condenser with ice water passing through it in the center port. Sulfuric acid 30.0 g (306 mmol) was then added and the mixture was heated to reflux for 1 hour. After 1 hr. the mixture was cooled and 85 mL of 5 M NaOH was added, then the product was steam-distilled. Upon collection of the milky white distillate, the product was extracted with three 30 mL portions of ether. The ether layer was removed using the rotary evaporator and the dark yellow oil was distilled at 83°C and 0.02 mm of Hg. Yield 21% (2.5 g, 12 mmol). *H NMR (CDC13) 5 7.31 (m, 2H), 7.63 (dd, 1H), 7.96 (m, 2H), 8.96 (dd, 1H). 8-a-hydroxyethylquinoline. 8-Bromoethylquinoline 2.5 g (12 mmol) and 50 mL of THF were placed in a dry Schlenk flask equipped with a stir bar. The mixture was cooled to -78°C and 9.2 mL of 1.3 M sec-butyllithium was added and stirred. After 5 min 1.4 mL (24 mmol) of acetaldehyde was added and the mixture was allowed to warm to room temperature. After 1.5 hr. 3 M hydrochloric acid was added until litmus paper indicated neutral. The product was then extracted with three 20 mL portions of CH2C12 and the solvent was removed via the rotary evaporator to 47 give a yellow oil. The oil was then chromatographed using aluminum oxide; activated neutral, (Brockmann I, standard grade, 150 mesh, 58 angstroms, CAMAG 507-C-l. Surface area 155 m /g), using a medium-sized column with a mixture of hexanes and ethylacetate 7:1 as the solvent. The product was collected as a clear, colorless oil. Yield 48% (1.0 g, 5.8 mmol), ‘h NMR (CDC13) 5 1.70 (d, 3H), 5.44 (q, 1H), 6.12 (s, 1H), 7.35 (m, 1H), 7.44 (m, 1H), 7.53 (m, 1H), 7.64 (dd, 1H), 8.12 (dd, 1H), 8.82 (dd, 1H). 8-ethylquinoline-a-phthalic ester. 8-a-hydroxyethylquinoline 0.9 g (5.2 mmol) was dissolved in 20 mL of CH2C12. To the mixture 0.77 g (5.2 mmol) of phthalic anhydride was added and then stirred for 24 hours. After 24 hr. the solvent was removed via the rotary evaporator to give a white solid. Yield 90% (1.5 g, 4.7 mmol). 'H NMR (CDC13) 5 1.78 (d, 3H), 4.35 (q, 1H), 7.1-8.2 (m, 9H), 9.01 (dd, 1H), 9.75 (s, 1H). Asymmetric reduction of 8-acetylquinoline to 8-a-deutero- hydroxyethylquinoline. Lithium aluminum deuteride 0.42 g (0.01 mol) was dissolved in 10 mL of dry ether and cooled to 0°C to which 6.52 g (23.0 mmol) of chirald [(2S1 , 3/?)-(+)-4-dimethylamino-l,2-diphenyl-3-methyl-2-butanol] was added. 1.1 g (6.4 mmol) of 8-acetylquinoline was added to the mixture and stirred for 24 hours. After 24 hr. 20 mL of water was added and the product was extracted with three 20 mL portions of ether. The ether layer was removed using the rotary 4 8 evaporator. The resultant slightly yellow oil was then chromatographed using aluminum oxide; activated neutral, (Brockmann I, standard grade, 150 mesh, 58 angstroms, CAMAG 507-C-l. Surface area 155 m2/g), using a medium-sized column with a mixture of hexanes and ethylacetate 5:1 as the solvent. The product was collected as a clear, colorless oil. Yield 60% (0.66 g, 3.8 mmol), 70% ee via NMR and tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato], europium(III) chiral shift reagent. ‘H NMR (CDC13 ) 6 1.70 (d, 3H), 6.12 (s, 1H), 7.35 (m, 1H), 5 7.44 (m, 1H), 7.53 (m, 1H), 7.64 (dd, 1H), 8.12 (dd, 1H), 8.82 (dd, 1H). 1.4.4 Resolution of a-methylbenzyl alcohol. (+) and (-)-a-methylbenzyl acid phthalate. r/Z-a-methylbenzyl alcohol was 30 converted to its acid phthalate by the method of Kenyon and Houssa with slight modification. To 37 mL of dry pyridine 52.5 g (43.0 mmol) of <7/-a-methylbenzyl alcohol was added with stirring. Once the alcohol had been added, 63.7 g (43.0 mmol) of the anhydride was added and the reaction mixture was heated to 100°C for two hours. At the end of two hours the reaction mixture was poured onto enough dilute hydrochloric acid so that litmus paper indicated acidic. The resultant oil was extracted with three 30 mL portions of ether. The extract was washed with water and dried over sodium sulfate. The ether was removed via the rotary evaporator and the oil was recrystallised from benzene with the addition of petroleum ether. Yield 88%, 30 H oussa, J., H., K enyon, J. 1930, 2 2 6 0 -2 2 6 3 . 4 9 (103 g, 0.38 mol). Mp 108°C (lit. Mp 108°C), 'H NMR (CDC13) 6 1.65 (d, 3H), 6.14 (q, 1H), 7.24-7.28 (m, 9H). Resolution of <//-a-methylbenzyIhydrogen phthalic ester via the brucine salt. The acid ester 103.3 g (0.380 mol) was dissolved in 3 L of warm acetone. Brucine 149.9 g (0.380 mol), was added to this mixture slowly with stirring, insuring that all of the brucine had dissolved {extreme caution should be taken when handling Brucine, it is a strychnine derivative, LDS 0 = 1 m g / 1 Kg ). When almost all of the brucine had been added a white precipitate formed. The mixture was allowed to stand overnight in the freezer in a corked Erlenmeyer flask. Then the white precipitate was collected on a Buchner funnel and recrystallised twice from ethyl acetate. The salt which appeared as white crystalline needles was then decomposed by washing with dilute hydrochloric acid. The collected oily material, hydrogen phthalic ester, was extracted with three 50 mL portions of ether and the ether was removed via the rotary evaporator. The oil was recrystallised from carbon disulfide and petroleum ether at -20°C to give white needle like crystals of hydrogen phthalic ester. Yield 21%, (22 g, 0.08 mol). Optical Rotation; solvent: ethanol, L = 1 dm, C = .5g/10 mL, a o b s = 1.8 [a]5 g 9 = 36°, 90.4 % enantiomeric excess.3 1 S'-(-)-a-methylbenzyl alcohol. The /-hydrogen phthalic ester 21.5g was dissolved in 100 mL of 5 M NaOH. The solution was stirred for 1 hr and then the 3 1 Percent enantiom eric ex cess based on a literature value o f [a ] 589 = 39.8°; H oussa, J., H., K enyon, J. J. Am. Chem. Soc., 1930, 2 2 6 0 -2 2 6 3 . 50 alcohol was extracted with three 20 mL portions of ether. The combined extracts were dried with Na2S 0 4 and then the ether was removed via the rotary evaporator to give a clear, slightly yellow oil. The oil was placed in a Kugelrohr distillation apparatus and distilled at 16 mm o f Hg and 60°C to give a clear, colorless oil. Yield 50%, (4.4 g, 0.04 mol). 'H NMR (CDC13) 5 1.46 (d, 3H), 4.9 (q, 1H), 7.35 (m, 5H). [a ]589 = -47° (L = 1, ethanol, C = .05), >99% ee based on CRC Handbook of Chemistry and Physics, [a ]589 = -45.5° (MeOH, C = 5). Aldrich32 reports [a ]5g9 = - 41.3°, neat. 1.4.4 Preparation of 8-(l?)-(-)-a-deuteroethylquinoline via /?-(-)-Mandelic acid. Methyl /?-(-)-mandelate. /?-(-)-Mandelic acid 100 g (0.66 mol) (Aldrich33 99+%, (C= 2.5, H20 ) [a ]23 - 153°), was placed into a 500-mL dry, snuggle-necked, round-bottom flask equipped with a stir bar. To this 53 mL (1.31 mol) of MeOH, 81 mL (659 mmol) of 2,2-dimethoxypropane (DMP, from a fresh bottle) and 3 mL (59 mmol) of H2S 0 4 were added. The mixture was refluxed for 4 hr. after which the solvent was removed via the rotary evaporator. The red/brown residue was then dissolved in 3.5 L o f boiling hexanes, charcoal was added, and the solution was filtered. The filtrate was then placed in the freezer overnight to give a white precipitate. The precipitate was collected on a Buchner funnel and washed with cold 33 A ldrich C hem ical C om pany, Inc., 1001 W est Saint Paul A v e., M ilw aukee, WI 53233 51 pentane. Yield 80%, (88 g, 0.53 mol), 'H NMR (CDC13) 8 3.55 (s, 3H), 3.73 (s, 1H), 5.16 (s, 1H), 7.3 - 7.5 (m, 5H). /?-(-)-l-phenyI-l,2-ethanediol. Lithium aluminum hydride 24.1 g (0.64 mol) was placed in a 2000-mL single-neck, round-bottom flask containing 700 mL of 1,2- dimethoxyethane (DME, from a fresh bottle). To the 2000-mL single-neck round- bottom flask in an ice bath while stirring, methyl (/?)-(-)-mandelate 87.5 g (0.53 mol) dissolved in 300 mL of DME was added slowly. After the addition was complete, the ice bath was removed and the mixture was continuously stirred for 12 hr. at room temperature. At the end of 12 hr., 150 mL of saturated NH4C1 and 150 mL of 3 M HC1 were added sequentially to hydrolyze the product. The salts were then filtered and washed with 200 mL ether, 100 mL of dilute HC1 and then extracted with three 75 mL portions of ether. The ether/DME layers were combined and removed via the rotary evaporator to give a yellow oil. The crude diol was then crystallized from benzene and hexanes to give a white solid. Yield 87%, (64 g, 0.46 mol). 'H NMR (CDC13) 8 2.6 (broad, 2H), 3.70 (m, 2H), 4.78 (dd, 1H), 7.33 (m, 5H). /?-(-)-l-phenyl-l,2-ethanediol 2-tosylate. /?