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A modified synthesis, C-functionalization, esolutionr and racemization kinetics of cross -bridged tetraazamacrocycles
Antoinette Yolanda Odendaal University of New Hampshire, Durham
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Recommended Citation Odendaal, Antoinette Yolanda, "A modified synthesis, C-functionalization, esolutionr and racemization kinetics of cross -bridged tetraazamacrocycles" (2009). Doctoral Dissertations. 481. https://scholars.unh.edu/dissertation/481
This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. A MODIFIED SYNTHESIS, C-FUNCTIONALIZATION, RESOLUTION AND
RACEMIZATION KINETICS OF CROSS-BRIDGED
TETRAAZAMACROCYCLES
By
Antoinette Yolanda Odendaal
B.A., University of Southern Maine, 2003
DISSERTATION
Submitted to the University of New Hampshire
in Partial Fulfillment of the Requirements for the Degree of
Doctor of Philosophy
in
Chemistry
May 2009 UMI Number: 3363725
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ttionlDirector
Weisman
Professor of Chemistry
S^Z>(AJ~*W^&)' Edward H. Wong
Professor of Chemistry
Charles K. Zercher
Professor of Chemistry
Arthur Greenberg
Professor of Chemistry
Donald C. Sundberg
Emeritus Professor of Material Science
te R\o daft Date DEDICATION
In memory of my grandfather Jacob Smit
September 2, 1920-May 4, 1989
in ACKNOWLEDGMENTS
Funding Sources:
Chemistry Department Teaching Assistantship (September 2003-Decmeber 2005).
NSF GK-12 PROBE Fellowship (May 2006-May 2007).
NIH Research Assistantship (January 2006-May 2006, May 2007-January 2009).
People:
I thank my advisor Gary Weisman and my co-advisor Ed Wong for their mentorship, guidance and support over the years. I would like to acknowledge my
committee members and thank them for all their suggestions.
This research was aided directly and indirectly by contributions from the
Weisman/Wong group members past and present.
I would also like to thank the Chemistry Department at UNH and Professors
Charles Zercher, Arthur Greenberg, Denny Chasteen, Howard Mayne, Roy Planalp, Glen
Miller, Richard Johnson, Sterling Tomellini, Chris Bauer, Pat Wilkinson, Meg
Greenslade, Rudy Seitz.
I greatly appreciate all the help and support from Cindi Rohwer and Peggy Torch.
Special thanks:
Abe, Nicolette, Orjana and my family.
iv TABLE OF CONTENTS
DEDICATION iii
ACKNOWLEDGMENTS iv
TABLE OF CONTENTS v
LIST OF FIGURES xi
LIST OF SCHEMES xiv
LIST OF TABLES xviii
LIST OF GRAPHS xix
ABSTRACT xx
CHAPTER 1: A TRICYCLIC BISAMINAL ROUTE TO CROSS-BRIDGED
CYCLAM AND HOMOCYCLEN, AND THE MICROWAVE-
ASSISTED DOUBLE REDUCTIVE RING OPENING OF
DIBENZYL BISAMINAL SALTS
I. Introduction 1
II. Background 10
III. Results and Discussion 23
1. Synthesis of A^,Ar'-bis(2-aminoethyl)-l,3-propanediamine (23). 23
2. Synthesis of cw-octahydro-lH,4H,7H-l,3a,6a,9- 24
tetraazaphenalene (49).
3. Synthesis of cz's-decahydro-lH^H-Sa^a^a, 10a- 24 tetraazapyrene (13).
4. Synthesis of c«-decahydro-5H-2a,4a,7a,9a- 26
tetraazacyclopentaphenalene (12).
5. Microwave-assisted reductive ring opening of 14,15 and 16. 27
6. Alkylation of c/s/fr tetraazapyrene (13) followed by microwave-assisted reductive ring-opening. 7. Synthesis of 2a,7a-(prop-2-en-l-yl)decahydro-5H-4a,9a- 32 diaza-2a,7a-diazoniacyclopenta[cd]phenalene dibromide (54). 8. Synthesis of 4,1 l-di(prop-2-en-l-yl)-l,4,8,11- 34 tetraazabicyclo[6.5.2]pentadecane (55). 9. Synthesis, characterization, and properties of copper(II) 1,4,8,11- 35 tetraazabicyclo[6.5.2]pentadecane (9) complex. 10. Synthesis and copper (II) complexation of 4,11-bis- 39 (carboxymethyl)-1,4,8,1 l-tertaazabicyclo[6.5.2]pentadecane (58). IV Conclusions 45 CHAPTER 2: PROGRESS TOWARDS A C-FUNCTIONALIZED CROSS- BRIDGED CYCLAM I. Introduction 46 II. Background 49 III. Results and Discussion 54 VI 1. Attempted synthesis of a carbonyl-functionalized cyclam 54 bisaminal 85. 2. The synthesis of c/s-2-methylidenedecahydro-lH,6H- 56 3a,5a,8a,l Oa-tetraazapyrene (92). 3. Attempted ozonolysis of 92. 59 4. Attempted alkylation of 92. 60 5. The synthesis of c/s-3a,8a-bis(phenylmethyl)-2- 60 methylidenedecahydro-lH,6H-5a,10a-diaza-3a,8a- diazoniapyrene dibromide (98). 6. The synthesis of 4,11 -bis(phenylmethyl)-6- 61 methylidene, 1,4,8,1 l-tetraazabicyclo[6.6.2]hexadecane (99). 7. The synthesis of c«-2-methylidine-3a-8a-bis(naphthalene-2- 63 ylmethyl)decahydro-l H,6H-5a,l 0a-diaza-3a-8a-diazoniapyrene (100). 8. The synthesis of 6-methylidene-4,11 -bis(napththalene-2- 64 methyl)-1,4,8,1 l-tetraazabicyclo[6.6.2]hexadecane (101). 9. The attempted deprotection of 99 and 101. 64 10. The synthesis of cw-decahydro-lH,6H-3a,3a,10a-tetraazapyren- 66 2-yl methanol (104). 11. The synthesis of 3a,8a-di(phenylmethyl)-2- 71 (hydroxymethyl)decahydro-1 H,6H,a, 10a-diaza-3a,8a- diazoniapyrene (107). 12. The synthesis of 4,11-di(phenylmethyl)-1,4,8,11- 71 vii tetraazabicyclo[6.6.2]hexadec-6-yl) methanol dihydrobromide monohydrate (108«2HBr»H2O). IV. Conclusions 73 CHAPTER 3: RESOLUTION OF RACEMIC CROSS-BRIDGED CYCLAM BY DIASTEREOMERIC SALT FORMATION AND THE RACEMIZATION KINETICS OF ENANTIOPURE CROSS- BRIDGED CYCLAM I. Introduction 74 II. Background 76 III. Results and Discussion 83 1. Resolution of bicyclo[6.6.2]tetraamines by selective 83 crystallization of their diastereomeric salt mixtures. 1.1. Preparation of 4,1 l-bis(phenylmethyl)-l,4,8,ll- 84 tetraazabicyclo[6.6.2]hexadecane (5',5)-(+)-dibenzoyl- D-tartrate (1:1 diastereomeric mixture) (119). 1.2. Preparation of 4,1 l-bis(phenylmethyl)-l,4,8,11- 85 tetraazabicyclo[6.6.2]hexadecane L-(+)-tartrate (1:1 diastereomeric mixture) (120). 1.3. Preparation of 1,4,8,11 -tetraazabicyclo[6.6.2]hexadecane 86 di-(15)-(+)-camphorsulfonate (1:1 diastereomeric mixture) (121). viii 1.4. Preparation of 1,4,8,11 -tetraazabicyclo[6.6.2]hexadecane 86 (5',5)-(+)-dibenzoyl-D-tartrate (1:1 diastereomeric mixture) (122). 1.5. Preparation of 1,4,8,11 -tetraazabicyclo[6.6.2]hexadecane 87 L-(+)-tartrate (1:1 diastereomeric mixture) (123). 1.6. Preparation of 1,4,8,11 -tetraazabicyclo[6.6.2]hexadecane 93 D-(-)-tartrate (1:1 diastereomeric mixture) (125). 2. Racemization kinetics of enantiopure (S^-IO. 96 IV. Conclusions 102 CHAPTER 4: COMPUTATIONAL INVESTIGATION OF NITROGEN LONE PAIR ORIENTATION EFFECTS ON THE METHINE NMR PARAMETERS OF TRICYCLIC ORTHOAMIDES I. Introduction 103 II. Background 105 III. Results and Discussion 106 1. Computational methodology 106 2. Computational results 107 IV. Conclusions 111 CHAPTER 5: EXPERIMENTAL DETAILS I. General methods 112 II. Solvents 113 ix III. Reagents 115 IV. Column Chromatography 116 V. Experimental Procedures 116 VI. Fractional Crystallization of 123 (1:1 diastereomeric salt mixture). 144 VII. Recovery of enantiopure free base (S,S)-10 and the preparation of 147 (S,S)-4,\ 1-bis-(carbo-tert-butoxymethyl)-1,4,8,11- tetraazabicyclo[6.6.2]hexadecane (133). VIII. Optical rotation of (S.S^cross-bridged cyclam (10). 150 IX. Kinetics of racemization of cross-bridged cyclam (10). 152 APPENDIX A: SPECTRAL INDEX 156 APPENDIX B: COMPOUND INDEX 210 REFERENCES 216 x LIST OF FIGURES Figure Page 1 Cis and trans configurational geometries. 3 2 Cross-bridged cyclam (10). 3 3 Copper(II) complexes of 3 and 10 with the hydrogens omitted. 7 4 Ligands CB-TE2A (20), TE2A (21) and bioconjugate 22. 8 13 ! 5 C{ H} and 'HNMR spectra (C6D6) of 13 containing a minor 30 amount of 40. U : 6 C{ H} and 'HNMR spectra of 16 in D20 (ref. MeCN). 31 7 "C^H} and 'H NMR spectra of dibenzyl cross-bridged cyclam 19 in 32 C6D6. 8 [CuC104'9](C104) Dimer (extra C104 omitted for clarity). 37 9 The copper(II) complexes of 8 and 10. 38 = 10 Visible spectra (A,max 575 nm) and pseudo-first order kinetics plot of 39 the acid-decomplexation of [CuC104«9](C104) in 5M HC1 at 50 °C. 11 X-ray crystal structure of Cu«58 with the hydrogens omitted. 41 12 Visible spectra (Xmax = 607 nm) and pseudo-first order kinetics plot of 43 the acid-decomplexation of Cu«58 in 5M HC1 at 50 °C. 13 Comparative kinetic inertness of Cu»60, Cu»58 and Cu»20. 43 14 Comparative X-ray structures of Cu»60, Cu»58 and Cu»20. 44 15 The *H NMR spectra of 92 and 93 in CDC13. 58 16 Ortep diagram of 98 (hydrogens omitted). 61 xi 17 Ortep diagram of the 99«HPF6 salt (ligand hydrogens omitted). 63 18 Possible hydroboration-oxidation reaction outcomes. 67 19 Approximate coupling constants expected for H2eq of 104 and 105. 68 20 Crystal structure of 104»2HBr (ligand hydrogens omitted). 69 21 The intermolecular hydrogen bonds between two 104 molecules 70 (ligand hydrogens omitted). 22 Equatorial methanol C-functionalized JV.iV'-dibenzyl cross-bridged 72 cyclam 108»2HBr»H2O. 23 Dideuterated cross-bridged[6.6.2]tetraamines. 79 24 Enantiopure chiral acids considered for 1:1 diastereomeric salt 83 formation. 25 'H NMR spectra of 123,123a and 123b in MeOH-d4 (TMS). 90 26 1:1 Diastereomeric mixture of 123. 90 27 X-ray structure of 124 (anions and C-H hydrogens omitted for 93 clarity). ! 28 H NMR spectra of 125,125a, 125b and 127 in MeOH-d4 (TMS). 95 29 1:1 Diastereomeric mixture of 125. 95 30 Diastereomer 127. 96 31 Kinetics experiment: !H NMR spectra of diastereomeric salts 123 in 97 MeOH-d4 (TMS). 32 Hyperconjugation and dipolar interaction. 104 33 Tetrahydropyran. 105 34 Optimized structures: B3LYP/6-311G+(d,p). 107 xii 35 Fractional crystallization of 123 (1:1 diastereomeric mixture). 146 xiii LIST OF SCHEMES Scheme Page 1 Cross-bridged tetraazamacrocycles synthesis. 4 2 cis-Tetracyclic bisaminal dialkylation (dialkylation of one 5 conformational enantiomer of 13). 3 Double-reductive ring expansion. 6 4 Pendant-armed cross-bridged tetraazamacrocycles. 7 5 van Alphen's cyclam synthesis. 10 6 Synthesis of a tetraazamacrocycles from tosyl-protected polyamine- 11 polyamides 24. 7 The Stetter-Richman-Atkins macrocyclization to polyamines. 11 8 The use of an inorganic base in macrocycle synthesis. 12 9 A tricyclic bis-amidine route to tetraazamacrocycles. 13 10 A diamide intermediate to cyclam. 14 11 A metal-templating synthesis of cyclam. 14 12 A bisaminal tetraazamacrocycle synthesis. 15 13 A dimethyl tricyclic bisaminal route to cyclic polyamines. 15 14 A pyruvic aldehyde condensation. 16 15 Thermodynamic and kinetic isomers of tricyclic bisaminal. 17 16 The use of a cz's-tricyclic bisaminal in the synthesis of cross-bridged 19 tetraazamacrocycles 9 and 10. 17 Synthesis of JV,iv"-bis(2-aminoethyl)-l,3-propanediamine (23). 23 xiv 18 The synthesis of tricyclic bisaminal 49. 24 19 Synthesis of cz's-decahydro-lH,6H-3a,5a,8a,10a-tetraazapyrene (13). 25 20 Formation cis and trans isomers 13 and 40, respectively. 26 21 Synthesis of c/s-decahydro-5H-2a,4a,7a,9a- 26 tetraazacyclopentaphenalene (12). 22 Microwave-assisted reductive ring opening. 28 23 The synthesis of 19 from 13 containing a minor amount of trans 40. 29 24 Synthesis of tricyclic tetraamines from A^N'-diallyl cross-bridged 33 tetraazamacrocycles. 25 Synthesis of 54. 33 26 Microwave-assisted reduction of 54 with NaBH4. 34 27 A conventional reductive ring opening of 54 with NaBI-bCN. 35 28 Synthesis of CuCl2'9. 35 29 Synthesis of [CuC104'9](C104). 36 30 Synthesis of 58. 40 31 Preparation of Cu»58. 40 32 Condensation of an acyclic tetraamines with a substituted diethyl 47 malonate. 33 A metal-templating approach to a C-functionalized 47 tetraazamacrocycle 67. 34 A tricyclic bisaminal route to C-functionalized tetraazamacrocycles. 49 35 Preparation of a di-benzyl C-functionalized cyclam derivative using 50 the tricyclic bisaminal route. xv 36 Preparation of a C-functionalized cross-bridged cyclam bifunctional 51 chelator. 37 The proposed strategy for the synthesis of a C-functionalized cross- 53 bridged cyclam derivative. 38 Attempted synthesis of a carbonyl-functionalized tricyclic bisaminal. 54 39 Attempted alkylation of 49 with an acetal. 55 40 Claisen condensation followed by a decarboxylation to 1,3-di- 55 morpholin-4-yl-propan-2-one (89). 41 A proposed route to 85 by a Claisen condensation and subsequent 56 decarboxylation. 42 Synthesis of c/s-2-methylidenedecahydro-lH,6H-3a,5a,8a,10a- 57 tetraazapyrene (92). 43 Preparation of 3-bromo-2-(bromomethyl)-l-propene (94). 59 44 The attempted ozonolysis of 92. 59 45 Attempted alkylation of 92. 60 46 Benzylationof92. 61 47 Microwave-assisted reductive ring opening of 98. 62 48 Synthesis of c/s-2-methylidine-3a-8a-bis(naphthalene-2- 63 ylmethyl)decahydro-lH,6H-5a,10a-diaza-3a-8a-diazoniapyrene (100). 49 Microwave-assisted reductive ring opening of 100. 64 50 Potential route to an olefinic C-functionalized cross-bridged cyclam 65 103. 51 Proposed hydroboration/oxidation of 92. 66 xv i 52 Hydroboration/oxidation of 92. 68 53 Synthesis of 107. 71 54 C-Functionalized dibenzyl cross-bridged cyclam 108»2HBr»H2O. 72 55 In/out isomerism of the ammonium salts of bicyclo[k.l.m]amines. 77 56 Homeomorphic isomerization. 77 57 Preparation of dideuterated cross-bridged[6.6.2]tetraamines. 79 58 Preparation of a 1:1 diastereomeric mixture of 114. 81 59 Preparation of a diastereomeric carbamate cyclam derivative. 81 60 Preparation of a 1:1 diastereomeric salt mixture. 83 61 The preparation of 119 (1:1 diastereomeric mixture). 85 62 The preparation of 120 (1:1 diastereomeric mixture). 85 63 The preparation of 121 (1:1 diastereomeric mixture). 86 64 The preparation of 122 (1:1 diastereomeric mixture). 86 65 The preparation of 123 (1:1 diastereomeric mixture). 88 66 Recovering enantiopure 10. 92 67 The preparation of 125 (1:1 diastereomeric mixture). 94 68 Recovery of enantiopure (S^-IO. 147 69 Preparation of enantiopure 133. 147 XVII LIST OF TABLES Table Page 1 Conventional reaction times and yields of the reductive ring expansions. 20 2 Microwave-assisted reductive ring opening of bisaminal salts 14-16. 28 3 [CuC104'9](C104) Selected bond lengths. 37 4 Selected bond lengths for complexes A and B of Cu»58. 42 5 Percent enantiomeric excess as a function of time (kinetics run no. 1). 98 6 Percent enantiomeric excess as a function of time (kinetics run mo. 2). 100 7 Energy barrier for racemization of 19-da, 112-d2116 and 10. 101 8 Calculated and experimental methine VCH and 8H- 107 9 Stabilization energies (O*CH ) per nitrogen lone pair. 108 10 Calculated stretching frequencies and bond lengths. 110 11 Optical rotation measurements. 151 12 Percent enantiomeric excess (ee) as a function of time at 82 ± 1 °C 153 (kinetics run no. 1). 13 Uncertainty in In (ee) 153 14 Collective data for kinetics run no. 2. 154 15 Collective data for kinetics run no. 3. 155 16 Results from the three kinetics runs. 155 xviii LIST OF GRAPHS Graph Page 1 In ee vs. Time (hours), kinetics run no. 1. 99 2 In ee vs. Time (hours), kinetics run no. 2. 100 3 Coupling constants (! JCH ) vs. methine chemical shifts (8R). 108 4 Stabilization energy vs. 'JCH and 5H- 109 5 Mulliken charges for the methine hydrogens vs.' JCH and 6H- 110 xix ABSTRACT A MODIFIED SYNTHESIS, C-FUNCTIONALIZATION, RESOLUTION AND RACEMIZATION KINETICS OF CROSS-BRIDGED TETRAAZAMACROCYCLES by Antoinette Yolanda Odendaal University of New Hampshire, May 2009 Modifications to the literature-reported procedure for the synthesis of cross- bridged cyclam and homocyclen tetraamines are presented. The synthesis involves the use of a cM-tricyclic bisaminal intermediate for the preparation of tetracyclic bisaminals and the microwave-assisted reductive ring opening of iV.iV'-dibenzyl bisaminal salts. The m-tricyclic bisaminal was also used in the preparation of a C-functionalized cross- bridged cyclam. The resolution of racemic cross-bridged cyclam by selective crystallization of its diastereomeric salt of L-(+)-tartaric acid is described. Additionally, the kinetics of racemization of enantiopure cross-bridged cyclam is presented. xx CHAPTER 1 A TRICYCLIC BISAMINAL ROUTE TO CROSS-BRIDGED CYCLAM AND HOMOCYCLEN, AND THE MICROWAVE-ASSISTED DOUBLE REDUCTIVE RING OPENING OF DIBENZYL BISAMINAL SALTS I. Introduction Macrocyclic polyamines cyclen (1), homocyclen (2) and cyclam (3) and their JV- functionalized derivatives 4 have been studied extensively1"13 as versatile ligands for metal cation complexation.14"18 The cation-binding ability and ligation properties of these tetraazamacrocycles expanded their utility with contributions to the areas including •J T 1 Q -J A -J 1 bioinorganic chemistry, catalysis, ' ion recognition," '" magnetic resonance 9'? "y\ 1H Od. 00 0^ imaging,""'" anti-viral agents " and radiopharmaceuticals.""" m r^ r^ NH HN NH HN NH HN NH HN NH HN NH HN L_J L_J ^ 1 2 3 Cyclen Homocyclen Cyclam 1^"*-™ R= H CH3 CH2CONH2 NR RN CH2C6H5 CH2CH2OH CH2CH2CN f J CH2C6H4N02 CH2CH2CH2OH C6H5 NR RN CH2C6H4NH2 CH2C02H ^ m,n = 0, 1 1 The inherent structural constraints and topological donor atom arrangements of tetraazamacrocycles lead to metal complexes with enhanced thermodynamic stability and kinetic inertness, compared to their acyclic analogues.3'26"29 The favorable enthalpy and entropy changes associated with tetraazamacrocycle complex formation can in part be explained by the chelate and macrocyclic effects." '" '" The chelate effect describes the positive entropy change for linked donor atoms compared to separate donor atoms. Metal binding of pre-organized ligand donor atoms in a cyclic array also leads to a favorable macrocyclic enthalpy change. The macrocyclic and chelate effects also aid in rationalizing the significantly higher dissociation energy of tetraazamacrocyclic complexes compared to those of acyclic analogues.28 Structural modification to the skeletal backbone of tetraazamacrocycles include bridging of adjacent nitrogens (separated only by carbons) with an alkyl chain (5a-b) 30~33 or by connecting nonadjacent nitrogens (6) and C-functionalization (7a-b). " These modifications can increase the topological constraint of the macrocycles, which can improve complex stability and alter metal-ligand coordination geometries. A™ f) ^ V^ r-> N HN ^N N^ ^—N ^N-\ NH HN .NH HN ^NTHI\r ^N N^ V_r/ VV ^NHHir V^NH HN'X y >-rfl ^-rfi "f^\ X ' 5a 5b 6 7a 7b Tetraazamacrocycles can adopt several cis and trans configurational geometries upon cation complexation (Figure 1) where the cis/trans assignments describe the N-H bond orientation.1 Additional structural reinforcement introduces rigidity to the ligands and can limit accessible configurational geometries.18'32'35 Similarly, TV-substituted 2 azamacrocycles with metal coordinating functional groups provide additional complex stability and limit configurational geometries.6'14'39 JKcrS'v 7ra«*-/ Trans-II Trans-Ill Trans-lV *TVH ^?