New Class of Constrained-Geometry Bicyclic Tetradentate Ligands for Coordination to Transition Metals: Synthesis of Key Intermediates, Coordination Studies and Ring-Opening Metathesis Polymerization
Delwar Hossain
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GRADUATE PROGRAM IN CHEMISTRY YORK UNIVERSITY TORONTO, ONTARIO
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¦+¦ Canada New Class of Constrained-Geometry Bicyclic Tetradentate Ligands for Coordination to Transition Metals: Synthesis of Key Intermediates, Coordination Studies and Ring-Opening Metathesis Polymerization
By Delwar Hossain
A thesis submitted to the Faculty of Graduate Studies of York University in partial fulfillment of the requirements for the degree of
MASTER OF SCIENCE
© 2010
Permission has been granted to: a) YORK UNIVERSITY LIBRARIES to lend or sell copies of this dissertation in paper, microform or electronic formats, and b) LIBRARY AND ARCHIVES CANADA to reproduce, lend, distribute, or sell copies of this dissertation anywhere in the world in microform, paper or electronic formats and to authorize or procure the reproduction, loan, distribution or sale of copies of this dissertation anywhere in the world in micro- form, paper or electronic formats. The author reserves other publication rights, and neither the dissertation nor extensive extracts from it may be printed or otherwise reproduced without the author's written permission. Abstract
Our group is interested in studying rigid ligands that constrain pentavalent complexes into the square-pyramidal geometry and to study these complexes as candidates for the activation of small molecules, such as molecular nitrogen. Towards that end, we are currently preparing a number of tetradentate ligands with a C2, a C4, a C5 and a Co backbone. As a long-term goal of the current research, the e«Jo-tetrasubstituted norbornane derivative (C6 backbone) will be prepared. Density functional theory calculations on the corresponding tantalum (IV) and molybdenum (IV) complexes show potential for the activation of dinitrogen, as evidenced by lowering IR frequencies and by lengthening of the N-N bond compared to those of free dinitrogen. In this thesis, we describe (a) the synthetic strategies and characterization of two new substituted ligand systems, cw-e«¿/o-bicyclo[2.2.1]hept-5-ene-2,3-diamine (la, lb) and two new cyclic ureas, 3,5-diazatricyclo[5.2.1.0]dec-8-en-4-one (12, 19); (b) the coordination of la and corresponding lithiated derivative 14a to early transition metals; and (c) the ring-opening metathesis polymerization (ROMP) of 12 and 19.
IV To
Rionna,
Tamanna
&
My parents, Monzusha and Rais U. Lasker.
? Acknowledgements
I would like to thank my supervisor, Prof. Gino G. Lavoie for providing me with this great opportunity. The completion of this work would not be possible without his help, guidance, support and encouragement throughout the research process. I feel very blessed and privileged to be part of his research group. Prof. Lavoie taught me the value of hard work and persistence. I would also like to thank the members of my Master's examining committee, Prof. A. B. P. Lever, Prof. Dennis V. Stynes, Prof. Pierre G. Potvin and Prof. Regina S. K. Lee for taking time out of their busy schedules to make the defense of my Master's thesis possible. I must thank Dr. Sarim Dastgir for his help throughout my graduate studies at York. I thank my labmates, Anna Badaj, Barbara Skrela, Jameel Al-Thagfi and Tim Larocque for their support and friendships. I would like to thank Chris Dares and Dr. S. I. Gorelsky for their help with DFT calculations. I am indebted to Tamanna Rob who did an extraordinary job by performing high resolution mass spectrometric analysis. I acknowledge Prof. Douglas Stephan at University of Toronto for allowing me using GPC in his lab and I am grateful to Dr. Sharonna Greenberg for helping me running the polymer samples and obtaining MALDI data. I would like to thank Prof. Edward Lee- Ruff for sharing with me some of his organic knowledge that was valuable for my research. Thank you Dr. Howard Hunter for your help regarding NMR issues. I like to thank Mohammed Khanfar, Jason Chu, and Dr. Tareque Abedin for their support during my graduate studies at York. I like to thank Prof. Michael Organ and his research group
vi for sharing some chemicals during my research. I owe special thanks to Prof. Derek J. Wilson, Dr. Robert R. Hudgins, and Prof. Dasantila Golemi-Kotra for their support to me and my family.
Finally, I express my deep gratitude to my mother-in-law Prof. Nilufar Nahar for her love, support and encouragement everyday in every way. Thank you!
vii Table of Contents
LIST OF FIGURES X
LIST OF SCHEMES ???
LIST OF TABLES XV
ABBREVIATIONS, ACRONYMS AND SYMBOLS USED IN TEXT XVI
CHAPTER 1 - INTRODUCTION 1 1. 1 Nitrogen Fixation 1 1. 2 Introduction to Current Research 7 1. 2. 1 Scope of Current Research 8
CHAPTER 2 - EXPERIMENTAL 13 2. 1 General Considerations 13 2. 1. 1 Starting materials, Reagents and Solvents 15 2.2 Syntheses of the new compounds 15 2.3 Ring-opening Metathesis Polymerization (ROMP) 28 2.3.1 General Considerations 28
CHAPTER 3 - RESULTS AND DISCUSSION 32 3. 1 Attempted Synthesis of Target Tetradentate Ligand 1 via all-exo-Tetraol 2 32 3. 2 Attempted Synthesis of Target Ligand 1 via Cobalt Dinitrosoalkane Complex 3 34 3. 3 Attempted Synthesis of la via Curtius Rearrangement 35 3. 4 Synthesis of la via Cyclic Urea Formation 41 3. 5 Nucleophilic Substitution Reaction 62
viii 3.6 Coordination Chemistry 3. 7 Ring-Opening Metathesis Polymerization ofNorbornene Derivatives
3. 8 Functionalization of Second Olefinic Bond of Norbornene Scaffold
3. 9 Computational Studies 3.10 Summary and Future Work
IX List of Figures
Figure 1. s-Donation from the N2 to the metal and p-back-donation from metal orbitals to the 7t*-orbitals of the N2 molecule. 3 Figure 2. Structure of Fe-Mo cofactor. 4 Figure 3. [HIPTN3N] Mo (N2) complex. 5 Figure 4. Design concepts for rigid tetraamine ligands of varying backbone sizes. 7 Figure 5. Diamide complexes prepared by McConville et al. 1 0 Figure 6. Design concept for the endo-diamide complexes. 1 1 Figure 7. A generalized example of ROMP reaction. 1 1 Figure 8. 1H NMR (300 MHz) spectrum of 5 in CDCl3. 38 Figure 9. 1H NMR (300 MHz) spectrum of 12 in CDCl3. 46 Figure 10. 1H NMR (300 MHz) of 13 in C6D6. 48 Figure 12. 1H NMR (400 MHz) spectrum of 14a in C6D6. 52 Figure 13. 1H NMR (300 MHz) spectrum of la in C6D6. 53 Figure 14. 1H NMR (300 MHz) spectrum of 15 in CDCl3. 56 Figure 15. 1H NMR (300 MHz) spectrum of 17 in CDCl3. 58 Figure 16. 1H NMR (400 MHz) spectrum of 18 in C6D6. 63 Figure 17. JMOD (400 MHz) spectrum of 18 in C6D6. 64 Figure 18. 19F NMR (300 MHz) spectrum of 18. 65 Figure 19.1H NMR (400 MHz) spectrum of 19 in C6D6. 67 Figure 20. 13C NMR (400 MHz) spectrum of 19 in C6D6. 68
? Figure 21. 19F NMR (400 MHz) spectrum of 19 in C6D6. 69 Figure 22. 1H NMR (400 MHz) spectrum of lb in C6D6. 73 Figure 23. 13C NMR (400 MHz) spectrum of lb in C6D6. 74 Figure 24. 19F NMR (400 MHz) spectrum of lb in C6D6. 75 Figure 25. 1H NMR (300 MHz) spectrum of 14b in C6D6. 77 Figure 26. 1H NMR (400 MHz) spectrum of Ic (top) and 14b (bottom). 80 Figure 27. 1H NMR (400 MHz) spectrum of 12; polymer, 12a20 (20-mer, top) and monomer (bottom) in CD2CI2 83 Figure 28. 1H NMR (400 MHz) spectrum of 12; polymer, 12a40 (40-mer, top) and monomer (bottom) in CD2CI2 84 Figure 29. MALDI-TOF mass spectrum of polymer 12a2o. 86 Figure 30. MALDI-TOF mass spectrum of 12a40. 87 Figure 31. 1H NMR (400 MHz) of 19 ; monomer (bottom) and polymer 19a (top) in (CD3)2CO. 89 Figure 32. 1H NMR (300 MHz) spectrum of 11 in CDCl3. 92 Figure 33. 2D NOESY (400 MHz) experiment of 11 in CDCl3. 93 Figure 34. Geometry optimized structure of a) [Ta](N2) 20 and b) [Mo](N2) 21 complexes. 95 Figure 35. MO Compositions for [Ta](N2) 20 for both a (top) and ß (bottom) spin orbitals. Breaks are shown between occupied and unoccupied orbitals. NBD represents norbornane backbone. 96
Xl Figure 36. MO Compositions for [Mo](N2) 21. Molecular orbital 55 is the HOMO, while 56 is the LUMO. 97 Figure 37. Predicted electronic spectra for [Ta](N2), 20 and [Mo](N2) 21. The ß subscript denotes an orbital with a beta spin. 98 Figure 38. Change in electron density distribution for 21 for a) peak 2, and b) peak 3, in the calculated absorption profile. Red indicates excess charge in the ground state, while green indicates excess charge in the excited state. 99 Figure 39. Change in electron density distribution for 20 for a) peak 1, and b) peak 2 and c) peak 3, in the calculated absorption profile. Red indicates excess charge in the ground state, while green indicates excess charge in the excited state. 100 Figure 40. [Ta](N2) complex, 20'. A new model system with nitrogen replaced by oxygen. 102 Figure 41. [Mo](N2) complex, 21'. A new model system with nitrogen replaced by oxygen. 103
XIl List of Schemes
Scheme 1. Proposed intermediates in the reduction of dinitrogen by [HIPTN3N] Mo. 6
Scheme 2. Retro synthetic analysis of tetradentate ligand 1. 8 Scheme 3. Overall synthetic approach to 1 at a glance. 9
Scheme 4. Synthesis of 2. 32 Scheme 5. Attempted synthesis of target ligand 1. 33
Scheme 6. Attempted synthesis of 1 via cobalt complex. 35
Scheme 7. Synthesis of dicarbonyl azide 5. 36 Scheme 8. Attempted synthesis of la via Curtius rearrangement. 39 Scheme 9. Attempted synthesis of la via sequential Curtius rearrangement. 40 Scheme 10. Synthesis of cyclic urea 10. 41
Scheme 11. Attempted synthesis of 12b by Buchwald-Hartwig C-N coupling reaction. 43
Scheme 12. Attempted synthesis of 12b by Cu-catalyzed aryl-amidation reaction. 44 Scheme 13. Synthesis of 12 by copper catalyzed aryl-amidation reaction. 45
Scheme 14. Attempted ring-opening of 12. 47 Scheme 15. Synthesis of 13 and 14. 47 Scheme 16. Proposed mechanism for the formation of 13 and 14. 50
Scheme 17. Synthesis of la via 14a using MeLi. 51 Scheme 18. Proposed mechanism for the formation of la via 14a using MeLi. 54
Scheme 19. Synthesis of 15 through LAH reduction. 55
xiii Scheine 20. Synthesis of 17. 57 Scheme 21. Synthesis of la using ethylenediamine. 59 Scheme 22. Proposed mechanism to la using ethylenediamine. Norbornene backbone is
not shown for the clarity. 60 Scheme 23. Synthesis of 16. 61 Scheme 24. Buchwald-Hartwig C-N coupling reaction using 16 to prepare la. 61 Scheme 25. Nucleophilic substitution reaction of 16. 62
Scheme 26 . Proposed mechanism for the formation of 19. Norbornene backbone is not
shown for the clarity. 70 Scheme 27. Attempted coordination of 14a to titanium. 76
Scheme 28. Attempted coordination of la to zirconium. 78 Scheme 29. Attempted coordination of 14a to zirconium. 79
Scheme 31. ROMP ofp-tolyl substituted urea 12. 83
Scheme 32. ROMP of 19. 88
Scheme 33. Epoxidation of 9. 91
Scheme 34. Proposed pathway to prepare target ligand 1. 106
XlV List of Tables
Table 1 : GPC and MALDI-TOF MS data of 12a20 and 12a40. 85
XlIl Abbreviations, Acronyms and Symbols used in text
Ac acetyl
amu atomic mass unit
Ar aryl, aromatic
b broad
BINAP 2,2'-bis (diphenylphosphino)- 1 , 1 '-binaphthyl Bu butyl
caled. calculated
COSY correlation spectroscopy Cp cyclopentadienyl Cp* pentamethylcyclopentadienyl
d doublet
Da Dalton
d chemical shift
DMF dimethylformamide
DMSO dimethylsulfoxide eq equation equiv equivalent(s) ESI electro spray ionization
XVl GPC gel permeation chromatography
HOMO highest occupied molecular orbital
HPLC high-pressure (performance) liquid chromatography
HRMS high resolution mass spectrometry
i iso (as in /-Bu)
IR infrared
J coupling constant in Hertz
JMOD J-moduled spin echo
L litre
LAH lithium aluminum hydride
? wavelength
LUMO lowest unoccupied molecular orbital
m meter or multiplet
M molar (mol/L)
MALDI matrix-assisted laser desorption ionization
Mn number average molecular weight
Mw weight average molecular weight
Me methyl
min minute
mol mole
mmol millimole
XVIl MS mass spectrometer µ micro (IO"6) ? normal (as in n-hexane)
NBD norbornane
NMO TV-methyl morpholine iV-oxide NMR nuclear magnetic resonance
obsd observed
% percent (part per hundred) Ph phenyl ppm part per million p-tol para-to\y\ py pyridine
q quartet
ROMP ring-opening metathesis polymerization
s singlet t triplet tert tertiary (as in tert-Bu)
THF tetrahydrofuran TLC thin-layer chromatography TOF time-of-flight
ToI toluene xviii UV-Vis ultraviolet-visible
XlX Chapter 1 - Introduction
/. 1 Nitrogen Fixation Molecular nitrogen is the major component of the Earth's atmosphere, making it easily accessible and therefore appealing as a raw material for industrial processes.1,2 However, molecular nitrogen is extremely inert. Chemists thus have sought ways to
activate it under mild conditions. One of the reasons dinitrogen is difficult to activate is because of the high strength of its triple bond. It also lacks a dipole moment, is a poor s-
donor and a weak p-acceptor. The orbital energies of dinitrogen also help to explain its
inertness. The energy gap between the highest occupied molecular orbital and lowest unoccupied molecular orbital is 22.9 eV.4 Such a large energy gap makes it difficult for the molecule to undergo electron transfers or Lewis acid-base reactions. Despite these hurdles, some systems are able to fix nitrogen. Non-biological natural nitrogen fixation is an oxidative process that takes place under very hot conditions as it found in wildfire, lightning or volcano eruptions. The main products of such processes are nitrogen oxide (NO) and nitrogen dioxide (NO2). These oxides dissolve in rain, forming nitrite (??2~) and nitrate (NO3), which are carried
to earth. These non-biological natural processes accounts for about 10% of the total N2 fixed globally.5 In 1909, the German chemist Fritz Haber achieved the first chemical nitrogen fixation
at very high temperature and pressure to produce NH3. In 1910, Carl Bosch successfully 1 commercialized the process, which is collectively known as the Haber-Bosch process. The process involves reaction of nitrogen (N2) and hydrogen (H2) at elevated temperature and pressure over an iron catalyst doped with promoters, such as aluminium oxide (Al2O3) and potassium oxide (K2O) to produce ammonia (eql). The Haber-Bosch process is extremely energy extensive, using 1-2 % of the world's total energy supply.6
NN2(g) + 3H2(g)3H [Ru] or [Fe] ? 2NH,iri (1) 300 atm l8j 5000C
This fertilizer production is now the largest source of artificial fixed nitrogen on the Earth. In terms of industrial development, the Haber-Bosch process is the most successful and preferred method to synthesize ammonia. Considering that ammonia fertilizers sustain much of the world population, scientists have been working to find new, less energy-intense industrial methods to activate N2 for the synthesis of ammonia and other derivatives. After the discovery of the first dinitrogen complex [Ru(NH3)5(N2)] in 1965, research in chemical nitrogen fixation focused on the study of well-defined transition metal complexes resulting in a number of dinitrogen complexes.7'8 However, progress has been slow and the catalytic reduction of dinitrogen to ammonia in solution with protons and electrons has proven to be extraordinarily challenging.9'10'11 The activation of dinitrogen by transition metals is dependent on several factors: the metal centre, the oxidation state of the metal, and the ligand environment.12 This activation can be categorized as either weakly activated or strongly activated. Such distinction is determined by the ability of the metal to reduce the nitrogen-nitrogen bond by donating electron density in the anti-bonding orbitals of the dinitrogen molecule (Figure 1). The degree of back-bonding is measured by the weakening of the nitrogen- nitrogen bond. An increase in back-donation from the metal leads to a longer and weaker N-N bond. This can be quantified by X-ray crystallography or IR spectroscopy.13'14
Figure 1. s-Donation from the N2 to the metal and p-back-donation from metal orbitals to the p*- orbitals of the N2 molecule.