-(-)-l-phenyl-l,2-ethanediol 64 g (0.46 mol) was dissolved with stirring in 1.5 L of fresh pyridine. p-Toluenesulfonyl chloride 92.1 g (483 mmol) (recrystallised from CHC13 and petroleum ether) was added slowly at 0°C. After the addition, the ice bath was removed and the solution, which turned a bright yellow, was stirred for an additional 24 hr. under argon. At the 52 end of the reaction time, the mixture was poured onto an ice/acid mixture and the solution was made acidic, as indicated by litmus paper. The solution was then extracted with three 100 mL portions of ether. The ether was dried with M gS04 and concentrated on the rotary evaporator to give an off-white solid. Yield 78% (106 g, 0.36 mol). 'H NMR (CDC13) 6 2.42 (s, 3H), 2.70 (s, 1H), 4.05 (m, 2H), 4.95 (dd, 1H), 7.30 (s, d, 3H), 7.74 (d, 2H). S-(-)-a-methylbenzyl alcohol. /?-(-)-1 -phenyl-1,2-ethanediol 2 -tosylate 106 g (0.36 mol) was placed in a 2-L single-neck round-bottom flask containing 1L of fresh ether. To this 15.0 g (395 mmol) of lithium aluminum hydride was added slowly at 0°C. After the addition, the ice bath was removed and the reaction was stirred for 3 hr. under an argon atmosphere. Water was added to the mixture and the salts were washed with water and ether. The aqueous layer was extracted with three 50 mL portions of ether and the ether layers were combined. The combined ether layers were dried with M gS04 and concentrated using the rotary evaporator to give a yellow oil. The oil was distilled under vacuum, 2 microns of Hg at 35°C to give a clear, colorless oil. Yield 75% (33.9 g, 0.27 mol). [a ]589 = -44.4°, L = 1, C = .0502, % ee = 97.6% based on the reported value by the CRC Handbook of Chemistry and Physics o f -45.5° (MeOH, C = 5). 'H NMR (CDC13) 5 1.46 (d, 3H), 4.9 (q, 1H), 7.35 (m, 5H). 53 S-(-)-a-methylbenzyl chloride. To distilled S0C12 50.2 mL (688 mmol), S-(-)- sec-phenylethyl alcohol 33.9 g (0.27 mol) was added slowly, with stirring. After the addition, the mixture was stirred for an additional 30 min at 25°C. At the end of the 30 min, a short path distillation head was attached to a two-neck cow receiver and two round bottom flasks placed in an ice bath. The excess SOCl2 was removed via vacuum distillation and the product was distilled at 28°C 10'5 mm Hg, to give a clear colorless oil. Yield 79% (30 g, 0.21 mol). 'H NMR (CDC13) 8 1.86 (d, 3H), 5.1 (q, 1H), 7.37 (m, 5H). [a ]589 = -45.4° L = 1, C = .0543. 90.3% enantiomeric excess.34 /?-(-)-a-deuteroethylbenzene. LiD 3.97 g (95 mmol) and LAD 1.36 g (36 mmol) were added to a flamed out 500-mL three-neck round-bottom flask with a stir bar and fitted with a condenser. To these, 200 mL of dry THF was added. To the mixture S-(-)-sec-phenethyl chloride 30 g (0.21 mol) was added rapidly and the solution was refluxed under argon for 24 hr. After 24 hr. water was added and then the mixture was poured onto a dilute H2S 0 4-ice solution. The product was then extracted with pentane using three 20 mL portions. The extracts were combined and dried with CaCl2. The solvent was then removed using the rotary evaporator to give a slightly yellow oil. The oil was then distilled at 130°C to give a clear, colorless oil, 340 tt. B er., 1928, 2 1 2 4 , reports the sp ecific rotation to be -50.3 and Eliel E., L. J. Am. Chem . Soc., 1949, 3 9 7 0 , obtains m aterial w ith [ a ] 589 = - 49.2°. 54 yield 65% (14.7 g, 0.14 mol), [a ]589 = 0.648° (1=10 dm, neat) 92% enantiomeric excess.35 'h NMR (CDC13) 6 1.27 (d, 3H), 2.57 (q, 1H), 7.30 (m, 5H). 4 and 2-(fl)-(-) -a-deuteroethylnitrobenzene. H N 03 11.7 mL (292 mmol) was placed in a 100-mL two-neck round-bottom flask with a stir bar. H2S 0 4 13.1 mL (257 mmol) was then added slowly, keeping the temperature below 50°C by using an ice bath. To this mixture /?-(-)-cc-deuteroethylbenzene 14.7 g (0.14 mol) was added slowly with stirring, maintaining a temperature between 20-25°C. After the addition the mixture was heated to 60°C for 30 min. After 30 min the mixture was poured into a beaker containing ice and water. The water was then decanted from the ortho and para /?-(-)-a-deuteroethylnitrobenzene and extracted with three 25 mL portions of ether. The extracts were added to the 7?-(-)-a-deuteroethylnitrobenzene and washed with four 50 mL portions of water. The ether layer was then dried with Na2S 0 4 and concentrated on the rotary evaporator. Yield 94% (19.9 g, 132 mmol) of a light tan/orange oil. This material was not further purified. 'H NMR (CDC13) 8 1.25 (m, 6 H), 2.72 (qq, 1H), 2.89 (qq, 1H), 7.33 (m, 4H), 7.55 (d, 1H), 7.85 (d, 1H), 7.95 (d, 2H). Separation of 4 and 2-(/?)-(-) -a-dcuterotethylnitrobenzene. The 4 and 2-(/?)- (-)-a-deuteroethylnitrobenzene 19.9 g (132 mmol) were placed in a 50-mL two-neck round-bottom flask with a stir bar. A thermometer was placed in one side and a 35 M osher, H. S., Elesenbaum er, R. L. J. Org. C hem ., 1979, 4 4 (4 ), 6 0 0 -6 0 4 and references therein, reported the sp ecific rotation to be -0.70°. 55 spinning band column in the center. The spinning rate was set at 2000 rpm and a vacuum of 16mm Hg. Distillation began with a pot temperature of 135°C and a head temperature of 110°C which was obtained after several hours o f equilibration. The first and second fractions obtained were pure ortho derivative, however, the third and future fractions all contained para compound. These fractions were then placed back into the pot and re-distilled until no more pure ortho derivative could be obtained. Yield 19% (3.7 g, 24 mmol) of a light yellow oil. *H NMR (CDC13) 5 1.24 (d, 3H), 2.85 (q, 1H), 7.3 (m, 2H), 7.5 (m, 1H), 7.85 (m, 1H). -a-deuteroethylaniline. Ammonia was condensed by use of a dry ice acetone bath into a dry flamed-out Schlenk flask (containing sodium to dry the ammonia and a stir bar) connected to an argon bubbler and a lecture bottle of ammonia tilted at a 60° angle using a short piece of tygon tubing. Once = 75 mL of ammonia had condensed over, the lecture bottle was removed and the Schlenk flask was connected to a 500-mL three-neck round-bottom flask containing a stir bar via the small piece of tygon tubing. The ammonia was then transferred to the round bottom flask which was at -78°C with a cold finger type condenser in the center port also at -78°C. In the third port was an addition funnel containing 2-(R)-(-)-a- deuteroethylnitrobenzene 3.7 g (24 mmol) and MeOH 9.7 mL (239 mmol). After all the ammonia had condensed over, the Schlenk flask connection was removed and a glass stopper was placed in the port. At this point the mixture in the addition funnel 56 was added slowly to the ammonia over 15 min. Once complete, the addition funnel was removed and a septum was placed in the port. Lithium 1.33 g (192 mmol) washed with hexanes was then carefully placed in the round bottom flask by removing the septum. The solution turned a dark orange with blue spots. After all the lithium was added, the solution turned to a cream-orange color with blue streamers. The cold finger was kept charged for the next 2 hr. but the dry ice acetone bath was removed from the round bottom flask. At the end of two hours, the cold finger was allowed to warm to room temperature, so that the ammonia would evaporate. After the ammonia had evaporated 20 mL of water and ether were added respectively. The lithium salts dissolved and the product was extracted with three 20 mL portions of ether. The ether extracts were dried over Na2S 0 4 and then removed on the rotary evaporator to give an orange-tan oily material. Crude yield 3.4 g (0.03 mol). ‘H NMR (CDC13) 8 1.25 (d, 3H), 2.5 (q, 1H), 3.56 (s, 2H), 6.69 (m, 1H), 6.78 (m, 1H), 7.1 (m, 2H). 8-(^?)-(-)-a-deuteroethylquinoline 2-(/?)