/H ^n^H \ i ^ /TN /v" /""¥*' Trans-V Cis-l Cis-ll Cis-V Figure 1: Cis and trans configurational geometries. Cross-bridged (CB) tetraazamacrocyclic ligands 8, 9 and 10 are structurally- modified cyclic polyamines with an ethylene chain connecting two nonadjacent nitrogens.40"44 These cross-bridged ligands are useful chelators for small metal cations as all four nitrogen lone pairs may be directed toward the ligand cavity to form low-strain cis-V folded metal-cation complexes exclusively (Figure 2).44"48 (TD CT) CT) ^NH^rT ^NH^lsT ^NhTNV 8 9 10 CB-Cyclen CB-Homocyclen CB-Cyclam IT a I "(S "H ^H H Cis-V Figure 2: Cross-bridged cyclam (10). 3 The synthetic route to the three bicyclo[5.5.2], [6.5.2] and [6.6.2] tetraazamacrocyclic ligands, developed by Weisman and Wong at the University of New Hampshire, is shown in Scheme 1.40~44 The first reaction involves the condensation of macrocyclic ligands 1-3 with glyoxal to give tetracyclic bisaminals 11-13. The highly regio and stereoselective dialkylation of 11-13 with benzyl bromide (BnBr) gives the dibenzyl bisaminal salts 14-16, which upon reductive ring expansion give the dibenzyl cross-bridged tetraazamacrocycles 17-19. Catalytic hydrogenolysis of 17-19 then generates the parent cross-bridged species 8-10. VNH HNT MeCN ^N^hrr MeCN N^Kr lm = n = 0 llm = n = 0 14m = n = 0 2m=l,n = 0 12m=l,n = 0 15m = l,n = 0 3m = n=l 13m = n=l 16m = n=l 1)NaBH4, 95%EtOH I I ,Bn 1) H2, 10% Pd/C I I N N rt, 4-16 days / \ v. HOAc > r^S ^ 2)HCI L L J 2)KOH L L J N 3)KOH Bn- N Benzene NH N Benzene ^ur >*r 17m = n = 0 8m = n = 0 18m=l,n = 0 9m=J,n = 0 19m = n=l 10m = n=l Scheme 1: Cross-bridged tetraazamacrocycles synthesis. There are two important features to the cross-bridged tetraazamacrocycle synthesis. First, the regioselective dibenzylation of the cis tetracyclic bisaminals 11-13 is a critical step in this synthesis as it leads to the cross-bridged species upon a reductive double ring expansion.43 For example, C? symmetric cis tetracyclic bisaminal 13 has two exo nitrogen lone pairs and two endo nitrogen lone pairs (Scheme 2). 4 endo (Tj7 V-x end0 13 J exo exo i BnBr Scheme 2: c/s-Tetracyclic bisaminal dialkylation (dialkylation of one conformational enantiomer of 13). The enantiomers of bisaminal 13 undergo rapid enantiomerization by inversion of all four nitrogens and the two piperazine rings (15 kcal/mol).49"52 However, the first exo alkylation of 13 locks the enantiomerization process. As a result the second alkylation then occurs at the second exo nitrogen to give the dialkylated bisaminal salt 16. Secondly, the double reductive ring expansion of the dibenzyl bisaminal salts 14- 16 gives the cross-bridged bicyclo[5.5.2], [5.6.2] and [6.6.2]tetraamines 17-19.43 This is accomplished using NaBH4 and each ring expansion is a result of the reduction of an iminium ion intermediate (Scheme 3). For example, since the alkylation of 16 occurs at the exo nitrogen lone pairs, the reduction of the iminium ion intermediates leads to the ethylene chain connecting two nonadjacent nitrogens (meaning separated by another nitrogen as well as carbons on the perimeter backbone) to give the cross-bridged species, as shown in the conversion of 16 to 19. 5 Bn' f H j Bn' f H j 16 iminium ion I I ,Bn I I Bn 11,Bn L J L J C J iminium ion 19 Scheme 3: Double-reductive ring expansion. The addition of the ethylene cross-bridge to the tetraazamacrocycles improves the kinetic inertness of their metal complexes towards acid-decomplexation compared to that of their non-bridged analogs.44'5 As mentioned before, the coordination geometry of these cross-bridged tetraamines is limited to a cis-Vfolded configuration, whereas the coordination geometry of the ligands 1-3 is quite variable (see Figure 1). For example, the structure of the copper(II) complex of CB-cyclam (10) shows that the cation fits snugly in the ligand cavity with a cw-F-folded geometry;43 all four nitrogen lone pairs coordinate to the metal and the bicyclic ligand has a [2323]/[2323]54 conformation (Figure 3). The copper(II) complex of cyclam (3), on the other hand, has a trans-III configuration.55 Their half-lives in 5 M HC1 at 30 °C are 2.7 days and 18.5 days for Cu(II)-Cyclam and Cu(II)-CB-Cyclam, respectively, which indicates that the Cu(II)-CB- Cyclam complex is significantly more kinetically inert.53 6 • Cu(C104)2-3 Cu(ClO4)2'10 Cu(II)-Cyclam Cu(II)-CB-Cyclam Figure 3: Copper(II) complexes of 3 and 10 with the hydrogens omitted. Alkylation of the parent cross-bridged tetraazamacrocycles 8-10 at the secondary amine nitrogens gives access to iV-JV'-dialkylated pendant-armed cross-bridged tetraazamacrocycles (Scheme 4).4 ' '53'56~60 Functionalization of the cross-bridged cyclic amines provides additional complexation ability and expands these ligands' utility. m = n = 1,R= m = n = 0, R= m = 1,n = 0, R = RX CH2CON2H CH2CON2H CH2CON2H m - CH2C02H CH2C02H CH2C02C(CH3)3 CH2CH2CO2H CH2CH2CO2H NH N CH2C02C(CH3)3 CH2C02C(CH3)3 m ,n = 0,1Schem e 4: Pendant-armed cross-bridged tetraazamacrocycles. JV,iV"-Bis(carboxymethyl) pendant-armed cross-bridged cyclam (CB-TE2A) 20 has been investigated as a bifunctional chelator (BFC) for radiopharmaceutical applications (Figure 4).53'57'61 7 Linker CN \ N^C0D 2" "02C^C> DN^C0 2" ^CN I N >^Y - •02CV> N^ •02CX> N^ ,C02- "02C^N N Biomolecule v BFC 20 21 22 CB-TE2A TETA CB-TE2A (Bioconjugate) Figure 4: Ligands CB-TE2A (20), TETA (21) and bioconjugate 22. The copper(II) complex of 20, Cu(II)-CB-TE2A, has significantly enhanced kinetic inertness towards acid-decomplexation over the non-bridged analogue copper(II) complex of 21, Cu(II)-TETA.53 The half-lives in 5 M HC1 at 90 °C were determined to be 154 hours for Cu(II)-CB-TE2A and only 4.5 min for Cu(II)-TETA. This enhanced resistance towards acid-decomplexation of Cu(II)-CB-TE2A along with its quasi- reversible electrochemical Cu(Il)/Cu(I) reduction make 20 a good candidate as a BFC as it is more resistant to demetallation compared to 21. These in vitro stability assays correlate with in vivo animal studies.56 The biological evaluation of copper-64 labeled CB-TE2A bioconjugate 22, with one carboxyl group functioning as a linker for conjugation to the octapeptide Tyr3- octreotate, suggests this chelator to be a superior tumor-imaging agent for neuroendocrine tumors compared to the bioconjugate of 21.62'63 It has also been reported that 22 is an improved bifunctional chelator for the imaging of melanomas.64 As mentioned above, the ability of cross-bridged tetraazamacrocyclic ligands to form stable metal complexes makes them valuable ligands for a variety of applications. Recently the manganese and iron complexes of dimethyl cross-bridged cyclen and cyclam have been studied as catalysts for olefin epoxidation.65"68 These complexes also 8 mimic biological systems and they are useful in studying the epoxidation of olefins with biological oxidants. It has also been reported that the Cu(I) dimethyl cross-bridged cyclam complex has superior catalytic activity in atom transfer radical polymerization. Because of this broad utility of cross-bridged tetraazamacrocycles, further improvement to the reported synthetic procedure was undertaken.40"44 9 II. Background The high cost and unreliable availability associated with commercially-available tetraazamacrocycles such as 1-3 prompted researchers to develop alternative cost- effective, versatile and practical synthetic methods. A large number of literature-reported procedures for cyclic polyamines exist, only some of which will be discussed here. The first synthetic methodology for cyclic polyamine synthesis was reported by van Alphen.70 This synthesis involved the alkylation and cyclization reactions of an acyclic tetraamine 23 with a bis-electrophile 1,3-dibromopropane to give 1 in a two-step synthesis (Scheme 5). (19%) (54%) l^J 23 3 Scheme 5: van Alphen's cyclam synthesis. This initial approach was later followed by the synthesis of 1-3 from 24 (Scheme 6).71 The tosyl-protected cyclic polyamine-polyamides 24 were synthesized from the alkylation of bissulfonamide sodium salts 25 with 2-bromoacetic acid, followed by treatment with thionyl chloride to give 26. The subsequent acylation-cyclization of 26 with 1,2-ethanediamine or 1,3-propanediamine gave 24. Detosylation and amide reduction of 24 gave 1-3 in modest overall yields. The use of protected amines allowed for the synthesis of a series of tetraazamacrocycles by varying the chain lengths of the acyclic amine and the alkylating agent. 10 o Na+ Na+ 2> SOCI^ o o m=0,1 25 26 TS"N N'TS NMH HHNN . 1 m = n = 0; 27% overall H,N'^>rVNH, T ^ LAH ( ^ 2 m = 0, n = i; 36% overall 2 wn z I I I I 3 m = n = 3; 38% overall CT NH HN"^0 *" NVJHH HHNN n = 0,1 24 1-3 Scheme 6: Synthesis of a tetraazamacrocycles from tosyl-protected polyamine- polyamides 24. Expanding on the protecting group chemistry, the most common method for the synthesis of tetraazamacrocycles follows the Stetter-Richman-Atkins approach and its variations (Scheme 7).72"78 This method involves the cyclization of a bis-sulfonamide disodium salt 27 and an alkylene dibromide or ditosylate 28 to form tetratosyl tetraazamacrocycles 29 in good yields. The detosylation of 29 yields the parent tetraazamacrocycle analogues 1-3. This versatile method opened the door for the synthesis of a large number of cyclic polyamines of varying ring sizes. TS TS H Ts mTs _ DMF ;N NC 2S04 NH HN^ N N TsN^ -^^ -^NTs + x^^x ^ |- ^ ^ f > Na+ Na+ 1 C 10 C k X = Br,Ts °°° > N^s °° NHHN^ m = 0,1;n = 0, 1 TS Vfn >-fn m = n = 0; 80% overall m = 1, n = 0; 77% overall m = n = 1; 70% overall 27 28 29 1-3 Scheme 7: The Stetter-Richman-Atkins macrocyclization to polyamines. 11 Although this Stetter-Richman-Atkins method allows for the synthesis of a series of tetraazamacrocycles, it requires medium dilution reaction conditions, has very poor atom economics, and requires harsh as well as massive waste-generating conditions for removal of the tosyl protecting groups. Other protecting groups such as triflamides have also been used, but these require sodium and liquid ammonia for the deprotection step. Use of ditosylates rather than dihalides as the bis-electrophile improved the reaction yields (Scheme 7).73'74 The use of K2CO3 or CS2CO3 as a base in this macrocycle synthesis has resulted in improved yields and fewer polyamine side-products.80'81 The alkylation-cyclization of a tetratosyl-protected acyclic tetraamine 30 with a dihalo alkane 31 gave access to 29 (Scheme 8). The tetratosyl-protected cyclic tetraamines were isolated in 61, 62 and 70% on yields for 1, 2 and 3 respectively, for the alkylation-cyclization steps. This variation on the Stetter-Richman-Atkins approach allows for the preparation of cyclic tetraamines in fewer steps. U U TS-1 J,'-TS N M K2C03 or Cs2C03 ^N N Ts'N--^N^H^N^-N^Ts + Br^W^Br — -*- f 1 fs Ts _ DMF S < m = 0.1 n=°'1 TS'k^ m = n = 0; 61% overall 1n n m = 0, n = 1; 60% overall m = n = 1; 70% overall 30 31 29 Scheme 8: The use of an inorganic base in macrocycle synthesis. Since the protection-deprotection approach is time consuming, other methods for synthesizing tetraazamacrocycles have been investigated. For example, the condensation of acyclic tetraamine 32 with a dithiooxamide gives tricyclic bis-amidines 33, which can 12 be reduced to give tetraazamacrocycles 1 and 2 (Scheme 9).82"84 This is a short two-step synthesis reported by Weisman and coworkers to access the tetraazamacrocycles 1 and 2, successfully avoiding additional protecting group chemistry. .N N g ^N^N DIBALH .NH HN ^M M EtOH kA,, ^K1U UKIJ N N N ^N NH HN HV„H W„ W„ m = 0, n = 0;R = H; 45% overall, R = CH3CH2 57% overall m = 1, n = 0; R = CH3CH2; 52% overall 32 33 1 m = n = 0 2m = l,n = 0 Scheme 9: A tricyclic bis-amidine route to tetraazamacrocycles. Access to tetraazamacrocycles can also be achieved by the reaction of 1,3- diamino propane with chloroacetyl chloride to generate a dichloro bisamide 34, which can undergo a cyclization with 1,3-diamino propane to give a dioxo cyclam bisaminal 35 (Scheme 10).85 The reduction of 35 then gave 3. This method uses a similar strategy reported by Stetter and Mayer,71 but avoids the use of protecting groups by using K2CO3 as a base for the deprotonation after the alkylation steps. No information regarding the yields and purity were reported in this patent.85 Bradshaw and coworkers reported on the synthesis of a series of 7V-functionalized cyclams using this approach with yields > 60%.86 13 CI CH N H2N^^NH2 + C,-^ ^_ °Y V° O K2C03 kc| aJ 34 H H vo'-~o H N-^^NH O^NH HN^.0 + NH HN 2 2 Na MeCN, K2C03 ^NH HN^ T0|uene NH HN 35 3 Scheme 10: A diamide intermediate to cyclam. A template strategy using NiCb to aid in the condensation of acyclic tetraamine 36 with glyoxal has also been reported to be an improved method for the synthesis of cyclam (3).87'88 A bisimino nickel intermediate 37 was generated and reduced to give a Ni(II)-cyclam complex 38. Complex 38 was then treated with sodium cyanide to give 3 (Scheme 11). H.r^.H Hj 1,H ^N N^ NH HN N NaBH Ns /K NaCN ^N N\\ Ni(CI04)2 4 r C X J N N NH HN C"N HN, OHC-CHO N N H' l^J >H 65% H' I I ~H H'1 J~H 63% 36 37 38 3 Scheme 11: A metal -temp lating synthesis of cyclam The preparation of cyclam bisaminal isomers has been reported by the reaction of acyclic tetraamine 36 with glyoxal and benzotriazole to give bisaminal adduct 39 (Scheme 12). This adduct was then reduced in the presence of sodium borohydride to generate cyclam bisaminal isomers 13 and 40. 