Nature has successfully managed to activate nitrogen and convert it to ammonia by a bacterial enzyme called nitrogenase which consists of two metalloproteins: the Fe- protein and the Mo-Fe-protein (Figure 2).15 This is known as biological nitrogen fixation (eq 2). This process accounts for about 65% of the total annual yield of fixed nitrogen.
, Nitrogenase N2 + 8H+ + 8e" + 16 ATP *? 2NH3 + H2 + 16 ADP + 16 PO43" (2) Nitrogenase uses electrons and protons to reduce dinitrogen to ammonia with the aid of adenosine triphosphate (ATP) molecules. The first crystal structure of nitrogenase was reported in 1992.16'17 The only structurally characterized state is the resting state (Figure 2). This structure does not provide much insight in the mechanism of dinitrogen reduction. It does however provide some clues on the nature of the binding site and the possible binding mode of dinitrogen. Einsle and co-workers18 speculated that the interstitial six-coordinate atom (Figure 2) is nitrogen. This postulate is supported by previous observations19 and theoretical studies.
S-Fe^ ^Fe~7S\ ° \ Cys-S-Fe—¦SFei^OhuFe''s^-Mor,vv0' ^° S Fe^S^Fe—^S N H|S
Figure 2. Structure of Fe-Mo cofactor.
The ultimate goal of the scientists working in chemical nitrogen fixation is to synthesize ammonia at ambient conditions by mimicking the Fe-Mo cofactor of
9 1 99 nitrogenase catalysis in biological nitrogen fixation ' that has overcome: (i) the very
low reactivity of dinitrogen; (ii) the relatively weak affinity of the Fe-Mo cofactor for N2 as evidenced by theoretical studies; (iii) the rather recent availability of the first crystal
structure of the Fe-Mo cofactor and its very recent higher-resolution version; and (iv) the lack of knowledge of the mechanism of the Fe-Mo cofactor.24'25 In early 1970's, ammonia was prepared by the stoichiometric protonation of cis- [W(N2)2(PMe2Ph)4] using mineral acids such as HCl, H3PO4 and H2SO4 in methanol.26 In the 1990's, Schrock and co-workers studied the stoichiometric synthesis of NH3 at
ambient conditions using Cp*M(Me)3 systems, where M = Mo or W. Nitrogen complexes
were isolated as dimers, with nitrogen bridging to two metal centres. Ammonia was
4 generated in up to 90% yield by reduction and subsequent protonation of {Cp*M(Me)3}2(R-N2).27'28'29 Catalytic reduction of dinitrogen in methanol to a 10:1 mixture of hydrazine and ammonia has been reported by Shilov30'31 using an ill-defined heterogeneous Mo(III) catalyst. The catalyst further requires Mg(OH)2, some strong reducing agents such as Ti(OH)3, mercury electrode, sodium amalgam and additives such as phosphines and phosphatidylcholine. The reduction is thought to proceed through the electron transfer from the sodium amalgam to a nitrogen-bound complex. Shilov has favoured the idea that at least two metal centres (presumably Mo) are required to bind and reduce dinitrogen. However, convincing data in support of that proposal have not been published. The first and only homogeneous catalytic system converting nitrogen to ammonia at room temperature and one atmosphere was reported in 2003 by R. R. Schrock. The catalyst is based on a highly substituted trisamidoamine molybdenum complex (Figure 3).
'Pr
Pr W 1Pr HIPTV 1J HIPT^'M' N ?
Figure 3. [HIPTN3N] Mo (N2) complex (HIPT = 3,5-bis(2,4,6-triisopropylphenyl)phenyl or hexaisopropylterphenyl).
5 Schrock isolated eight complexes thought to be intermediates in the catalytic reduction of dinitrogen (Scheme I).33-34-35
+N2 Mo(III) Mo Mo-N? a Mo(III) j -NH3 Mo(III) m Mo-(NH3) Mo-N=N" b Mo(IV) •t 1 H+ Mo(IV) 1 {Mo-fNH3)}+ Mo-N=N-H c Mo(VI) H t j H+ Mo(IV) k Mo-NH2 {Mo=N-NH2}+ d Mo(V) •t Ie Mo(V) j {Mo-NH2}+ Mo=N-NH2 e Mo(V) H+| 1 H+ Mo(V) Mo=NH {Mo=N-NH3}+ f Mo(IV) e J H+ j e-NH3 Mo(VI) {Mo=NH}+ -* — MoSN g Mo(VI)
Scheme 1. Proposed intermediates in the reduction of dinitrogen by [HIPTN3N] Mo.
These include paramagnetic Mo(N2) (a), diamagnetic [Mo(N2)]" (b), diamagnetic Mo-N=N-H (c), diamagnetic [Mo=N-NH2]+ (d), diamagnetic ???? (g), diamagnetic [Mo=NH]+ (h), paramagnetic [Mo(NH3)]+ (1), and paramagnetic Mo(NH3) (m). With the exception of g, all are extremely sensitive to oxygen. The study of these isolated intermediates shed light on the catalytic cycle. All intermediates successfully reduced dinitrogen catalytically to ammonia.36 Furthermore, nitrogen binds in an end-on fashion to Mo, with the bulky HIPT (hexaisopropylterphenyl) substituents preventing formation of the stable and nonreactive Mo-N=N-Mo dimer.37 Protonation is achieved with a pyridinium cation, which is accompanied by a noncoordinating tetrafluoroborate counteranion. The reduction is achieved through chromium metallocene CrCp2*. The 6 lifetime of the catalyst is however short with only a few turnovers. Nonetheless, this well-defined Mo complex represents a milestone in dinitrogen reduction, since this catalytic process can generate ammonia under mild conditions.39'40
1. 2 Introduction to Current Research
The catalyst developed by Schrock (Figure 3) adopts a trigonal bipyramidal geometry with three frontier orbitals that are approximately dz2, dxz and dyz in character.41 In spite of having similar frontier orbitals, the coordination chemistry of square- pyramidal complexes has not been explored widely. Our group is therefore interested in preparing tetradentate ligands that constrain metal centres into this square pyramidal geometry. A number of ligand scaffolds based on ethane (C2), cyclobutane (C4), cyclopentane (C5), and norbornane (Co) have been evaluated (Figure 4).
NH HN ? \ / ? X«*w\ / -X R1-^111 ?" HN
C2 C4 C5 C6
X = OH (a), NHAr (b) R=H, CH3, Ph Ri=Ar
Figure 4. Design concepts for rigid tetraamine ligands of varying backbone sizes.
These complexes are excellent candidates (as will be demonstrated later through
DFT calculations) for the activation of small molecules, such as molecular nitrogen. Aryl groups on the nitrogen donors will prevent bimolecular decomposition and allow
7 tailoring of the sterics and electronics of the complex. This thesis describes the work done towards preparing the e«i/o-tetrasubstituted norbornane derivative (Ce backbone).
1. 2. 1 Scope ofCurrent Research
The long-term goal of the present research is to synthesize tetrasubstituted norbornane derivative 1 (Scheme 2 and 3) and to coordinate the corresponding deprotonated ligand to transition metals for their study in small molecule activation, such as dinitrogen.
N-Ar A>H HNÜ^Ar HN^ArHN-
Scheme 2. Retro synthetic analysis of tetradentate ligand 1.
As a short-term goal of the current research, the synthetic strategies and characterization of two new substituted ligand systems, ci,s-e«i/o-bicyclo[2.2.1]hept-5- ene-2,3-diamine (la, lb) and two new cyclic ureas, 3,5-diazatricyclo[5.2.1.0]dec-8-en-4- one (12, 19) will be described. Attempted coordination of la and its lithiated derivative 14a to early transition metals will also be discussed. Furthermore, the ring-opening metathesis polymerization (ROMP) of all new norbornene derivatives will also be studied. 8 The synthetic pathways evaluated for the synthesis of 1 are presented in Scheme
3.
I SOCl2 ) Curtius Rearrangement COOH II) NaN3JHFZH2O ?£??3 H) Ar-X, C-N coupling 3 COOH 5 CON3 Ì K3PO4 ,Cui i) MeLi,THF,-78 °C-refkjx _ ¡ N-H 4-lodotoluene T H Ar ¡¡J Recrystallized in wet 10
?,??^,?e??
N-Ar 15 N^ C6F6, MeCN, K2CO3 Ar 9O0C, 36h HN-C6F5 18 NH2
MeOH C6F6, DMSO, K2CO3 NH2 .HCl IN-C6F5 aq.KOH NH2 .HCl 10O0C, 48h N~^ 16 19 C6r5G F °
C6F6, DMSO, K3PO4 10O0C, 40h HN-C6F5 1b NH C6F5
Scheme 3. Overall synthetic approach to 1 at a glance.
1. 4. 1. 1 Diamine Ligand la and Corresponding Transition Metal Complexes Vicinal diamines are of medicinal importance in drug preparation and can serve as intermediates in the synthesis of polyamides, heteromacrocycles, and bifunctional
chelating agents.42,43,44 More importantly, diamine ligands and their corresponding transition metal complexes have proven to be good catalysts for polymerization. 45,46 9 The chemistry of Group 4 olefin polymerization catalyst precursors such as CP2MX2 and CpMX3 derivatives has been greatly studied. However a more recent interest has grown to find alternative ligands to replace the Cp ligand in order to alter the catalytic activity, comonomer incorporation, and stereoregularity of the polymerization process.47 For instance, one or two of the Cp ligands can be replaced by an amine group to form Cp(R.2N)MX2 or (NR_2)2MX2, respectively; wherein the amine donor can be bound to the other ancillary ligand to form a chelate.48'49 McConville reported the synthesis, characterization and fluxional behavior of a number of mono and bis(alkyl) derivatives of zirconium and titanium bearing diamine ligands (Figure 5a).50'51 The sterics of the diamine ligand can be altered readily by varying the size of the substituents.
CNR Cl (b)
M=Ti, Zr R=2,6-iPr2-C6H3, 2,6-Et2-C6H3, 2,6-Me2-C6H3 Figure 5. Diamide complexes prepared by McConville et al. 47'51
McConville also reported the titanium diamide complexes (Figure 5b) as active catalyst precursors for the polymerization of 1-hexene.52 These diamide catalyst systems generate high molecular weight polymers with narrow molecular weight distributions. This precedent work in the literature involving diamine ligands and its corresponding early transition metal complexes has directed the present research to 10 investigate the possibility of preparing bicyclic endo-diamide complexes Ic and Ie (Figure 6). Attempted synthesis of Ic and Ie is discussed in the section 3.6.
Ar=
M = Ti(Ic) M = Zr(Ie)
Figure 6. Design concept for the endo-diamide complexes.
/. 4. 1. 2 Ring-Opening Metathesis Polymerization (ROMP) Ring-opening metathesis polymerization (ROMP) has attracted much attention due to the remarkable development of well-defined transition metal catalysts, including molybdenum (Mo) and ruthenium (Ru) complexes.53 ROMP is a chain growth- polymerization process where cyclic olefins are converted into linear polymers with narrow molecular weight distribution (Figure 7).54>55·56
ROMP ?
Figure 7. A generalized example of ROMP reaction.
The mechanism of the polymerization involves olefin metathesis, a unique metal- mediated carbon-carbon double bond exchange process.57'58 As a result, any unsaturation associated with the monomer is preserved during ROMP in contrast to classic olefin
11 addition polymerizations. As with other ring-opening polymerizations, the reaction is driven by the release of ring strain at the expense of entropy loss.59'60 The most common monomers used in ROMP are cyclic olefins that possess a considerable degree of strain (45 kcal/mol) such as cyclobutene, cyclopentene, cw-cyclooctene, and norbornene.61 Norbornene derivatives containing various functional groups undergo ring- opening metathesis polymerization to give functional polymers such as hydrogels,62 biologically active polymers,63 and liquid crystalline polymers.64'65'66 The catalysts used provide good control over tacticity, backbone configuration, molecular weight, and molecular weight distribution.67'68 Considering that some of the intermediates prepared in our work are norbornene derivatives (e.g. 12 and 19), we therefore decided to evaluate their polymerization using the first-generation Grubbs catalyst. These are a very good addition to the library of existing bicyclic monomers69 with different sterics and electronics and therefore, different properties. Detailed discussion on ROMP of norbornene derivatives are depicted in the section 3.7.
12 Chapter 2 - Experimental
2. 1 General Considerations All manipulations involving air-sensitive reagents were carried out in oven-dried glassware and performed under nitrogen using standard Schlenk line techniques or in an inert atmosphere glove box. Chromatographic separations were performed using silica gel 60 (230 - 400 mesh) supplied by Merck. Analytical thin layer chromatography (TLC) was carried out on glass-coated with silica gel 60 F254, using short wavelength (254 nm) ultraviolet light, iodine, basic potassium permanganate, /»-anisaldehyde or ninhydrin
stains to visualize components. Melting points of the solid samples were recorded on a Fisher-Johns melting point apparatus and are uncorrected. Air-sensitive NMR samples were prepared under nitrogen in 5 mm Wilmad 507-PP J. Young valve NMR tubes. Otherwise standard NMR tubes were used. 1H, 13C and 19F spectra were acquired on Bruker AV 300 or Bruker AV 400 spectrometers at room temperature. 1H and 13C assignments were confirmed by JMOD and other two-dimensional 1H-1H, 19F-19F and 13C-1H correlation NMR experiments. 1H spectra were referenced internally to residual protio-solvent and C resonances were referenced internally to the deuterated solvent resonances and are reported relative to tetramethylsilane d = 0 ppm. J-coupling constants are reported in Hertz (Hz). F spectra were referenced externally to trifluorotoluene. The multiplicity of signals is reported as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br) or a combination
13 of any of these. The proton or carbon attributed to the resonance is sometime italicized for clarity. Infrared samples were prepared as Nujol mulls or KBr pellets and the spectra recorded on a Thermo Genesis II FTIR spectrometer. Data are quoted in wavenumbers (cm1) with following abbreviations: strong (s), medium (m) and broad (br). High- resolution mass spectra were recorded on QSTAR® Elite, a hybrid quadrupole time-of- flight mass spectrometer (QqTOF) from Sciex, MDS Analytical Technologies. Computational studies using Gaussian 09 were carried out employing density functional theory (DFT) using the hybrid exchange-correlation functional B3LYP. The LANL2DZ basis set was used for the molybdenum and tantalum complexes shown in Figure 34, while the DGDZVP basis set was used for the structures shown in Figures 40 and 41.71'72 A tight convergence (10~8 au) was used for all DFT calculations. A spin- restricted wavefunction was used for the closed-shell species, while a spin-unrestricted wavefunction was used for the open-shell species. The stability of all wavefunctions was determined using the "stable = opt" keyword. Vibrational frequency calculations were performed on all converged structures to confirm that an energy minimum had been achieved. Natural population analyses were performed and used by AOMIX (Program revision 6.46) to determine the molecular orbital compositions. Time-dependent DFT (TD-DFT) methods were utilized to determine the predicted electronic transitions. The predicted electronic transition assignments and absorption profiles were calculated using the SWarlock program (Program revision 3.71).