-(-)-a-Deuteroethylaniline 3.4 g (0.03 mol), FeS04»7H20 1.04 g (4.0 mmol), and nitrobenzene 1.79 mL (17.0 mol) were added to a 50-mL single-neck round-bottom flask with a stir bar and a condenser fitted with an ice water supply and connected to an argon bubbler. Next, a cooled solution of boric acid 1.82 g (29.0 mmol) and glycerol 8.8 mL (120 mmol) was added. Finally H2S 0 4 5.2 mL (102 mmol) was added slowly (exothermic) with 57 stirring. Heat was applied slowly until a gentle reflux was maintained. (It is imperative that the heat is applied slowly since the reaction becomes extremely exothermic once the reaction initiates.) After 20 min the solution turned black and the mixture was refluxed for an additional 24 hr. After 24 hr. the mixture was allowed to cool and then 50 mL o f water was added and any nitrobenzene was steam- distilled off. The mixture was then basified with ammonia hydroxide according to litmus paper and again steam distilled to remove the product. The 8-(R)-(-)-a- deuteroethylquinoline was then extracted away from the aqueous layer with three 20 mL portions of ether. The product was removed from the ether with dilute HC1 and diazotized at 0°C to remove any primary amines. This solution was neutralized with NaOH and extracted with three 10 mL portions of ether. Removal of the solvent using the rotary evaporator gave a dark orange oil. This oil (8-(R)-(-)-a- deuteroethylquinoline) was treated with nitric acid in an ethanol-ether solution to precipitate out the 8-(R)-(-)-a-deuteroethylquinoline nitrate salt as white crystals MP 134-136°C (lit. Mp 146°C).3 6 Decomposition of the salt by treatment with NH4OH and extraction with three 10 mL portions of ether gave a clear, slightly yellow oil. This oil was Kugelrohr-distilled at 16 mm Hg and at 75°C to give a clear, colorless oil. Yield 53% (2.5 g, 16 mmol). !H NMR indicated that the product contained free quinoline; therefore, chromatography was done to obtain pure 8-(R)-(-)-a- deuteroethylquinoline. Chromatography was done using aluminum oxide; activated 36 B ailey, J. R., G lenn, R. A . ./. Am. Chem . Soc., 1941, 63, 6 3 9 -6 4 1 . 58 neutral, (Brockmann I, standard grade, 150 mesh, 58 angstroms, CAMAG 507-C-l. Surface area 155 m /g), using a medium sized column with a mixture of hexanes and ethylacetate 7:1 as the solvent. The 8-(/?)-(-)-oc-deuteroethylquinoline separated form the quinoline to give a clear, colorless oil. Yield 43% (2.0 g, 13 mmol), [a] = -0.363° at [589] c = 0.0386 M, / = 1 dm, a o b s = -0.014. *H NMR (CDC13) 5 1.35 (d, 3H), 3.35 (q, 1H), 6.67 (m, 1H), 7.12 (m, 1H), 7.24 (m, 2H), 7.5 (d, 1H), 8.7 (d, 1H). Determination of optical purity of 4 and 2-(/?)-(-)-a-deuteroethylaniline. A fifty percent mixture of 4 and 2-(/?)-(-)-oc-deuteroethylaniline 1.0 mg (.008 mmol) was dissolved in 0.5 mL of CDC13 and placed in a 5 mm NMR tube. The shift reagent obtained from Aldrich (stock # 23,722-1) Tris[3- (heptafluropropylhydroxymethylene)-(+)-camphorato] ytterbium (III) 250 mg (0.206 mmol) was dissolved in 1.5 mL of CDC13. The chiral compound was placed in the probe and the temperature was regulated to 298 K at which time a spectrum was taken (no shift reagent added). Following this the shift reagent was added at 50 pL intervals until the maximum shift was obtained. The separation obtained, after the addition of several hundred microlitres, was sufficient enough to determine the optical purity. At no time was complete separation obtained, however. Therefore, 37 optical purity was determined by using the line fit analysis software and taking the 37 N U T S N M R data processing softw are obtained from Acorn N M R , used at the U SC N M R facility. 59 average of several intervals. Using this method, the optical purity was determined to be 54% enantiomeric excess (see text for calculation), 'h NMR (500 MHz, CDC13) of the relevant 2-(R)-(-)-cxdeuteroethylaniIine peak; No shift reagent, 8 2.49 (q, 1H); 50 pL o f shift reagent, 5.15 (s with shoulder, 1H); 100 pL of shift reagent, 6.29 (s, 1H) and 6.49 (s, 1H); 150 pL of shift reagent, 6.77 (s, 1H) and 7.70 (s, 1H); 200 pL of shift reagent, 7.07 (s, 1H) and 8.55 (s, 1H); 250 pL of shift reagent, 7.25 (s, 1H) and 9.16 (s, 1H), 300 pL of shift reagent, 7.43 (s, 1H) and 9.72 (s, 1H), 350 pL of shift reagent, 7.54 (s, 1H) and 10.10 (s, 1H), 400 pL of shift reagent, 7.63 (s, 1H) and 10.42 (s, 1H), 450 pL o f shift reagent, 7.71 (s, 1H) and 10.72 (s, 1H). 38 Determination of optical purity of 8-(/?)-(-)-a-deuteroethylquinoIine. 8-(7?)- (-)-a-deuteroethylquinoline 1.0 mg (.006 mmol) was dissolved in 0.5 mL of CDC13 and placed in a 5 mm NMR tube. The shift reagent obtained from Aldrich (stock # 23,722-1) T ris [3 -(heptafluropropy lhydroxymethylene)-(+)-camphorato] ytterbium (III) 250 mg (0.206 mmol) was dissolved in 1.5 mL of CDC13. The chiral compound was placed in the probe and the temperature was regulated to 298 K at which time a spectrum was taken (no shift reagent added). Following this the shift reagent was added at 50 pL and 100 pL intervals until the maximum shift was obtained. The separation obtained after the addition o f several hundred microlitres was sufficient enough to determine the optical purity. At no time was complete separation obtained, however. Therefore, optical purity was determined by using the line fit 38 The sam e procedure w as used on the racem ic sam ple. 60 39 analysis software and taking the average of several intervals. Using this method the optical purity was determined to be 33% enantiomeric excess (see text for calculation). ]H NMR (500 MHz CDC13) of the relevant peak; No shift reagent, 8 3.35 (q, 1H); 300 pL of shift reagent, 9.1 (s with shoulder, 1H); 500 pL of shift reagent, 10.18 (s, 1H) and 10.26 (s, 1H); 700 pL of shift reagent, 10.86 (s, 1H) and 10.95 (s, 1H); 800 pL of shift reagent, 11.15 (s, 1H) and 11.23 (s, 1H); 1.1 mL of shift reagent, 11.72 (s, 1H) and 11.81 (s, 1H). 39N U T S N M R data processing softw are obtained from Acorn N M R , used at the U SC N M R facility. 61 Chapter 2 The Stereochemical Consequences of C-H Activation via Cyclometallation of 8-(/?)-(-)-a-deuteroethylquinoIine 2.1 Introduction Through the understanding o f the mechanism of C-H activation we can design compounds that maximize the full potential of this process, ultimately leading to the clean or catalytic transformation of methane into a more useful substance, such as, methanol or higher alkanes. One area o f C-H activation which has had minimal attention is the study of the stereochemistry of C-H activation.40 The utility of investigating the mechanism of the stereochemistry of C-H activation is to better understand this process, so that, it can be applied towards the formation of optically active compounds via C-H activation, for example asymmetric synthesis. Our investigation into the stereochemistry of C-H activation takes advantage of the newly synthesized ligand 8-(i?)-(-)-a-deuteroethylquinoline.4 1 The methodology behind choosing such a unique molecule to study the stereochemistry of C-H 40 A thorough search o f the C hem ical Abstracts, revealed that no study to date had sp ecifically addressed the issue o f w hether C-H activation by m eans o f cyclom etallation occurs w ith retention or inversion o f configuration. 4 1 S ee Chapter O ne. 62 activation stems from the results of Deeming and Rothwell.4 2 They report that 8- methylquinoline and 8-ethylquinoline easily form cyclometallated complexes with palladium, but, 8-isopropylquinoline does not. This result seems unusual, since one of two possible configurations of the isopropyl derivative prior to C-H activation has the methylene proton pointing directly into the metal center, ideally set up for C-H activation, Figure 1. Figure 1 As it turns out, Deeming and Rothwell determined via X-ray crystallography that structure A (Figure 1) possesses the correct configuration, which is reasonable considering the steric implications of the isopropyl group. Furthermore, the fact that no cyclometallation occurs even under forcing conditions,4 3 suggests that only one of two possible mechanisms was operating, (i.e., path D of Figure 2, which would not support the cyclometallation of the isopropylquinoline derivative). 42 D eem in g A ., J., R othw ell I . , P. J. O rganom et. Chem ., 1981, 205, 117-131. 43 D eem in g A ., J., R othw ell I., P. J. O rganom et. Chem ., 1981, 205, 117-131. R eactions were conducted at 25°C in CHC13 for 3 days and refluxing CHC13 for 5 hours. A lso, refluxing C H 3OH for 10 hours and refluxing neat CH 3C 0 2H for 1 hour produced no cyclom etalated material. 