14 2 OHC CHO - .liji B, NaBH4 tyj, U^N 36 ,£#.. ^kf*™ ^^ H (80%) (50%) 50 cis :3 trans 39 13 40 Scheme 12: A bisaminal tetraazamacrocycle synthesis. The use of a dimethyl tricyclic bisaminal 41 has led to a reasonable synthesis of tetraazamacrocycles by Handel and coworkers (Scheme 13).90 The condensation of butanedione with the acyclic tetraamine 42 gives the dimethyl bisaminal 41 in which a geminal insertion is favored, generating a maximum of three fused six-membered rings and a cis dimethyl bisaminal configuration. The alkylation and subsequent cyclization of 41 to the tetracyclic bisaminals 43, followed by acid hydrolysis leads to the cyclic polyamines 1-3 (Scheme 13). ^ N JUS N ^ 0 ^N4-NN Br^H^Br ^N^S HCI. EtOH ^NH HN H2N^^ """TV "^NH2 »• [ T 1 - [ T ] >• [ J k MeCN,-7°C ^N^fV K2C03,MeCN Sj'jV NH HN^ • H ' H I ' I (100/o) | | m = 0; 90% m = n = 0; 60% ^uri S^ m = 1;95% m = 1,n = 0;90% Kl w m = n = 1; 90% 42 41 43 1-3 Scheme 13: A dimethyl tricyclic bisaminal route to cyclic polyamines. The bisaminal carbons of 41 function as a template to pre-organize the acyclic polyamines, setting it up for an effective one-pot alkylation-cyclization with the bis- electrophile. This approach offers fewer reaction steps, eliminates the use of protecting groups and improves the overall yields. Alternatively, pyruvic aldehyde has also been used to form a cis mono methyl tricyclic bisaminal 44, which upon cyclization generates 15 the corresponding tetracyclic bisaminal 45 used to prepare the mono-alkylated tetraazamacrocycle 46 shown in Scheme 14.91'92 N N NN N H H 5 ^N.j>/ -vU . N Br^>fiP'BBr^Mn^Br ^ ^<- vp^ -^N 1DBnBr.MeC) BnBr, MeCNN ^ ^NNHH HNV^ H?N' ^ ^^^ \^NH;? r T i _ r T i ^r MeCN, 4^ ' L JV K2C03,MeCN* LN^NJ Hcfor^aOH ' \H J (80%) n = 0;69% >^n n = 0; 46% KiJ n = 1;68% r' n = 1;42% "n 2 steps 23 44 45 46 Scheme 14: A pyruvic aldehyde condensation. The condensation of acyclic tetraamines with glyoxal, "' ' pyruvic aldehyde ' and butanedione94 for the synthesis of a variety of tricyclic bisaminals has thus become a versatile method for the preparation of tetraazamacrocycles. The condensation reaction between a dicarbonyl species and an acyclic tetraamine can lead to a mixture of bisaminal isomers.95"98 First, the insertion of the dicarbonyl can be in the vertical position, which gives rise to geminal (gem) isomers, such as 47. On the other hand, horizontal insertion will give rise to vicinal (vie) bisaminal isomers, such as 48. Secondly, the dicarbonyl insertion can give access to either the cis or trans bisaminal configuration. Several factors contribute to the outcome of these condensation reactions: the size of the starting acyclic tetraamine, the substitution at the dicarbonyl species and the temperature at which the reaction is run (kinetic vs. thermodynamic control). ri?? (^ r4*? r"T CI) CI) C*H«) CRKB) N^N N : N N l\T N N HRH n,HRH HH „.HH m = 0, 1 m = 0, 1 R = H, CH3 R = H, CH3 gem-cis 47 gem-trans vic-cis 48 vic-trans 16 The use of cyclohexanedione as an alternative dicarbonyl has also led to bisaminal formation.96 It reduces the number of possible stereoisomers generated from the condensation reactions and improves reaction yields. In all the examples mentioned and reported in literature, the bisaminal functions as a template as it is removed after the final cyclization to the tetracyclic bisaminal in order give the parent tetraazamacrocycles 1-3. Although the use of tricyclic bisaminal templates for the synthesis of tetraazamacrocycles has only recently become popular, the bisaminal intermediates have been synthesized much earlier.49'52'93'94'" The structural and conformational properties of a variety of tricyclic and tetracyclic bisaminals were also reported. More recently, Handel has described the kinetic and thermodynamic aspects of the condensation reaction of acyclic tetraamines with dicarbonyl species (Scheme 15).98 As mentioned above, several isomers can be generated from this condensation reaction and temperature can play a critical role in the outcome. For example, if the condensation of 23 and glyoxal is run at low temperature, the cis tricyclic bisaminal 49 is the major species, a kinetic product. However, if the reaction is heated to reflux the thermodynamic trans isomer 50 predominates. -N^ ^ „N. ~ U S N-" N < ^Y H,N ^ ^ ^ ^ NH, (95%) 23 49 50 Kinetic Isomer Thermodynamic Isomer Scheme 15: Thermodynamic and kinetic isomers of tricyclic bisaminal.98 17 Bisaminal diastereomers 49 and 50 have distinctly different NMR spectra, which allow identification of the isomers and their isomeric ratio.50'98 The trans isomer 50 has l two bisaminal protons antiperiplanar with a 3JHH = 7 Hz in its H NMR spectrum and is strongly biased towards the conformation shown below.50 The cis isomer 49 is conformationally equilibrating with the two bisaminal protons approximately gauche = 93 with a 3JHH 3 Hz. The enantiomerization of 49 requires 4 nitrogen inversions and two piperazine ring inversions. r7 ^1 |HN NH| H'H K'H 49 The research reported herein utilized the cis tricyclic bisaminal 49 as a building block for the synthesis of cross-bridged tetraazamacrocycles 9 and 10 (Scheme 16). As mentioned above, tricyclic bisaminal has most commonly been used as a template for the synthesis of tetracyclic bisaminals, as the bisaminal-bridge is eventually removed to give tetraazamacrocycles. Here, the goal is to incorporate the bisaminal bridge into the final macrocycles as the cross-bridge unit. The acyclic tetraamine 23, A^,A^'-bis(2- aminoethyl)-l,3-propanediamine, is commercially available but costly and was instead synthesized from less expensive commercially-available starting materials. ' 18 o u u ii i H I I Hi I I r^-PS Br^>^Br fN-P\ ^ f T I H2N' ^-" v^\*- \^^NH2 »> >- r i H H H 23 49 n = 0, 1 12 n = 0 9 n = 0 13n=l 10n=l Scheme 16: The use of a c/s-tricyclic bisaminal in the synthesis of cross-bridged tetraazamacrocycles 9 and 10. For the tricyclic bisaminal route in Scheme 16 to be a viable route to the desired cross-bridged tetraazamacrocycles, the condensation of glyoxal with the acyclic tetraamine 23 has to give the cis tricyclic bisaminal 49. This allows the final cyclization to give access to the cis tetracyclic bisaminals 12 and 13, which will alkylate twice at the exo nitrogens, as described above in Scheme 2.40"44 Two methods on the use of 49 to synthesize 13 have been reported, both in patents. The alkylation reaction has been carried out in MeCN at room temperature over 24 hours with 1.5 equivalents of 1,3-dibromopropane and 4 equivalents of N,N'-d\- isopropylethylamine.102 The patent reports a 90% yield with 93% cis 13. However, no detailed information regarding the purification of the product is provided. Alternatively, 49 has been alkylated with either 1,3-dibromopropane or 1,3-propanediol di-(p- toluenesulfonate) in ethanol with K2CO3 at reflux for 8 hours to generate cis 13.103No information regarding the final product yield and isomeric ratio were reported. Based on kinetic and thermodynamic aspect of cis 49 reported by Handel,98 it can be assumed that refluxing 49 in ethanol will lead to its isomerization to trans 50. This will result in mixtures of cis 13 and its trans isomer 40. 19 An additional goal of this research involves a modification to the previously- reported synthesis of the dibenzyl cross-bridged tetraazamacrocycles 17-19 (see Scheme 1) by the double reductive ring expansion of the dibenzyl bisaminal salts 14-16.40"44 These reductive ring expansions are achieved with NaBrLj at room temperature in 95 % » EtOH (Scheme 1). These original room temperature reductions work well and give pure product, but the reactions are slow, requires reaction times from 4 to 16 days depending on the starting substrate (Table 1). Attempts at using conventional heating to decrease long reaction times resulted in impure products and problematic purifications. The alternative modified synthesis reported here employs microwave irradiation for the reductive ring-opening step with the goal of decreasing reaction times.104"106 Table 1: Conventional reaction times and yields of the reductive ring expansions. Conventional Reactions Substrate Room Temperature Yield (%) 14 4 days44 50-quant 15 10 day107 quant 16 16 days43 88 Microwave synthesis can have several advantages including shorter reaction times, higher yields and improved purity of products.104"106 Over the past several years microwave irradiation has been employed in a variety of organic reactions, which has led to dramatically increased reaction rates and chemical transformations that were difficult to achieve with conventional heating.108 Although it is well established that microwave dielectric heating results in enhanced reaction rates, there is still active debate on the origin of microwave effects. Microwave-enhanced reactions are described in terms of 20 microwave effects (kinetic and thermal), specific microwave effects (thermal effects) and nonthermal microwave effects. Microwave dielectric heating has the advantage of effective internal heating with energy being transferred to the entire reaction vessel content, unlike conventional conductive-heating that slowly transfers energy from the reaction vessel wall to the vessel contents.109"112 The dielectric heating is a result of the dipolar polarization and ionic conduction as dipoles or ions align and realign to the alternating electrical field of the applied microwave frequency. Microwave effects are the consequence of this rapid uniform high temperature heating and rate accelerations are explained by the Arrhenius equation.113 Thermal effects that are not simply explained by rapid uniform dielectric heating have been termed specific microwave effects. These transformations cannot be achieved under conventional heating methods. One example is the selective heating of one component in the reaction matrix, such as a catalyst.109 The so-called nonthermal microwave effect has been described as an enhancement due to the interaction of polar molecules with the electrical field.109 The result of this interaction is described to lower the activation energy and permits transformations that cannot be achieved under conventional laboratory conditions. Although it is clear that microwave dielectric heating is more effective than conventional heating sources as far as transferring energy to the reaction matrix, there is still an active debate on the energy-cost efficiency of microwave irradiation over traditional heating methods.114 21 The research reported here will employ microwave irradiation in order to shorten reaction times for the double-reductive ring opening of dibenzyl tetracyclic bisaminal salts 14-16 to dibenzyl cross-bridged tetraazamacrocycles 17-19. 22 III. Results and Discussion 1. Synthesis of Ar^-bis(2-aminoethyl)-l,3-propanediamine (23). The synthesis of 23 was accomplished by following the literature-reported procedure with commercially-available ethylenediamine and 1,3-dibromopropane jn the presence of KOH (Scheme 17).100' U5 van Alpen did not report on the yield or purity of the final product. However Pruckmayr reported a 63% yield without mentioning the purity of the final product. Following the literature procedures, 23 was prepared in 50% yield as a clear viscous oil. The 13C{'H} NMR spectrum indicated the presence of a minor species (ca 1%) which could be a carbamate species from the reaction of the primary amine with atmospheric CO2.116 After the clear oil sat in a capped flask under N2 for a few days, a fine white residue was visible, which could be the impurity seen in the '^{'H} NMR spectrum above. H H /\ NHo ^\ /\ Absolute EtOH ^~ N ^ N .^ KOH 50% 23 Scheme 17: Synthesis of A^,Af'-bis(2-aminoethyl)-l,3-propanediamine (23). Several attempts were undertaken to improve on the yield of the reaction. First, changing the solvent to MeCN resulted in no increase in yield. Also, changing the base to K2CO3 instead of KOH did not result in clean product formation as the *H NMR spectrum indicated several species. When the reaction was run neat with excess ethylenediamine and KOH, no increase in the yield beyond what was reported was observed. 23 2. Synthesis of czs-octahydro-lH^HJH-Ua^a^-tetraazaphenalene (49). The synthesis of 49 was achieved following Handel's general procedure for the synthesis of tricyclic bisaminals (based upon earlier literature procedures).98 Handel reported the final product, 49, to be a colorless oil, which was purified by extraction with toluene. However, no purification method was given to separate 49 from trans isomer 50. Fuchs reported on the purification of 49, which was achieved by recrystallization from petroleum ether, but no additional information was reported on the product isomeric ratio or the final crystallized product isomer ratio." The crude product isolated from the reaction reported herein, Scheme 18, was a sticky off-white residue in 67% yield with 3% of trans 50 according to the 'H NMR spectrum. The crude material was recrystallized from distilled hexane to give 55% of cis 49, with less than 1% of trans 50 by *H NMR. o H H f ft). s~^ ^NU ^^ ^N^ ^-\ O H2N^^ ^^^ ^^NH2 EIOH, -5°C 3h r CP H H H 55% 23 49 Scheme 18: The synthesis of tricyclic bisaminal 49. It must also be noted that the solvent of this reaction was removed at 0-4 °C. When the solvent was removed at or above room temperature, a larger ratio of cis/trans isomers was observed. This was consistent with the work reported by Handel in which cis 49 is converted to trans 50 upon heating.98 3. Synthesis of c/.s-decahydro-lH.6H-3a.5a.8a.l0a-tetraazapyrene (13). The alkylation of 49 with 1,3-dibromopropane to give 13 was accomplished in 24 MeCN over 4 days to give a 97% crude yield of 13 (Scheme 19). The !H NMR spectrum indicated the presence of 4% of the trans isomer 40, which was removed upon recrystallization from hexane at 6 °C to give a final yield of 46% for the synthesis of 13. 49 Br- — -Rr .NJ.N, MeCN, K2C03 * ^N4NVK 4d | H | 46% \/ 13 Scheme 19: Synthesis of cw-decahydro-lH,6H-3a,5a,8a,10a-tetraazapyrene (13). Prior to purification by recrystallization several other attempts were made to separate 13 from its trans isomer (40). The purification by Kugelrohr distillation at 80 °C (25 mTorr) resulted in the distillation of both isomers. Attempts at basifying the crude material with KOH and extracting it with either toluene or CHCI3 resulted in both 13 and its trans isomer (40) being recovered in each case. The reaction was also run in EtOH rather than MeCN, however the same outcome was observed with a similar cis/trans isomer ratio. It was also thought that the addition of triethylamine to the reaction mixture as a relay base might aid in rapid deprotonation of the quaternary amine after the alkylation step. This would help to avoid the formation of the iminium ion, which has two diastereotopic faces that can undergo nucleophilic attack to give the cis/trans diastereomers (Scheme 20). With the addition of 1 equivalent of triethylamine to the reaction mixture the amount of the trans isomer 40 in the crude product was 3% by !H NMR spectroscopy. This outcome was the same for the reaction run without the addition of triethylamine. 25 ' CD CD HHA R + NH 40 (X) -c ,NHR HH i. R i i R H H R = (CH2)3Br iminium ion diastereotopic faces - CD HH^NXNRL 13 Scheme 20: Formation cis and /raws isomers 13 and 40, respectively. 4. Synthesis of c/,s-decahydro-5H-2a.4a.7a.9a-tetraazacyclopentaphenalene (12). Compound 12 was prepared from the alkylation of 49 with 1,2-dibromoethane in MeCN (Scheme 21). Brv. Br 49 MeCN, K2C03 CT-) 60 °C, 4d H 69% 12 Scheme 21: Synthesis of c/s-decahydro-5H-2a,4a,7a,9a- tetraazacyclopentaphenalene (12). Initial attempts at running the reaction at room temperature for 4 days resulted in some unreacted 49 in the crude product. The addition of Nal did not appear to improve the reaction outcome as a large amount of unreacted 49 was still present in the crude recovered material. When the alkylation was attempted with 1,2-ethanediol-di-(p- toluenesulfonate), a significant amount of unreacted 49 was likewise observed in the crude product. However, running the alkylation-cyclization reaction with 1,3- 26 dibromoethane at 60 °C for 4 days gave the desired product, which was purified by column chromatography on basic alumina using chloroform eluent to give isomerically pure 12 in good yield (69%).60 The formation of the 5-membered ring to give 12 appears to be more challenging than the formation of the 6-membered ring to give 13. This slow intramolecular ring closure to give 12 may be due the configuration of cis 49 and the trajectory of nucleophilic attack for the ring closure after the initial alkylation with 1,2-dibromoethane. 5. Microwave-assisted reductive ring opening of 14,15 and 16. Open-vessel microwave reactions using the single-mode CEM Discover® microwave reactor were used for the reductive ring opening of all three dibenzyl bisaminal salts 14,15 and 16. The reagents and solvents used for the microwave reactions were the same as the original conventional room temperature reactions.41'43'44 The general procedure for a 1 gram-scale microwave reaction was as follows. The bisaminal salt was dissolved in 95% EtOH (0.04 M) in a 100 mL round bottom flask, and NaBH4 (50 equivalents) was added over a period of 20-40 minutes (Scheme 22 and Table 2). The vessel was then transferred to the microwave reactor, and the flask was equipped with a water condenser, topped with an air condenser and Na inlet. An initial reaction temperature was set at or below 50 °C and the temperature was then slowly increased to 78 °C. This temperature was increased at 5 °C/min to 70 °C, then 2 °C/min to 78 °C to avoid temperature overshoot. The reaction was then kept at 78 °C for 10 to 15 minutes. After completion of the reaction, it was worked-up in the same manner as the conventional reaction procedure. 27 1)NaBH4, 95%EtOH 78 °C, MW,10-15min 2)HCI 3) KOH, Benzene 14, m = 0, n = 0 17, m = 0, n = 0 15, m = 1, n = 0 18, m = 1, n = 0 16, m = 1,n = 1 19,m = 1,n= 1 Scheme 22: Microwave-assisted reductive ring opening. The resulting yields and purities of 14,15 and 16 were comparable to those of our conventional reactions.41'43'57'107 Clearly, microwave irradiation significantly reduced reaction times of the reductive ring expansion of all three dibenzyl bisaminal salts 14-16 to give their corresponding cross-bridge derivatives 17-19 (Table 1 and Table 2). Table 2: Microwave-assisted reductive ring opening of bisaminal salts 14-16. Amount of 95% Equivalents of Reaction time at Substrate Scale % Yield EtOH NaBH4 78 °C 96.2 mg 5 mL 50 10 min 91% 14 0.1794 mmol 1.0086 g 46 mL 50 12 min 100% 1.8805 mmol 102.2 mg 5 mL 51 10 min 78% 15 0.1857 mmol 0.7499 g 35 mL 50 15 min 98% 1.3625 mmol 98.4 mg 4.5 mL 52 10 min 99% 16 0.1743 mmol 1.0097 g 45 mL 50 8 min 79% 1.7890 mmol In summary, the open vessel microwave-assisted double reductive ring opening of the bisaminal salts to their dibenzyl cross-bridged derivatives significantly reduces the reaction times while maintaining high yields and comparable product purities by 'H NMR. Future work on this microwave-enhanced reaction may include running the 28 reactions at high concentrations of bisaminal salts 14-16 and perhaps decreasing the equivalents of NaBFLt. 