14 2. 1. 1 Starting materials, Reagents and Solvents
Pentane, C6D6 and THF were dried by refluxing over Na and benzophenone. They were distilled, degassed and stored under nitrogen over a potassium mirror or stored in the glove box over activated 4 Â molecular sieves. DMF was dried over activated 4 Á molecular sieves and degassed prior to use. c«-eni/o-Bicyclo[2.2.1]hept-5-ene-2,3- dicarboxylic anhydride, hexafluorobenzene and hydantoin were purchased from TCI America and were used as received. l,3-Dihydroimidazol-2-one 7, e«Jo-3,5-diacetyl-3,5- diazatricyclo[5.2.1.0]dec-8-en-4-one 9, and l,3-diacetyl-l,3-dihydroimidazol-2-one 8, were synthesized according to literature procedures.73
2.2 Syntheses ofNew Compounds cis-endo- N, iV'-Di(p-tolyl)bicyclo[2.2.1]hept-5-ene-2,3-diamine (la) Lithiated salt 14a (300 mg, 0.986 mmol), described on p. 23 was recrystallized in » non-anhydrous pentane at room temperature and the pentane- --/-^n. G |T soluble part was concentrated in vacuo to get la as a brown- ¿ x|_l yellow gummy solid (275 mg, 0.90 mmol, 95%). IR (vmax, KBr): 3380 (br), 2956 (m), 2915 (s), 2858 0 (m), 1616 (s), 1515 (s) cm-1; 1H NMR (300 MHz, C6D6): d 6.94 (d, J = 8.3 Hz, 2H, aromatic CHCH), 6.42 (d, J = 8.3 Hz, 2H, aromatic CiZCCH3), 5.96 (s, 2H, olefinic), 3.65 (s, 2H, CHN), 3.58 (br s, 2H, Nfl), 2.88 (s, 2H, bridgehead), 2.16 (s, 6H, CH3), 1.34 (d, J = 9.1 Hz, IH, apical), 1.10 (d, J= 9.1 Hz, IH, apical) ppm;
15 13CNMR (C6D6): d 146.1 (aromatic CN), 135.7 (olefinic), 130.0 (aromatic CCN), 126.2 (aromatic CCH3), 113.7 (aromatic CHCCH3), 57.7 (aliphatic CN), 46.9 (bridgehead), 45.0 (apical), 20.3 (CH3) ppm; HRMS-ESI (M+H+)m/z: caled for CnH24N2, 305.2018; obsd, 305.2019.
Compound la was also synthesized by the following alternative pathway: Compound 15 (90 mg, 0.28 mmol), described on p. 24, and jP-toluenesulfonic acid (150 mg, 0.871 mmol) were suspended in ethylenediamine (3 mL, 2.7 g, 45 mmol)
and heated in a stirred sealed tube at 1 50 0C for 48 h. The colour of the reaction mixture
turned dark amber. After cooling to room temperature, the reaction mixture was diluted with H2O (10 mL), extracted with dichloromethane (4^5 mL), combined organic phases were dried over anhydrous MgSO4 and concentrated in vacuo to give a dark brown oil.
The crude product was purified by column chromatography on silica gel (n- hexane/EtOAc 9:1) to give diamine la as a yellow gummy solid (15 mg, 48 µp???, 18%).
cis-e«í/o-iV,iV-Di(perfluorophenyl)bicyclo[2.2.1]hept-5-ene-2,3-dianiine(lb) cz's-e«í/o-Bicyclo[2.2.1]hept-5-ene-2,3-diamine dihydrochloride, 16 (20 mg, 90 µ????) and K3PO4 (149 mg, 702 µ????) were suspended in F DMSO (1.5 mL) and stirred at 90 0C under nitrogen for Ih. After cooling to room temperature, hexafluorobenzene N H ? (1 12 mg, 0.601 mmol) was added and the suspension was heated at 100 0C for 48 h. The colour of the suspension
turned to amber from beige. The reaction mixture was cooled to room temperature. Water
16 (10 mL) was added and the product was extracted with chloroform (3x5 mL). The combined organic phases were dried over anhydrous Na2SO^ filtered and concentrated under reduced pressure to give a yellow solid. This crude solid was then purified by flash chromatography over silica gel (hexane: EtOAc 15:1) to give lb as a clear oil (3.00 mg, 6.60 µ????, 7%). 1H NMR (300 MHz, C6D6): d 5.82 (t, J= 1.7 Hz, 2H, olefinic), 3.68 (s, 2H, CHN), 3.33 (br s, 2H, N//), 2.62 ( s, 2H, bridgehead), 1.20 (d, / = 9.3 Hz, IH, apical), 0.82 (d, J = 9.3 Hz, IH, apical) ppm; 13C NMR (C6D6): d 145.7, 143.2, 139.5, 137.0 (aromatic Cs), 135.0 (olefinic), 67.5 (CHNH), 47.3 (bridgehead), 44.0 (apical) ppm; 19F NMR (C6D6): d -159.4 (d, 4F, ortho), -163.7 (t, 4F, meta), -170.4 (t, 2F, para) ppm; HRMS-ESI (M+H+)m/z: caled for Ci9H10F10N2, 457.0763; obsd, 457.0749. cis-£n
17 M.P : 176-177 0C; IR (Nujol) 2929 (m), 2856 (m), 1710 (s) cm"1 ; 1H NMR (400 MHz, CDCl3 + DMSO-J6): d 11.60 (s, 2H, COOH), 6.08 (s, 2H, olefinic), 3.13 (s, 2H, CZfCO2H), 2.96 (s, 2 H bridgehead), 1.29 (d, J = 8.3 Hz, IH, apical), 1.25 (d, J= 8.3 Hz, IH, apical) ppm; 13C NMR (CDCl3 + DMSO-J6): d 174.0 (C=O), 134.5 (olefinic), 48.4 (apical), 48.0 (C-CO2H), 46.0 (bridgehead) ppm. ciW«
18 brown solid. After purification by column chromatography over silica gel (3:1 hexane/EtOAc), 5 was obtained as a white crystalline solid (93 mg, 0.40 mmol, 36%). IR (vmax, Nujol): 2923 (m), 2850 (m), 2142 (mb), 1725(s) cm-1; 1H NMR (300 MHz, CDCl3): d 6.29 (s, 2H, olefinic), 3.25 (s, 2H, CHCO), 3.20 (s, 2H, bridgehead), 1.50 (d, J= 8.7 Hz, IH, apical), 1.35 (d, J = 8.7 Hz, IH, apical) ppm; 13C NMR (CDCl3): d 179.1 (C = O), 135.0 (olefinic), 51.0 (C-CO), 48.6 (apical), 46.8 (bridgehead) ppm; HRMS-ESI (M+H+) m/z: caled for C9H8N6O2, 233.0787; obsd, 233.0783. en
19 (apical), 44.4 (CCN) ppm; HRMS-ESI (M+H+) m/z: caled for C8Hi0N2O, 151.0871; obsd, 151.0870.
ewepoxide), 2.54 (s, 6H, CH3), 1.45 (d, J = 9.3 Hz, IH, apical), 0.9 (d, J = 9.3 Hz, IH, apical) ppm; 13C NMR (CDCl3): d 171.0 (urea C=O), 152.6 (C=O-CH3), 55.6 (CHN), 47.5 (C-O-C), 39.6 (bridgehead), 24.5 (CH3), 24.0 (apical) ppm; HRMS-ESI (M+H)+ m/z: caled for Ci2Hi4N2O4, 251.1032; obsd, 251.1036.
20 e«
Compound 10 (1.01 g, 6.60 mmol), 4-iodotoluene (4.34 g, 19.8 mmol), Cui (260 ? mg, 1.40 mmol) and K3PO4 (2.84 g, 13.4 mmol) were /J< j Tj suspended in dioxane (25 mL) and stirred for 30 min. I N trans- 1 ,2-Diaminocyclohexane (226 \\L, 204 mg) was N-\ added under nitrogen with stirring and the suspension 12 0 was heated at 120 0C for 24 h. The colour of the reaction mixture turned from off white to dark grey. After cooling to room temperature,
the suspension was filtered through a plug of silica gel and the solid was washed with CH2CI2 (2x25 mL). The light green filtrate was concentrated to dryness in vacuo and
further purified by flash chromatography over silica gel (hexane: EtOAc 5:1) to give 12 as a white crystalline solid (1.80 g, 5.32 mmol, 80%). M.P: 175-176 0C; IR (V1113x, Nujol): 2944 (m), 2861 (m), 1691 (s) cnT1; 1H NMR (300 MHz, CDCl3): d 7.52 (d, J = 8.4 Hz, 2H, aromatic CHCN), 7.16 (d, J = 8.2 Hz, 2H, aromatic CiZCCH3), 6.00 (t, J = 1.6 Hz, 2H, olefinic), 4.63 (t, J = 1.3 Hz, 2H, CHN),
3.40 (t, J=IA Hz, 2H, bridgehead), 2.33 (s, 6H, CH3), 1.70 (d, J= 9.5 Hz, IH, apical), 1.42 (d, J = 9.5 Hz, IH, apical) ppm; 13C NMR (CDCl3): d 155.6 (C=O), 136.9 (aromatic CN), 134.3 (olefinic), 132.6 (aromatic CCH3), 129.4 (aromatic CHCCH3), 119.3 (aromatic CHCN), 58.3 (aliphatic CHN), 46.2 (bridgehead), 44.4 (apical), 20.8 (CH3) ppm; HRMS-ESI (M+H+)m/z: caled for C22H22N2O, 331.1810; obsd, 331.1811.
21 Lithium cís-e/i
22 product was extracted with CHCl3 (3x7 mL). The combined organic phases were dried over anhydrous MgSO4, filtered and the filtrate was concentrated under reduced pressure to give 14 as an orange-brown solid (50 mg, 0.14 mmol, 48%). 1H NMR (300 MHz, C6D6) : d 7.06, 6.81 (8H, aromatic), 6.60 (IH, N//), 5.67 (IH, olefinic), 5.33 (IH, olefinic), 4.83 (IH, CHN), 4.40 (IH, CHN), 2.86 (IH, bridgehead), 2.55 (IH, bridgehead), 2.22 (3H, CH3), 2.03 (3H, CiZ3), 1.6 (3H, CH3), 1.25 (2H, apical) ppm.
Lithiated Salt (14a) To a solution of 12 (1.01 g, 3.05 mmol) in dry THF (20 mL) was slowly added MeLi (1 M, 12 mL, 12.0 mmol) under nitrogen at -78 0C. The solution was stirred at low temperature for 25 min and was then slowly warmed to room temperature over 30 min. The colour of the solution N " + turned clear to light yellow. It was then refluxed at 80 0C - 2Li for 12 h. After cooling to room temperature, all volatiles P 14a were removed under reduced pressure to get a dark brown solid. This crude solid was recrystallized in dry pentane at -78 0C. The pentane-soluble part was concentrated in vacuo to get 14a as a pale yellow solid (376 mg, 1.18 mmol, 39%). 1H NMR (300 MHz, C6D6): d 7.31 (d, J = 8.0 Hz, 2H, aromatic CHCN), 6.79 (d, J= 8.0 Hz, 2H, aromatic CiZCCH3), 6.45 (s, 2H, olefinic), 3.90 (s, 2H, CuN), 3.00 (s,
23 2H, bridgehead), 2.04 (s, 6H, CH3), 1.18 (d, J = 9.1 Hz, IH, apical), 0.77 (d, J= 9.1 Hz, IH, apical) ppm.
Trimethylsilyl adduct (14b) To a stirred solution of 14a (20 mg, 63 µ????) in dry pentane (3 mL) at 0 0C under
nitrogen was added dropwise trimethylsilyl chloride (0.32 mmol). The solution was subsequently stirred at room
temperature for 24 h. All volatiles were removed under N Nn SiMe3 reduced pressure to get a light yellow solid. This solid was SiMe3 dissolved in dry pentane at room temperature and the P 14b pentane soluble part was concentrated in vacuo to get 14b as a light yellow gummy solid (22 mg, 50 µ????, 79%). 1H NMR (300 MHz, C6D6): d 7.37 (d, J = 8.0 Hz, 2H, aromatic CHCK), 6.75 (d, J = 8.0 Hz, 2H, CTZCCH3), 6.45 (s, 2H, olefinic), 4.00 (s, 2H, CHN), 2.66 (s, 2H, bridgehead), 1.93 (s, 6H, CH3), (apical proton resonances could not be assigned for being overlapped with residual pentane resonances), 0.1 l(s, 18H, Ci/3, trimethylsilyl) ppm. e«i/o-3,5-Di(p-tolyl)-3,5-diazatricyclo[5.2.1.0]dec-8-ene (15) A solution of compound 12 (300 mg, 0.907 mmol) in dry THF (4 mL) was added
to a suspension of L1AIH4 (210 mg, 5.50 mmol) in dry THF (2 mL) with stirring under nitrogen at 0 0C. The
suspension was warmed to room temperature and refluxed MnI for 1 h. The colour of the reaction mixture turned light grey to dark grey. Heating was stopped and the reaction mixture was cooled to room temperature. Water (2 mL), a 2 M solution of aqueous NaOH (2 mL) and H2O (2 mL) were added sequentially to quench the reaction. A copious amount of white aluminum salts crashed out immediately. The reaction mixture was filtered through a small pad of
Celite and the solid was washed with diethyl ether (10 mL). The resultant filtrate was extracted with diethyl ether (3 ? 7 mL), combined organic phases were dried over anhydrous MgSO4 and concentrated to dryness to get 15 as a white crystalline solid (200 mg, 0.632 mmol, 70%). M.P: 166-168 0C; IR (vmax, Nujol): 2974 (m), 2944 (m), 2880 (m), 2838 (m), 1618 (s) cm"1; 1H NMR (300 MHz, CDCl3): d 7.15 (d, J = 8.3 Hz, 2H, aromatic C/ZCN), 6.63 (d, J = 8.5 Hz, 2H, aromatic CZfCCH3), 5.98 (s, 2H, olefinic), 4.70 (d, J = 2.9 Hz, IH, CH2N), 4.64 (d, J = 2.9 Hz, IH, CH2N), 4.54 (s, 2H, NTZ2), 3.50 (s, 2H, bridgehead), 2.33 (s, 6H, CiZ3), 1.74 (d, J = 9.3 Hz, IH, apical), 1.61 (d, J = 9.2 Hz, IH apical) ppm; 13C NMR (CDCl3): d 142.6 (aromatic CN), 134.6 (olefinic), 130.0 (aromatic CCN), 126.0 (aromatic CCH3), 111.4 (aromatic CCCH3), 69.4 (CH2), 64.6 (aliphatic CN), 46.6 (apical), 46.0 (bridgehead), 20.3 (CH3) ppm; HRMS-ESI (M+H+) m/z: caled for C22H24N2, 317.2011; obsd, 317.2012.
Unsymmetrical compound (17) Compound 15 (55 mg, 0.17 mmol) was suspended in 5 M aqueous HCl solution (5 mL) and heated to 100 0C for 2 h. After cooling to room temperature, the mixture was treated with 10% aqueous NaOH solution to approximately pH 13, and the product was
25 extracted with CH2Cl2 (3x10 mL). The combined organic extract was dried over anhydrous MgSC«4, filtered, and concentrated under reduced
pressure to get unsymmetrical methylated compound 17 as a brown solid (50 mg, 0.14 mmol, 83%). IR Ow, Nujol): 3398 (b), 2946 (m), 2856 (m), 1640 (m) cm-1; 1H NMR (300 MHz, CDCl3) : d 7.20, 7.04, 6.85, 6.65 (8H, aromatic), 6.35 (IH, olefinic), 6.15 (IH, olefinic), 4.37 (IH, methylene), 4.21 (IH, methylene), 4.00 (IH, CHN), 3.70 (IH, CHN), 3.07 (IH, bridgehead), 2.83 (IH, bridgehead), 2.38 (3H, CiZ3), 2.22 (3H, CH3), 1.47 (2H, apical) ppm. c/*-e/i
26 filtered and concentrated under reduced pressure to give a light yellow semi-solid. It was then purified by flash chromatography over silica gel (hexane: EtOAc 7:1) to give 18 as a light yellow oil (199 mg, 0.685 mmol, 69%). 1H NMR (400 MHz, C6D6): d 5.94 (s, IH, olefinic), 5.82 (s, IH, olefinic), 5.02 (s, IH, N//), 3.55 (s, IH, CHNH), 2.98, 2.92, 2.37 ( s, 3H, ŒNH2 and bridgehead), 1.28 (d, J = 9.1 Hz, IH, apical), 0.90 (d, J= 9.1 Hz, IH, apical) ppm; 13C NMR (C6D6): d 136.0, 135.0 (olefinic Cs), 56.2 (CHNH), 53.0, 49.0, 48.0 (CHNH2 and bridgehead Cs ), 45.0 (apical) ppm; resonances for C6F5 ring could not be assigned due to low intensity. 19F NMR (C6D6): d -161.2 (d, 2F, ortho), -165.5 (t, 2F, meta), -174.7 (t, W, para) ppm; HRMS-ESI (M+H+)m/z: caled for Ci3HnF5N2, 291.0921; obsd, 291.0940. e«<15 mL) and washed with H2O (2x10 mL). The combined organic phases were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a brown crude solid. It was then
27 purified by flash chromatography over silica gel (hexane: acetone 9:1) to give 19 as a white solid (165 mg, 0.342 mmol, 26%). M.P: 118-120 0C; IR (V1113x, Nujol): 2950 (m), 2850 (m), 173 l(s) cm-1; 1H NMR (300 MHz, C6D6): d 6.07 (s, 2H, olefinic), 3.93 (t, J=IA Hz, 2H, CHN), 2.48 (s, 2H, bridgehead), 1.32 (d, J = 9.6 Hz, IH, apical), 0.64 (d, J = 9.6 Hz, IH, apical) ppm; 13C NMR(C6D6): d 154.9 (C=O), 146.2, 143.0, 139.5, 136.3 (aromatic Cs), 134.4 (olefinic), 60.76 (CHNH), 45.4 (bridgehead), 44.5 (apical) ppm; 19F NMR (C6D6): d -141.7, -145.6, -154.8, -161.3, -162.0 ppm; HRMS-ESI (?+?+): caled for C20H8Fi0N2O, 483.0550; obsd, 483.0522.