63 Pd 3-Centered T.S. CH3 Stereochemistry ? CH Back-Side Electrophilic Metal Assisted T.S. Figure 2 As Figure 2 illustrates, path C possesses a three-centered transition state in which the hydrogen could be displaced by an ancillary ligand on the palladium, followed by closure o f the ring. Path D depicts the ancillary ligand removing the proton by means of a back-side electrophilic metal assisted transition state, followed by ring closure. Although 8-isopropylquinoline is ideally set up to C-H activate via path C, it does not, which suggests that path D is operating. Deeming and Rothwell, however, claim that path C may still be the dominate pathway for the following reason. The addition of two moles of ligand per palladium undergoes cyclometallation more slowly than when one mole of ligand is present per palladium. This may indicate, as they suggest, the need for a vacant in-plane coordination site 64 for cyclometallation to proceed, meaning that a three centered transition state is required (i.e., path C Figure 2). In order to prove this point, they proposed that a ligand cis to 8-methylquinoline (coordinated in it’s vertical conformation) must be lost so that the quinoline can rotate into the coordination plane occupying the vacant cis position allowing cyclometallation to occur. Also, they observed that if the quinoline ligand possesses a methyl group in the 2 position as well as the 8 position, cyclometallation does not occur. This may be due to the fact that the methyl group in the 2 position does not allow the ligand to rotate into the coordination plane, because it collides with the other cis ligands around the palladium. This lack of rotation is exemplified in Figure 3. CH H c 3C w Pd Figure 3 As Figure 3 illustrates and Deeming and Rothwell have substantiated via NMR, 2,8- dimethylquinoline does not rotate freely about the metal nitrogen bond, even at elevated temperatures as indicated by no NMR line broading of the two NMe2 singlets. 8-Methylquinoline, however, does rotate freely about the metal nitrogen 65 center at room temperature, resulting in coalescence of the two NMe2 singlets. As a result of this observation, it was concluded that this process requires loss of the cis H20 ligand, so that rotation about the metal nitrogen bond can occur, allowing the ligand to pass through the coordination plane. Therefore, cyclometallation of 2,8- dimethylquinoline does not proceed because it can not form the required three- centered transition state in the coordination plane (see Figure 2 path C, vide supra). As a result of this phenomenon and the lack of 8-isopropylquinoline to cyclometallate, Deeming and Rothwell could not predict which pathway was operating during the cyclometallation of 8-alkylquinoline. Since both transition states postulated are reasonable (see Figure 2, vide supra), we have developed a methodology in which the two mechanistic pathways could be distinguished. In order to determine which mechanistic pathway was operating, it was necessary to know what to look for. Upon reviewing the proposed mechanisms, it was noted that the stereochemistry of the alpha carbon of the 8-alkylquinoline may be altered depending on which transition state was followed, Figure 4. 66 Retention of Configuration via three-centered T.S. Inversion of Configuration via metal assisted T.S. Figure 4, orientation of the chiral center after cyclometallation. As illustrated in Figure 4, the rules for assigning the configuration of a chiral center dictate that upon cyclometallation of chiral 8-alkylquinoline an inversion of configuration results in an R assignment and retention of configuration yields S. The ligand 8-(/?)-(-)-a-deuteroethylquinoline was developed, as discussed in Chapter 1, to determine the stereochemical change that takes place upon C-H activation via cyclometallation. If the reaction proceeds through path C (Figure 2, vide supra), then 8-(i?)-(-)-a-deuteroethylquinoline will undergo no stereochemical change (i.e., retention of configuration, S). If the reaction follows path D (Figure 2, vide supra), however, then there will be an inversion of configuration (i.e., R configuration) about 67 the alpha carbon o f 8-(/?)-(-)-a-deuteroethylquinoline. The least desirable possibility, is that racemization may occur about the chiral center, suggesting that both pathways are operating; resulting in no distinction between the two postulated mechanisms. The general reaction pathway that will be explored is illustrated in Figure 5. Once 8-(7?)-(-)-a-deuteroethylquinoline is reacted with the palladium source, it will be converted into a diastereomeric complex by means an optically pure amine ligand of known configuration. The resultant diastereomeric complexes will be separable potentially through fractional crystallization into its optically enriched form. In this state, an X-ray structure will determine the absolute configuration of the alpha carbon using the ancillary chiral amine ligand as a handle. Having established the absolute configuration o f the newly synthesized metal derivative, it would be possible to determine whether inversion or retention of configuration had occurred about the chiral center of 8-{7?)-(-)-a-deuteroethyIquinoline during the reaction with palladium(II) salts. Diastereom eric ^ Formation ‘RNH2 (S) (D)H (D)l R o r S Configuration RSor SS? Figure 5 68 In order to measure the diastereomeric ratio of the alpha carbon, several different types of chiral reagents were examined in order to produce the desired diastereomeric complex. O f these complexes that were synthesized, fractional crystallization was performed in an attempt to separate the diastereomers. Upon separation of the diastereomers, the absolute configuration of the newly formed metal carbon center may be assigned. Furthermore, an isotope effect was measured using racemic 8-a- deuteroethylquinoline. This measurement would determine if the bond breaking process had occurred during the rate determining step. Also, the size of the isotope effect would indicate how selectively the hydrogen was removed compared to the deuterium; a larger effect would yield a dimer of high deuterium content. However, a smaller effect would result in a complicated determination of the stereochemical outcome, (vide supra). Upon assignment o f the absolute configuration of the newly synthesized chiral center, it could be possible to differentiate between the mechanistic pathways C and D (Figure 2, vide supra). Distinction of the mechanisms can be made by assigning an R or S configuration to the 'H NMR signals of the diastereomers by utilizing the absolute configuration. The significance of assigning the R and S signals of the ’H NMR to the diastereomers is that an enhancement of one of the signals of the R or S diastereomer will be seen depending on which mechanistic pathway was followed. If 69 the reaction proceeds with retention of configuration (i.e., S enhancement, Figure 4, pg. 65), then the reaction follows path C, a concerted insertion. If inversion occurs (i.e., R enhancement, Figure 4, pg. 65), however, then the reaction proceeds via path D, an electrophilic back-side metal assisted SN 2 type reaction. 70 2.2 Results and Discussion 2.2.1 Formation of Palladium 8-(/{/S)-a-deuteroethyIquinoline Dimer According to Deeming and Rothwell, the reaction of potassium tetrachloropalladate(II) with 8-ethylquinoline proceeds readily. In work previously carried out by Nakanishi,4 4 it was established that the reaction of potassium tetrachloropalladate(II) with 8-ethylquinoline proceeds when combinations of methanol and water (3 : 2, respectively) were used as the solvent. In an effort to improve on the previous work, the reaction was optimized over various reaction times and different buffering agents, as illustrated in Table 1. Solvent Ratio Buffer Reaction Time Yield MeOH : H20 (3:2) Na2C 0 3 10 hr. 0 % MeOH : H20 (3:2) N aH C 03 5 hr. 40% MeOH : H20 (3:2) NaOAc 4 hr. 0 % MeOH : H20 (3:2) None 40 hr. 46% MeOH : H20 (3:2) None 24 hr. 54% Table 1, the reaction of potassium tetrachloropalladate(II) with 8- ethylquinoline. The optimum reaction yield was obtained when methanol and water were used in a 3 : 2 ratio, respectively, for a period of 24 hours, as illustrated in Table 1. Potassium 44 V isiting scholar w orking with Dr. Flood. 71 tetrachloropalladate(II) was dissolved in a water methanol solvent combination, and subsequently 8-ethylquinoline was added and the mixture was stirred. After 24 hours, the bright yellow solid was filtered and the product was extracted with benzene, resulting in a 54% yield of the chloride bridged dimer complex, as depicted in Scheme 1 and illustrated by Figure 6. Scheme 1 CH MeOH : H2O (3:2) 250C Pd Two other palladium complexes; palladium dichloride and palladium acetate were investigated in an attempt to optimize the yield of the chloride bridge dimer. In both cases each compound was examined under conditions similar to that of potassium tetrachloropalladate(II). Table 2 illustrates the results when palladium dichloride was subjected to reaction with 8-ethylquinoline under different conditions. The reaction proceeds similarly to that of potassium tetrachloropalladate(II), yielding the dimer as a bright yellow solid. 