6. Alkylation of c/5//ram,-decahydro-lH,6H-3a,5a,8a,10a-tetraazapyrene (13) followed by microwave-assisted reductive ring opening. In order to determine whether the presence of a small amount of trans 40 impacts the alkylation of 13, the following experiments were conducted. Following the general literature-reported procedure,43 a mixture of cis 13 containing 15% trans 40 (!H NMR: Figure 5) was alkylated with benzyl bromide (Scheme 23). ^Bn i)NaBH4, 95% EtOH /N4-N^, fNvf-'N BnBr f T+^l 78 °C, MW.11 min f'S ^i ^N-4-N^ ^N^N^ MeCN >"TN^ 2)HCI ^N V |HJ [HJ Bn I^U2Br 3) KOH, Benzene Bn'M 74% 98% 85% 15% 13 40 16 19 Scheme 23: The synthesis of 19 from 13 containing a minor amount of trans 40. 29 85% 15% 13 40 130 120 110 100 90 SO 60 SO 40 30 20 ppm H2e q 13 "2eq 40 ' %%t- ' 1 ' 4.0 2.0 1.0 ppm 13/-irli Figure 5: C{ H} and H NMR spectra (C6D6) of 13 containing a minor amount of 40. Since the trans 40 has Civ symmetry, only four carbon signals were expected by 13^Cf{l , H} NMR. On the other hand, cis 13 has C2 symmetry and six carbons signals were seen in the 13C{]H} NMR spectrum. The two sets of signals for 13 and 40 were visible in the 49 89 spectra of Figure 5. ' The cis/trans ratio was determined by integration of H2eq proton signals (dm) in the !H NMR spectrum, with the signals of 40 down-field from that of 13. After alkylation of this mixture with 14 equivalents of benzyl bromide, the NMR spectra 30 of the isolated white solid 16 were only consistent with a single product, cis 16. Only very minor impurities are visible in its lH NMR spectrum (Figure 6). 16 WW" '"Jfc •J-4*- 130 120 110 100 90 80 70 60 SO 40 30 20 10 ppm I iff ", ppm 2.19 0.14 0.15 0,03 2.13 4.44 2.06 2.00 0.08 0.07 2.12 8.96 2.07 0.01 6.91 0.10 0.18 0.912.11 Figure 6: ^C^H} and 'H NMR spectra of 16 in D20 (ref. MeCN). The microwave-assisted reductive ring opening of 16 to 19 gave a clean product with no evidence of any impurities (Figure 7). These reactions illustrate that the omission of an additional purification of 13 to separate out trans 40 may not be detrimental to the outcome of the subsequent benzylation and reduction reactions. Benzylated trans product does not appear to crystallize from the reaction mixture and the subsequent reduction product has no evidence of impurities. 31 C"N ON Bn'l^j 19 140 120 100 0 ppm 1" ill J I 1 li hh 1.99 1.99 2.00 1.99 1.98 Figure 7: C{ H} and H NMR spectra of dibenzyl cross-bridged cyclam 19 in C6D6. 7. Synthesis of 2a,7a-(prop-2-en-l -yl)decahydro-5H-4a,9a-diaza-2a,7a- diazoniacyclopenta[cd]phenalene dibromide (54). Weisman and Wong have been interested in the synthesis of tricyclic tetraamines such as 6,34 with the ability to tightly encapsulate a proton within the ligand cage. Several former students in the Weisman research group have been involved in the preparation of tricyclic tetraamines.117'118 Widger and Bryde prepared 51 from 52, which was accomplished by the protonation of 52, followed by a ring-closing metathesis reaction to 1 1 R generate adamanzenes 51 (Scheme 24). The reduction of the olefin gave adamanzanes 32 53. Following is the preparation of a A^jV'-diallyl cross-bridged homocyclen analog of 52, which in the future can be used for the generation of the homocyclen analog of the tricyclic tetraamine cases such as 53. Grubbs'seconGrubbs' second Vrt, SH ^-^ ., __, _ A.(15 . "N—s ^T^L i N ^N CI"R _ .N ^N'' TsOH VN ^N"^1 EtOH ^N ""N^ CI" "^Ph n = 0, 53% LJ OTs n = 0, 99% KJ OTs P(Cy)3 n n = l,l2% "n n = l,99% r'n Grubbs^ second generation catalyst 52 51 53 Scheme 24: Synthesis of tricyclic tetraamines from jV.iV'-diallyl cross-bridged tetraazamacrocycles. Compound 54 was prepared by alkylation of 12 with allyl bromide in MeCN over 17 days, after which the product was collected by centrifugation (Scheme 24). Although 10 equivalents of alkylating agent were used, the yield of this alkylation reaction was modest (53%). The NMR spectra indicated the desired dialkylated 54 with no evidence of a monoalkylated species. Since the supernatant of this reaction was not recovered, it is not known whether any MeCN soluble monoalkylated 12 was present. However, the possibility cannot be ruled out. N V N ^"^Br f^'N ^N^TrvT MeCN, 17 d ^N-T^hT 00 * ' (53%) s ' 12 54 Scheme 25: Synthesis of 54. 33 8. Synthesis of 4,1 l-di(prop-2-en-l-yl)-1,4,8,1 l-tetraazabicyclo[6.5.21pentadecane (55). The attempt at a microwave-assisted reductive ring opening of 54 to 55 (Scheme 26) resulted in a crude reaction mixture with a small amount of impurities revealed by its 'H NMR spectrum. It is possible that de-allylation of 54 took place during the course of this reaction. This could occur via a SN2' reaction upon the allylic functionality by hydroxide generated during this reaction. The reductive ring opening of an inside protonated mono-allyl bisaminal could lead to the formation of an adjacent-bridged species. The :H NMR spectrum was very complicated and since 55 is Ci-symmetric, two possible adjacent-bridged species 56 and 57 can be obtained. The 13C{'H} NMR spectrum indicated a large number of minor signals, more than what was required for a single adjacent-bridged species. Attempted purification by column chromatography using a RediSep® Amine Column (SiCtbCHaNH? functionalized) eluting with 5% MeOH in CH2CI2 did not remove the observed impurities. This material was basified and extracted with benzene, but no purification resulted from this. ^^^ 1)NaBH4,95%EtOH C\^ NON C^*T~^ N . N 78.CMW.18m.,, ^^ + , ^ + Q N 2Br ^V© " 3) KOH, Benzene ^^L_J ^^'\__/ possib|e U_J 91% crude yield Impurities 54 55 56 57 Scheme 26: Microwave-assisted reduction of 54 with NaBH4. A conventional reductive ring-opening of 54 with NaBlHbCN in MeCN at refluxing temperature was accomplished in good yield (Scheme 26). The 13C{'H} NMR spectrum only corresponded to 55, however the 'H NMR spectrum did show evidence of 34 a small amount (< 5%) of an impurity that could correspond to protonated 55, which can be deprotonated by a base extraction. f^ly, j? 1)NaBH3CN, MeCN I A/-^ N ? N 80°C,2d , (\ ^ Ni^N^ 2,HCI /\> N <^V\ H / 2Br- 3) KOH, Benzene ^"^ \ / (79 %) 54 55 Scheme 27: A conventional reductive ring-opening of 54 with NaBtbCN. 9. Synthesis, characterization, and properties of the copper(II) 1,4,8,11- tetraazabicyclo[6.5.2]pentadecane (9) complex. A copper(II) complex of 9 was prepared in MeOH with CuCb^HiO to give plate-like crystals after Et20 diffusion (Scheme 28). Elemental analysis revealed the composition of the compound to be CuCl2»9»0.75(H2O). Two IR bands at 3500 and 3385 cm"1 were observed for the asymmetric and symmetric N-H stretching vibrations. The 1 1 UV-Vis in MeOH had an absorption A,max at 597 nm (e = 71.5 M" cm" ). Cyclic voltammetry conducted in 0.1 N sodium acetate showed an irreversible reduction with Ep=-0.71 V(Ag/AgCl). N HN CuCI -2H O N HN MeO2 Hz CUC 2 \)-J " LNHLNJ' ' \—l (81%) \ ' 9 CuCl2«9 Scheme 28: Synthesis of CuCl2'9. The copper perchlorate complex of 9 was also prepared in MeOH using Cu(C104)2'6H20 and plate-like crystals were collected after Et20 diffusion (Scheme 29). 35 The elemental analysis indicated the composition of this compound to be 1 [CuC104*9](C104). Two broad 1R bands at were observed, a broad band at 3444 cm" which corresponds to an OH stretch and a band at 3283 cm"1 which corresponds to a N-H 1 1 stretching vibration. UV-Vis in MeOH had an absorption X,max at 589 (e = 84.6 M" cm" ). The cyclic voltammetry run in 0.1 N sodium acetate revealed an irreversible reduction with Ep= - 0.73 V (Ag/AgCl). N HN Cu(CI04)2-6H20 N HN L L. J • Cu(CIO) CI0 ^NHV MeOH 4 4 \ / (86%) 9 [CuC104-9](C104) Scheme 29: Synthesis of [CuCKV9](C104). An X-ray structure was obtained for [CuC104»9](C104) which showed a distorted octahedral dimer with a cis-VMgand conformation of [333]/[2233] (Figure 8). The structure was solved by Katie J. Heroux in the laboratory of Arnold L. Rheingold at the University of California, San Diego, La Jolla, CA. Relevant bond lengths are listed in Table 3. The N(3)-Cu(l)-0(4) bond angle was 170.4° and the N(3)-Cu(l) and C(l)-0(4) bonds displayed Jahn-Teller elongation with bond lengths of 2.110 and 3.053 A, respectively. The combined angles of the four equatorial cis donor atoms sum to approximately 357 °. Furthermore, the coordinated perchlorates were significantly disordered. 36 Figure 8: [CuC104-9](C104) Dimer (extra C104 omitted for clarity). Table 3: [CuC104«9](C104) Selected bond lengths. Bond Bond Length (A) Cu(l)-N(l) 2.039(5) Cu(l)-N(2) 1.974(6) Cu(l)-N(3) 2.100(7) Cu(l)-N(4) 1.950(6) Cu(l)-0(1) 2.083(5) Cu(l)-0(4) 3.053 By comparison, the axial N(2)-Cu(l)-N(4) bond angle for the 19 [CuC104(MeOH>8](C104) is 165.3(5)' and for [CUC1O4'10](C1O4) was almost linear at 43 176.9(2) (Figure 9). As indicated in the X-ray structure, [CuC104(MeOH>8]C104 shows a six-coordinate copper with one perchlorate and one MeOH coordinated, and the copper cation is significantly distended from the ligand cavity. Complex [CuClO4»10](ClO4)has one perchlorate directly coordinated, the Cu(l)-0(1) bond length was 2.083 A, to form a five-coordinate complex in which the copper is held within the ligand cleft with a [2323]/[2323] distorted diamond-lattice ligand conformation.43 All three copper(II) complexes of 8-10 have the cis-Vfolded coordination configurations. 37 [CuC104(MeOH)«8](C104) [CUC1O4'10](C1O4) N(2)-Cu(l)-N(4) 165.3(5)° exo N(2)-Cu(l)-N(4) 176.9(2)° endo N(l)-Cu(l)-N(3) 84.7(1)° N(l)-Cu(l)-N(3) 88.4(9)° Figure 9: The copper(II) complexes of 8 and 10. The acid dissociation of [CuC104«9](C104) in 1 M HC1 at 30 °C, conducted under pseudo-first order conditions by E. H. Wong of the University of New Hampshire, indicated a half-life for decomplexation of 4.8 hours (Figure 10). In comparison, the half- life of decomplexation for [CuC104(MeOH)»8](C104)is < 1 minute in 1 M HC1 at 30 °C, 53 while that of [CUC1O4«10](C1O4) is 18.5(7) days in 5 M HC1 at 50 °C. The cyclic voltammogram of [CuC104(MeOH)»8](C104) had an irreversible reduction with Ep= - = 0.66 V, where as [CUC1O4»10](C1O4) has a quasi-reversible reduction of Ered -0.68 V (AE = 180 mV). Complex [CuC104»9](C104) had an irreversible reduction with Ep= - 0.73 V (Ag/AgCl). 38 1.0 < 0.4 0.2 0.0 500 600 700 800 900 Wavelength (nm) Figure 10: Visible spectra (Xmax = 575 nm) and pseudo-first order kinetics plot of the acid-decomplexation of [CuC104'9](C104) in 1M HC1 at 30 °C. In summary, when comparing all the data given above, it is clear that the copper(II) cation's fit within the ligand cavity improves as the ligand's size increases. The inertness increased from [CuC104(MeOH>8](C104) < [CuC104«9](C104) < [CUC1O4»10](C1O4). Regarding the reversibility of the respective Cu(II)/Cu(I) reduction, only [CUC1O4«10](C1O4) gives a quasi-reversible cyclic voltammogram. 10. Synthesis and copper (II) complexation of 4,11 -bis-(carboxymethyl)-(l.4.8.11- tertaazabicyclo[6.5.2]pentadecane (58). The 4,1 l-bis(carbo-tert-butoxymethyl)-l,4,8,11- tetraazabicyclo[6.5.2]pentadecane 59 was prepared from 9 according to the procedure of Peng (Scheme 30).60 The deprotection of 59 with trifluoroacetic acid (TFA) gave 58 associated with 3.7 equivalents of TFA as calculated by mass. The 'H NMR spectrum of 59 has a broad singlet at 11.64 ppm that integrated for six protons. Compound 59 was subsequently used in the copper(II) complexation. 39 H N HN X0X^Br N N^y°-< TFA:CH2CI2 N N^y° Q>iH>J r MeCNN 'v^ l"^: ? LU: \:' ° * fi/ k CA^ N" J °' 37TF'3.A ^w A HCHO^>A (61%) (quant) 9 59 58 H2-CB-TR2A Scheme 30: Synthesis of 58. Ligand 58 was taken up in 95 % EtOH and basified with 1 N NaOH to pH 8. Copper perchlorate hexahydrate was added to this solution, then refluxed for 1 day. Blue crystals of the Cu»58 complex were isolated after slow Et20 diffusion into a 95% EtOH solution of complex (Scheme 31). Elemental analysis of Cu»58 was consistent with a composition of Cu»58«l .2Na(C104)#2H20. Two strong broad IR bands were observed, one at 1610 cm"1, which corresponds to the carboxylate stretching vibration and another at 1098 cm"1, which corresponds to the perchlorate stretching vibration. The UV-Vis 1 spectrum in H2O has an absorption A,max at 608 nm (e = 32.1 M'cm" ). Cu(CI04)2-6H20 ^N ^C^Y 59 95% EtOH ' 9 C I J ° ,CU+2 pH 8, 1 N NaOH n^^ V 95% EtOH/ Et20 Diffusion * ' (47%) Cu-58 Scheme 31: Preparation of Cu*58. An X-ray crystal structure determination of Cu»58 was obtained after a second slowEt20 diffusion into a solution of complex in 95% EtOH. The structure was solved by James Golen in the laboratory of Arnold L. Rheingold at the University of California, San Diego, La Jolla, CA. The structure showed the presence of three unique cis-V-fo\ded 40 complexes each with a six-coordinated distorted octahedral copper, but each with a different ligand conformation (Figure 11). Complex A had a [333]/[2233] ligand conformation, complex B had a [333][2323] ligand conformation, while complex C was disordered and possible between [333]/[2233] and [333]/[2323] conformations. Due to significant disorder, the quality of the crystal was poor, as the refinement index value was Rl = 0.0784. Figure 11: X-ray crystal structure of Cu#58 with the hydrogens omitted. Important bond lengths for complexes A and B of Cu»58 are given in Table 4. Complex A has a N(l)-Cu(l)-N(2) bond angle of 176.8(2)° and a 0(3)-Cu(l)-N(4) bond angle of 167.0(2)°. Complex B has a N(5)-Cu(2)-N(6) bond angle of 168.7(2) and a 0(7)-Cu(2)- 41 N(7) bond angle of 174.0(2)°. Each complex has four equatorial cis donor atoms whose combined angles sum to approximately 360°. Jahn-Teller elongated bonds were observed for each complex; N(3)-Cu(l)-0(3) for Complex A and N(8)-Cu(2)-0(6) for Complex B (Table 4). Table 4: Selected bond lengths for complexes A and B of Cu»58. Complex A Complex B Bond Bond Length (A) Bond Bond Length (A) Cu(l)-N(l) 1.968(6) Cu(2)-N(5) 1.975(5) Cu(l)-N(2) 1.956(6) Cu(2)-N(6) 1.988(5) Cu(l)-N(3) 2.244(6) Cu(2)-N(7) 2.051(5) Cu(l)-N(4) 2.041(5) Cu(2)-N(8) 2.228(6) Cu(l)-0(2) 2.502 Cu(2)-0(6) 2.513 Cu(l)-0(3) 1.981(4) Cu(2)-0(7) 1.960(4) The acid-decomplexation half-life of Cu»58 was determined to be 10.8(4) h in 5 M HC1 at 30 °C, conducted under pseudo-first order condition by E. H. Wong (Figure 12). This is between the half-lives Cu»2043,53 and Cu«60 (Figure 13).57 Although not as kinetically inert as Cu»20, Cu»58 is significantly more resistant to acid decomplexation than Cu»60 whose ligand cavity is smaller (Figure 13). The cyclic voltammogram of Cu«58 has a quasi-reversible reduction with Em= - 0.95 V (Ag/AgCl), AE = 138 mV. This is between the values found for Cu*20 (Ei/2= -1.08 V, quasi-reversible reduction, AE 53 = 120 mV) and Cu»60 (Ep= -0.85 V, irreversible reduction), and indicates that Cu*58 is more resistant to reductive demetallation than Cu*58, though not as resistant as Cu»20. 42 500 600 700 800 900 Wavefength (nmj Figure 12: Visible spectra (Xmax = 607 nm) and pseudo-first order kinetics plot of the acid-decomplexation of Cu»58 in 5M HC1 at 30 °C. -co? „N^ N .N N N N •Cu+ cu+2 Cu+2 N XNJ (A J - C \) - N N ^N N o2c- •o2c-^\—( -0zC^[^j Cu-CB-D02A Cu-CB-TR2A Cu-CB-TE2A Cu-60 Cu'58 Cu«20 Acid-decomplexation 5M HC1,30 °C < 1 minute 10.8(4) hours >1 year 1 (Cu'VCu ) Reduction Elfl vs (Ag/AgCl), 0.1 N sodium acetate -0.85 V -0.95 V -1.08 V Figure 13: Comparative kinetic inertness of Cu»60, Cu»58 and Cu«20.43,53,5 7 Similar IR (KBr) bands were observed for Cu#60 and Cu»20 with two strong asymmetric carboxylate stretching vibrations at 1595 and 1624 cm"1 . 119 Cu*58 on the other hand had only one strong broad carboxylate stretching vibration at 1609 cm"1. 43 When comparing the three copper(II) complexes Cu»60, Cu»58 and Cu#20, all three complexes have a 6-coordinate distorted octahedral geometry with all four nitrogens and both acetate pendant-arms (a N4O2 donor set) coordinated to the copper (Figure 14). Each complex has a Jahn-Teller distortion along a N-Cu-0 direction and four equatorial cis angles at the copper centers sum to approximately 360°. The N(l)-Cu(l)- N(2) bond angle of Cu«58 Complex A is exo though to a lesser extent than for Cu#60 in which the copper cation is distended (Figure 14). On the other hand, the Cu»20 complex indicates a good fit for the copper(II) cation within the ligand cleft. The observed structural trend seems to be related to the ligand cavity size and metal's fit within the ligand cleft. Cu-CB-D02A Cu-CB-TR2A«Complex A Cu-CB-TE2A N-Cu-N 159.0° exo N-Cu-N 168.7° exo N-Cu-N 177.5° endo Figure 14: Comparative X-ray structures of Cu«60, Cu«58 and Cu*20. 