2.3 Ring-opening Metathesis Polymerization (ROMP)
2.3.1 General Considerations
General experimental considerations are given in section 2.1 with the following additions. MALDI-TOF mass spectra were acquired using a Waters Micromass MALDI micro MX. Spectra were acquired using the following conditions: positive polarity mode, reflectron flight path, 12 kV flight tube voltage, 10 Hz laser firing rate, 10 shots per spectrum, pulse 1950V, detector 2350 V. The instrument was calibrated using polyethyleneglycol (PEG). The matrix consisted of 6 mg of a-cyano-4-hydroxycinnamic acid (CHCA) in 1 mL of a 6:3:1 mixture OfCH3CN : CH3OH : H2O. The analyte solution consisted of 3-5 mg of polymer in 1 mL of CH2Cl2. Samples were prepared using the
28 layer method: 1 µ? of matrix was spotted onto the sample plate at room temperature, the sample plate was allowed to dry in air, whereupon 1 µ?. of analyte was spotted onto the sample plate and the plate was allowed to dry again. Polymer molecular weights were determined by gel permeation chromatography (GPC). Relative molecular weights were determined using a Waters liquid Chromatograph equipped with a Waters 1515 HPLC pump, Waters Styragel columns (4.6x300 mm), HR 4EX3, Waters 2414 differential refractometer (refractive index detector, ? = 880 nm). A flow rate of 1.0 mL/min was used and samples were dissolved in THF (ca. 2 mg/ mL) and prepared in air. Polystyrene standards were purchased from Polymer Laboratories, with molecular weight 21000 Da.
2.3.2 Starting materials, Reagents and Solvents: General considerations for starting materials and reagents are given in section 2.1.1. Polymerizations were performed in a glovebox under a nitrogen atmosphere. CH2Cl2 was dried by refluxing over CaH2, distilled under nitrogen, degassed and stored in a glovebox over activated 4 Â molecular sieves. Grubbs first-generation catalyst was purchased from Sigma-Aldrich and used as received.
ROMP of 12: Representative procedure for 40-mer (12a) To a solution of Grubbs first-generation catalyst, [Cl2(PCy3)2Ru=CHPh] (6.20 r.—? mg, 7.50 µ????) in dichloromethane (1.5 mL) was added V=/ a solution of monomer 12 (100 mg, 0.302 mmol) in \^ I^ n dichloromethane (2 mL) with stirring for 42 h at room XXYtX 12a temperature. The colour of the solution changed from light purple to light yellow. Polymerization was terminated by stirring with an excess of ethyl vinyl ether (0.5 mL) for 1 h. The polymer solution was brought outside the glovebox and added dropwise to MeOH (50 mL). The resulting off-white floppy solid was filtered and washed with methanol (2x10 mL). The solid was dried in a vacuum oven at 50 0C for 12 h (65 mg, 65%). IR (vmax, KBr): 3026 (m), 2915 (ms), 2854 (m), 1700 (s), 1508 (s) cm"1; 1H NMR (CD2Cl2): d 7.27, 7.14, 6.76 (aromatic), 4.86, 4.66, (olefinic and CHN), 2.88 (HC-CH2), 2.34 (CiZ3), 1.16, 0.88 (CH2) ppm.
ROMP of 19: Procedure for 40-mer (19a) To a solution of Grubbs first-generation catalyst, [Cl2(PCy3)2Ru=CHPh] (3.5 mg, 4.3 mmol) in dichloromethane (1.5 mL) was added a solution of monomer 19a (80 mg, 0.17 mmol) in dichloromethane (2 mL) with stirring for 48h at room temperature. The colour of the solution changed from light purple to light brown. N. .N Polymerization was terminated by stirring with an
excess of ethyl vinyl ether (0.4 mL) for 1 h. The F F 19a polymer solution was brought outside the glovebox and added dropwise to MeOH (50 mL). The resulting light grey floppy solid was filtered and washed with methanol (2x10 mL). The solid was dried in a vacuum oven at 50 0C for 12 h (70 mg, 88%).
30 IR(vmax, KBr): 2962 (m), 2927 (m), 1747 (s), 1511 (bs) cm"1; 1H NMR :{(CD3)2CO, 400MHz} d 7.30, 7.20 (aromatic), 5.45, 5.04 (olefinic and CHN), 2.68 (HC-CU2), 1.40, 1.15 (CiZ2) ppm.
31 Chapter 3 - Results and Discussion
3. 1 Attempted Synthesis of Target Tetradentate Ligand 1 via all-exo-Tetraol 2 The initial pathway evaluated to synthesize the target ligand 1 was through all exo-tetraol 2, already reported in the literature76 (Scheme 4), which would result in inversion in the stereochemistry to the desired a\\-endo tetramine. Compound 2 was prepared by treating 2, 5-norbornadiene with TV-methyl morpholine TV-oxide (NMO) and osmium tetroxide in the presence of water. Purification was achieved through the acetylated product. Subsequent treatment with sodium methoxide followed by protonation yielded the pure tetraol 2.
NMO1OsO4 HO^lX^OH
-^ *- HO^LJTOH¡n situ AcgO.Py HOv^^^OH i) CH3ONa AcO^^^OAc HCk/JL^OH ^ Ac0^£L^/0Ac N) H+
Scheme 4. Synthesis of 2. To get the enJo-tetramine 2d from 2 (Scheme 5), conversion of the hydroxyl groups into a better leaving group such as tosylate was required to allow for the targeted nucleophilic attack of tetramethylsilyl azide. Compound 2 was treated with four equivalents of tosyl chloride in the presence of pyridine at low temperature to get the tetratosylate 2a (path A). Reaction of 2 with boron trifluoride etherate to generate the
32 boron trifluoride adduct of the tetraol, 2b in situ was also explored (Path B). The resulting activated alcohol should facilitate nucleophilic attack by trimethylsilyl azide (TMSN3).
PathA , TsCI-py ?. TsO^L^OTsTsO^,^^oTs 2a TMSN3 HOv^/X^OH 2 N3 N, 3
Path B in situ BF3. Et2O 2b
Zn, NH4CI Ar-X1[Pd] C-N coupling Ar-NHAr^'NHHN„ArArIHN-*,. H'NH HNHN-H 1 2d
Scheme 5. Attempted synthesis of target ligand 1. In either cases (Scheme 5, Path A and B), SN2 nucleophilic attack by azide would have given the intermediate tetraazide 2c in situ with inversion of configuration. Due to the extremely reactive nature of the tetraazide, the compound would not be isolated, and reduction using zinc/ammonium chloride77'78 would be immediately performed. This resulting tetramine 2d would then be converted to the aryl substituted tetraamine 1 through Pd catalyzed C-N coupling with an aryl halide. Unfortunately, these reactions did not proceed as expected. For Path A, 1H NMR indicated the formation of 2a. The desired
33 product could not however be isolated from the large number of other compounds formed. Although conversion of alcohol to its corresponding tosylate is an established j 79 80 8 1 82 procedure, ' ' ' conversion of all four alcohols on this molecule was not trivial. The outcome of the reaction could have been different if conversion of each alcohol to the tosylate had been done sequentially. This approach might be worth investigating. 1H NMR showed that Path B only yielded unreacted starting material. It is worth noting that the tetraol was only soluble in methanol. Even though precautions were taken by using anhydrous tetraol and methanol, residual water might still have been present, thereby deactivating BF3.
3. 2 Attempted Synthesis of Target Ligand 1 via Cobalt Dinitrosoalkane Complex 3 Synthesis of the target ligand 1 via all-exo-tetraol (Scheme 5) suffered from the limitations of converting four alcohols simultaneously with inversion of configuration and dealing with resultant intermediate tetrazide 2c. It is worth mentioning that 2c has C/N <1, which is highly explosive, even as a transient intermediate species.83 Considering the above issues, Scheme 6 was evaluated. Complex 3a was synthesized in 60% yield by bubbling nitric oxide through a toluene solution of CpCo(CO)2. Formation of 3 from 3a with 2,5-norbornadiene in the presence of NO has been observed by Bergman,84 though no work has been reported on 3. Bergman also reported the cleavage of the nitrosyl-cobalt bond of the corresponding 2- norbornene system using PPh3/I2.
34 NO CpCo(CO)2 *- (CpCoNO)2 ?? *~ CpCo-SJ^YX-J ? 60/060% 3a ?0 ^N0 71,^000P0? 3
PPh3/ I2 ) Na1EtOH HON^5A HON^ ^C1NOH ·*-?- Ar ?? Ar C-N coupling 3b
Scheme 6. Attempted synthesis of 1 via cobalt complex.
Therefore, similar techniques could be employed to generate 2,3,4,5- tetraoximonorbornane 3b from 3 (Scheme 6). Reduction of 3b to the corresponding endo- amine would be achieved by refluxing in sodium/ethanol, the strategy explored by Eugene85 in preparing enantiomerically pure e«Jo,e«do-2,6-diaminobicyclo[3.3.1]-
Qv: QT 00 nonane from the corresponding oxime. A C-N coupling reaction ' ' with aryl halide would have given the target ligand 1.
Unfortunately, when the synthesis of 3 was attempted in our lab, characterization of 3 was not possible since it was highly insoluble in all of the organic solvents.
Therefore, achieving tetrasubstituted target ligand 1 by this pathway has not been successful.
3. 3 Attempted Synthesis ofla via Curtius Rearrangement In contrast to the sections 3.1 and 3.2 above, following sections focus on synthesizing enJo-diamine la by derivatizing one side of the molecule at a time. Rather
35 than trying to prepare a molecule that had four amine groups, the first key intermediate we attempted to prepare had two amine groups (la). This key intermediate la could be used as a bidentate ligand after deprotonation, could be converted to the tetradentate ligand 1 by fiinctionalizing the olefinic bond or alternatively, could be used as a monomer for ROMP. Various synthetic approaches to la were evaluated and presented in sections 3.3 and 3.4. The first pathway investigated is outlined in Schemes 7 and 8. Compound 4a was synthesized from its corresponding anhydride 4 in an environmentally friendly and
an unprecedented pathway by performing a simple acid hydrolysis at room temperatare.
Very slow addition of HCl (over the period of 5-10 min) under vigorous stirring was found to be crucial for getting an optimum yield. We synthesized this compound in 25- 50 gram scale in our laboratory with 90% yield. Additionally, there are no published spectroscopic data available of compound 4a.
H3O+, rt COOH COOH 4 O 90% 4a SOCI2 cat.DMF 800C THF/H20 CON3 NaN3, 0 0C COCI CON3 COCI 36% in situ
Scheme 7. Synthesis of dicarbonyl azide 5.
36 The reaction was monitored by IR spectroscopy. Disappearance of anhydride stretching frequencies at 1810 cm1 and appearance of new stretching frequencies for carboxylic acid at 1708 cnT1 indicated the formation of 4a.The structure of 4a was confirmed by ID and 2D NMR spectroscopy. The acid chloride 4b was generated in situ by treating the dicarboxylic acid 4a with excess thionyl chloride in presence of catalytic amount of DMF. Due to its extreme sensitivity to moisture, 4b was not isolated. The dicarbonyl azide 5 was isolated in 36% yield as a new compound from the reaction of the acid chloride 4b with an aqueous solution of sodium azide at low temperature in THF. In the IR spectrum, the appearance of stretching frequencies for the azide group at 2142 cm"1 and carbonyl group at 1726 cm-1 and disappearance of the carboxylic group at 1708 cm'1 indicated the formation of 5. The 1H NMR spectrum of 5 in CDCI3 shows five distinct resonances with the appropriate integral ratios (Figure 8). The olefinic protons (Hi) of the norbornene moiety resonate at 6.29 ppm and apical protons (H^s) at 1.50 and 1.35 ppm as a pair of doublets, as expected for the norbornene backbone. Resonances of the methine protons (H2) next to the carbonylazide resonate at 3.25 ppm, slightly deshielded than that of bridgehead protons due to electron withdrawing nature of the carbonyl group. Carbon of the carbonylazide appears at 179.1 ppm in 13C spectrum which distinguishes from carbon of the carboxylic group that appears at 173.6 ppm. Molecular formula of the compound 5 was confirmed by high-resolution mass spectrometric technique. The mass was found to be 233.0787 amu which differs by 1.7 ppm from the calculated mass (233.0783 amu).
37 ? "? ci ?? ON Tt «? Tj- © ON On "?
4,5
1 TCON3 * EtOAc CON3
CHCl,
* bUL
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1 .5 ppm
Figure 8. 1H NMR (300 MHz) spectrum of 5 in CDCl3.
Carbonylazides undergo the Curtius rearrangement to form isocyanates.
Subsequent aqueous work-ups lead to hydrolysis of the isocyanate to the primary amine.89'90 Therefore, carbonylazide 5 was heated to reflux in anhydrous toluene for 12 h. Upon observing no starting material by TLC, the reaction mixture was quenched with
H2O. 38 Curtius Rearrangement ¿£?G"> Ar—X, C-N coupling CON3 X* 5 CON33 5c NHNH22 1a HN^ArJ[^Ar
Scheme 8. Attempted synthesis of la via Curtius rearrangement. A large number of products were observed by 1H NMR and TLC under UV. Many attempts were made to isolate the vicinal primary amine 5c by employing recrystallization and chromatographic technique over neutral alumina. Attempts to isolate as a bis-hydrochloride salt of 5c was not successful either. A trace amount of brown solid was recovered after treating the reaction mixture with ethereal HCl but this quantity was not enough to analyse. The pathway to prepare the dicarbonylazide 5, using Scheme 7 was not repeated due to the explosive nature of the target product and one of the reactants, sodium azide, as well as their toxicity. In H2O and in acidic medium, sodium azide liberates the very toxic hydrazoic acid.91'92'93'94 Azides can be isolated if the ratio between the carbon to nitrogen is greater than I.83 Groaz95 however recently reported an spontaneous explosion of trans-dicarbonyl azide. As a result of the potential risks involved in this part of the project, this pathway was abandoned. An alternative pathway with a similar idea was explored (Scheme 9). In this approach trimethylsilyl azide replaced the more explosive sodium azide.96 Witiak97 reported the synthesis of cw-l,2-diamino-cyclohex-4-ene dihydrochloride from 1,2,3,6- tetrahydrophthalic anhydride by using trimethylsilylazide employing sequential Curtius
39 rearrangement. Considering Witiak's approach, commercially available dicarboxylic anhydride 4 was purified by heating under reflux for 5 h with acetic anhydride and hexane. The reaction mixture was then treated with trimethylsilylazide in anhydrous dioxane. The trimethylsilylester product 4c would have been subjected to subsequent chlorination reaction with thionyl chloride in presence of catalytic amount of DMF in CCl4 to get the acyl chloride 4d. Curtius rearrangement of 4d could lead to 4e.