72 Solvent Ratio Buffer Reaction Time Percent Yield MeOH : H20 (3 : 2) None 30 hr. 53% MeOH : H20 (3 : 2) NaOAc 21 hr. No Reaction Table 2, reaction of palladium dichloride with 8-ethylquinoline. Table 3 depicts the various conditions that were tested when palladium acetate was subjected to reaction with 8-ethylquinoline. The product o f this reaction was the acetate bridged dimer, which possesses a complex spectrum, Figure 7. In those instances when a buffer was used, it was noted that palladium metal started to precipitate. The acetate bridged dimer was then treated with lithium chloride according to the procedure of Pfeffer and Goel,4 5 so that the acetate bridge would be substituted with a chloride ion. The product of this reaction, the chloride bridged dimer, has the same spectrum as that of the product of the potassium tetrachloropalladate(II) reaction with 8-ethylquinoline. 45 P feffer M ., G oel, A ., B. In organ ic S yn th esis, 1989, 26 , 21 1 -2 1 4 . 73 Solvent Ratio Buffer Reaction Time Percent Yield4 6 CH2C12 Na2 C 0 3 5 hr. 13% c h 2 c i2 N aH C03 5 hr. 9% c h 2 c i2 NaOAc 4 hr. 10% c h 2 c i2 None 17 hr. 14% Et3 N None 1 hr. No Reaction MeOH : H20 (3:2) NaOAc 4 hr. No Reaction MeOH : H20 (3:2) None 4 hr. 10% Table 3, reaction of palladium acetate with 8-ethylquinoline. O f the three metal sources, potassium tetrachloropalladate(II) proved to be the most useful when submitted to reaction with 8-ethylquinoline. Once optimally synthesized, subsequent chemistry was performed on the dimer to characterize it, such as determination o f an isotope effect and production o f a diastereomeric complex, so that the absolute configuration may be established. 46 Reported y ield is o f the chloride bridged dimer. 74 ppm Figure 6, 'il NMR of the cyelomctallated 8-cthylquinoline chloro-bridgcd palladium (II) dimer. j O C r . 0 f - r : r . - . * • - o j Figure 7, ‘H N M R of the cyclometallatcd 8-cthylquinoline acetate-bridged palladium(II) dimer. 2.2.2 Determination of the Isotope Effect In order to determine the isotope effect of cyclometallation, racemic 8-a- deuteroethylquinoline was submitted to reaction with potassium tetrachloropalladate(II). From the isotope effect, it was possible to determine if removal of the proton was the rate determining step. The reaction was monitored via 'if NMR and the isotope effect was calculated utilizing equation 1. k H _ Deuterium Retained k d Deuterium Transfered 1 equation 1 The amount of deuterium retained can be obtained from equations 2 and 3, the amount of deuterium transferred can be calculated by subtracting the amount of deuterium present (91%, see Chapter One) from the amount of deuterium retained (equation 3). H not Activated = Area o f a Proton - Area of H in Deuterium Site equation 2 Deuterium Retained = Area of Ring Proton - Area o f H not activated equation 3 From Figure 8 and using equation 2, a value of 0.10 for the peak area of the alpha proton and 0.09 for the amount of hydrogen in the deuterium site 77 (100% - 91% = 0.09 amount of hydrogen in the deuterium site)4 7 yields 0.01 for the amount of hydrogen not activated. Using the value of 0.90 for the peak area of a ring proton (see Figure 8), and subtracting the amount of hydrogen not activated (0.01) gives 0.89 as the amount o f deuterium retained (equation 3). Using the amount of deuterium retained (0.89) and the amount of deuterium transferred (0.02) in equation 1, gives a KH /KD o f 45. Since the value of the isotope effect was substantially large, it was reasonable to postulate that the proton was solely involved in cyclometallation. For that reason, of the four possible pathways (Figure 9), only two; E and G which show the proton being abstracted are relevant. Furthermore, as a result of the unusually large isotope effect, the loss of deuterium during the transformation of /?-(-)-ethylbenzene to 8-(/?)- (-)-a-deuteroethylquinoline was minimized. Therefore, the difficulties in the optical analysis of the product that may have arisen from a low deuterium content (i.e., all four products o f Figure 9 would have to be considered), can be ignored. 47 S ee Chapter O ne. 78 R' = quinoline Figure 9 79 ppm Figure 8, ‘H N M R of the cyclometallated racemic 8-a-deuteroethyiquinoline chloro-bridged palladium(II) dimer, O C O 2.2.3 Synthesis and Resolution of the Diastereomers In order to monitor the stereoselectivity of cyclometallation during the reaction of palladium with 8-(/?)-(-)-a-deuteroethylquinoline, it was necessary to split the dimer with a chiral reagent and produce diastereomers; so that the absolute configuration of the newly synthesized metal carbon center may be assigned, Scheme 2. Scheme 2 Knowing the absolute configuration, the mutual assignment of the !H NMR signals of the R and S diastereomers could be achieved. Once again in an effort to capitalize on previously published work, we chose to cleave the racemic palladium dimer with (-)-a-phenethylamine, resulting in the formation of diastereomer 1 (Figure 10), which should be resolvable according to the published results of Sokolov.4 8 48 Sok olov, V .I., Sorokina, T. A ., Troitskaya, L. L., S o lo v iev a , L. I., R eutov, O. A . J. O rganom et. Chem. 1972, 36, 3 8 9 -3 9 0 . 81 ppm Figure 10, *H N M R of the cyclometallatcd 8-cthylquinoIinc a-plicncthylam inc palladium(II) complex. oo Cl 1 Unfortunately, as we have discovered in the past, we were unable to reproduce Sokolov’s procedure and therefore, we could not separate the diastereomers. Even after running through a gambit of fractional crystallization techniques, utilizing various solvents, we could not separate the diastereomers ('H NMR and X-ray diffraction indicated diastereomers). As a result of this, we discarded Sokolov’s procedure (once and for all). Subsequently, an attempt was made to utilize (+)-emfo-bornylamine, which when subjected to reaction with the racemic dimer, produced 2 illustrated by the ‘H NMR given in Figure 11. NH 2 83 Two equivalents of (+)-tj«c/o-bornylamine were subjected to reaction with the racemic dimer in dichloromethane for 1.5 hours. After work up, the yellow solid was crystallized from hexanes and chloroform to give yellow, needle-like crystals in 71% yield. After an extensive effort of resolving this complex through fractional crystallization, 1 II NMR indicated that a one-to-one mixture of the diastereomers remained. Therefore, another method was sought to achieve the separation needed, in order to determine the absolute configuration of the newly formed cyclometallated material. The assignment of the absolute configuration and ultimately the determination of the stereoselectivity of cyclometallation, was achieved by utilizing the recently published work of Pfeffer,4 9 using /-leucine to split the chloride bridged dimer racemate, producing the diastereomeric derivative, 3 as illustrated by the 'H NMR spectrum Figure 12. NH- 3 49 P feffer M ., M aassarani F., Spencer J., Fisher J., DeCian A. T etrahedron: A sym m etry, 1994, 5(3), 3 2 1 -3 2 4 . 84 The racemic dimer was treated with /-leucine and sodium carbonate in methanol for two hours. Following work up, the diastereomers were obtained as a yellow colored solid in 90% yield. The diastereomers were then separated by means o f a quick crystallization at - 23°C to yield the R diastereomer in >90% de, based on the peak areas from the integrals of the !H NMR, as indicated in Figure 13. At this point, it was necessary to determine the absolute configuration of 3 utilizing X-ray crystallography; so that upon reaction of 8-(7?)-(-)-a-deuteroethylquinoline with palladium and subsequent treatment with /-leucine, the relative amounts of the R and S diastereomers could be determined. Once these amounts are known, the answer to the question o f whether inversion or retention of configuration of 8-(/?)