44 IV. Conclusions The synthesis of 12 and 13 via a cis tricyclic bisaminal route has been achieved in good purity and reasonable yields. Employing microwave irradiation for the reductive ring-opening of dibenzyl tetracyclic bisaminals 14-16 to their corresponding dibenzyl cross-bridged tetraazamacrocycles 17-19 has dramatically reduced reaction time from 4- 16 days to 15 minutes. Products recovered from the microwave-enhanced reductive ring- opening reactions were in high yield and excellent purity. The microwave-assisted reductive ring-opening of the diallyl homocyclen bisaminal species 49 was not successful, and may be attributed to the reactivity of the allyl groups. However, reductive-ring opening under conventional conditions was achieved in good yield by using NaBH3CN instead of NaBH4. Synthesis and structural and kinetic inertness studies of copper(Il) complexes of 1,4,8,1 l-tetraazabicyclo[6.5.2]pentadecane 9 and 4,1 l-bis-(carboxymethyl)-(l,4,8,11- tetraazabicyclo[6.5.2]pentadecane 52 were accomplished. When comparing all data and structures to 8 and 10 and their dicarboxymethyl pendant-armed derivative 60 and 20, a trend in increased kinetic inertness was observed that can be attributed to the specific ligand cavity size increase and the copper(II) cation's fit within it the ligand cleft. Comparison of the kinetic inertness of these copper(Il) complexes follows the order: Cu- CB-Cyclam > Cu-CB-Homocyclen > Cu-CB-Cyclen. This is also consistent with the kinetic inertness order observed for their dicarboxymethyl pendant-armed derivatives: Cu-CB-TE2A > Cu-CB-TR2A > Cu-CB-D02A. 45 CHAPTER 2 PROGRESS TOWARDS A C-FUNCTIONALIZED CROSS-BRIDGED CYCLAM I. Introduction C-Functionalized tetraazamacrocycles are cyclic polyamines in which a substituent is incorporated into the tetraazamacrocycle carbon backbone.4'5',20 The advantage of C-functionalized tetraazamacrocycles is in retaining all four nitrogen donor atoms or pendant arm groups for metal cation coordination. > - > — The additional C- functionality can then be either used for additional metal binding, or can undergo subsequent chemical transformation to function as a linker for conjugation to other molecular or biochemical components.6'122"126 Several synthetic approaches have been reported for the preparation of C- functionalized tetraazamacrocycles. These include the Stetter-Richman-Atkins approach described in Chapter 1, the condensation of acyclic tetraamines with substituted diethyl malonates, and the metal-templating approaches.4'5'15'127 The condensation of acyclic tetraamine 23 with a substituted malonate 61 gives a C-functionalized cyclic diamide 62 (Scheme 32).128 Subsequent amide reduction of 62 affords the C-functionalized cyclam derivative 63. Although the overall yield of this synthetic approach is modest, the advantage is that a variety of C-functionalized cyclic tetraamines can be generated in only two steps. - • - • 46 R = (Yields; Step 1, Step 2) o. 1. BH , THF 3 Cr^Cgr^ (25, 65%) HpN NH2 + EtO.JL.OEt HOT r^ HN 2 6 N HC| ^H HN N CH2CH2OH H II if I J o ™,„ " L J o o NH HN^ 3. KOH/MeOH >JH HN" ru%^u VM l^y ^^y (30,70%) 23 61 62 63 Scheme 32: Condensation of an acyclic tetraamines with a substituted diethyl malonate. Another method for the synthesis of C-functionalized tetraazamacrocycles utilizes a metal cation-templating approach.131"136 For example, the reaction of ethylenediamine with 3,3'-dichloropivalic acid (64) in the presence of copper chloride and base gives the copper(II) complex intermediate 65 (Scheme 33). The addition of paraformaldehyde, nitroethane and triethylamine affords the C-functionalized tetraazamacrocyclic copper(II) complex 66 (diastereomeric mixture). Isolation of 67 as a hydrochloride salt is accomplished by reduction with Zn/HCl.132 A variety of mono and di-C-functionalized tetraazamacrocycle complexes have been synthesized by this metal-directed method.131" 136 Most of the reported procedures use copper(II) as the templating cation. CO, H C02H 1. Reflux at 90 °C % N. HPN„ S + Cl CI *" CI" NH 2 2. NaOH-MeOH (excess) 3. CuCI -2H 0 O 2 2 64 M i i H (50%) HH H 65 CO, C02H HJ I.H (CH3CH2)3N^ Zn, HCI .NH HN 65 ci- HCHO C > ) NH HN CH3CH2N02 (57%) X NO, NH2 66 67 Scheme 33: A metal-templating approach to a C-functionalized tetraazamacrocycle 67. 47 C-Functionalized cyclam-based bifunctional chelators have been synthesized for use as radiolabeled agents." ' " ' ' The condensation of substituted diethyl malonates and acyclic tetraamines have been successfully used for this purpose.139"141 As mentioned above, the advantage of these bifunctional chelators, such as 68, is that all four of their nitrogen metal-donating substituents are free for coordination to a radiometal cation, while the C-functionality can be used for linkage to a biomolecule.140 — Biomolecule Linker — Four Metal Coordinating f" " N Carboxylate Groups 02C-^ l J ^—C02" 68 48 II. Background A series of C-functionalized tetraazamacrocycles have been synthesized via a tricyclic bisaminal route discussed in Chapter 1. Guilard et al. reported on the condensation of acyclic tetraamine 23 with butadione to give 69 (Scheme 34).142 The tricyclic bisaminal 69 was alkylated with substituted bis-electrophiles to generate a series of C-functionalized tetracyclic bisaminals, 70, which upon acid hydrolysis gave the corresponding C-functionalized cyclam derivatives 71. C-Functionalized cyclen and homocyclen were also synthesized by this method in modest yield (20 to 52% overall).142 The advantage of this method lies in the generation of a large library of C-functionalized tetraazamacrocycles in three steps with moderate to good overall yields. O " _^ rN"PS R ^N^HCI,60°C ^NHHN H2N^N^^N^ .NH, -^ > H H MeCN 0°C S\J-^|\r MeCN, Reflux ^N^TN^ 48 h ^NH HrT 2h H H 48 h R = OH, COOMe, COOH X = Br, OTs R R 71-87% overall 23 69 70 71 Scheme 34: A tricyclic bisaminal route to C-functionalized tetraazamacrocycles. iV-Benzyl and iV,iV"-dibenzyl C-functionalized cyclam derivatives were also prepared by employing the tricyclic bisaminal route described above.143 Archibald and co-workers reported on the alkylation of 69 with an aryl substituted 1,3-dibromopropane to give the tetracyclic bisaminal 72 (Scheme 35). The axial and equatorial diastereomers of 72 were separated by column chromatography and the axial isomer of 72 was used in the subsequent reactions. The tetracyclic bisaminal 72 was treated with acid to remove the bisaminal-bridge to give 73. The condensation of 73 with glyoxal afforded a second 49 tetracyclic bisaminal 74, which was alkylated with benzyl bromide at the exo-nitrogen lone pairs to give 75. Acid hydrolysis of 75 gave the C-functionalized A^TV'-dibenzyl cyclam derivative. It was not made clear by the authors why they chose to use butadione instead of glyoxal for the initial condensation of the acyclic tetraamine 23 (Scheme 34) since it was later used for the synthesis of the tetracyclic bisaminal 74. An initial glyoxal condensation should give the same outcome and possibly cut down on the number of steps in their overall synthesis. A similar procedure was followed for the synthesis of a mono ./V-benzyl cyclam derivative. Br MeCN, K2C03 ,N J^N^ HC| 60°c NH HN 60°C,5d liJ — C,HHJ N02 (74%) K\J {9o%) Ar Ar Ar 69 72 73 O II -Bn I I ,Bn N N N O MeCN ^ ^ -i- x BnBr, MeCN (-' 4' + ^ HCI, EtOH .NH N c -5;; 3^ L I J rt,3d' U| J ».c.3- L J l Bn" I H I Bn' i i (60%) \S Br <80%) L-y"J (60%) 2 Ar Ar Ar 74 75 Scheme 35: Preparation of a dibenzyl C-functionalized cyclam derivative using the tricyclic bisaminal route. The synthesis of a C-functionalized cross-bridged cyclam bifunctional chelator was recently reported by Archibald and coworkers (Scheme 36). This was accomplished by using the tricyclic bisaminal route and the cross-bridged cyclam methodology developed by Weisman and Wong, described in Chapter 1. The double-reductive ring opening of 75 with sodium borohydride gave the cross-bridged derivative 76. 50 Hydrogenolysis of 76 and reduction of the aryl nitro group afforded 77.143 The protection of the aryl amine gave 78, followed by the functionalization of the secondary amines as carboxymethyl pendant arms, and deprotection of the imine gave 79 with an isothiocyanate aryl group. The final product 79 was reacted with biotin ethylenediamine to generate a biotin bioconjugate. It is noteworthy that the authors suggested that the cross-bridge species 79 exists as a 1:1 diastereomeric mixture. However, since the cross- bridged species itself exists as a set of enantiomers, four stereoisomers are expected for 79, two pairs of enantiomers. ^*. ^\ ^"N. 1.2 eq t-Butylbromoacetate ^v. II Bn 'I ' ' 'I ,^-COoH NaBH4 N N' H2, Pd/C ,N HN 1eqBenza|dehyde N HN K2C02, MeCN, rt,3d,(50%) N N _ MeOH* L L J AcOH*kNHUNJ MeOH, rt, 0/n " ^NH^N^ 2. HCI, 100°C, 2d (100%) ^N ^N^ rt 14d . Bn'i I rt, 3d i i i i HO r._/1 i 2 l J U \^ \/ 3. CI2CS, CHCI3/H20, pH 8 \/ (78%) T (79%) L (93%) I I Ar Ar Ar rt 0/n (g5%) Ar P Ar=^^-N02 Ar=^-^jKNH2 *= ^^J^H^ ^ Ar= ^^(JHNCS 76 77 78 79 Scheme 36: Preparation of a C-functionalized cross-bridged cyclam bifunctional chelator. The work herein will utilize the cis tricyclic bisaminal 49 as a building block for the synthesis of a C-functionalized cross-bridged cyclam derivative. The current cross- bridged bifunctional chelator developed by Weisman and Wong, 20 (CB-TE2A), has two nitrogen carboxymethyl pendant-arms, one for the conjugation to the biomolecule and one for binding to the copper(II) radiometal, 22.53'57'61 The overall charge of this bioconjugate is +1. The goal is to synthesize of a C-functionalized cross-bridged bifunctional chelator in which both JV-functionalized pendant-arms are available for 51 complexation to the copper(II) cation and the C-functionality available for conjugation to a biomolecule, 80. This would give a charge-neutral copper(II) bioconjugate. *N- •^-"--(pepiiaefr [peptide^, ^ Jl .o, ' o H 22 80 CB-TE2A Bioconjugate A Proposed C-Functionalized CB-TE2A Bioconjugate There are two features required for a C-functionalized cross-bridged cyclam derivative. First, the C-substituent must be able to undergo a chemical transformation to a functional group that can be conjugated to a biomolecule as shown in 80. Secondly, its stereochemistry should be such that it would not put any steric strain on the six- membered copper(II) coordinating ring of 80. This would require the substituent to be in the equatorial position of the six-membered coordinating ring, with the ligand in a [2323J/2323] diamond-lattice conformation. The proposed synthesis for a C-functionalized cross-bridged cyclam derivative is shown in Scheme 37. A C-functionalized tetracyclic bisaminal 81 can be synthesized from 49. The stereoselective chemical transformation of 81 to an axial-oriented substituted cis tetracyclic bisaminal 82 is required to ensure the correct stereochemistry for the chelate ring in 80. The subsequent reactions of 82 to a C-functionalized cross- bridged cyclam derivative 83 followed by elaboration to 84 are based on the synthesis developed by Weisman and Wong (Scheme 1) 40-44 52 r^i r^i r^i r^ H ^^OH wNIN - NiwN -UNiN J •••—w~~N N - iwN N >r ' N'N N'N N • N N N , ,_^s. -N N H H H |^| ^ H I^J HC^ l^ XXX X 49 81 82 83 84 Scheme 37: The proposed strategy for the synthesis of a C-functionalized cross-bridged cyclam derivative. 53 III. Results and Discussion 1. Attempted synthesis of a carbonyl-functionalized cyclam bisaminal 85. The initial approach for the synthesis of a carbonyl-functionalized cyclam bisaminal involved the alkylation of 49 with 1,3-dichloroacetone to give 85 (Scheme 38). Various reaction times and temperatures were considered, but there was no evidence of the desired species by either NMR spectroscopy or by ESI mass spectrometry. A 1,3- diiodoacetone alkylating agent was also tried without success. The failure of this reaction could be due to nucleophilic attack at the carbonyl by a secondary nitrogen of 49. The crude products of these attempted reactions provided no evidence of either the starting bisaminal 49 or a carbonyl-substituted species. ^M^VM^ .. N l I N N N MeCN, K2C03 H H H 7 o 49 85 Scheme 38: Attempted synthesis of a carbonyl-functionalized tricyclic bisaminal. A second approach was undertaken with the attempted alkylation of 49 by a cyclic acetal-protected dichloroacetone (1,3-dioxolane) to generate 86 (Scheme 39). The goal was then to deprotect this acetal in acid to give 85.144 However, the reaction did not proceed at all as both reagents were visible by !H NMR spectroscopy with no evidence of alkylated species 86. Running the reaction at elevated temperatures gave the same result. The acetal-protected reagent is clearly too sterically hindered due to the neopentyl-like acetal for nucleophilic attack to occur at a reasonable rate. 54 N N N^pN CI^^CI .N^N H20,catH* ^ ^ ^ L J WW MeCN,K2C03 NiN N^N 49 86 85 Scheme 39: Attempted alkylation of 49 with an acetal. A final attempt at synthesis of 85 was based on a Claisen condensation followed by a subsequent decarboxylation (Scheme 40).145'146 MacMillan reported the alkylation of morpholine (87) with ethyl bromoacetate to give 88, which was treated with half an equivalent of sodium ethoxide followed by decarboxylation with sodium hydroxide to give the l,3-di-morpholin-4-yl-propan-2-one derivative 89 (Scheme 40).146 ° o /N\ Br /N 1.0.5eqNaOEt N N ^0^ Toluene ^QJ 2. NaOH L JL.-.J (92%) (62%) 87 88 89 Scheme 40: Claisen condensation followed by a decarboxylation to l,3-di-morpholin-4- yl-propan-2-one (89). The synthetic approach for the synthesis of 85 via such a Claisen condensation followed by a decarboxylation is shown in Scheme 41. The goal was to dialkylate 49 with ethyl bromoacetate to give a tricyclic bisaminal diester 90, which can then be treated with half an equivalent of sodium ethoxide, followed by sodium hydroxide to give 85. 55 rNi"% Br OEt rN>fNNi ia5eqNa0Et rN"PN^ S^ K2C03,CH3CN ^N'KT 2. NaOH ^N-1>/ H H H EtO^J H L^OEt m O 0 5 49 90 85 Scheme 41: A proposed route to 85 by a Claisen condensation and subsequent decarboxylation. The desired intermediate 90 was obtained after column chromatography in -19% yield when the alkylation was carried out at room temperature according to the conditions of Scheme 41. The major species isolated after chromatography was a trans monoalkylated species 91 (31%), which was identified by NMR spectroscopy. When the reaction was run in toluene only the trans mono-alkylated species 91 was observed (33%). Failure to maintain the cis bisaminal configuration could be due to rapid bicyclic iminium ion formation after the initial alkylation, with generation of the trans monoalkylated species upon reclosure to the bisaminal. CN O;"N H H 'v .OE t O 91 2. The synthesis of c/s-2-methylidenedecahydro-lH,6H-3a,5a,8a,10a-tetraazapyrene (92). Another approach to a C-functionalized cyclam bisaminal derivative is shown in Scheme 42. Bisaminal 49 was alkylated with 3-chloro-2-(chloromethyl)-l-propene to give exo-methylene tetracyclic bisaminal 92. Initially the reaction was run at 60 °C for 4 56 days, after which the product was purified by column chromatography on silica gel (MeOH elution with CH2CI2 (1:10)). Two bisaminal species were isolated, the desired cis 92 (Rf 0.07), and a trans isomer 93 (Rf 0.2). The 'H NMR spectra of the cis/trans isomers are shown in Figure 15. The desired cis 92 has slow-exchange Ci symmetry and both diastereotopic olefinic protons were broad singlets at 4.78 and 4.93 ppm, while trans 93 with rigid Cs symmetry exhibits the homotopic olefinic protons as a singlet at 4.88 ppm. However, when the reaction was run at room temperature for approximately 96 hours, no evidence of the trans 93 was observed by NMR spectroscopy. The crude product was then purified by Kugelrohr distillation at 80-100 °C (25 mTorr) to give the desired cis 90. ^NJV ci ci ^ rNH^S ^M^hrT K2C03, CH3CN ^N'1>^ H H H rt, 4 d I H ' (89%) 49 92 Scheme 42: Synthesis of cz's-2-methylidenedecahydro-lH,6H-3a,5a,8a,10a- tetraazapyrene (92). H trans 93 57 ^s cis 92 ( if* 2.04 1.02 3.01 3.08 1.16 1.04 3.10 /—H-^y j trans 93 6.08 0.99 3.19 1.02 2.04 4.01 1.00 0.00 ] Figure 15: The H NMR spectra of 92 and 93 in CDC13. The alkylating agent used above was 3-chloro-2-(chloromethyl)-l-propene as indicated in Scheme 42, but 3-bromo-2-(bromomethyl)-l-propene (94) which was prepared from 2,2,2-^ra(bromomethyl)ethanol (95), was also used with success (Scheme 43).147 The literature-reported procedure used nitric acid for the oxidization of 95 to 2,2,2-/7"zXbromomethyl)acetic acid (96). The thermal decarboxylation of 96 afforded 94. Thus, alkylating agent 94 can be obtained in two steps from inexpensive commercially- available material. 58 Br OH Br OH HN°3 C ^ 255 °C (82%) f 1 (80%) Br Br Br Br Br Br 95 96 94 Scheme 43: Preparation of 3-bromo-2-(bromomethyl)-l-propene (94).147 3. Attempted ozonolysis of 92. The initial ozonolysis attempt used conventional reaction conditions in which olefin 92 was treated with O3 in CH2CI2 at -78 °C until the reaction mixture was a light blue color, indicating a saturated O3 solution (Scheme 44).148'149 The reaction mixture was then flushed with N2 and the ozonide decomposed with PPI13. However, from the NMR spectra there was no evidence of carbonyl-containing species 85. It has been reported in the literature that tertiary amines can be used to break down (reduce) the ozonide intermediate.150"152 With this in mind, another approach was attempted in which the bisaminal 92 was treated with trifluoroacetic acid in order to protonate the amines prior to ozonolysis.153'154 The crude mixture, however, was extremely complicated as shown by NMR spectroscopy with no evidence of desired product 85 in the 13C{'H} NMR spectrum. N ^N^r.N 1.03,CH2CI2-78°C / X>V >1> 2:^"""* LI J o 92 85 Scheme 44: The attempted ozonolysis of 92. 