Me3SiN3 ¿£?G>? S0C'2, catDMF 0 Dioxane~ ^*" ^TCOOSiMe3"J1 ? ? ? 4 ö ~° 9 i) Hydrolysis ¿~Kji^N=C=O Me^SiNqd ? HnÎ1^1" ii)Ar-X,C-Ncoupling 4e N=C=0 Dioxane in situ Scheine 9. Attempted synthesis of la via sequential Curtius rearrangement. Hydrolysis of the bis-isocyanate 4e could have given the corresponding primary amine and the C-N coupling reaction la. Unfortunately, the reaction did not proceed as expected. Instead of 4c, 100% unreacted starting material 4 was observed repeatedly. Changing reaction conditions such as changing solvent, reaction time, temperature and trimethylsilylazide equivalences did not work. The reason could be sterics. The carbonyl 40 group of anhydride is less accessible to nucleophilic attack by trimethylsilylazide. Therefore, progress was not made to synthesize la in this pathway. 3. 4 Synthesis ofla via Cyclic Urea Formation Synthesis of la via Curtius rearrangement (Section 3.3) did not proceed further. Therefore, an alternative synthetic pathway to la was explored. This pathway began with the synthesis of a cyclic urea 10 (Scheme 10). This urea 10 can be derivatized by using different substituents on the nitrogen atoms which could either be used as monomers for ring-opening metathesis polymerization or be converted to the endo-diamine ligands upon ring-opening. Ox H H ? ? B I VN\ i) DlBAH1THF1O 0C, 3h ^K Ac20,reflux ^N L^N^0 ¡i) MeOH(aq)l Reflux, 12h*- ^nÍ ^o 15h *- ? N>=0 H H ?- 60% 7 95% ° 150°C,23h MeOH(aq) 75% N-V KOH 10 H 84% Scheme 10. Synthesis of cyclic urea 10. The dienophile 8 was prepared in two steps via a modified literature procedure by addition of diisobutylaluminum hydride (DIBALH) to commercially available hydantoin 6 followed by methanolysis to give the l,3-dihydro-imidazol-2-one 7.73,98 After refluxing 7 for 1.5 h with an excess of acetic anhydride, the desired l,3-diacetyl-l,3-dihydro- 41 imidazol-2-one 8 was produced and isolated in 95% yield after recrystallizing from dichloromethane. The observed yield reported in literature73 was 65% in which 7 was refluxed for only 30 min and purified the product by recrystallizing from diethyl ether. Compound 8 was then heated with an excess of dicyclopentadiene in a sealed tube at 145 0C for 24 h which gave the Diels-Alder adduci 9 in 20% yield. In an attempt to optimize the yield of the reaction, various reaction conditions were evaluated. One of the first reactions that was tried was repeating the reaction at an elevated temperature (155 0C) for 3 days. This resulted in an increase in yield to 40%. The reaction was further repeated with excess freshly distilled cyclopentadiene at 145 0C for 23 h. The yield was improved to 75%. Thus, cracking of dicyclopentadiene was crucial for obtaining higher yield. Compound 9 was purified by several pentane washings prior to flash column chromatography. The cyclic urea 10 was obtained by base hydrolysis of 9 with aqueous KOH in refluxing methanol for 4. 5 h in 84% yield. This urea was first observed by Eissenstat and co-workers74 in 1993 but there was no further work done on 10. Neither any spectroscopic evidence nor any structure of 10 was published in the literature. It was also independently reported in 1998 by Marks and co-workers75 as a patent application with only 1H NMR as spectroscopic evidence. Therefore, well-defined synthetic procedure as well as detail spectroscopic data including high-resolution mass spectrometry are reported in this thesis. A broad stretching frequencies at 3201 cm"1 and a sharp stretching frequencies at 1691 cm"1 are observed by IR spectroscopic technique for the N-H and C=O groups of 10 respectively. 42 1H NMR data shows the olefinic proton resonance at 6.16 ppm together with that of apical proton at 1.60 and 1.20 ppm, as expected for the norbornene backbone. Aminic protons resonate at 4.68 ppm as a broad singlet. This broadness arises due to the quadrupolar nature of 14N as well as an exchange between acidic aminic protons and that of water. Methine protons adjacent to nitrogen appear at 4.13 ppm which are fairly deshielded (due to electron withdrawing nature of the urea moiety) compared to bridgehead protons which resonate at 3.02 ppm. Assignment of all NMR resonances is done with the help of ID and 2D techniques such as 13C, HSQC, HMBC and COSY. Molecular formula of the compound 10 was confirmed by high-resolution mass spectrometry. The mass was found to be 151.0871 amu which differs by 0.6 ppm from the calculated mass (151.0870 amu). As presented in Scheme 3, arylation of 10 through various C-N cross-coupling protocols were evaluated. The first route involved Buchwald-Hartwig cross-coupling reaction of 2-iodo-l,3-dimethylbenzene with secondary amine of the urea 10 (Scheme 1 1) in the presence of BINAP, sodium teri-butoxide and Pd2(dba)3 as ligand, base and catalyst precursor, respectively. ?-«NA -JX^^i^\ PJ"dbabBINAPNaOfBu,dioxane ?' ?-N"A -XlJ 10 H J 12b Ar Scheme 11. Attempted synthesis of 12b by Buchwald-Hartwig C-N coupling reaction. 43 A variety of conditions were evaluated, ranging from using different solvents such as toluene, dioxane; base and ligand equivalents, temperature and reaction time. In all of the cases, instead of getting desired product 12b, 100% unreacted starting material was recovered. In one instance, 1H NMR spectroscopy showed the disappearance of olefinic resonances possibly due to Heck coupling. Palladium is in fact known to catalyze the arylation of alkenes.99'100'101 This methodology could be useful to prepare derivatives by functionalizing olefinic bonds of norbornene compounds, such as bicyclic ureas and amines. base, CuI, solvent ~frans-1,2-diaminocyclohexane X *" Tn-N-Ar Scheme 12. Attempted synthesis of 12b by Cu-catalyzed aryl-amidation reaction. No cross-coupling reaction of bicyclic urea derivatives has been reported yet. In order to develop such a new approach to prepare aryl-bicyclic urea 12b from 10, we chose the cross-coupling reaction of imidazole derivatives with aryl halide, reported by Hafner and co-workers.102 Therefore, we attempted C-N cross-coupling of 2-iodo-l,3- dimethylbenzene in excess with 10 using ira«s-l,2-diaminocyclohexane as ligand and copper iodide as catalyst (Scheme 12). Various bases such as K3PO4, Cs2CO3, and CaCO3, and solvents such as toluene, dioxane, DMF, and DMSO were evaluated. 44 Unfortunately in all of the cases, 100% unreacted starting material was observed. Using the less sterically hindered 4-iodotoluene in excess as aryl halide gave the corresponding urea 12a in 80% yield (Scheme 13). K3PO41CuI, dioxane,120 0C , N-H T+ U[\ ? " TN-Ar N—\ J^ fra/7s-1,2-diaminocyclohexane, 24 h n~\ 10H ° ! 12 Ar' ° 80% Scheme 13. Synthesis of 12 by copper catalyzed aryl-amidation reaction. Reaction conditions were optimized using wet dioxane with an increased catalyst and ligand loading. Compound 12 was isolated by washing with hexane to remove excess 4-iodotoluene and was further purified by flash column chromatography. The structure of 12 was elucidated by IR and NMR spectroscopic techniques. A sharp carbonyl stretching frequency at 1691 cm"1 is observed by IR spectroscopy. The 1H NMR spectrum of 12 in CDCI3 shows 8 distinct resonances, which possess appropriate integral ratios (Figure 9). The two aromatic resonances of the tolyl group resonate at 7.52 and 7.15 ppm. Each appears as a doublet having an integration of 8 altogether. In order to distinguish between the meta and ortho protons of the tolyl group, additional information was obtained from the COSY and HMBC spectra based on correlations observed from the methyl group. The methyl resonance appears as a sharp singlet at 2.33 ppm. Molecular formula of the 45 compound 12 was confirmed by high-resolution mass spectrometric technique. The mass was found to be 331.1811 amu which differs by 0.3 ppm from the calculated mass (331.1810 amu). \l\i/ \M/ 4,5 6 7 4,5 • ? ¦ · ¦ · ? · · ¦ · ? ¦ · · ¦ ? · · ¦ · ? · · ¦ · ? ¦ ¦ ¦ ¦ ? ¦ ¦ ¦ ¦ ? ¦ ¦ · · ? · · · ¦ ? ¦ ¦ ¦ ¦ ? ¦ ¦ · ¦ ? · · · · ? ¦ ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm il fi—.1 ?«·1 IsI Figure 9. 1H NMR (300 MHz) spectrum of 12 in CDCl3. After successful preparation of 12, challenge was ahead to open up the cyclic urea ring to get la. Several reaction conditions to open the cyclic urea were attempted. Hydrolysis with KOH in MeOH at 150 0C for 3 days in a pressure tube,Error! Bookmarknot defined. refluxing with KOH in ethanol, and reaction with potassium féri-butoxide in water 46 and DMSO103 were not successful. These approaches had been reported for related substrates. Microwave irradiation of 12 in the presence of HCl at various concentrations and duration did not generate la either.104 ^r Ar= 12 Ar Conditions evaluated : i) aq KOH, MeOH, 150 0C ii) aqHCI, MW iii) NaO1Bu, H2O, DMSO iv) LiOMe, MeOH Scheme 14. Attempted ring-opening of 12. Reaction with L1OCH3 in methanol105 was also performed. In all of cases, 100% unreacted starting material was recovered (Scheme 14). The steric congestion created by bulky tolyl group might make the carbonyl group less accessible to nucleophilic attack. THF, MeLi, 2 equiv HoO Ar , N-Ar N ?? rt , N-Ar / O Ar 63% N^ 48% Ar'^V0 12 13 Ì Ar gu® 14 Ar= Scheme 15. Synthesis of 13 and 14. 47 Rimmler106 reported the ring opening of 1,3-diphenyl urea derivatives using MeLi to prepare corresponding diamine. Therefore, cyclic urea 12 was treated with two equivalents of MeLi at room temperature. Instead of a ring-opened product, a methylated compound 13 (Scheme 15) was observed. Aqueous work-up gave an unsymmetrical acetylated compound 14. Both the compounds 13 and 14 were isolated and characterized. CNJ T G- CM m en m o co m U^ s? io m rH co r- >£> CM CS) co r- r- r- vo vo m ro co cm V F/ C6D5-H Peritane #THF OEt2O # ö JULi ' I ' 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm ? .^ Figure 10. 1H NMR (300 MHz) of 13 in C6D6. 48 The compound 13 shows the appearance of a sharp methyl resonance (H9) at 1.25 ppm (Figure 10). The integral and peak-height ratio of this resonance (H9) and that ofp- methyl (Hs) is 1 :2. It indicates that the methyl group is part of 13 and reinforces the peak assignments. Part of the residual solvent resonances are overlapped with that of apical and methyl (H9) protons. All the resonances were assigned with the aid of 13C and 2D NMR techniques. co 00 o ? s? s? CO G- G- *3* CQ CN VO T VD mOJlfli-HCNl^TCOVOr-Jr-iair-rOCD G????-????????G-G- so ?? so CO CO CO OJCM CO irXNHO^tOfgcNCMCIHHHH ClCO (M OsICNlCNCMr-t.-H.-HrHrHrHi-Hi-li-l.-l 1W^ V V WV^W 7,8 14 13 F Et2O Starting Material 12 15 # Peritane CD.-H acetone t, 7,8 ^JJ UJU \L .0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm M. Mi ? ? y. Mk ? /! Figure 11. 1H NMR (300 MHz) spectrum of 14 in C6D6. 49 H spectrum of the compound 14 shows 16 resonances in an unsymmetrical pattern with proper integral ratios which are consistent with the structure of 14. Resonances of apical protons are overlapped with that of Et2Û and pentane. Me-Li + Vo-Lr N Me Ar 13 HoO H-OH Ar/ 4 ^ N r~- iv^NH Xo" rsl Me Ar Ar 14 13a Scheme 16. Proposed mechanism for the formation of 13 and 14. Norbomene backbone is not shown for the clarity. A proposed mechanism for the formation of 13 and 14 is shown in Scheme 16. Nucleophilic attack of MeLi to the carbonyl carbon gives 13. Upon aqueous work-up, the transient species 13a is generated. Subsequent decomposition of 13a gives methylated product 14. It is peculiar that two equivalents of MeLi required opening up the cyclic urea ring partially, whereas it actually required only one equivalent. Given that MeLi solution was titrated in isopropyl alcohol not in the THF, the actual concentration of 50 MeLi thus has changed in presence of residual water content in anhydrous THF used for the reaction. Similar trend was observed for Scheme 17 as well. MeLi, 4 equiv ,J-A wetrecrystallizedperitane in N-Ar ¿V reflux, 6h ?£" „IHN^ a' ? /T 2Li 12 * 39%onn/ 14a Ar 95% Ar= Scheme 17. Synthesis of la via 14a using MeLi. When 12 was treated with four equivalents of MeLi and heated at 70 0C for 6 h, the dilithiated salt 14a formed, which upon work-up using non-anhydrous pentane gave vicinal enc/o-diamine la (Scheme 17). The 1H NMR spectrum of 14a in C6D6 shows 8 distinctive resonances, which are consistent with the structure of 14a (Figure 12). The resonances maintain the expected integral ratios as well. Upon complete ring opening, resonances of methyl resonances at 1.37 ppm of 13 (unsymmetric compound, Figure 10) disappeared which indicated formation of 14a. The aromatic protons of 14a resonate at 7.30 and 6.80 ppm, assigned to the symmetric ortho and meta protons of the tolyl group, respectively. Methine protons next to the nitrogen atoms are deshielded by the 51 electronegativity of nitrogen and resonate at 3.89 ppm, fairly downfield from that of bridgehead protons. s? o co CN eg m CO ?? OO VD LO OO SP lOiH nom i-i (Ti m .H VO SP iH ST Oi r- COVO en ? ? co r- sp OJ O O O OO ^H1H G» G- f— G— G- VD VO VD CN N W(N ? V W/ \ C6D5-H 7 8 7 3 4,5 JuLJwl_ JU> I ¦ ' ¦ ¦ I ¦ ¦ ' ¦ I ' ¦ ¦ ¦ I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ¦ · ¦ ? - ¦ ¦ ? ? ¦ - ? ¦ ¦ ¦ ? ¦ ¦ ? ¦ .0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm Figure 12. 1H NMR (400 MHz) spectrum of 14a in C6D6. 1H NMR spectrum in Figure 13 shows correct number of resonances and integral ratios which correspond to the structure of la. The aminic protons resonate at 3.6 ppm 52 which is further confirmed by IR stretching frequency at 3380 cm"1 due to N-H functional group. HMBC and 1H-1H COSY show correlation between /?-CH3 (H8) and H7, which reinforces the peak assignments. Molecular formula of the compound la was confirmed by high-resolution mass spectroscopy. The mass was found to be 305.2019 amu which differs by 0.3 ppm from the calculated mass (305.2018 amu). s? N. H 4,5 JLl JJL 7.0 6.0 5.5 3.5 2.5 1.5 1 .0 ppm Figure 13. 1H NMR (300 MHz) spectrum of la in C6D6. 53 Some small resonances appear in the spectrum of la, especially around j9-methyl resonances which could not be assigned. This unidentified side product could not be removed. A proposed mechanism for the formation la via 14a is outlined in the Scheme 18. Nucleophilic attack of MeLi to the carbonyl carbon gives the partial ring opened product 13. Further attack to quaternary carbon by MeLi opens up the ring completely to give dilithiated salt 14a. Ia is obtained upon treating 14a with water, generating lithium hydroxide as side product. Me-Li + Me" Li + Ar Ar/ 0"Li+ -K^"Me Ar 12 13 13b Ar H9O LiOH N>4fO"LiH ? Me Ar 1a 14a 13c Scheme 18. Proposed mechanism for the formation of la via 14a using MeLi. Norbornene backbone is not shown for the clarity. 54 Synthesis of diamine la via 14a using MeLi suffered from difficult purification procedure. Some unidentified impurities/side-products were highly soluble in all organic solvents including pentane, even at -78 0C. Even after multiple pentane washings, the 1H NMR spectrum of la still showed some impurities (Figure 13). Basic or neutral alumina could not separate the side-products from the compound la. It decomposed on silica gel. TLC on neutral alumina showed single spot but 1H NMR showed more than one product. Various solvent systems, such as different compositions of n-hexane/EtOAc, n- hexane/CHCl3, and w-hexane/acetone, were employed to purify la. Unfortunately none of them was successful. J^>I N-Ar THF'LiAIH4" "77 > J^TN-Ar Ar^Ar_fSIL J m\ reflux, 1.5 h ^ \^ 12 Ar 15 Ar 70% Scheme 19. Synthesis of 15 through LAH reduction. Considering the issues of ring-opening MeLi, we therefore investigated a new approach to synthesize the endo-diamine la. Graf and co-workers107 attempted the conversion of the l,3-imidazolidin-2-one derivatives into the corresponding diamine by hydrolysis under both acidic and basic conditions at elevated temperature which were not successful. Then they converted the l,3-imidazolidin-2-one derivatives into corresponding reduced species in order to make it susceptible to hydrolysis. We therefore explored Graf and co-worker's approach. 