-(-)-a- deuteroethylquinoline occurs during cyclometallation with palladium(II) salts will be at hand. 85 Figure 11, 'FI NMR of the cyclonictallated 8-ethyIquinolinc bornylam ine palladium (II) complex. Figure 12, 1II N M R of the cyclomctnlhitcd 8-cthyIquinoIinc palladium (ll) leucine derivative, 3. OO " ■ J 3.15 Figure 13, ‘il NMR of 3, after a quick fractional crystallization at -23"C resulting in >90% de. OO 00 2.2.4 X-ray determination of compound 3 As discussed previously, the resolution of the diastereomeric complexes 4a and 4b in an effort to determine the absolute configuration of the newly synthesized chiral center failed. Even though each complex formed stable crystals, X-ray crystallography (Figures 14 and 15 ) showed an equal population of each diastereomer. As Figure 14 depicts, complex 4a possesses a structure which is triclinic having a space group of p-1. The disorder o f the compound is shown by the equal population distribution of the a- methyl of the a-phenethylamine group. Although this disorder was illustrated in the wrong position, the ultimate consequences remain the same.50 In every attempt to isolate one of the diastereomers by fractional crystallization, the same result was obtained; an equal population of the diastereomers. This result also held true for the bornylamine derivative 4b, which is illustrated in Figure 15.5 1 The unit cell of 4b 50 T he disorder should have been placed on the chiral center o f the quinoline ligand sin ce a - phenethylam ine is 99% ee. H ow ever, do to a loss o f the x-ray data, resulting from a com puter crash, w e w ere unable to fix the a-ph en eth ylam ine ligand. Therefore, the disorder is illustrated in the a-p h en eth ylam in e ligand instead o f the quinoline ligand. 5 1 N o x-ray data is given for this m olecule, since the R value w as to high. Therefore, this Figure is H CH3 4a, RNH2 = (+)-a/p/ta-phenethylamine 4b, RNH2 = (+)-e«£fo-bornylamine 89 was determined to be triclinic with a space group of p-1, having an equal population of the a-methyl of the newly formed chiral center. As with 4a, every attempt to isolate one o f the diastereomers o f 4b failed. As a result of this, a greater effort was placed on resolving the leucine derivative 3 {vide infra) from which preliminary 'H NMR data suggests, the dimer synthesized through the reaction of 8-(7?)-(-)-a-deuteroethylquinoline with palladium(II) salts possesses retention of configuration, when compared to 1 I I NMR data obtained from Pfeffer.52 To remove any doubt as to whether the use of leucine as an ancillary chiral ligand was suitable for the determination of the optical purity, the following test reaction was performed. 8-(/?)-(-)-a-deuteroethylquinoline was subjected to reaction with palladium dichloride and subsequently the dimer was split with leucine and (-)- a-phenethylamine. In both cases the percent diastereomers excess 15% and 19% respectively, fell within the ±3% error for determination of the diastereomeric excess by *H NMR. Therefore, the utility of using leucine for the determination of the diastereomeric excess and the absolute configuration was reasonable. After an exhaustive effort, the absolute configuration of 3 could not be determined by x-ray crystallography. Even though crystals of >90% de were obtained (measured by *H NMR), all attempts at determining the absolute configuration failed, due to the decomposition of the crystals while being subjected on ly an exam ple o f w hat 4b should look like. 52 C om paring the N M R data obtained from P feffer to ours. 90 to x-rays by the diffractometer, even at temperatures of -150°C. Therefore, we chose to utilize the information published by Pfeffer for assigning the configuration of R or 53 S to our complex. Armed with this information, it was determined that when 8- (7?)-(-)-a-deuteroethylquinoline was subjected to reaction with PdCl2, K2PdCl4 or Pd(OAc)2 and subsequently cleaved with /-leucine, yielded 3 having a dominate configuration o f S as shown in Table 4 and by Figures 14, 15, and 16 respectively. Pd(II) % retention of configuration 'H NMR (S) Ho54 'H NMR (R) Ho5 3 1. PdCl2 56% 8.8 ppm (lit: 8.82 ppm) 8.7 ppm (lit: 8.77 ppm) 2. K2PdCl4 72% 8.8 ppm (lit: 8.82 ppm) 8.7 ppm (lit: 8.77 ppm) 3. Pd(OAc)2 97% 8.8 ppm (lit: 8.82 ppm) 8.7 ppm (lit: 8.77 ppm) Table 4, reac tion of 8-(/?)-(-)-a-deuteroethylquinoline (36% ee) with palladium. Furthermore, the result of the reaction between 8-(/?)-(-)-a-deuteroethylquinoline (36% ee) and palladium acetate (entry 3, Table 4) indicates that retention had occurred with a high degree of stereospecificity,55 supporting the proposed three- centered transition state mechanism (i.e., path C, Figure 2, vide supra). 5 3 Pfeffer M ., M aassarani F., Spencer J., Fisher J., DeCian A. T etrahedron: A sym m etry, 1994, 5(3), 3 2 1 -3 2 4 . 'h N M R signals obtained from the crystal structure o f 3, p ossessin g an additional m ethyl group in the 4 position o f the quinoline ring should not be significan tly different from those o f the non-m ethylated species. 54 This is the proton signal ortho to the nitrogen o f the quinoline ring. Literature values are taken from; P feffer M ., M aassarani F., Spencer J., Fisher J., DeC ian A . T etrahedron: A sym m etry, 1994, 5(3), 3 2 1 -3 2 4 . 55 Based on the 36% ee o f the starting m aterial, see Chapter One. 91 C l 8 0 6 N2 CIO C8 Pdl 0 2 C5 C4 C6 C2 CIL CI2L Figure 14, x-ray structure of the 8-ethylquinoline a-phenethylamine palladium(II) derivative. 92 Figure 15, x-ray structure of the 8-ethyIquinoIinc bornyia palladium(II) derivative. 5 3 Figure 16, 'FI NMR of 3 at 20% tie, obtained from the reaction of PdCR with 8-(R)-a-deuterocthy!quinoline (36% ee). 4^ F igu re 17, *H N M R o f 3 at 2 6 % dc, ob tain ed from the reaction o f P d C l4 w ith 8 -(R )-a -d e u tc r o c th y lq u in o lin e (36% ee)* v O L /i p p m F ig u re 18, ' i l N M R o f 3 at 3 5 % dc, ob tain ed by reaction o f P d (O A c)2 w ith 8 -(R )-a -d e u tc r o c th y lq u in o lin e (36% ee). v O Cv 2.2.5 Reactivity of compound 3. In an effort to determine how dilute acid might effect the cyclometallated chiral center of the leucine derivative, 3 (59% de) was subjected to reaction with acetic acid in methanol for 24 hours (Scheme 3). Scheme 3 NH- HOAc M eOH, 24hr. RT 3 (59% de) LiCl MeOH N H 2 h 3c 26% de After work up, the acetate bridged dimer was subjected to reaction with lithium chloride in methanol to produce the chloride bridged dimer. The dimer was then cleaved with (-)-a-phenethylamine to yield a diastereomer of 26% diastereomeric excess, illustrated by the 'H NMR Figure 19. This result suggests that protonolysis may be occurring at the palladium-carbon bond, resulting in loss of optical activity. 97 Also, It has been published in the literature that cyclometallated complexes of 8- methylquinoline insert alkynes into the metal carbon bond.56 In an effort to exploit this chemistry, the reactivity o f the racemic 8-ethylquinoline chloride bridged palladium dimer toward insertions and potentially its effect on the chiral center was investigated. Hexafluorobute-2-yne was reacted with the dimer in toluene at 50°C for 7 days. After work up, and conversion to the leucine derivative, 6 was obtained. CF NH- 6 This new complex was identified via 'h and l9F NMR (Figures 20 and 21) as well as elemental analysis. The !H NMR and 1 9 F NMR indicated that two species exist in solution, the dominate structure having the nitrogen’s trans and the other resulting from the nitrogen’s being cis. The stereochemistry of the insertion o f hexafluorobute- 2 -yne into the optically active metal-carbon center of the chloride bridged dimer awaits further investigation as a future project; to determine what effects, if any, this process may have on the chiral center. 56 D ehand, J., B ahsoun, A ., Pfeffer, M ., Z insius, M. J. C. S. D a lto n , 1979, 5 4 7 -5 5 6 . 98 Figure 19, *H NMR of the cyclomctallatcd ethylquinoline palladium (II) a-phenethylam inc derivative at 26% de obtained from reaction of acetic acid, lithium chloride and a-phcncthylam ine 011 3 (at 59% de). SO SO I Figure 20, *H NMR of 6 , the product resulting from the insertion of hcptafluorobutc-2-yne into the cyclomctallatcd 8- — ethylquinolinc palladium (II) chloro-hridgcd dim er and subsequent reaction with leucine, o Figure 21, UF NMR of 6, the product resulting from the insertion of hcptafluorobute-2-yne into the cyclomctallatcd 8- ethylquinolinc palladium (II) chloro-bridgcd dim er and subsequent reaction with leucine. 2.3 Summary In conclusion, it has been shown that 8-(/?)-(-)-a-deuteroethylquinoline (36% de) undergoes cyclometallation yielding a chiral center of S configuration at 35% de, through the action o f a three-centered transition state which yields retention o f configuration. In addition to the above, we have demonstrated that these complexes undergo insertion chemistry readily and that the doorway for studying the mechanism of this process has been opened. 