59 4. Attempted alkylation of 92. Attempted alkylating 92 with bromoacetamide, ethyl bromoacetate and f-butyl bromoacetate to give bisaminal salts 97 were all unsuccessful (Scheme 45). All three reactions gave multiple alkylated products by 'H NMR spectroscopy. Attempts at purification by recrystallization to isolate the desired product were unsuccessful in all three cases. Since 92 is slow-exchange Ci symmetric, two possible monoalkylated species as well as the desired dialkylated species 97 are possible products, which may explain the complicated NMR spectra. It is also possible that the allylic amine functionality can undergo a SN2' reaction155'156 with the bromide anion after the initial alkylation, which would result in a tricyclic bisaminal species. m i~- o rNf"Si A^N' VKiH^ J MeCN, K2C03 R_XNH V R = NH2, OCH2CH3, OC(CH3)3 || 2 Br 92 97 Scheme 45: Attempted alkylation of 92. 5. The synthesis of c/s-3a,8a-bis(phenylmethyl)-2-methylidenedecahydro-lH,6H-5a,10a- diaza-3a,8a-diazoniapyrene dibromide (98). The alkylation of 92 with benzyl bromide was accomplished in MeCN over 14 days, after which the product was collected as a white solid by suction filtration and washed with CH2CI2 to remove excess alkylating agent (Scheme 46). No additional purification was required. An X-ray crystal structure (Figure 16) of bisaminal 98 was obtained from crystals grown by slow evaporation of an aqueous solution. The structure was solved by James Golen in the laboratory of Arnold L. Rheingold at the University of 60 California, San Diego, La Jolla, CA. The structure showed the expected dialkylation of 92 at the exo nitrogens. N - >^ N>rl, ^ // f J ^) BnBBnBrr r(-' -»l"'+N ^~ ^N'T^T MeCN, 14d/rA_J^N^N^ 2B' (95%) 92 98 Scheme 46: Benzylation of 92. Figure 16: Ortep diagram of 98 (hydrogens omitted). 6. The synthesis of 4.1 l-bis(phenylmethyl)-6-methylidene. 1,4.8.11- tetraazabicyclo|"6.6.2]hexadecane (99). An open-vessel microwave reaction (of the type described in Chapter 1) with a single-mode CEM Discover® microwave reactor was used for the reductive ring opening of 98 (Scheme 47). Bisaminal salt 98 was dissolved in 95% EtOH and the reduction was done with NaBlTt. This microwave reaction was set up with an initial temperature of 50 °C and slowly increased to 78 °C, with increments of 5 °C/min to 70 °C, then 2 °C/min to 78 °C to avoid temperature overshoot. A 78 °C reaction temperature was then maintained 61 for 18 min. After the reaction was completed, excess NaBH4 was decomposed with 6 M HC1, the mixture was concentrated, basified and extracted to give 99 in 97% yield. | H I —/ \ 1) NaBH4, 95%EtOH ^•N^N \^ 78°C, MW,18min /N\ N\ V_^ ^A>J>J 2Br" ^ " ^J> V <•' >-^^ i H i 3) KOH, Benzene < x>— I I (97%) 98 99 Scheme 47: Microwave-assisted reductive ring opening of 98. An X-ray quality crystal of 99»HPF6 was obtained from the reaction of NH4PF6 with 99 in CH3OH, which resulted in crystallization of a white solid. The solid was dissolved in MeCN and slow evaporation gave the 99«HPF6 salt (Figure 17). The structure was solved by James Golen in the laboratory of Arnold L. Rheingold at the University of California, San Diego, La Jolla, CA. The ligand had a [2233]/[2323] conformation with the inside proton held within the ligand cavity. The 10-membered rin£ containing the exo-cyclic methylene had the [2233] conformation, which is expected to have a slightly higher strain enthalpy.54 The sp2 hybridized carbon was located at a non- corner position.157'158 As in 99»HPF6, proton H4 points towards nitrogen N3 with a relatively short transannular intramolecular hydrogen bond (TvU-FLfNa) distance of 2.055 A.159 62 Figure 17: Ortep diagram of the 99»HPF6 salt (ligand hydrogens omitted). 7. The synthesis of c/5-2-methylidine-3a-8a-bis(naphthalene-2-ylmethyl)decahydro- lH,6H-5a,10a-diaza-3a-8a-diazoniapyrene (100). The alkylation of 92 with 2-(bromomethyl)naphthalene was accomplished in MeCN over 18 days, after which the off-white solids were collected and washed with Et20 to remove excess alkylating agent (Scheme 48). The product was isolated as a white solid in good yield and no additional purification was required. ^N^N BrCH2NAP MeCN, 18 d (95%) 92 100 Scheme 48: Synthesis of cw-2-methylidine-3a-8a-bis(naphthalene-2- ylmethyl)decahydro-1 H,6H-5a, 10a-diaza-3a-8a-diazoniapyrene (100). 63 8. The synthesis of 6-methylidene-4,l l-bis(napththalene-2-methyl)-1,4,8,11- tetraazabicyclor6.6.21hexadecane (101). An open-vessel microwave reaction using the single-mode CEM Discover® microwave reactor were again used for the reductive ring opening of the dibenzyl bisaminal salt 100 (Scheme 49). Bisaminal salt 100 was dissolved in 95% EtOH and the reduction was done with NaBELi. This open-vessel microwave reaction was set up with an initial reaction temperature at 50 °C. The temperature was then slowly increased to 78 °C, at increments of 5 °C/min to 70 °C, then 2 °C/min to 78 °C, where the temperature was maintained for 11 min. After the reaction was completed, excess NaBH4 was decomposed with 6 M HC1, the mixture was then concentrated down, basified and extracted to give 101 in 89% yield. N^NI^^A //~\ DNaBH4,95%EtOH -™^™^ \—? W 78°C, MW.11 min 2 Br" 2) HCI 3) KOH, Benzene (89%) 100 101 Scheme 49: Microwave-assisted reductive ring opening of 100. 9. The attempted deprotection of 99 and 101. To expand the utility of the new olefinic C-functionalized cross-bridged cyclams 99 and 101, benzyl and 2-napthalenemethyl deprotection attempts were undertaken. The aim was to generate an olefinic cross-bridged cyclam 102 that can subsequently be modified by alkylation at the secondary nitrogens to give 103 (Scheme 50). 64 j^\ ^N N R (' \J ^ I I |^| Br^ I^|,R 1HN1 Ji N N NH\ N ) °.~ R' w 99 R = NH2 OCH2CH3 OC(CH3)3 102 103 101 Scheme 50: Potential route to an olefinic C-functionalized cross-bridged cyclam 103. An attempt at a dissolving-metal reduction160 of 99 with lithium in ethylenediamine, triethylamine and THF resulted in the recovery of the starting material as revealed by the 'H NMR spectrum of the crude product. Another debenzylation attempt by treatment of 99 with a-chloroethyl chloroformate161'162 followed by refluxing in 1,2-dichloroethane resulted in complicated mixtures by !H NMR spectroscopy with no evidence of the desired debenzylated 102. Similarly, the deprotection of the 2- naphtathalenemethyl groups of 101 via a-chloroethyl chloroformate formation and by oxidative cleavage using 2,3-dichloro-5,6-dicyanoquinone were unsuccessful. The H NMR spectra of the crude product mixtures of both these deprotection attempts were complicated with no evidence of the desired deprotected product, 102. As mentioned above, one possible reason for failure of the a-chloroethyl chloroformate deprotections161'162 may be that the olefin functionality underwent a SN2' reaction with the chloride ion. This could explain the complicated NMR spectra observed. 65 10. The synthesis of c/5-decahydro-lH,6H-3a,3a,10a-tetraazapyren-2-yl methanol (104). The general synthetic scheme for the hydroboration-oxidation of 92 is given in Scheme 51. There were several considerations that had to be taken into account. First, the choice of the borane reagent for the hydroboration reaction was considered. A smaller borane reagent such as BFb'THF may deliver the borane reagent to either the axial or equatorial positions to generate 104 and 105 respectively, whereas larger borane reagents such as 9-borabicyclo[3.3.1]nonane (9BBN) may favor the equatorial delivery of the borane to give only axial product 104 (Figure 18).163"167 A second consideration was the regioselectivity of the hydroboration reaction in which a larger borane reagent such as 9BBN or catecholborane may favor the anti-Markovnikov borane delivery to give the primary alcohol 104. A smaller borane reagent such as BH3 may not be as selective, and although the primary alcohol would be expected as the major product, a tertiary alcohol 106 may also be generated. ^.N^N (1) Hydroboration r y^S ^N-ihr -'—» S H N ' (2) Oxidation L^J "OH 92 104 Scheme 51: Proposed hydroboration/oxidation of 92. 66 104 105 104 106 Axial or Equatorial Alcohol Axial Alcohol 3° Alcohol Figure 18: Possible hydroboration-oxidation reaction outcomes. It is also noteworthy that the formation of an amine-borane complex may occur, in which case a directing effect of the borane reagent could be observed. ' The formation of a strong amine-borane complex must also be taken into account during product isolation. After completion of the hydroboration-oxidation, any amine-borane complex must be decomposed by treatment with acid.170'171 A final consideration was the oxidizing agent. The two oxidizing reagents considered were hydrogen peroxide (H2O2) and sodium perborate tetrahydrate (NaBCb^HiO), a milder oxidizing agent.172'173 Hydroboration attempts using BH3»S(CH3)2/NaOH followed by H2O2 resulted in the recovery of the starting olefin as the major component in the crude product mixture. The use of catecholborane/NaOH followed H2O2 resulted in a crude mixture that did not have the starting olefin present, but there was no evidence of the bisaminal functional 13 group in the C{'H} NMR spectrum. On the other hand, the use of BH3*THF with either 67 H2O? or NaB03»4H20 as the oxidizing agent did give both a primary and tertiary alcohol in a —1/1 ratio. When the reaction was run with 9BBN the desired product was isolated in a 49 % yield, with the major species being 104 (Scheme 52).170 A minor tertiary alcohol species was also visible by 13C{!H} NMR (CDCI3) with a signal observed at 31.55 ppm for a methyl group. The product ratio was -50/1 and the minor species was easily removed by washing the material with anhydrous acetone. A final yield of 34% of pure 104 was obtained. Confirmation that the axial alcohol 104 was indeed the isolated product was obtained from the *H NMR (CDC13, 400 MHz). A broad multiplet ranging from 1.68- 1.76 ppm, integrated for only one hydrogen and this range (32 Hz) corresponds to the approximate combined coupling constants174 expected for primary alcohol's methine hydrogen (H2eq) as indicated in Figure 19. A much larger multiplet range would be expected of the equatorial alcohol's methine hydrogen. f I ^ 0)4equiv9BBN-THF [ T | j*Hj (2)NaOH, H202 I Hj f| (3) HCI ; (34%) ^OH 92 104 Scheme 52: Hydroboration/oxidation of 92. H l2ax H2eq HO. fV^ u2a x r7^,N : ^Hax =2x4Hz ""lI n ^$d^Nr-7 NN-^ /7 V« q>^N ^/ iyHax =2x11 Hz J /Heq =2x4 Hz W2^ 2^/^yJ V /^ ^CH20H = 2x7Hz Total =28 Hz *-^~~^-\* /-""~^-|\T Total = 44 Hz 104 105 Figure 19: Approximate coupling constants expected for H2 of 104 and 105. 68 During the reaction workup (Scheme 52), the amine-borane complex was decomposed by refluxing the crude product in 2 M HC1 followed by the removal of the 1,5-cyclooctan-diol byproduct by overnight continuous liquid-liquid extraction with CH9CI2. In an initial attempt at recovering the major species 104 from the above reaction, a small amount of 104 was reacted with two equivalents of HBr to form the 104»2HBr salt. The NMR spectra did show the presence of the desired 104»2HBr salt, which then crystallized from MeOH-d4 in the NMR tube. The crystals were subjected to crystal structure analysis. The structure was solved by James Golen in the laboratory of Arnold L. Rheingold at the University of California, San Diego, La Jolla, CA. The stereochemistry of the reaction product was then further confirmed to be the desired axial alcohol 104 (Figure 20). As indicated by the structure of 104«2HBr, protonation occurred at the more basic endo nitrogen positions Ni and N3. These diprotonation positions were the same as reported for the diprotonation of tetracyclic bisaminal 13 prepared by Busch and coworkers.35 This inside protonation is also consistent with the anomeric stabilization.175 Figure 20: Crystal structure of 104»2HBr (ligand hydrogens omitted). 69 An X-ray quality crystal of 104 free base was obtained by recrystallization from hot acetone (Figure 21). The structure was solved by Katie J. Heroux in the laboratory of Arnold L. Rheingold at the University of California, San Diego, La Jolla, CA. It was hypothesized that the hydroxyl group of 104 can be either directed towards the ligand cavity to form an intramolecular hydrogen bond to an endo nitrogen lone pair or it could point away from the ligand cavity to form an intermolecular hydrogen bond with an adjacent bisaminal's nitrogen lone pair. Here, the X-ray crystal structure revealed two hydrogen-bonded 104 molecules each with an intermolecular hydrogen bond to an endo nitrogen lone pair of the partner. The hydrogen bonds between the two molecules are at the more basic endo nitrogens (Figure 21). Figure 21: The intermolecular hydrogen bonds between two 104 molecules (ligand hydrogens omitted). 70 11. The synthesis of Sa^a-d^phenylmethyQ^^hydroxymethyDdecahydro-lH^RaJOa- diaza-Sa^a-diazoniapyrene (107). The synthesis of 3a,8a-di(phenylmethyl)-2-(hydroxymethyl)decahydro- li/,6//,a,10a-diaza-3a,8a-diazoniapyrene (107) was accomplished by reacting 104 with 14 equivalents of benzyl bromide in MeCN over 17 days (Scheme 53). The crude product recovered by suction filtration was washed with EtaO to remove excess alkylating agent. The !H NMR spectrum of the recovered material did show the presence of a minor impurity, which was then removed by dissolving the crude material in MeOH and placing it in an EtiO diffusion chamber. The crystallized material was pure 107 in 32% yield. r7\ r^^x 7/ ll J MeCN.ni7d /r^S4-NJ L^J (32%) {JT^ k^l 2 Br ^OH ^OH 104 107 Scheme 53: Synthesis of 107. 12. The synthesis of 4,11-di(phenylmethyl)-1,4,8,1 l-tetraazabicyclo[6.6.2]hexadec-6-yl)- methanol dihydrobromide monohydrate (108*2HBr*H?O). The 4,1 l-di(phenylmethyl)-l,4,8,1 l-tetraazabicyclo[6.6.2]hexadec-6-yl)methanol dihydrobromide monohydrate (108»2HBr»H2O) was prepared from the microwave- assisted reduction of 107 in 95% EtOH with NaBH4 (Scheme 54). An open-vessel microwave reaction was set up in a CEM Discover® microwave reactor with an initial temperature of 50 °C followed by an increase in temperature at 5 °C/min to 70 °C, then 2 71 0C/min to 78 °C, which was maintained for 14 minutes. After the reaction was completed, excess NaBH4 was decomposed with 6 M HC1. The mixture was then concentrated, basified and extracted to give 108. The *H NMR spectrum of free base 108 indicated the presence of a minor impurity. The crude product was then dissolved in EtOH and two equivalents of HBr were added. Thereafter the solution was concentrated to a white solid which was recrystallized from EtOH to give 58% of 108»2HBr»H2O with good purity NMR spectra. The 'HNMR spectrum (MeOH-d4 (TMS), 500 MHz) of 108«2HBr«H2O had a multiplet ranging from 2.52-2.62 ppm that integrated for only one hydrogen. This range (50 Hz) corresponded to the axial methine hydrogen H6ax (Figure 22) as it correlated to the approximate combined coupling constants174 expected for axial methine hydrogen (H6ax) (as indicated in Figure 19). A much smaller multiplet range would be expected if alcohol's methine hydrogen had been in the equatorial position. As a result, it is confirmed by 'H NMR that the desired stereochemistry is obtained for the proposed BFC 84. xNXN^\i 1)NaBH4,95%EtOH N N' [ | + | 78 °C, MW,14min ill /f^V^Hl 2)~Hci ~^~\ N N 2HBr.H20 \—/ K^J 2 Br 3) KOH, Benzene \=/ ^^ E 4) 2 eq HBr j \)H ^OH (58%) 107 108«2HBr«H2O Scheme 54: C-Functionalized dibenzyl cross-bridged cyclam 108»2HBr*H?O. 2 Br Bn H2Q Figure 22: Equatorial methanol C-functionalized iV,iV'-dibenzyl cross-bridged cyclam 108'2HBr'H7O 72 IV. Conclusions The direct attempt at synthesizing a cis carbonyl-functionalized tetracyclic bisaminal 85 from alkylation of the cis tricyclic bisaminal intermediate 49 was not achieved. Instead an cis olefinic tetracyclic bisaminal 92 was synthesized from 49, this intermediate was used for the synthesis of a series of C-functionalized cross-bridged cyclam derivatives. The hydroboration/oxidation of 92 gave axial methanol-C- functionalized cis tetracyclic bisaminal 104 as indicated by its X-ray crystal structure. A ./V.iV'-dibenzyl methanol-C-functionalized cross-bridged cyclam dibromide salt 108«2HBr«H?O was then prepared with the desired stereochemistry for the future preparation of the proposed bifunctional chelator 84. 