12 was heated to reflux with excess lithium 55 aluminum hydride (LAH) in dry THF under nitrogen to get a reduced species 15 (Scheme 19). It was characterized by using ID and 2D NMR techniques as well as high resolution mass spectrometry. 1H NMR shows unsymmetrical methylene protons appear at 4.70 and 4.63 ppm as doublet of doublets (Figure 14). Another pair of doublets appear at 1.72 and 1.61 ppm due to the unsymmetrical apical protons of the norbornene backbone. The methine protons next to the nitrogen appear at 4.54 ppm due to electronegative nitrogen deshields these protons by pulling electron towards itself. G- y- © "Ñt ?? N mo h-Mt SOr- (NJ ^j ^ ? S G- \? \C ? «? (NJ ^. — ^ r^ r^ P^ *¿ \o W V Wl 4,5 ?-? 9,10 Ar 4,5 I I I "fi _L • ? · · · ? ' ' ' ' ? ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ¦ ¦ ? ¦ ¦ ¦ ¦ I ' ¦ ' ' I ' ' ¦ ' I ' ¦ ¦ ¦ I ' ¦ ' ' I ¦ ¦ ' ¦ I ¦ ¦ ¦ ¦ I ¦ 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 ppm 3 ,-, oidi öl—' Figure 14. 1H NMR (300 MHz) spectrum of 15 in CDCl3. 56 Two aromatic resonances appear at 6.61 and 7.15 ppm. Relative position of the ortho and meta protons of the tolyl group was determined with the help of 2D NMR by establishing a correlation with methyl group appears at 2.33 ppm. Assignment of all the resonances was done with the aid of 13C, COSY, HSQC, HMBC and JMOD. Molecular formula of the compound la was confirmed by high-resolution mass spectrometric technique. The mass was found to be 317.2012 amu which differs by 0.3 ppm from the calculated mass (3 17.201 1 amu). We attempted base hydrolysis of 15 using aqueous KOH in MeOH at various temperatures. In all of the cases, 100% starting material was recovered. 15 was suspended in 5M HCl and stirred at room temperature for 2 days. There was no reaction took place as monitored by TLC and 1H NMR. The reaction was repeated with stirring at 100 0C for 2 h (Scheme 20). aqHCI N-Ar Ar= Reflux 83% 17 Ar Scheme 20. Synthesis of 17. Partially ring-opened unsymmetrical compound 17 was observed by 1H NMR. This scenario demonstrated that even a poor nucleophile such as chloride could effectively ring open to give 17 from 15. 1H spectrum of the compound 17 shows 16 resonances in an unsymmetrical pattern with proper integral ratios which are consistent with the structure of 17 (Figure 15). Part of the resonances of aromatic protons is overlapped with 57 that of residual protic solvent. Aminic proton resonances could not be assigned possibly due to the rapid exchange of this proton with that of the residual water. fl& t*i (TS ?*9 C-! r) Ci i-r-r-r-f^r-r- <*<**» *r m * j ¡13,14 Starting material 15 CHCI3, N H17 aromatic H's 11 J ^15'16 14 H2O aromatic H's 7,8 I 15,16 5,6 2,3 1,4 ! .· i ¦I '< * 1 \ M * * 5 * . O S. 5 8.0 7 . $ /.0 t> . * 6 . Q >,ì ^. O 4.S Ï.P 3.C 2.5 2.0 1,5 1 .S pps ß? <-¦ «·> «? >* CS «3· '*H •e r- co o Oj ?; Figure 15. 1H NMR (300 MHz) spectrum of 17 in CDCl3. Other nucleophiles were thus considered. Heating 15 with an excess ethylenediamine in a sealed tube at 150 0C in presence of />-toluenesulfonic acid successfully yielded la (Scheme 21). Although the yield increased from 10% to 18% when temperature was increased from 100 0C to 150 0C but it did not go any higher even 58 after heating at 160 0C for 3 days. In this approach, ethylenediamine was used as a solvent together with 3 equivalents of TsOH. Ä-AT + H N^NH2 TSOK150X' ^VV + HN^NH / 18% HNKAr 15 Ar 1a Ar= Scheme 21. Synthesis of la using ethylenediamine. A proposed mechanism for this reaction is shown in Scheme 22. The reaction begins with the protonation of one of the tertiary aminic nitrogens (I) by tosic acid. Partially ring opened product III forms when electron deficient methylene carbon of II undergoes an intermolecular nucleophilic attack by ethylenediamine. Proton transfer followed by an intramolecular nucleophilic attack to methylene carbon by ethylenediamine gives target compound la, together with imidazolidine as a side- product. 59 Ar Ar ? N H+-QTs $?? > ? N ^ Ar Ar H2N' -NH, Ar Ar -NH -NH ?^\ ~?T HN "Y HoN Ar Ar NH, NH, IV III Ar Ar NH -NH NHc HNVUNH22 'NH Ar HN Ar 1a Scheme 22. Proposed mechanism to la using ethylenediamine. Norbomene backbone is not shown for die clarity. Compound la has been prepared successfully using two different pathways, as shown in Scheme 17 and 21. In order to expand the horizon of alternative synthetic pathway to la, a primary amine 16 was synthesized according to literature procedure by hydrolysis of 10 with aqueous KOH in MeOH at 140 0C followed by protonation (Scheme 23). 60 i)MeOH,aq.KOH, 140 0C, 23 h ------? ii) H+ T NH2 .HCl NH2 .HCl 10 h 16 50% Scheine 23. Synthesis of 16. Wolfe and co-workers108 investigated the Buchwald-Hartwig cross coupling reaction of aryl halides with various primary and secondary amines. Therefore, we explored the possibilities to prepare la by cross coupling reaction of 2-iodo-l,3- dimethylbenzene with 16 using ?G??? as ligand, Pd(II) as catalyst and sodium tert- butoxide as base (Scheme 24). Pd2(dba)3, BINAP NH2,NH2.HClHCl Ar-X, NaO'Bu,, dioxane ^ HfilTThN^Ar 16 Ar = Scheme 24. Buchwald-Hartwig C-N coupling reaction using 16 to prepare la. A variety of conditions were evaluated, ranging from using different solvents, base and ligand equivalents, temperature and reaction time. In the end, a mixture of large number of unidentified species was observed by TLC and 1H NMR. In an instance, 1H NMR 61 spectroscopy showed the disappearance of olefinic resonances possibly due to Heck coupling. 3. 5 Nucleophilic Substitution Reaction To study the electronic effects on the bicyclic scaffold, we decided to prepare pentafluorophenyl-substituted derivatives using 16. Schrock and co-workers used similar methodologies to prepare triaminotriethylamine (TREN) ligand with pentafluorophenyl substituents.109'110'111 C6F6, MeCN, K2CO3 N-C6F5 90 0C, 36h 18 NH2 69% C6F6, DMSO, K2CO3 NH2 .HCl' . N-C6F5 T N-C6F5 NH2-HCI 10O0C, 48h N-A NH2 16 ' O 18 19 C6F5 26% 50% C6F6, DMSO, K3PO4 N-C6F5 + N-C6F5 NH 100 0C, 4Oh 18 NH2 1b C6F5 7% 54% Scheme 25. Nucleophilic substitution reaction of 16. 62 When 16 was treated with excess potassium carbonate and hexafluorobenzene in acetonitrile at elevated temperature, pentafluorophenyl monosubstituted amine 18 was obtained. mm co r-i U)-CJ* O OO oo m CM OJ Oi CO CN CNJ W /\ 6 1 TNH2 3,4 5 6 9 2 7,8 JLL ¦ I ¦ ? ¦ ¦ I ¦ I ¦ ' ' ' I ' ' ' ' I ' ' ¦ ' I ' ' ' ' I ' ¦ ¦ ¦ ? ¦ ¦ ' ¦ ? ¦ ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' · ' 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm Figure 16. 1H NMR (400 MHz) spectrum of 18 in C6D6. H NMR of 18 shows 8 distinct resonances in asymmetric pattern with proper integral ratios (Figure 16). Each resonance integrates to one proton other than the resonance at 2.92 ppm which integrates to 2 protons due to the overlap of one of the 63 bridgehead protons and methine protons next to primary aminic nitrogen. This was confirmed by 2D NMR spectroscopic techniques, such as COSY, HSQC and HMBC. The primary aminic protons could not be observed possibly due to the rapid intermolecular exchange with that of water. H lfi IC "Ï· >i "3- «sr ? C-J id m r- 0 r- tsj r- co O LD -* O CO IO 01 CM COfOH Oi CO If) O IT) 6 1 TNH2 yy*fr>uf'*--ir 23 '* 4 "I I I ""I I 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm Figure 17. JMOD (400 MHz) spectrum of 18 in C6D6. 64 There are 7 distinctive carbon resonances observed for norbornene backbone in JMOD spectrum of 18 (Figure 17). Resonances of methylene carbon appears in the opposite directions to that of the 6 methine backbone carbons, which are expected and reinforces the assignments. ^o r- o fi ¦#¦ «t? ^CfO'rf — Vl OO G? ITi V» «-> VC O \C t^OOOOCTi o O — -*' "? ^t ^OOOQQOO*û 1C 1O ^O ? ^O"Í ^O^? ^D"Í ^D^! G- l~~ t> 7 7 7 7 7 7 7777 L L -155 -160 -165 -170 -175 -180 Figure 18. 1T NMR (300 MHz) spectrum of 18. 19F exhibits a spin quantum number 1=1/2 and the resonances of carbon atoms up to distance of about four bonds are split by coupling to 19F. Weak signals are common 65 problem in fluorinated aromatic species and very often they cannot be assigned explicitly. This problem is further intensified in case of weak sample. Thus, aromatic carbon resonances of perfluorophenyl substituents of 18 are not observed. We observed the similar situation in NMR spectra of 13C of all pentafluorophenyl-substituted derivatives in the current research. There are three resonances in 19F spectra of 18 (Figure 18). They possess proper integral ratio of 2:2:1 for ortho, meta and para fluorines respectively. The resonances are assigned with the help of 19F-19F 2D COSY. There are small resonances observed in the region of -161.5 to -162.5 and at -175 ppm, which belong to unidentified impurities. Molecular formula of the compound 18 was confirmed by high-resolution mass spectrometric technique. The mass was found to be 291.0940 amu which differs by 6.0 ppm from the calculated mass (291.0921 amu). As shown in Scheme 25, compound 18 was observed repeatedly while acetonitrile was used as solvent. Regardless of the reaction conditions (base and perfluorobenzene equivalents, temperature, and reaction time), bis-aryl compound was not even observed. Interestingly, when acetonitrile was replaced with DMSO as reaction solvent, the bis(pentafluorophenyl)-substituted cyclic urea 19 was obtained. IR spectrum shows a sharp carbonyl stretching frequency at 1731cm1 and a medium-broad pentafluorophenyl stretching at 1508 cmT1 which indicate the formation of 19. It was characterized by multinuclear (1H, 13C and 19F) ID and 2D NMR techniques. In the 1H NMR spectrum of 19, There are 5 distinctive resonances observed with proper integral ratios representing the norbornene backbone of 19 (Figure 19). Methine protons adjacent to the nitrogen 66 resonate at 3.92 ppm which is ca. 1.5 ppm more downfield than that of bridgehead protons, due to strongly electron withdrawing effect of the pentafluorophenyl substituents. ,— o Tt *— "?? os s\ \? ^O rf ? V V/ 4,5 C6H6 4,5 CHCI, JL^JÜ ?,? 1 ' ' ' ' ' ' ' ' '· ' ' ' ' ' ' ' ' ' ' ' ? ' ' ' ' ? ' ' ' ' ? ' ' ' ¦ ? ' ' ¦ ¦ ? ' ' ¦ ¦ ? ¦ ¦ ' ¦ I ' ¦ ' ¦ ? ¦ ¦ ¦ ' ? ' ¦ ' ¦ ? ¦ ¦ ¦ ¦ ? 75 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm Figure 19.1H NMR (400 MHz) spectrum of 19 in C6D6. 67 There is a quaternary carbon resonance appears at 155.3 ppm in C Spectrum of 19 (Figure 20). An HMBC experiment shows a correlation between this carbon and the methine proton next to the nitrogen which confirms that this is the carbonyl carbon of the urea moiety. C6D5-H r aromatic CHCl, S Cs JL Mf*r»M»«M|M|»*Mfe' ¦ I I1" ¦¦ I I" ' 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm Figure 20. 13C NMR (400 MHz) spectrum of 19 in C6D6. In contrast to analogous compounds 18 and lb, 19F spectra of 19 shows five resonances (Figure 21). It could possibly be due to the hindered rotation between N-C6F5 bonds. Additionally, there are three resonances at -156.2, -159.0 and -161.3 ppm belong 68 to an unidentified impurity which could not be removed. 19F-19F confirms that this impurity is not a part of 19 since they do not belong to the same spin system as 19. The assigned structure was confirmed by high resolution mass spectrometric technique. Molecular formula of the compound 19 was confirmed by high-resolution mass spectrometric technique. The mass was found to be 485.0522 amu which differs by 5.6 ppm from the calculated mass (483.0550 amu). ss **t On oo vc \o so ^T OO (N 00 " m I I I I I I C6F5 1,5 2,4 ¦ iwihIwiiiiM iniwii il ?\µ*>"»» li ululili un m/V>»hihh ?—¦— -145 -155 -160 y u Figure 21. '9F NMR (400 MHz) spectrum of 19 in C6D6. 69 As shown in Scheme 25, 19 was obtained after changing the reaction solvent from acetonitrile to DMSO. Therefore, it is concluded that DMSO plays a very important role in the formation of the cyclic urea by generating in situ a carbonyl source, possibly decafluorobenzophenone (CoFs^CO. Formation of decafluorobenzophenone has been confirmed as a thermolysis product of 1,1 bis-(pentafluorophenyl)methyl sulfoxide, (CöF5)CHSOCH3 in the reaction of perfluorobenzene and potassium methylsulfinylmethide. Step 1: Generation of free primary amine,16a -NH2HCI -NH, + K2CO3 + CO2 + 2 KCl + H2O NH2HCI ^ MH2 16 16a Step 2: Formation of pentafluoro-phenyl substituted amine, 1b NHv-F -2HF Fv 'NH Scheme 26 (part A). Proposed mechanism for the formation of 19. Norbornene backbone is not shown for clarity. 70 Step 3: Generation of decafluorobenzophenone CH3SCH2-K+ Il K2CO3 + CH3SCH3Il O O *~ CH3SCH2FsCr CH3SCH2 ? CnF16r6 It It O O CH3SCHF5C6 + CH3SCH3 CH3SCH2F5C6Il CH3SCH2-K+it Il I' 0 0 o o -? CH3SCH(F5C6)2 CH3SCHF5C6 > C6F6 It Ö O CH3SCn^F5C65 c6F5^C-0-SCH,M -*- C6F5V0^C6F511 + CH3SH O F5Ce C6F5 O Decafluorobenzophenone Step 4: Formation of bis (pentafluoro-phenyl) substituted urea, 19 Ar Ar Ar_ -NH ^-~*\\ r-C* ^irilH'0 'NH "NH Ar ? Ar Ar H^ cArN?2 Aj^ -ArH 2 -N^O 'NH 'Jh Ar Ar = C6F6r5" Ar Ar Ar Ar Ar ? -N 1x° ArH >=o 'NH Ar !Ar Ar 1 \J* Ar 19 Scheme 26 (part B). Proposed mechanism for the formation of 19. Norbornene backbone is not shown for the clarity. 71 A proposed mechanism for the synthesis of 19 is shown in Scheme 26. It is believed that dimethyl sulfoxide (DMSO) is deprotonated by potassium carbonate to give a nucleophile, potassium methylsulfinylmethide (CH3SOCH2"). This nucleophile reacts with perfluorobenzene to generate 2,3,4,5,6-pentafluorobenzyl methyl sulfoxide C6F5CH2SOCH3 and is readily deprotonated by CH3SOCH2- to give (C6F5)2CHSOCH3, which upon thermolysis in presence of excess perfluorobenzene gives (C6F5)2 CO. Cyclic ureas in general are synthesized using expensive and toxic ?,G-carbonyl- diimidazole114' 115, triphosgene116'117'118 and phosgene.119'120 There are literature precedence to use carbon dioxide as a carbonyl source in the presence of transition metal catalysts for the synthesis of cyclic urea.121'122'123,124 Cyclic ureas are also formed from corresponding cyclic thioureas.125'126 Cyclic urea synthesis is also reported from secondary amine using carbon monoxide and a transition metal catalyst.127 Our observation that cyclic urea can be prepared from substituted amine using metal carbonate, like potassium carbonate, is novel. Potassium carbonate is cheap and relatively non toxic. ' We have used only one substrate to synthesize a cyclic urea using this approach. Furthermore, this strategy could be widely applicable to synthesize derivatives of cyclic urea 10. The bis(pentafluorophenyl)-substituted diamine lb was generated when potassium phosphate was used as a base in place of potassium carbonate (Scheme 25); albeit in very low yield (7%). Attempts were made to increase yield by changing reaction conditions such as changing base and hexafluorobenzene equivalences, temperature, 72 duration of the reaction. In all of the cases mono (pentafiuorophenyl) amine 18 remained to be the major product (by 1H NMR). Compound lb was characterized by multinuclear (13C, 1H and 19F) ID and 2D NMR techniques. In the 1H NMR spectrum of lb, there are 6 distinctive resonances observe with proper integral ratios which correspond to the norbornene backbone of lb (Figure 22). Methine protons adjacent to the nitrogen resonate at 3.62 ppm which is fairly down field than that of bridgehead protons, due to strongly electron withdrawing effect of the pentafiuorophenyl substituents. OO NH* 4,5 impurities"ities CHCl, wmwW W»* ,-JL 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm Ö 9° Figure 22. 