102 2.4 Experimental Section 2.4.1 General Methods. Chemical shifts of NMR spectra, recorded on Bruker AC 250-, AM 360-, or AM 500 MHz FT spectrometers, are reported in parts per million (8) down field from tetramethylsilane for 'H and l3C. Plots of the NMR spectra were performed using the NUTS software obtained from Acorn NMR. All reactions involving organometallic compounds, unless otherwise mentioned, were carried out in the air. When protection from oxygen was necessary, reactions were carried out under an atmosphere of nitrogen or argon purified over reduced copper catalyst (BASF R3-11) and Aquasorb, in flamed out glassware using standard vacuum line, and Schlenk techniques. When necessary, the glove box, a Vacuum Atmospheres Model HE-553-2 equipped with a DriTrain MO 40-2 inert gas purifier was used. The oxygen content of the dry box was monitored by Cr(acac)2, a light orange color indicating that it was sufficiently oxygen-free. Benzene, ether, hexanes, pentane, and THF were distilled from purple solutions of sodium benzophenone when necessary. CH2C12 was distilled twice from CaH2. Transfers of Hexafluorobute-2-yne was performed with a vacuum line, using standard gas transfer techniques. All known compounds that had been previously reported had only 'H NMR performed on them for verification, however, new compounds were authenticated either by elemental analyses or by X-ray 103 crystallography. Elemental analysis was performed by Microanalytical Laboratory, University of California Berkeley. X-ray crystallography was done at the University of Southern California under the supervision of Dr. Robert Bau. 2.4.2 Reactions Reaction of 8-(R)-(-)-a-deuteroethylquinoline with K2PdnCl4. Potassium tetrachloropalladate(II) 1.5 g (4.6 mmol) was placed in a 300-mL single-neck round- bottom flask with a stir bar. To this was added 135 mL of MeOH and 90 mL of H20 . The mixture was stirred and formed a nearly homogenous orange-yellow solution. To the solution, 8-(R)-(-)-a-deuteroethylquinoline 1.4 g (8.9 mmol) was added. After several hours, a yellow precipitate began to form. After 24 hr., the bright yellow precipitate was filtered and washed with three 20 mL portions of H20 and three 50 mL portions o f Et20 . The bright yellow powdery solid was then dried in vacuo. Yield 54% (1.5 g, 2.5 mmol). 'H NMR (CDC13) 8 1.25 (d, 3H), 4.5 (q, 1H), 7.44 (dd, 1H), 7.54 (d, 1H), 7.64 (dt, 2H), 8.32 (dd, 1H), 9.0 (s, 1H). Literature *H NMR (CDC13) 8 1.27 (d, 3H), 4.55 (q, 1H), 12-1.1 (3H), 8.02 (dd, 1H), 8.26 (dd, 1H).57 Reaction of 8-(/?)-(-) -a-deuteroethylquinoline with palladium acetate. The palladium acetate 1.00 g (4.5 mmol) was dissolved in 20 mL of CH2C12 to give a deep red solution. Upon addition of 8-(/?)-(-)-a-deuteroethylquinoline (0.74 g, 4.7 57 D eem in g A ., J., R othw ell I . , P. J. O rganom et. Chem ., 1981, 2 05, 117-131. V alues w ere recorded at 100 H z on a Varian H A 100 spectrom eter. 104 mmol) the solution remained unchanged. After 17 hr., the solution was a deep brown color, at which point, it was filtered and the solvent was removed in vacuo to give an oily dark brown material which was washed with three 20 mL portions of pentane. The solid that remained was dried in vacuo. The solid was then dissolved in acetone (100 mL) and to it LiCl 0.95 g (0.022 mol) was added and the mixture was gently heated on a hot plate to pre-boiling. Heating was continued until all of the initial yellow precipitate formed had mostly dissolved. At this point the solution was filtered and 100 mL of water was rapidly added to the solute to give a yellow precipitate. The yellow solid was filtered and washed with 20 mL of ether and 20 mL of pentane and dried in vacuo. Yield 14% (0.37 g, 0.62 mmol). NMR (CDC13) 5 1.25 (d, 3H), 4.5 (q, 1H), 7.44 (dd, 1H), 7.54 (d, 1H), 7.64 (dt, 2H), 8.32 (dd, 1H), 9.0 (s, 1H). Reaction of 8-(f?)-(-)-a-deuteroethylquinoline with palladium dichloride. Palladium dichloride .213 g (1.20 mmol) was placed in a 100-mL single-neck round- bottom flask with a stir bar. To this was added 23 mL of MeOH and 15 mL of H20 . To the solution, 8-(7?)-(-)-a-deuteroethylquinoline .394 g (2.50 mmol) was added. After several hours, a yellow precipitate began to form. After 30 hr., the bright yellow precipitate was filtered and washed with three 20 mL portions of H20 and three 50 mL portions of Et20 . The bright yellow powdery solid was then dried in 105 vacuo. Yield 53% (.315 g, .63 mmol). 'H NMR (CDC13) 6 1.25 (d, 3H), 4.5 (q, 1H), 7.44 (dd, 1H), 7.54 (d, 1H), 7.64 (dt, 2H), 8.32 (dd, 1H), 9.0 (s, 1H). Cleavage of the chloride dimer with (-)-a-phenethylamine. The chloride dimer 124 mg (0.268 mmol), was dissolved in 10 mL of CH2C12 and stirred at room temperature. To this dark orange solution was added /?-(-)-a-phenethylamine (75.6 mg, 0.624 mmol). The resultant mixture turned to a yellow color after several minutes. After 1.25 hr. the solvent was removed via vacuum to give a bright yellow waxy material. This material was then washed with several portions of hexanes to give a yellow solid. Yield 87% (980 mg, 0.234 mmol). 'H NMR (CDC13 ) 5 1.13 (d, 3H), 1.25 (d, 3H), 1.79 (d, 3H), 1.85 (d, 3H), 3.7 (q, 2H), 3.9 (q, 2H), 4.3 (m, 1H), 4.6 (m, 1H), 7.1-7.5 (m, 9H), 8.15 (dd, 1H), 9.4 (dd, 1H). Cleavage of the chloride dimer with (/?)-(+)-bornylamine. The chloride dimer 130 mg (0.282 mmol), was dissolved in 10 mL of CH2C12 and stirred at room temperature. To the dark orange solution was added i?-(+)-bornylamine 86.4 mg (0.563 mmol). The resultant mixture turned to a yellow color after several minutes. After 1.5 hr. the solvent was removed via vacuum to give a bright yellow waxy material. This material was then washed with several portions o f hexanes to give a yellow solid. Yield 71% (900 mg, 0.199 mmol). *H NMR (CDC13 ) 5 0.89 (dd, 3H), 1.25 (dd, 3H), 3.8 (q, 1H), 3.9 (q, 1H), 7.35 (dd, 1H), 7.45 (dd, 1H), 7.55 (dd, 2H), 8.2 (dd, 1H), 9.45 (dd, 1H). 106 Cleavage of the optically active chloride dimer (formed from K2PdnCl4) with 5'-(+)-leucine. The palladium dimer 105 mg (0.227 mmol) was suspended in 15 mL of MeOH in a 50 mL round bottom flask equipped with a stir bar. To this suspension was added Na2C 0 3 470 mg (0.443 mmol) and leucine 580 mg (0.442 mmol) respectively, while stirring. After 10 min, the solution became nearly homogenous with a light brown yellow tint to it. Following 2 hr. of stirring, the solution was clear with a slight bit of white precipitate. At this point water was added and the product was extracted with three 10 mL portions of CH2C12. The organic layers were combined, dried with Na2S 0 4 and removed using the rotary evaporator to give a tan colored solid, which was then washed with pentane. Yield 90% (620 mg, 0.158 mmol). *H NMR (CDC13) 8 1.0 (m, 6H), 1.25 (dd, 3H), 1.6-2.4 (m), 3.6 (q, 1H), 3.9 (m, 1H), 7.0 (dd, 1H), 7.1 (dd, 1H), 7.3-7.6 (m, 3H), 7.82 (dd, 1H), 8.9 (dd, 1H) 8.75 (dd, 1H), 8.85 (dd, 1H). 23% diastereomeric excess based on the integration area of the peaks at 8.75 ppm and 8.85 ppm. The dominate structure being (S) based on the assignment of Pfeffer.58 Cleavage of the optically active chloride dimer (formed from Pd(OAc)2 ) with S-(+)-leucine. The palladium dimer 69 mg (0.149 mmol) was suspended in 15 mL of MeOH in a 50 mL round bottom flask equipped with a stir bar. To this suspension 58 P feffer M ., M aassarani F., Spencer J., Fisher J., DeC ian A. Tetrahedron: A sym m etry, 1994, 5(3), 3 2 1 -3 2 4 . 107 was added Na2C 0 3 30.5 mg (0.288 mmol) and leucine 37.7 mg (0.287 mmol) respectively, with stirring. After 10 min the solution became nearly homogenous with a light brown yellow tint to it. Following 2 hr. of stirring the solution was clear with a slight bit of white precipitate. At this point, water was added and the product was extracted with three 10 mL portions of CH2C12. The organic layers were combined, dried with Na2S 0 4 and removed using the rotary evaporator to give a tan colored solid which was then washed with pentane. Yield 99% (121 mg, 0.309 mmol) due to the presence of HzO. ‘h NMR (CDC13) 5 1.0 (m, 6 H), 1.25 (dd, 3H), 1.6-2.4 (m), 3.6 (broad q, 1H), 4.4 (broad m, 1H), 6.85 (dd, 1H), 6.95 (dd, 1H), 7.4- 7.5 (m, 3H), 7.75 (dd, 1H) 8 8.75 (dd, 1H), 8.85 (dd, 1H). 32% diastereomeric excess based on the integration area of the peaks at 8.75 ppm and 8.85 ppm. The dominate structure being (S) based on the assignment of Pfeffer.59 Reaction of 3 (59% de) with acetic acid, lithium chloride and (-)-a- phenethylamine. The leucine derivative (3, 59% de) 300 mg (0.76 mmol) and methanol 8 mL were placed in a 20 mL single-neck round bottom flask with a stir bar. To the solution 0.17 mL (3.04 mmol) of acetic acid was added and the mixture was stirred for 24 hr. After the allotted reaction time, LiCl 193 mg (4.56 mmol) was added and the mixture was stirred for 20 min. The solvent was then removed in 59 Pfeffer M ., M aassarani F„ Spencer J., Fisher J., DeC ian A . T etrahedron: A sym m etry, 1994, 5(3), 3 2 1 -3 2 4 . 