73 CHAPTER 3 RESOLUTION OF RACEMIC CROSS-BRIDGED CYCLAM BY DIASTEREOMERIC SALT FORMATION AND THE RACEMIZATION KINETICS OF ENANTIOPURE CROSS-BRIDGED CYCLAM I. Introduction The production of enantiopure compounds plays an important role in drug development.176 Although some racemic drugs may have equipotent enantiomers, others only have a single beneficial enantiomer, where the other enantiomer is either inactive or may even have severe negative biological effects. The synthesis of chiral pharmaceuticals 17*7 178 relies heavily on asymmetric synthesis of single enantiomers. ' However, the resolution of enantiomers provides an alternative route to optically-active compounds.177' 179 Common methods for the resolution of racemic mixtures into separate enantiomers include column chromatography on a chiral stationary phase and chemical separation, where chiral resolving agents are used to generate diastereomeric salt i n-j i on mixtures or diastereomeric derivatives. ' Diastereomers can then be separated by crystallization or by chromatography. After the separation, the recovered diastereomers can then be converted back to their respective parent enantiomers. The separation of enantiomers by diastereomeric salt formation is especially attractive as both enantiomers of common chiral resolving agents are commercially 74 available.181 This means that either enantiomer can be obtained enantiomerically pure based on the selected enantiomer of the chiral resolving agent. Nowadays, a wide range of chiral organic acid or base resolving agents are commercially available with numerous related literature-reported examples.182 Only a few optically active cyclam derivatives have been reported in the literature. Burrows and Wagler synthesized a chiral C-functionalized cyclam derivative, (S)-5-(hydroxymethyl)-1,4,8,11-tetrazacyclotetradecane (109), which was prepared using the Stetter-Richman-Atkins approach described in Chapter l.183 This macrocycle was synthesized from a ditosyl-protected chiral (5)-2,4-diaminobutyric acid, which provided the stereocenter. They also reported on the synthesis of a series of chiral C-functionalized dioxocyclam derivatives 110, which were prepared from enantiopure amino acids and utilized the malonate condensation reactions described in Chapter 2.184 .NH HN. .NH HNL Bn f J jT J CH2CH(CH3)2 - NH HN FT^NH Hlvr 'R CH(CH3)2 109 110 Alfonso reported on the preparation of an optically active C-functionalized cyclam derivative in which chirality was introduced using a ditosyl-protected (S,S)- cyclohexane-l,2-diamine.185 Similarly, the Stetter-Richman-Atkins synthetic approach was used to synthesize the chiral cyclohexane-functionalized cyclam derivative 111. NH HN. a*NH HN 111 75 II. Background Briefly, molecular chirality was described by Cahn, Ingold and Prelog in terms of the non-superimposable molecular reflection.186'187 A chiral compound cannot be superimposed on its mirror image and these two isomers are referred to as enantiomers. Symmetry elements are useful in defining whether a compound is indeed chiral, as it will not be superimposable on its mirror image by translation, inversion or rotation.1 The configurations at stereogenic centers188 are described using the Cahn, Ingold and Prelog (CIP) nomenclature,186 which is based on the sequential priority arrangement of substituents at a chiral center. Experimentally, enantiopure chiral compounds rotate the plane of polarized light189 (+/-) and the optical purity of chiral compounds can be described in terms of their optical rotations. As discussed in Chapter 1, JV.JV'-dicarboxymethyl pendant-armed cross-bridged cyclam (CB-TE2A) 20 has been investigated as a BFC for radiopharmaceutical application.62'63 This BFC is a racemic mixture as it is prepared from racemic 10. Cross- bridged cyclam (10) is a chiral C2 symmetric tetraazamacrocycle with two non- superimposable enantiomers 10a and 10b. The interconversion of these enantiomers requires the ethylene bridge tucking through the 14-membered ring along with inversion of all four nitrogens. ' ^V^S Enantiomerization fN ",HN> NH N NH''N 10a 10b The isomerization of bicyclic amines has been described in the context of in/out isomerism.190"192 The stereoisomers of the ammonium salts of bicyclo[k.l.m]amines were 76 investigated by Simmons and Parker using H NMR spectroscopy. " " They reported that nitrogen inversions led to three possible bicyclic stereoisomers that describe the direction of the bridgehead amine protons as out/out, in/out or in/in (Scheme 55). They also reported that the in/out isomer was only observed for large bicyclic amines in which k, 1, and m > 10 due to torsional and nonbonded repulsion effects. ^—(CH2)k-^ ^- c|^CH2,^c|. c|^CH2)l_^ c|^CH2)l_^c|. out/out in/out in/in Scheme 55: In/out isomerism of the ammonium salts of bicyclo[k.l.m]amines.190"192 The conformational isomerism of bicyclo[k.l.m]amines occurs via the in/out isomerism described above due to nitrogen inversions.193 Furthermore, conformational change can also be described in terms of a bridge tuck process in which the central chain of a three-stranded bicyclic amine is passed through the ring (Scheme 56). This process is defined as homeomorphic isomerization.193 This conformational change converts the bridgehead nitrogens from out/out to in/in. (CH2)k (CH2),-^ \^-— ^-(CH2)m—^ V_(CH2)m_^ out/out in/in Scheme 56: Homeomorphic isomerization. The resolution of 10 into its respective enantiomers would allow for the preparation of a single enantiopure compound that can be used in the preparation of an enantiopure BFC.62 Furthermore, Weisman and Wong are interested in utilizing the enantiopure 10 as a chiral ligand for stereoselective synthesis.117'194'195 77 As mentioned above, the cross-bridged cyclam enantiomerization has been shown to occur by a homeomorphic isomerization as well as the net inversion of all four nitrogens.117 The energy barrier (AG*) associated with the enantiomerization of dibenzyl cross-bridged cyclam (19)41 was investigated by Weisman and Hines using 'H DNMR spectroscopy.117 Their goal was to determine AG* of enantiomerization in order to establish whether 19 could be resolvable into its respective enantiomers. They pointed out that if the AG* of enantiomerization was > 25 kcal/mol at 25 °C then 19 should be resolvable, since its half-life would then be 66 hours and racemization would be relatively slow. The ambient temperature ]H NMR spectrum of 19 indicated the benzylic protons of 19 to be diastereotopic as shown by its AX pattern and the ethylene bridge to exhibit an AA'XX' pattern. In the variable temperature study performed by Hines (at 291, 364 and 397 K), significant chemical shift changes were observed for both the downfield and upfield portions of the benzylic AX subspectrum. An upfield shift for the AA' portion of the ethylene bridge AA'XX' subspectrum with increasing temperature was also observed. * However, no significant broadening or coalescence was observed during the variable temperature study for either of the subspectra. Hines was able to determine a lower limit 196 for the AGc* using a coalescence temperature approximation (with Tc > 145 °C) and determined that AG* > 19.85 kcal/mol.117 Additional experiments were performed to get a better estimate of the lower limit of the AG+ of enantiomerization for cross-bridged[6.6.2]tetraamines or to directly measure the kinetics.117 This was accomplished by preparing diastereomeric mixtures of dideuterated 19 and dimethyl cross-bridged cyclam 112 (Scheme 57).40 The 78 diastereomeric (isotopomeric) mixtures were prepared by the kinetically-controlled reductive ring expansion of dibenzyl and dimethyl cyclam bisaminal salts 16 and 113 respectively, with NaBD4 in 95% EtOH. >R 1)NaBD4, 95% EtOH SS4-M J 2) HCI ^ L J R,N^N 3)KOH R^N " <^> 2 X" Benzene k^^ _ 16R = Bn, X = Br 19-d2 113R = Me, X = I" 112-d2 Scheme 57: Preparation of dideuterated cross-bridged[6.6.2]tetraamines.m For each reductive ring opening in Scheme 57, three dideuterated species were observed.117 Two of these diastereomers, a and b, shown as schematic diagrams, resulted from the trans delivery of the deuterons during the reduction (Figure 23). The third species (c) was a result of CM deuteron delivery during the reduction. Identification of the a/b diastereomers was accomplished by analysis of the !H NMR spectra before and after Kugelrohr distillation with heating. Integration of the 'H NMR spectra allowed Hines to establish that for each diastereomeric mixture (of 19 and 112) that a trans diastereomer (assigned as a) was the major species. ID 1 ,R I H 1 ,R ID I ,R H H C -t: J OH:0 CDH:HJ R^DJ <5 "'(5 b c 19-d2,R = Bn 112-d2, R = Me Figure 23: Dideuterated cross-bridged[6.6.2]tetraamines.117 79 Kinetic studies of the diastereomerization of a and b were then carried out and an equilibrium expression was written for the diastereomerization (Equation 1). According to Hines' initial measurements, at equilibrium [a] = [b] and therefore, kf = kr (i.e. there is only a small equilibrium isotope effect). The first-order approach to equilibrium is given by Equation 2, where k = kf + kr. (Equation 1) (Equation 2) kf k a - b a - (a, b)eq kr kf: Rate constant for the diastereomerization of a to b kr: Rate constant for the diastereomerization of b to a k: Rate constant for the first-order approach to equilibrium The kinetics experiments for 112-d2 and 19-d2were conducted in CeD6 at 71 ± 1 °C. !H NMR spectra were taken at recorded time intervals and integrations were used to generate nonlinear regression plots of the first-order kinetics. Hines found the rate 5 1 constant k for the diastereomerization of 19-d2 to be 1.182 ± 0.021 x 10" sec" , with t>/2 = t 16.29 ± 0.08 hours, and AG 344 = 27.99 ± 0.08 kcal/ mol. The rate constant k for the 5 1 diastereomerization of112-d? was determined to be 2.626 ± 0.001 x 10" sec" , with ty2 = t 7.33 ± 0.02 hours, and AG 344 = 27.44 ± 0.08 kcal/mol. With the assumption of small isotope effects, these results were taken as good estimates of the kinetics of racemization of enantiopure protio 19 and 112. The major implication of these results was that both 19 and 112 should be resolvable and it should be possible to store these resolved enantiopure bicyclo[6.6.2]tetraamines at low temperature without significant racemization. Hines also attempted the direct resolution of 19 by generating a diastereomeric mixture using (15)-10-(+)-camphorsulfonic acid (113) (Scheme 58).117 One equivalent each of 113 and 19 were combined in hot EtOH to give the diastereomeric mixture 114. 80 ,Bn V f^.BnV f^RnV ,NL N. ,N., N; Bn Bn 1^1 S03H l^J SO3- Bn ^J SO3- 19 113 114(1:1 Diastereomeric Mixture) Scheme 58: Preparation of a 1:1 diastereomeric mixture of 114.U7 It was then necessary to determine whether the diastereomers could be distinguished by NMR spectroscopy. Several deuterated NMR solvents were investigated. The *H NMR spectrum in acetone-d6 did not show any distinguishable signals that corresponded to the different diastereomers. However, the "C^H} NMR spectrum did show two separate ipso carbons for the phenyl ring, each belonging to one of the diastereomers. Hines attempted several solvent systems for the selective crystallization of one diastereomer over the other, but without success. He attributed the failed selective crystallization to the lack of cation/anion recognition. The protonation of 19 resulted in the encapsulation of the proton, which exposed a lipophilic ligand exterior. This could prevent any tight ion- pair formation with the camphorsulfonate anion. Hines also attempted an indirect resolution by generating the carbamate diastereomeric mixture 115 from the reaction of 10 with chloroformate 116 (Scheme 59). However, attempts at selective crystallization of one diastereomer over the other were unsuccessful. vO ci CH2Clg .N N;R excess K2C03 rt, 5d C;N ON 115 (Carbamate Diastereomeric Mixture) 117 Scheme 59: Preparation of a diastereomeric carbamate cyclam derivative. 81 Although Hines was unable to resolve the bicyclo[6.6.2]tetraamines 16 or 10, he was able to establish estimated energy barriers for the racemization of 19 and 112. He found that resolution should be possible and that any resolved material should be very stable to racemization at low temperature or when protonated. The goal herein is the investigation into the resolution of diastereomeric salt mixtures of 10 and 19, and the determination of the rate of racemization of the resolved cross-bridged cyclam 10. 82 III. Results and Discussion 1. Resolution of bicyclo[6.6.2"|tetraamines by selective crystallization of their diastereomeric salt mixtures. The following section describes the preparation of several 1:1 diastereomeric mixtures from bicyclo[6.6.2]tetraamines 10 and 19 (Scheme 60). As discussed in Chapter 1, cross-bridged tetraamines can adopt conformations in which all four nitrogen lone- pairs are directed towards the ligand cleft.43 For this reason, the use of chiral acidic resolving agents are especially attractive as the ligand can be twice inside-protonated to form an ion-pair with the resolving agent. I I I i iy—; + .1.N1 RNHIM. . Enanliopure ^|^1 ZNi> '~fD R R 2 R + Chiral Acid -/,N-.H'H l *" VH"^N^ R 10R = H,19R = Bn 1:1 Diastereomeric salt mixture Scheme 60: Preparation of a 1:1 diastereomeric salt mixture. Three acidic chiral resolving agents were investigated for the preparation of 1:1 diastereomeric salt mixtures: (5,,5)-(+)-dibenzoyl-D-tartaric acid (117), L-(+)-tartaric acid (118) and (lS>(+)-camphorsulfonic acid (115) (Figure 24). 0 u Prr"0 OH V HO*\ Figure 24: Enantiopure chiral acids considered for 1:1 diastereomeric salt formation. 83 The goal was to find a 1:1 diastereomeric salt mixture that can easily be distinguished by NMR spectroscopy. This would provide the means to monitor any enhancement of one diastereomer over the other during this resolution by selective crystallization. The following five 1:1 diastereomeric salt mixtures were prepared and investigated by NMR spectroscopy. 1.1 Preparation of 4.1 l-bis(phenylmethyl)-l,4,8Jl-tetraazabicyclo["6.6.2Jhexadecane (5',6r)-(+)-dibenzoyl-D-tartrate (1:1 diastereomeric mixture) (119). The diastereomeric mixture 119 was prepared by adding (5',S)-(+)-dibenzoyl-D- tartaric acid (117) to a solution of 19 in absolute EtOH. The reaction mixture was stirred at 75 °C for 5 min, at which time the reaction mixture was homogeneous (Scheme 61). This reaction mixture was then stirred without further heating overnight. It was hoped that upon cooling to room temperature that crystallization would occur. However, no crystallization was observed. The jH NMR spectrum of 119 in MeOH-d4 did not indicate any distinction between the two diastereomers. Significant broadening was observed for several resonances in the C{ H} NMR spectrum, indicative of overlapping resonances. There were two sets of resonances that did correspond to 1:1 diastereomers, a set at 55.37 and 55.40 ppm, and the other at 58.60 and 58.60 ppm. These were extremely close to one another as they broadened to overlap at the baseline and would not be reliable for measuring diastereomeric purity. Thus other chiral resolving agents were attempted. 84 * ^v O ^^^ 0 .. O n A P/ ph o EtOH N^%A N^A 2H 2 + + 0 CAJ • HO2CV° ^^r CN+VN) -o2cV° Q l N3 t* V *' Brf^Ji °YPh thenrt,0/n Bn C^J °YPh Bn Qv °YPh 19 117 119(1:1 Diastereomeric Mixture) Scheme 61: The preparation of 119 (1:1 diastereomeric mixture). 1.2 Preparation of 4,1 l-bis(phenylmethyO-1.4.8.1 l-tetraazabicyclo[6.6.21hexadecane L- (+)-tartrate (1:1 diastereomeric mixture) (120). The 1:1 diastereomeric mixture 120 was prepared by the addition of L-(+)-tartaric acid (118) to a solution 19 in absolute EtOH and stirred at room temperature for 1 hour (Scheme 62). The solvent was then removed under water-aspirator pressure to give 120. Neither 'H NMR nor C{ H} spectra in MeOH-d4 indicated any distinction between the two diastereomers. rO<" ?" BOH J^C* QH Pi'* OH 19 118 120(1:1 Diastereomeric Mixture) Scheme 62: The preparation of 120 (1:1 diastereomeric mixture). Since the dibenzyl cross-bridged cyclam (19) diastereomeric salt mixtures showed little or no distinction by NMR spectroscopy, the preparation of the diastereomeric salt mixture of 10 was undertaken. 85 1.3 Preparation of 1,4,8,1 l-tetraazabicyclo[6.6.2]hexadecane di-(l>S')-(+)- camphorsulfonate (1:1 diastereomeric mixture) (121). A 1:1 diastereomeric mixture of 121 was prepared by adding two equivalents of (15)-(+)-camphorsulfonic acid (113) to a solution of 10 absolute EtOH and the reaction mixture was stirred at room temperature for 1 hour and then concentrated under aspirator pressure (Scheme 63). Neither the !H NMR nor 13C{'H} spectra in acetone-d6 indicated any distinction between the two diastereomers. No attempts were made for the selective crystallization of this mixture, as other chiral resolving agents were investigated. N HN \ EtOH .N' N' V K'., N' H L^J S03H (quant) [H^J S03' H |^ Scheme 63: The preparation of 121 (1:1 diastereomeric mixture). 