1H NMR (400 MHz) spectrum of lb in C6D6. 73 There is a broad resonance at 1.35 ppm in 1H spectrum of lb in Figure 22 which does not show any correlation with any other resonances in 1H- H 2D COSY, that means, this resonance is not a part of lb. This is supported by 13C spectrum of lb (Figure 23) by showing 4 distinct resonances which correspond to the carbons of the symmetric norbornene scaffold. ¦^^HtHr-tooooocooor-r-r- CrF,6r5 aromatic CHCI3 carbon VrtWWn«!^?^»»?»???«^'?*»»'?*??^ îVmw»^»' WW***» '¦¦ ? ? ? ' ' ' 150 140 130 120 110 100 90 80 70 60 50 4 0 ppm Figure 23. 13C NMR (400 MHz) spectrum of lb in C6D6. 74 The carbon resonances of pentafluorophenyl substituents are not observed due to poor carbon signal. There are 3 resonances in 19F spectra of lb (Figure 24) which is consistent with the structure of lb. The resonances possess an integral ratio of 2:2:1 for ortho, meta and para fluorines respectively. 19F-19F COSY confirms the assignments. Molecular formula of the compound lb was confirmed by high-resolution mass spectrometric technique. The mass was found to be 457.0749 amu which differs by 3.0 ppm from the calculated mass (457.0763 amu). I— \A F ÍS Cl oím -3;» ci\q cir-; cir-. ooci _j_J_ ip«EWl|i HMnHMiWlWImmH^mtim» inHiM m -, . 1 , 1 . 1 . 1 . 1 ¦ 1 ¦ 1 ¦ 1 ¦ ?—· 1 ¦ ? ' r—1 ? ' ? -152 -154 -156 -158 -160 -162 -164 -166 -168 -170 -172 -174 -176 -178 ppm Figure 24. 19F NMR (400 MHz) spectrum of lb in C6D6. 75 3.6 Coordination Chemistry In the course of preparing target ligand 1, several intermediate norbornene derivatives including e«Jo-diamine la and corresponding lithiated salt 14a were synthesized. McConville49'52 studied the early transition metal complexes containing diamine ligands in polymerization catalysts, as described in the introductory part of the thesis (Section 1.4.1.1). Peritane, 0 °C W-S. . F©N-Ar2Li® + XsCISiMe3 *- ^TnCN SiMe3 AnAr= ^fl 14a Ar' 2U 14b_ p/ SiMe3 -35 ° C to 80 0C TiCI4,Toluene ,Ar Cl CIN^ Ar-^Ti- 'Cl Cl 1c Scheme 27. Attempted coordination of 14a to titanium. This precedent work encouraged us to study coordination of la and 14a to titanium and zirconium. As a first attempt, 14a was treated with excess trimethylsilyl chloride at low temperature to get trimethylsilyl adduct 14b (Scheme 27), as indicated by H NMR. 1H NMR resonances of 14b with appropriate integral ratios are shown in Figure 25. Due to the poor concentration of the sample, solvent resonances are very dominating. Thus, the resonances of apical protons are overshadowed by that of residual pentane. The characteristics methyl proton resonances of trimethylsilyl group at 0.1 1 ppm 76 together with resonances of the protons of the norbornene scaffold indicate the formation of 14b. Upon observing the formation of 14b, a toluene solution OfTiCl4 was added into the toluene solution of 14b at -35 0C and slowly warmed to room temperature, followed by heating at 80 0C 12 h. Attempted purification of Ic by recrystallizing with different solvents such as pentane, toluene and benzene was not successful. Everything was highly soluble in the recrystallizing solvents. Therefore, preparing titanium complex in this pathway did not proceed further. Peritane, Et20, 4,5, THF C6D5-H 1Tn: _,NS SiMe3 Ar SiMe3 g 7 3 aJLLl 2 THFEto 1 ? y wj • ? ' ' ' ' 5 ppm ?\ Ah M ? Figure 25. 1H NMR (300 MHz) spectrum of 14b in C6D6. 77 In an attempt to prepare zirconium complexes, compound la was treated with tetrakis(dimethylamido)zirconium (IV) in toluene at room temperature to get bis(dimethylamido)zirconium complex Ic (Scheme 28). Recrystallization of Id did not work due to high solubility in pentane. Zr(NMe2U ,Toluene, rt M ^ N'Ar or 3-N N- "Ar -2HNMe, HN^,Ar Ar"N~Zr-'NMe2 Me2N' "¡^Ar 1a NMe2 1d Ar= O ,Ar xs CISiMe3 or Cl' Ar Cl 1e Scheme 28. Attempted coordination of la to zirconium. Excess trimethylsilyl chloride was added to generate the dichloride complex le. A trace amount of pale yellow solid was recovered, but this quantity was not enough to analyse. Therefore, we were interested to prepare Ie directly, not via Id. Annunziata has prepared bis(amidomethyl)pyridine zirconium(IV) complexes by reaction of the corresponding lithiated salt with the THF adduct of zirconium tetrachloride. We, therefore, explored Annunziata's strategy to prepare Ic from 14a as shown in Scheme 29. 78 -35 °C to rt Nq-Ar + ZrCI4. 2THF )£*- ^^'N' °G T N'Ar Ar'"10,,2Li-T CI'£N^ Ar^^lCl 1c 14a Scheme 29. Attempted coordination of 14a to zirconium. Hence, 14b was treated with ZrCl4.2THF at -35 0C to get Ie, as shown in Scheme 29. The reaction mixture was stirred for 24 h. All volatiles were removed, the solid suspended in minimum amount of pentane. The pentane insoluble part showed some shift of the key resonances which were interesting. In the 1H NMR spectrum of Ic (Figure 26, top), one of the aromatic proton resonances shifted and overlapped with that of residual benzene. Resonances of methine protons next to nitrogen shifted downfield significantly. This could be due to the coordination of zirconium to the nitrogen of 14b. There is a broad resonance at 4.55 ppm which could not be assigned. Apical proton could not be observed for being overlapped by residual THF and pentane resonances. There is no significant shift in olefinic carbon observed which indicate that it is unlikely to have any coordination between the olefinic bond and metal. 79 C6D5-H Peritane aromatic H s L_A C.D.-H Figure 26. 1H NMR (400 MHz) spectrum of le (top) and 14b (bottom). 80 Unfortunately, like all other previous attempts, we could not purify this complex. We attempted recrystallization in various solvents such as benzene, pentane and toluene. A pure product has never been obtained. 3. 7 Ring-Opening Metathesis Polymerization ofNorbornene Derivatives Ring-opening metathesis polymerization (ROMP) of norbornene derivatives produce polymers with diverse characteristics, which can be tailored by the functional groups substituted at the backbone. In the course of synthesizing 1, several intermediate norbornene derivatives were prepared. Therefore, we investigated the ring-opening metathesis polymerization of these norbornene derivatives in order to observe the substituent's effect on polymerization process. Furthermore, it will be interesting to explore the properties of the resultant new polymers to enrich the collection of the existing polymer library. Additionally, bis(pentafluorophenyl)-substituted urea 19 will be an excellent candidate for ring opening metathesis polymerization since fluorinated polymers in general exhibit many useful properties, such as high thermal stability, chemical inertness, low dielectric constants and dissipation factors, good resistance to oxidation and aging, low flammability, and very interesting surface properties.131 Fluorinated polymers are very useful as protective coatings since the C-F bond is very stable towards visible and UV-light, making fluorinated polymers resistant to degradation in outdoor applications.132 In ROMP, [M]0 / [I]0 ratios are used to control molecular weight of the polymers; where [M]0 and [I]0 are the initial concentrations of monomer and initiator, respectively. 81 One of the key features of the ROMP is that it provides a uniform rate of the increase of molecular weight. Therefore, a linear correlation between the polymer molecular weight and the [M]0/[I]o ratio is observed.133 The [M]0/[I]o ratio corresponds to the "mer" value. As an example, if the feeding ratio of the monomer over initiator [M]o/[I]o is 20, the resulting polymer is expected to have 20 monomer units. Hence, the polymer is termed as 20-mer. Therefore "mer" value defines the length of the polymers and the theoretical molecular weight of that polymer will be 20 times of the molecular weight of the monomer. The molecular weight distribution is usually measured through determination of the sample's polydispersity index (PDI), which follows the equation: PDI = Mw/Mn, where Mw is the weight average molecular weight, Mn is the number average molecular weight.68 Norbornene derivatives bearing polar groups including amide, ester, and hydroxy groups have been successfully polymerized by ruthenium complexes due to their high functional group tolerances.134'135 Thus, Grubbs first-generation catalyst was chosen as an initiator for the current research since all intermediates norbornene derivatives contain nitrogen functionalities. The ROMP of the norbornene derivatives in current research was carried out in anhydrous dichloromethane at room temperature and terminated by vinyl ethyl ether, a method widely employed in systems of this general 136 type. 82 / \ P(Cy)3 I .ci CH2CI2, rt, 42h Cl r S> P(Cy)3 20mer:75% XXXXX initiator 40mer:65% 12a Scheme 30. ROMP of>-tolyl substituted urea 12. N. .N CDC-H CDCU-H acetone Figure 27. 1H NMR (400 MHz) spectrum of 12; polymer, 12a20 (20-mer, top) and monomer (bottom) in CD2Cl2 83 The resulting polymers were purified by precipitation from methanol and characterized by 1H NMR spectroscopy. A schematic representation of ROMP of 12 is shown in Scheme 30.The 1H NMR spectra of 20-mer (12a20) and 40-mer (12a40) are shown in Figure 27 and 28, respectively. The alkene proton resonances of the norbornene ring appeared at 6.0 ppm. Upon polymerization, these proton resonances disappeared. New broad resonances at 4.9-4.7 ppm for olefinic and methine protons adjacent to nitrogen were observed. CDCL-H e,g a, c jtrra , 12a,'40 I . ¦ . , - ¦ . . , I Ì.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm COCL-H acetone X_J_J I ¦ ¦ ' ¦ I ' ' ' ' I I ' ¦ ¦ ' I I . , , ? , . . . ? . . ? . ? 3.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 Figure 28. 1H NMR (400 MHz) spectrum of 12; polymer, 12a40 (40-mer, top) and monomer (bottom) in CD2Cl2 84 These are characteristics of polymers synthesized from ROMP of norbornene derivatives. ¦ ' 914° The number average molecular weights Mn of the polymers could not be calculated by end-group analysis from 1H NMR, because the resonances of the phenyl end-group overlapped with that of the main-chain tolyl groups (Figure 27 and 28). Thus, the molecular weights of the polymer was determined by gel permeation chromatography (GPC) relative to polystyrene standard and by Matrix Assisted Laser Desorption Ionization-Time of Flight (MALDI-TOF) mass spectrometry using a-cyano- 4-hydroxycinnamic acid as matrix. These are the techniques that widely used for analyzing ROMP of norbornene derivatives.141 The MALDI-TOF mass spectra of 12a20 and 12a40 are shown in Figure 29 and 30, respectively. These spectra show envelopes of polymers of 12 as well as peaks spaced by 330.42 m/z, the mass of each monomer units. Polymer molecular weight distributions are typically characterized by Mn and Mw. These are calculated from Mn = £ (NiMj)ZNi and Mw =S (NiMi2)/NiMi; where N¡ is the total number of macromolecules with a molecular weight of Mj, which corresponds to a degree of polymerization i. The results are tabulated in the table 1 . [Mytry GPC** MALDI*** Yield Mn M, Mw/Mn Mn Mw Mw/Mn Mn(calcd) (%) 20 2011 2903 1.44 3292 4481 1.36 6608 75 40 2152 3261 1.52 3973 4977 1.25 13216 65 Table 1: GPC and MALDI-TOF MS data of 12a20 and 12a40. *iinitial monomer:initiator ratio; **polystyrene standard; ***matrix: a-cyano-4-hydroxy- cinnamic acid 85 100 ^•1598.773 1928.876 2260.008 2590.151 2590.985 2920.906 3251.459 3582.157 3913.092 4244.350 4575.958 4907.989 54229ß? 6090.729 / ^ m/z 2000 3000 4000 5000 6000 Figure 29. MALDI-TOF mass spectrum ofpolymer Ha20- I obtained Mn values by MALDI and GPC for 12a20 are 3292 and 201 1 Da and for 12a40 are 2152 and 3973 Da, respectively. In either cases these values are much lower than those of calculated, 6608 and 13216 Da, respectively. The reason could be the poor solubility of the resulting polymers in THF. The GPC column was conditioned in THF. 86 The polymers were only partially soluble in THF although completely soluble in dichloromethane. Therefore, it is believed only the lower molecular weight polymer strands were analyzed leading to underestimated Mn and Mw. Similar observation was made by Greenberg142 where poor solubility of the polymers led to an underestimated molecular weight in GPC. 2770.786 3100.986 100 \ 3431.853 2769.957 3762.590 2439.766 4093.602 2110.528 1928.541 4424.962 1598.493 4756.739 5089.021 1597.514 5421.833 5755.315 6089.447 6424.404 6760.238 7096.991 7434.671 ul^Uif^i miz 2000 3000 4000 5000 6000 7000 8000 Figure 30. MALDI-TOF mass spectrum of 12a40. 87 In case of MALDI, lower molecular weight polymers might have ionized only which underestimated the molecular weights of the polymers of 12a. Attempted polymerization of 12 into 80 mer was not successful. When polymerization was attempted of la, 10 and 15 in different lengths, no monomer conversion to polymer was observed either. This is possibly due to coordination of the nitrogen atoms to the ruthenium metal centers of the catalyst and deactivates it. This "catalyst poisoning" is not surprising since ruthenium catalysts are sometimes susceptible to be poisoned by monomers with nitrogen functionalities such as nitriles and amines. 143 This "catalyst poisoning" can be prevented if the basicity of the nitrogen of the monomers is reduced by replacing />tolyl group with an electron withdrawing substituents such as pentafluorophenyl. This phenomenon is discussed next. P(Cy)3 I vCI CH2CI2, rt, 48h + Cl' N. .N P(Cy)3 88% Scheme 31. ROMP of 19. The schematic representation of ROMP of 19 is shown in Scheme 32. The alkene proton resonances of the norbornene ring appeared at 6.3 ppm. Upon polymerization, these proton resonances disappeared. Appearance of broad resonances at 5.4-5.0 ppm for 88 alkene and proton adjacent to nitrogen was observed (Figure 31). The number average molecular weight Mn of 21995 was estimated by 1H NMR spectroscopy and found to be larger than the calculated Mn of 19280 Da. In contrast, GPC underestimated the value of 17618Da. C3D5O-H N. N —? ¦ 1 ¦ 1 7.4 7.2 ppm I ' ' ' ' I ' ' ' ' I ' I ¦ ¦ ¦ ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ' ' ' ' I ¦ ¦ ¦ ? ¦ ¦ ¦ ? ¦ ¦ ¦ ¦ ? ¦ ¦ ¦ ¦ ? ¦ ¦ ¦ ? ¦ ¦ ¦ ? Ì.0 7.5 7.0 5.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm U ) K ? 'CfiF;·6G5 N 19 CD.O-H ?,? J 1 JL I ' ¦ ¦ ¦ ? ¦ ¦ ¦ ¦ ? ¦ ¦ ¦ ¦ ? ¦ ¦ ' ¦ ? ¦ ¦ ¦ ¦ ? ¦ ¦ ' ¦ ? ¦ ' ¦ ¦ ? ' ¦ ¦ ¦ t ¦ ? ¦ ¦ ¦ ? ¦ ¦ ? ¦ ¦ ¦ ? ¦ ¦ ¦ ¦ ? ¦ ¦ ? ì.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm Figure 31. 1H NMR (400 MHz) of 19; monomer (bottom) and polymer 19a (top) in (CD3)2CO. Expanded resonances of aromatic end-group ofpolymer is shown inset. The average molecular weight of polymer 19a was estimated by establishing a ratio of the intensity equal to the number of the protons that correspond to the polymer 89 multiplied by the repeating unit over the intensity equal to the number of protons that correspond to the end group. This can be shown by the equation below. 37.1/1= (4n+3)/5 ? = number of repeating units = 45.6 Mn = 45.6 ? 