108 vacuo and the tan solid was washed with three 10 mL portions of water and dried in vacuo. The chloride bridged dimer 150 mg (0.25 mmol) was then dissolved in 10 mL CH2C12 and to it was added 0.071 mL (0.55 mmol) of (-)-a-phenethylamine. After 45 min the solvent was removed via vacuum and the yellow solid was washed with three 10 mL portions o f hexanes and then dried in vacuo. Yield 80% (83.8 mg, 0.20 mmol), 26% de. 'H NMR (CDC13) 5 1.13 (d, 3H), 1.25 (d, 3H), 1.79 (d, 3H), 1.85 (d, 3H), 3.7 (q, 2H), 3.9 (q, 2H), 4.3 (m, 1H), 4.6 (m, 1H), 7.1-7.5 (m, 9H), 8.15 (dd, 1H), 9.4 (dd, 1H). Reaction of 3 with hexafluorobute-2-yne. The palladium dimer 250 mg (0.42 mmol) and toluene 50 mL were placed in a 75-mL single-neck thick-walled tube equipped with a stir bar and a 14/20 joint at the top. The yellowish solution was then degassed three times using standard vacuum techniques. Hexafluorobute-2-yne was vacuum transferred into a tared 5 mL round bottom flask until the mass of the flask was 1.28 g (7.98 mmol of alkyne). The alkyne was then vacuum transferred (utilizing liquid nitrogen to condense the alkyne) into the tube containing the palladium dimmer and the toluene. Once all of the alkyne had been transferred the tube was sealed and the solution was stirred for 24 hr., after which the sealed tube was placed in an oil bath at 60°C for one week with continued stirring of the solution. After one week the solution was cooled to -78°C and the vessel was opened carefully. The cream colored solution was filtered and the tan solid was crystallized 109 from CH2C12 and hexanes to give a white, hair like crystals. Yield 45% (96.5 mg, 0.19 mmol). 'H NMR (CDC13) 5 0.920 (m, 6H), 1.7 (dd, H), 2.0 (m, 2H), 2.6, 3.0, 3.6, 3.7, 4.6 (m, 1H), 7.3-7.8 (m, 4H), 8.05 (dd, 1H), 8.25 (dd, 1H), 9.4 (m, 1H). I9F NMR (CDC13) 8 -21 (q, 3F), -21.5 (q, 3F), -24.9 (qq, 3F). Elemental Analysis calculated for C2iH22N2F60 2Pd + 0.5 CH2C12 being present based on 'H NMR integral, calculated; C 43.23, H 3.88, N 4.69, found; C 43.66, H 3.93, N 4.75. 110 Appendix: X-ray data for the cyclometallated ethylquinoline-a-phenethylamine palladium(II) derivative. Table 1. Crystal data and structure refinement for 1. Identification code Empirical formula Formula weight Temperature Uavelength Crystal system Space group Unit cell dimensions Vo I Line 2 Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Refinement method Data / restraints / parameters Goodness-of-fit on F~2 Final R indices (l>2sigma(I)) R indices (all data) Largest diff. peak and hole lu02 C19.50 H21.50 C12.80 N2 Pd 6 78.91 295(2) K 0 . 71073 A t ricIinic p -1 a = 9.6610(10) A alpha = 80.690(10) deg. b = 10.8170(10) A beta = 68.910(10) deg. c = 12.312(2) A gamma = 73.566(6) deg. 1168.5(2) A'3 2 1.385 Mg/m‘3 1.103 mm'-l 682 0.6 x C.3 x 0.1 nm 1.78 to 22.69 deg. -1<-h<-9, -11<=k<=11, -12<=l< = 13 3575 2930 IR(int) = 0.0662) Full-matrix least-squares on F~2 2930 / 0 / 253 1.092 R1 = 0.0713. wR2 = 0.2327 R1 = 0.0756, wR2 = 0.2396 1.670 and -0.599 e.AA-3 111 Table 2. Atomic c o o rd in a te s ( x 10*4) and e q u iv a le n t is o tro p ic displacem ent p aram eters (A*2 x 10*3) fo r 1. U(eq) is defined as one t h i r d of th e tr a c e of th e o rth o g o n a liz e d Uij te n so r. X y z U(eq) Pd( 1 ) 507(1) 10176(1) 1753(1) 46(1) Cl(1) -2245(3) 10663(3) 2016(3) 67(1) N(1) 339(12) 9110(9) 3310(8) 61(2) N(2) 901(14) 11223(9) 146(9) 70(3) CO ) -852(18) 8758(12) 4021(11) 78(4) C(2) -885(24) 8109(15) 5127(14) 102(6) C(3) 363(29) 7950(15) 5467(13) 113(7) C(4) 1628(22) 8346(14) 4724(12) 92(5) C(5) 1640(17) 8923(11) 3607(11) 72(4) C(6) 2936(30) 8269(24) 5029(17) 143(10) C(7) 4088(29) 8670(26) 4255(24) 152(12) C(8) 4126(19) 9278(18) 3063(17) 108(6) C(9) 2866(15) 9329(13) 2762(11) 71(3) C(10) 2741(14) 9768(12) 1591(11) 63(3) C O D 3667(14) 8787(17) 730(12) 89(4) C(12) 446(29) 13340(15) 818(13) 128(8) C C14) 847(28) 13109(13) -1250(13) 97(6) C(15) -392(27) 13437(16) -1589(16) 111(6) C(16) -239(26) 14127(16) -2765(18) 108(6) C( 17) 1050(32) 14369(16) -3404(15) 112(7) cc 1 8) 2271(27) 14001(21) -3041(20) 125(7) C( 19) 2160(28) 13390(17) -1980(18) 114(6) C(1L) 5019(20) 3556(19) 2233(15) 47(5) C l(1 L) 4203(9) 4111(13) 3615(6) 128(4) CK2L) 3641(7) 3071(7) 1881(6) 82(2) CK3L) 5745(12) 4641(10) 1143(8) 115(3) C( 13) 90(45) 12545(22) 29(20) 89(11) C(13A) 1345(31) 12392(26) -151(21) 60(6) Table 3. S e le c te d bond lengths [A] and a n g les [deg] fo r 1 . Symmetry tra n sfo rm a tio n s used to g e n e ra te e q u iv a le n t atoms: f a b l e 4 . Bond l e n g t h s f A J and a n g l e s fd c g l for 1. Pdd)-c(io) 2.018(12) Pd(1)-N(1) 2.04S(9) Pd(l)-N(2) 2.075(10) C(6)-C(7)-C{8) 125(2) Pd(l)-CWI) 2.469(3) C(9)-C(8)-C(7) 116(2) Ncn-ccn 1.28(2) C(8)-C(9)-C(5) 118.1(14) N(1)C(5) 1.38(2) C(8) -C(9)-C(10) 124.3(14) N(2)'C(13A) 1.40(3) C(5)-C(9)-C(10) 117.6(11) H(2)-C(13) 1.43(3) C( 11)*C(10)-C(9) 112. 1(11) C( 1 >-C(2> 1-42(2) C(11)-C(10)-Pd(1) 111.0(9) C(2)-C(3) 1.37(3) C(9)-C(10)*Pd(1) 107.5(8) C(3)-C(4) 1.37(3) C( 13A)-C(12)-C(13) 42.0(14) C(4) -C(5) 1.41(2) C(15) -C(14)-C(19) 119(2) C(4)-C(6) 1.42(3) C(15)-C(14)-C(13) 99(2) C(5)-C(9) 1.39(2) C(19)-C(14)-C(13) 142(2) C(6)-C(7) 1.31(4) C(15)-C(14)-C(13A) 139(2) C(7)-C(8) 1.50(3) C(19)-C(14)-C(13A) 102(2) C(8)-C(9) 1.38(2) C( 13)-C(14)-C(13A) 41(2) CC9)-C(10) 1.48(2) C( 14)-C(15)*C(16) 117(2) C(10)'CC11) 1.48(2) C(17)-C(16)-C(15) 120(2) C(12)-C(13A) 1-54(3) C(16)-C(17)-C(18> 121(2) C(12)-C(13) 1.58(4) C(19)-C(18)-C(17) 121(2) C(14)-C(15> 1-34(3) C(14) *C(19)-CC18) 122(2) C(14)-C(19) 1.35(3) CI(2L)*C(1L)-CI(1L) 109.0(10) C( 14)-C(13) 1.58(3) Cl(?L)-C(1l)-Cl(3L) 108.3(11) C(14)-C(13A> 1.60(3) CI(1L)-C(1L)*CI(3L) 115.3(13) C(15)-C(16) 1.49(3) C(13A)-C(13)-H(2) 65(2) C(16)-C(17) 1.28(3) C(13A)-C(13)-C(14) 71(2) C( 17)-C(18) 1-34(3) N(2)-C(13)-C{14) 108(2) C(1fi)-C(19) 1.34(3) C(13A)-C(13)*C(12) 63(3) C(lL)-Cl(2U 1.77(2) M(2)-C(13)-C<12) 108(2) C(1l)-ClCU) 1.73(2) C(14 ) -C(13)-C(12) 104(2) C(1L)-Cl(3l) 1-71(2) C(13)-C(13A)-M(2) 69(2) 0(13)-C(13a) 1.12(4) C(13)-C(13A)-C(12) N(2)*C(13A)-C(12) 71(2) 111(2) C(10)-Pd(1)-N(1) 83.2(5) C(13)-C(13A)-C(14) 68(2) C(10)-Pd(1) -N(2) 91.3(5) N(2)-C(13A)-C(14) 109(2) N( 1)-Pdf 1)-N{2) 174.5(4) C(12)*C(13A)-C(14) 104(2) C(10)-Pd(1)-Cl<1) 178.3(3) W( 1) -Pd( 1 )-CU 1) 95.2(3) H(2)-Pd(1)-Cl( 1) 90.3(3) Symmetry transformations used to general C(1)-M(1)-C(S) 121.4(11) C(1)-N(1)-Pd(1) 126.6(10) C(5) -W(1J'PdC1) 111.6(8) C(13A)-H(Z)-C(13> 47(2) C(13A)-H(2)-Pd(1) 127.2(11) C( 13)-W(2)-Pd(1) 121.5(11) H(1)-C(1)-C<2> 122(2) C(3)-C(2)*C(1) 118(2) C(4)-C(3)-C(2) 120.2(14) C(3)C<4)-C(5) 120(2) C(3)-C(4)-C(6) 124(2) C(5)-C(4)-C(6) 117(2) K(1)-C(5)-C(4) 119(2) N(1)-C(5)-C(9) 116.3(10) C(4)'C15)-C(9) 125.2(14) C(7)-C(6)-C(4) 119(2) 113 Table 5. A n iso tro p ic displacem ent param eters (AA 2 x 10A 3) fo r 1. The a n is o tro p ic displacem ent f a c to r exponent takes the form: -2 p i A 2 [ hA 2 a* A 2 U11 + . . . + 2 h k a* b* U12 ] U11 U22 U33 U23 U13 U12 Pd(1) 47(1) 45(1) 46(1) -2(1) -16(1) -12(1) Cl(1) 50(2) 83(2) 64(2) -14(1) -16(1) -11(1) NCI) 78(7) 50(5) 50(5) -6(4) -15(5) -11(5) N C 2 > 101(8) 44(5) 58(6) 1(4) -20(5) -15(5) ecu 103(10) 64(7) 55(7) -2 (6 ) -6(7) -29(7) C(2) 136(15) 73(9) 64(9) 0(7) 8(9) -30(10) C(3) 182(21) 82(10) 43(8) -7(7) -33(11) 13(12) C(4) 132(14) 72(8) 50(8) -17(7) -40(9) 28(9) CCS) 101(10) 50(6) 61(7) -17(5) -48(8) 20(6) C(6) 152(20) 169(20) 76(12) -43(13) -68(13) 68(17) C(7) 127(18) 192(24) 151(20) -98(20) -107(17) 67(18) CC8) 78(10) 132(14) 128(14) -45(11) -66(10) 14(9) C(9) 65(8) 73(8) 73(8) -17(6) -30(7) 0(6) CC10) 58(7) 67(7) 69(7) -1(6) -24(6) -18(6) CC11) 49(7) 131(13) 74(8) -25(8) -21(6) 7(7) CC12) 252(26) 69(9) 66(9) -13(7) -60(12) -28(12) CC14) 177(19) 47(7) 58(8) 5(6) -40(11) -16(9) C C15) 148(18) 78(10) 93(12) -22(9) -16(12) -31(11) C C 16) 128(16) 77(10) 114(14) -32(10) -51(12) 12(10) CC17) 170(22) 74(10) 67(10) -7(7) -25(12) -9(12) C C 18) 120(16) 115(15) 123(17) -28(13) 7(13) -52(13) C( 19) 158(19) 85(11) 101(14) 1(10) -71(14) -1(11) C C 1L) 25(9) 58(11) 35(9) 2(8) -2(7) 10(8) CK1L) 82(5) 234(11) 55(4) -55(5) -32(4) 18(6) CK2L) 59(4) 88(4) 92(4) -37(4) -5(3) -16(3) CIC3L) 139(8) 122(7) 91(5) 22(5) -26(5) -74(6) C C 13) 135(30) 43(13) 41(13) -2(10) 0(15) 11(15) CC13A) 53(14) 76(16) 59(14) -5(12) -24(12) -18(13)
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