482 = 21995 Da. (molecular weight of a monomer is 482 Da) In case of Mn of NMR, the value is slightly overestimated. Even though the spin- lattice relaxation time, Ti of the NMR spectrometer was adjusted but seem to be aromatic protons still did not relax completely, therefore lower integration resulted. In case of Mn of GPC, the obtained value is relative to the polystyrene, not an absolute value. GPC underestimated the standard polystyrene sample by 3500 Da. Therefore, Mn of the sample also underestimated. Hence, there was no coordination took place between nitrogen atoms and ruthenium metal centre. The broad molecular weight distribution (Mw/Mn = 2.19) of 19a may be attributed to a rapid propagation rate versus slow initiation and to back-biting of the internal olefins during polymerization.136 Thus, Mn value in GPC and H NMR data indicate that in contrast to the tolyl substituted urea 12a, ROMP of the pentafluorophenyl substituted urea 19a was well behaved. The catalyst was not poisoned by the monomer, because of the much lower basicity of the pentafluorophenyl- substituted nitrogen atoms.144 MALDI-TOF of 19a attempted using a-cyano 4-hydroxycinnamic acid and a- cyano 4-hydroxycinnamic acid plus CuBr. Despite changing matrices, the concentration of the sample and the laser power, no ionization observed due to the unfavorable 90 interaction between the matrix and fluorinated polymer itself. This unfavorable interaction is common when hydrophobic samples such as the fluorinated polymers are analyzed. 5 To overcome that problem, other matrices, such as pentafluoro benzoic acid (PFBA) or pentafluoro cinnamic acid (PFCA) could have been used. 3. 8 Functionalization ofSecond Olefinic Bond ofNorbornene Scaffold Kiss and co-workers146 studied the epoxidation of the olefinic bond of cyclopentene derivatives in the presence of meto-chloroperbenzoic acid (mCPBA) in dichloromethane. CH2CI2, 0 0C N-Ac N-Ac mCPBA 64% Scheme 32. Epoxidation of 9. We explored the similar strategy to functionalize the second double bond of the norbornene scaffold. Compound 9 was oxidized using mCPBA at 0 0C in dichloro- methane to get the epoxide adduct 11 in 64% yield (Scheme 33). 91 r~ OO eg G- (Tí O CN r- eg en ^D fO CTi U3 pH o in ¦vT· ^T CO CO ci m eg 1 TN O 4,5 CHCI5 CH2CI2 J IL· ä·0 7·5 7·0 6·5 6-0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 ppm ? Figure 32. 1H NMR (300 MHz) spectrum of 11 in CDCl3. Although no further work was done with this molecule, it offers insights into how la could be further functionalized towards synthesizing the final target ligand 1, as outlined in Scheme 33 in the chapter on Future Work. There are six resonances observed in the H NMR spectrum (Figure 32) with correct integral ratios are consistent with the structure of 11. 92 1 3 H1TN O 4,5 3H NA 1 Ac O W i r * ,» 3.5 3.0 Figure 33. 2D NOESY (400 MHz) experiment of 11 in CDCl3. Disappearance of the olefinic protons and appearance of the new resonances at 3.02 ppm indicates the formation of an epoxide. The IR stretching frequency of the C-O from the epoxide functionality appears at 1240 cm-1, which reinforces the proposed structure. There are two sharp carbonyl stretching frequencies are observed at 1743 cm" and 1698 cm"1 for the acetate and urea moieties, respectively. 2D NOESY experiment (Figure 33) shows no spatial correlation between methine protons of the epoxide moiety and apical protons, which indicate that the epoxide is in exo position. 93 3. 9 Computational Studies Due to the high accuracy, Density Functional Theory (DFT) has been proved to be very powerful tools in manipulative molecular properties of the organometallic compounds. ' Together with experimental results, theoretical calculations provide mechanistic details about organometallic complexes and intermediates.149 Schrock's molybdenum catalyst (Figure 3) has been extensively studied by DFT calculation which contributed enormously to this catalytic system to understand mechanism, characterization of all isolated intermediates and to determine the most feasible state of the catalyst thermodynamically.150'151 Hence, DFT calculations were performed on the proposed molybdenum and tantalum complexes of the final target ligand 1. For Mo (IV), the spin-restricted singlet state was found to be 6.3 kcal/mol more stable than that of the spin-unrestricted triplet state. Furthermore, the singlet wave function was found to be stable, and therefore was used for subsequent calculations. The symmetry was determined to be Cs, with the dinitrogen tilted at an angle of 36° away from the normal, due to the effects of the lone-pair of electrons on the Molybdenum. The tantalum dinitrogen complex was converged in C2v with the dinitrogen aligned axially. The extent of dinitrogen activation can be estimated by i) the extent of elongation of N == N bond compared to that of free nitrogen; and ii) by a decrease in the IR dinitrogen stretching frequency. The greater the increase in bond length and a decrease in stretching frequency the better nitrogen activation has likely taken place.152,153 Upon coordinating to the metals, the N = N bond length increases by 0.10  and 0.07  for 20 94 : a) b) Figure 34. Geometry optimized structure of a) [Ta](N2) 20 and b) [Mo](N2) 21 complexes. and 21, respectively compared to that of free dinitrogen, which was calculated to be 1.09 Â. The calculated N-N IR stretching frequency for 20 and 21 were determined to be 1835 cm"1 and 2005 cm"1 respectively. The Vn = N of free dinitrogen is 2331 cm"1.154,155 Furthermore, the Ta-N2 bond length is calculated to be 2.03 Â, which is 0.06  shorter than that of molybdenum. Based on these observations, Ta would appear to be better at activating dinitrogen than Mo. 95 ..- .. · U 59 -B-" --"T' ,--<¦ ? I -;¦ - ? O 55 feSI 40 60 % Composition I Ta S&P F^-Tl Ta D I I NBD a " ¦ M -.::¦¦ ? bl al b2 b2 ¦¦·¦¦¦¦::-* · · ¦ ¦¦ · - i -1^- ? al -----: JM- .,.' t———r-t? 1.1. . ¦—r- al '·". ¦ "I bl O .b2 54 -K a2 bl 52-ES2 b2 ¡^ k'.;-w-','y""·''·! lai so -^???2?? b2 20 40 60 80 100 % Composition Ta S&P EgSl Ta D NBD ß Figure 35. MO Compositions for [Ta](N2) 20 for both a (top) and ß (bottom) spin orbitale. Breaks are shown between occupied and unoccupied orbitals. NBD represents norbornane backbone. 96 61 ¦ 60 // 59 58 -?. ¦_¦¦¦. 57 ¦-."" . ' 7:ff? 56 // * ^n- 55 _1 '¦-* - ¦ ¦¦ --.¿? 54 ¦ 1 // 53 52 // *£& S 49 O 20 40 60 80 100 % Composition Mo S&P G^~1 Mo D I 1 NBD ^H N2 Figure 36. MO Compositions for [Mo](N2) 21. Molecular orbital 55 is the HOMO, while 56 is the LUMO. The orbital compositions for 20 and 21 are shown in Figure 35 and 36. For 20 it can be seen that the a-spin SOMO and LUMO both have an appreciable amount of dinitrogen character. These orbitals are paired with the LUMO and LUMO+ 1 of the ß- spin. For 21 there is 22 % dinitrogen character in the HOMO, 43 % in the LUMO and 65 % in the LUMO+2. There is also a large amount of Mo (d) character in the HOMO (59%). The LUMO of 21 is highly mixed with 26 % Mo (d), 27 % norbornane backbone (nbd),43%N2. 97 3.H-3^L,H^L+3 [Mo](N2) [Ta](N2) 3. H-2ß^Lß f 2.H-I^L co U) (O l.Hp^Lp l.H^L 30000 25000 20000 15000 10000 5000 Wavenumbers /cm" Figure 37. Predicted electronic spectra for [Ta](N2), 20 and [Mo](N2) 21. The ß subscript denotes an orbital with a beta spin. The predicted electronic spectra for 20 and 21 are shown in Figure 37. The molybdenum complex shows a weak low energy HOMO->LUMO transition at 6850 cm"1. Two more intense transitions are observed in the visible region, the lower energy transition at 18500 cm1 is assigned as a HOMO-I^LUMO transition (Figure 38a). The higher energy transition (22900 cm"1) is the result of three nearly equal intensity transitions, which result in a highly mixed transition. Using SWarlock, this peak was determined to be 31% Mo (d), 62 % nbd -» 40 % nbd, 37 % Mo (d) (Figure 38b). For both 20 and 21, the compositions of the transitions in the visible region are highly mixed and somewhat misleading. The figures presented help to clarify matters and 98 show that there is quite a lot of nbd^metal/N2 LMCT/LLCT. The reason the contribution OfN2 is so low numerically is likely since it is only two atoms, while the electron density on the nbd ligand is distributed throughout more (ten non-hydrogen atoms) atoms smoothing over their visual effect. a b Figure 38. Change in electron density distribution for 21 for a) peak 2, and b) peak 3, in the calculated absorption profile. Red indicates excess charge in the ground state, while green indicates excess charge in the excited state. 99 a Figure 39. Change in electron density distribution for 20 for a) peak 1, and b) peak 2 and c) peak 3, in the calculated absorption profile. Red indicates excess charge in the ground state, while green indicates excess charge in the excited state. 100 The figures of the change in charge distribution for these two peaks indicate that the Mo-N (dinitrogen) bond is highly involved. The tantalum complex, 21, shows two weak low energy transitions. The charge in both cases originates in the SOMOß and ends at the LUMOp for the lower energy transition, and the LUMO+lp for the slightly higher energy transition. There is a single relatively intense transition in the visible region (25,250 cm"1), which is the result of two electronic transitions. These transitions are comprised of several orbitals interacting with both a and ß spins (albeit with the same spin for each orbital interaction). Overall, this transition is 71 % nbd, 18 % N2, 10 % Ta (d) -> 35 % Ta (d), 29 % nbd, 25 % N2, 1 1 % Ta (s & p), which is highly mixed. Dr. S.I Gorelsky also did calculations on our behalf where nitrogen donor atoms were substituted by oxygen (Figure 40 and 41). DFT calculations on the [Ta](N2) complex, 20' (Figure 40), showed no p-back-donation from metal to nitrogen. Sigma donation form N2 HOMO to the metal fragment LUMO is the dominant interaction. A p- electron donation from N2 HOMO-I and HOMO-2 to the metal fragment LUMO+1 is however also possible. Natural population analysis of nitrogen has a positive value of 0.165 suggests that there is a significant charge populated on the metal in 20' which help in activation of dinitrogen. This is further supported by the energy of interaction of -24.8 kcal/mol for 20' which is lower than that of21' (-1 1.8 kcal/mol, Figure 41). 101 Ta IVL-N2 Complex ,Ta .t~%. LUMO* 1 +3.0V«'·. LUMO +11.8%, d 92". Ta S HOMO 11.1% _^_H0MO-1 2.3% HOMO-2 4.1% p TalvL ...... &-*'· ¦wUöjnüion from N3 N, 's Donation from N. (j-spin orbitali Eint= -24.8 kcal mol·1 qNPA(N2)=+0.ie5 N-N: 1.19 A Figure 40. [Ta](N2) complex, 20'. A new model system with nitrogen replaced by oxygen. Only ß-spin orbitals are shown. Upon coordinating to tantalum, N = N bond length increases by 0.10  compared to that of free dinitrogen which is calculated to be 1.09 Â. This observation is consistent with our previous calculation on complex 20. The [Mo](N2) complex, 21' (Figure 41) indicate that upon binding, the dinitrogen donates electron density to the LUMO and LUMO+2 of the metal and participates in p- interactions with the metal fragment HOMO. 102 Mo,vL-N2 Complex "¦—¦?;.., M>>t! ^^^^ ^ /lUMO +7.6' LUMO+¿-<7.4% *ì* LUMO \ +2.8% p Back-donation to N, HOMO -10.8% ¦\. H / \ s Donation from N2 \ H HOMO * -8.6% N, E1n,= -11.8 kcal mol·1 B.O. (N-N) = 2.65 (1.14 A) to 2.32 (1.18 Á) ECT = -34.8 kcal mol·1 B.O. (Mo-N) = 0.43 (2.13 A) to 0.91 (1 .99 A) Back-donation and donation qNPA(N2)= -0.036 to -0.38 similar magnitude Complex Figure 41. [Mo](N2) complex, 21 '. A new model system with nitrogen replaced by oxygen. This results in the bond order of nitrogen to be reduced down to 2.65 from 3.00, while the bond order for Mo-N is 0.43. Another observation is the back-donation and donation is of a similar magnitude indicating comparable sharing of electrons between the ligand and metal. Natural population analysis of nitrogen has a negative value of 0.036 indicates that the charge distribution between metal and nitrogen favors nitrogen slightly. It is further supported by energy of charge transfer of -38.4 kcal/mol from metal-to-nitrogen. Thus nitrogen is poorly activated in 21'. Upon coordinating to molybdenum, N = N bond length increases by 0.05  compared to that of free dinitrogen 103 which is calculated to be 1 .09A. Ifthe system is reduced by one electron then the value of natural population analysis of nitrogen becomes -0.38 which means nitrogen gains more electron density through back-donation from metal. Therefore, bond order of nitrogen further reduced to 2.32 and the bond order for Mo-N becomes 0.91 . 3.10 Summary and Future Work As a short-term goal, ewflfo-diamine ligand systems la and lb were prepared, p- Tolyl substituted ligand la was synthesized via employing two different pathways: (a) through nucleophilic attack by MeLi, and (b) through addition of ethylenediamine in presence of /j-toluenesulfonic acid as a proton source. Pentafluorophenyl-substituted ligand lb was prepared via nucleophilic substitution reaction of hexafluorobenzene with primary amine 16. These bicyclic ligand systems, la and lb enhance the growing body of literature of ligand systems with rigid skeleton containing nitrogen donor atoms. New bicyclic ureas were prepared. />-Tolyl substituted cyclic urea 12 was prepared by cross-coupling of 4-iodotoluene with cyclic urea 10 catalyzed by CuI in presence of potassium phosphate as a base. On the other hand, bis(pentafluorophenyl)- substituted cyclic urea 19 was prepared in a novel synthetic pathway using metal carbonate as a carbonyl source. This is an economical and environmental friendly pathway to obtain cyclic ureas that usually require expensive and toxic phosgene119, triphosgene, or 1 , 1 '-carbonyl-diimidazole1 14. Another short-term goal was to study the ring-opening metathesis polymerization of two new cyclic ureas 12 and 19 employing Grubbs first-generation ruthenium catalyst. 104 In case of electron rich p-to\y\ substituted urea 12, the catalyst was poisoned by coordination of the electron rich nitrogen atoms. In contrast, the electron-withdrawing pentafiuorophenyl substituted 19 produced polymers with expected molecular weight illustrating the effect of the substituents on the catalytic activity. All the new molecules prepared as intermediates to the target tetrasubstituted ligand 1 were fully characterized. New chemistry developed, especially for the synthesis of bicyclic vicinal endo-amines (la, lb) and -ureas (12, 19). This new chemistry will undoubtedly flourish. Spectroscopic data of previously reported compounds 3 and 10 were described in this thesis since no data for those two compounds had been published. Coordination chemistry was attempted on the endo-âiamine la and corresponding lithiated salt 14a to Group 4 transition metals. Due to high solubility of the resulting products, purification by recrystallizing with different solvents such as pentane, toluene and benzene had not been successful. Target ligand 1 will be prepared from la via functionilaztion of the second olefinic bond, as proposed in Scheme 34. Oxidation of la could give 22. endo-Oiamine could be converted to the corresponding tosylate 22a by treating with />-toluenesulfonyl chloride (TsCl) in presence of pyridine. Nucleophilic attack by lithium anilide to 22a could then give a product 22b with three amine functionalities in endo position. 105 CH2CI2, O 0C to rt mCPBA HN-^A 1a Ar 22 Ar TsCI1Py ArNHLi+ NHAr 22a TsCI ¡) ArNHLi+ U)HCI NHAr FsN^Ar ArA;NHNHHNÍÍ^Ar.(4HCI) TsN^AAr 22c Scheme 33. Proposed pathway to prepare target ligand 1. The resulting exo-alkoxide will be converted to its corresponding tosylate. Nucleophilic attack by lithium anilide followed by protonation will give target ligand 1 as its hydrochloride salt. In conclusion, the work describe in this thesis has established the procedure to synthesize various intermediates for the preparation of the target ligand 1. 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