1.4 Preparation of 1,4,8,1 l-tetraazabicyclo[6.6.2]hexadecane (5',5r)-(+)-dibenzoyl-D- tartrate (1:1 diastereomeric mixture) (122). A 1:1 diastereomeric mixture 122 was prepared by adding one equivalent of (S,S)- (+)-dibenzoyl-D-tartaric acid (117) to a solution of 10 in absolute EtOH and the reaction mixture was stirred at room temperature for 1 hour and then concentrated under aspirator pressure (Scheme 64). N HN Pn X O ,_,_,, Nr^' h~N H PhA O r^M' 'Mu' PITA O 2 o o o 10 117 122(1:1 Diastereomeric Mixture) Scheme 64: The preparation of 122 (1:1 diastereomeric mixture). 86 Neither the 'H NMR nor the 13C{'H} spectra in D2O indicated any distinction between the diastereomers. However the 'H NMR spectrum in MeOH-d4 did show two sets of triplets of doublets (td) (3.44 ppm and 3.50 ppm with similar J values) each integrating for 2 protons, which indicated that these signals could each belong to a diastereomer. The solubility of the 1:1 diastereomeric mixture 122 was tested and the compound was found to be insoluble (at room temperature and with heating) in benzene, acetonitrile, CH2CI2, i-PrOH and EtiO. However, it was soluble at room temperature in MeOH and EtOH. A concentrated sample of 122 in EtOH was prepared and heated until the solution was homogeneous. Crystallization occurred when the solution was left at room temperature overnight. These crystals were collected by centrifugation and the ]H NMR spectrum of the crystals indicated that one of the td patterns was indeed enhanced. The diastereomeric enhancement was observed for the downfield td with a diastereomeric ratio (dr) of-3.3. These results suggested that 10 can indeed be resolved by selective crystallization from its diastereomeric mixture 122. One additional chiral resolving agent was investigated. 1.5 Preparation of 1.4.8.1 l-tetraazabicyclo[6.6.2]hexadecane L-(+)-tartrate (1:1 diastereomeric mixture) (123). Although the results reported in the preceding section were encouraging, one final diastereomeric salt mixture was prepared from the reaction of 10 with L-(+)-tartaric acid (118) in absolute EtOH (Scheme 65). The reaction mixture was stirred at room temperature for 2 hours and concentrated under aspirator pressure. The resulting oil was triturated with Et^O (4 x 50 mL), followed by the removal of EtaO under aspirator pressure. Residual solvent was removed under vacuum to give a 123 as a white solid. 87 H H NON QH BOH £\* OH I; V.' ° N0N °H (,-) H'^ OH H-N^N 6H 10 118 123 (1:1 Diastereomeric Mixture) Scheme 65: The preparation of 123 (1:1 diastereomeric mixture). The C{'H} spectrum of 123 in D2O indicated clear distinction between the diastereomers. Two sets of six carbon resonances were observed between 20-60 ppm. However, the !H NMR spectrum in D?0 did not indicate any distinction. By contrast, in ] 13 MeOH-d4, both H NMR and the C{'H} NMR spectra showed clear distinction between the diastereomers. This distinction of diastereomers was more encouraging than what was observed for 122 and so conditions for the selective crystallization of 123 were investigated in detail. Diastereomeric mixture 123 was insoluble at room temperature and even with heating in the following solvents: acetone, Et20, CH2CI2, CHCI3. It was soluble in hot MeCN and crystallized at room temperature, but the !H NMR spectrum did not indicate diastereomeric enrichment in the collected crystals. Several alcohol solvents were investigated for crystallization. The salt was soluble upon heating in i-PrOH, n-PrOH and n-BuOH (but not at room temperature). Unfortunately, no crystallization occurred when these solutions were cooled to room temperature even after several days. Cooling of these solutions at 6 °C in a refrigerator or at -15 °C in a freezer did not result in crystallization. Solubility of the diastereomeric mixture was then tested in absolute EtOH. The salt appeared to have some solubility at room temperature and completely dissolved upon heating. No crystallization occurred when the solution was cooled to room temperature 88 even after several days. Gratifyingly, needle-like crystals did form upon cooling to 6 ° C while cube-like crystals formed at -15 °C. 'H NMR spectra of both these crystals indicated dramatic enhancement of a single diastereomer, with a diastereomeric ratio (dr) of > 40 for the slow crystallization at 6 °C and a dr of > 200 for slow crystallization at -15 °C. The resolution was subsequently done at -15 °C. It is worth mentioning that EtOH from the crystallization was observed in the ]H NMR spectra even after the crystals were placed under vacuum overnight. However, heating these crystals at 40 °C (using a mineral oil bath) under vacuum resulted in the removal of most EtOH. For the scaled-up fractional crystallization, 4.9040 g of 123 was dissolved in 60 mL of hot absolute EtOH and allowed to crystallize slowly at -15 °C for 6 days. This crystallization yielded 1.4734 g of crystals. The !H NMR spectra of the 1:1 diastereomeric mixture 123, the crystals 123a and the solid remaining after solvent was removed from the mother liquor 123b are shown in Figure 25. The top spectrum of the 1:1 diastereomeric mixture 123 has two neighboring doublet of multiplets (dm) from 1.57-1.73 ppm (upfield dm, J= 16.6 Hz; downfield dm, J= 16.4 Hz) and combined they integrate for four protons, two protons for each diastereomer. These protons correspond to the H6ji3eq (Figure 26). There is also a downfield td at 3.61 ppm (J= 12.7, 2.7 Hz) that integrates for only 2 protons, indicating that this signal belongs to only one of the diastereomers. 89 123 1:1 Diastereomeric Mixture (td) A ii (2xdm) iwi[*> tm 0.25 0.45 17.34 4.04 123a First Crystallization, dr >200 EtOH EtOH M I a '.i i 2.00 1.35 0.03 123b Mother Liquor, dr 2.7 ! .y, fc] t EtOH s.o 4.S 4.0 3.5 3.0 2.5 2.0 1.5 12.82 0.01 36.95 0.01 0.01 0.06 2.67 0.03 2.69 0.09 0.01 Figure 25: 'H NMR spectra of 123,123a and 123b in MeOH-cU (TMS). 13 13 (^XH l,-nJ,H OH ,N N OH V X. N: OH 2 + "'I O ;^v^C02 CAi) -o* 1 HX ;N' OH H.N+ I.;.N J "O2 OH Figure 26: 1:1 Diastereomeric mixture of 123. 90 The results of the first recrystallization were encouraging as indicated by the middle and bottom spectra in Figure 25. The crystallized material, the middle spectrum (123a), had no evidence of the downfield td and only one of the upfield dm was evident which indicated a dr >200 upon integration of the dm and the td. A 30% recovery was calculated for 123a. The H NMR spectrum of the concentrated mother liquor (123b), the bottom spectrum in Figure 25, contains the downfield td and the downfield dm, both belonging to the same diastereomer. The integration ratio indicated a dr of 2.86. (EtOH was visible in both spectra and was taken into account when determining the final recovered mass for each sample.) Upon the recrystallization of 123a, the mother liquor (489.5 mg) indicated a dr of 69.4, which meant that 123a had a small amount of the other diastereomer present, although this was difficult to detect by !H NMR spectroscopy of the first crop. Upon completion of the fractional crystallization, 1.7988 g of a single diastereomer was recovered, a 37% recovery (with a maximum theoretical recovery of 50%). Diastereomerically pure 123a (1.0170 mg, 2.7015 mmol) was converted back to its free base, parent enantiopure 10 (Scheme 66). This was accomplished by dissolving it in FbO (5 mL) and basifying this aqueous solution to pH 14 using KOH. This basic solution was extracted with benzene (4x15 mL) and the combined benzene extracts were dried over anhydrous Na7S04 and concentrated under aspirator pressure to give 576.8 mg (94%) of (S,S)-10 as an off-white solid. 91 NOh* OH H K0H Nr^Hi r "i IS i coc 2- *°' r "i % L l/J -o2c^- ° • f I 1 N ;N OH ceH6 NH y H IsH^I (94%) ^J Diastereomerically Pure 123a Enantiopure 10 Scheme 66: Recovering enantiopure 10. Attempts at obtaining an X-ray quality crystal from recrystallization of the resolved diastereomer 123a were unsuccessful. However good crystals were obtained by protonating enantiopure free base 10 (14.7 mg) in anhydrous MeOH (0.1 mL) with excess NH4PF6 (51.1 mg) in anhydrous MeOH (0.1 mL). The resulting white crystals of 124 were washed with anhydrous MeOH (3 x 0.1 mL) and residual solvent was removed under vacuum. The resulting white solid was taken up in MeOH (0.5 mL) followed by the dropwise addition of H?0 until all solids were dissolved. Clear plate-like crystals suitable for structure determination were collected upon slow evaporation of this solution mixture. The X-ray structure of 124, obtained using anomalous dispersion by James Golen in the laboratory of Arnold L. Rheingold at the University of California, San Diego, La Jolla, CA. The absolute configuration of 124 was determined to be (S,S) (Figure 27). From this structure the stoichiometry of 124 was indicated to be H2-10(PF6)2- Each 10-membered ring of the chiral cw-folded 124 had a [2323] conformation. Both secondary nitrogens (N? and N4) are protonated, with these protons held within the ligand cleft through bifurcated transannular hydrogen bonds43 to the bridgehead tertiary amines (N2_H»N3 and N4-H-N] with hydrogen bond lengths of 2.015 and 2.153 A respectively). 92 Figure 27: X-ray structure of 124 (anions and C-H hydrogens omitted for clarity). The optical rotation ' of resolved enantiopure (S,S)-10 in anhydrous toluene was determined to be + 0.4610 ± 0.004°. The specific rotation198 was calculated using Equation 3, \a\ = + 40.0 ± 0.3 (c 0.1154, toluene). L J589 \a] = (Equation 3) L JA l(dm)*c(g/ml) where: a = recorded optical rotation A. = wavelength (sodium D-line 589 nm) ° C = temperature / = length of the optical cell c = sample concentration 1.6 Preparation of 1.4.8.1 l-tetraazabicvclo[6.6.2]hexadecane D-(-)-tartrate (1:1 diastereomeric mixture) (125). In order to determine whether the opposite enantiomer (R,R)-10 can also be obtained by selective crystallization of its diastereomeric salt using D-(-)-tartaric acid, the following reaction and crystallization were performed. D-(-)-Tartaric acid (126) was added to a solution of racemic 10 in MeOH, and the reaction mixture was stirred at room temperature for 20 minutes and concentrated (Scheme 67). 93 •XJI OH MeQH r^H OH £\H OH ^ OH (quant) H'^ OH >^ OH 10 126 125(1:1 Diastereomeric Mixture) Scheme 67: The preparation of 125 (1:1 diastereomeric mixture). The !H NMR spectrum (MeOH-cU) of the 1:1 diastereomeric mixture 125 had two neighboring doublet of multiplets (dm) from 1.58-1.73 ppm (upfield dm, J= 16.6 Hz; downfield dm, J= 16.4 Hz) (top spectrum in Figure 28), as was observed in the 'H NMR spectrum of 123. Together they integrate for four protons, two protons for each diastereomer. These protons correspond to the H6,i3eq (Figure 28). There was a downfield td at 3.62 ppm (J= 12.7, 3.1 Hz) that integrates for only two protons, indicating that this signal should belong to only one of the diastereomers. Upon crystallization from EtOH at -15 °C the cube-like crystals obtained (125a) had only the upfield dm present in its *H NMR (Figure 25), with very minor amounts of the downfield td (dr -33). This td corresponded to the major diastereomer observed in the JH NMR (Figure 28) of the concentrated mother liquor (125b). 94 H C J -H OH C-^\ H nw -N. N' 9H H., N' ?H i 125 1:1 Diastereomeric Mixture (Id) (2 x dm) \ \~.^v\% ft' A,. Av_ ,M( 1 .03 .__, _ 3.96 -^ 5.93 4.04 125a First Crystallization, dr 32 (2 x dm) (td) U 1 if ,51 1,1 125b From Mother Liquor, dr 4.! (td) (2 x dm) 11 I *" £%" OH "V. ™ (td, i d (dm) -127 4 ill MWA V. 3.0 2.5 2.0 1.96 6.36 1.97 6.36 8.23 Figure 28: 'H NMR spectra of 125,125a, 125b and 127 in MeOH-d4 (TMS). OH OH OH 6 6 Figure 29: 1:1 Diastereomeric mixture of 125. In order to determine which diastereomer of 125 corresponded to (S^-IO, a small sample of enantiopure (S,S)-10 (obtained from the resolution of 123) was reacted with one equivalent of D-(-)-tartaric acid (126) in MeOH-d4 to give 127 (Figure 30). Its H 95 NMR spectrum (bottom spectrum in Figure 28) corresponded to that of the major diastereomer in the mother liquor 125b, showing both the td and the downfield dm. .3'" OH 2 C 1.0 -o2cV° H-NL£JN 0H • Figure 30: Diastereomer 127. These results indicate that by using the respective enantiomer of the chiral resolving agent tartaric acid, one can select the specific enantiomer of 10 to be resolved. This confirms the successful resolution of both enantiomers of 10. 2. Racemization kinetics of enantiopure (S,S)-10. Kinetics experiments for racemization of enantiopure (S^-IO were conducted by heating the sample to 82 ± 1 °C in anhydrous toluene in a Polystat Circulating Constant Temperature bath. Aliquots were taken at recorded time intervals, concentrated down under aspirator pressure and reacted with one equivalent of L-(+)-tartaric acid (118). Their 'H NMR spectra in MeOH-d4 were recorded and are shown in Figure 31 with the t = 0 spectrum at the bottom of Figure 31. The integrations of the two diagnostic signals, the upfield neighboring dm (2dm) and the downfield dt, were recorded. Residual EtOH was present in some spectra since the preparation of these diastereomeric salts were carried out using EtOH as a solvent. 96 N'N'H 0H llf' >!|'H OH (td) (2 x dm) A > t = 896.12h 3^2! ^ynf iii"; I) 100 -H (67*M(5 . t-675.90 h lOOf.oV 55,14 ^ t = 576.18 h 37,. 06 .Wii; ~%K 22.02 JII! 4.48 - _t , ^j. _^_ __ ]\t :\>\ ;;j;i582.00 t = 363.27 h ;U M »:«. t = 267.30 h ioo. dpi\ t = 162.13 h _7.i';§4...iiji. T» ,' l0 13.38 - 111.33 h M° 36.57 16.97 t = Oh . -M,^ 100.00 •-T- 7-13,5^-26-^ i-r- ;7-r, r-r- r— - 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 ppm 18.56 100.00 6.53 Figure 31: Kinetics experiment: H NMR spectra of diastereomeric salts 123 in MeOH- d4 (TMS). Enantiomeric excess (ee)177'180' 199can be determined according to the definition: I/? — Si %ee = x\ 00 = \%R - %S\ \R + S\ ' ' Since the diastereomer integrations (Figure 31) correspond to the amount of each parent enantiomer, their ratios (td/2dm) correspond to the enantiomeric compositions (ec)200'201 for each data point with %ec defined by: R xlOO '/bee = R + SJ 97 For each data point, the %ee can therefore be determined by %ee = (1 - 2ec) x 100 since ec = (td/2dm). The derivation is shown below: R x ec( fractional) =' R + S) l-ec = R + S ee( fractional) = I 1 = (1 - ec) -ec = 1- lee At t = 0, the %ee is 100 and %ec = 0. These calculated %ee values and recorded time intervals are shown in Table 5. Table 5: Percent enantiomeric excess as a function of time (kinetics run no.l). Time (hours) %ee 95% Confidence limits 0.00 100.00 0.00 111.33 76.60 1.19 162.13 76.14 0.94 267.30 57.51 2.68 363.27 53.96 2.16 467.80 44.21 2.16 576.18 47.43 0.25 675.90 38.32 2.17 896.12 31.83 1.56 With the rate of racemization being twice the rate of enantiomerization the rate 202 expression for the racemization process is determined using Equation 4, where krac is the racemization rate constant. Equation 4 can then be simplified to give In ee = kract. \S\' 1 + [R] In = kract (Equation 4) [S] 1- [R] A linear plot of In ee vs. time was obtained for the racemization of 10 (Figure 26). The linear plot indicated first-order kinetics of racemization (y = mx + b), with the slope (m) corresponding to the rate constant (krac = -slope) (see Equation 2). The racemization half- 98 = life can be determined by ti/2rac ln2/krac which corresponds to reduction of enantiomeric 1 Q A purity from 100% ee to 50% ee. The endpoint of such a racemization is reached when %ee = 0. Graph 1: In ee vs. Time (hours), kinetics run no.l. (R2 = 0.946) 0.00 100.00 200.00 300.00 400.00 500.00 600.00 700.00 800.00 900.00 1000.00 Time (hr) A linear least-squares regression method was used to fit the data to a straight line and racemization rate constant krac was given by the slope. The value and the uncertainty of the slope are given by the linear least-squares algorithm as implemented by Excel. This 7 1 was determined to be krac= 3.41 ±0.31 x 10" s" , and the half-life was determined to be ti/2rac= 565 ± 56 hours. Using the Eyring Equation (Equation 5), AG^ss.is was determined to be 31.42 ± 0.07 kcal/mol using Equation 6. Errors quoted in ti/2rac and AG* are from the error in the slope. Since one half-life equals 565 hours, it can be seen that the data were collected over approximately 1 Vi half-lives. AG» KkbT RT k = ^rac e (Equation 5) 99 % AG =RT [ln(T/krac) + ln(Kkb/h) (Equation 6) AG* in cal/mol T = absolute temperature (K) of the experiment K = Transmission coefficient = 1 6 kb = Boltzmann constant = 1.380658(12) x 10" erg.K" h = Planck constant = 6.62605755(40) x 10"27 erg.sec. R = Molar gas constant = 1.987215(75) cal mor'K"1 The kinetics experiment was repeated (over three half-lives) and this data are shown in Table 6. A linear plot was generated (Graph 2) and the krac was determined to be 7 1 4.14 ± 0.53 x 10" s" , with ti/2rac = 466 ± 69 hours and AG^s.is = 31.29 ± 0.10 kcal/mol. Table 6: Percent enantiomeric excess as a function of time (kinetics run no. 2). Time (hours) %ee 95% Confidence limits 0.00 97.70 1.63 234.52 66.65 0.72 377.32 52.55 0.43 809.87 30.31 0.48 880.85 22.90 1.36 1145.52 10.99 1.10 1291.78 8.43 2.74 1849.51 8.88 0.77 Graph 2: In ee vs. Time (hours), kinetics run no. 2. (R2 = 0.910) e 0.00 200.00 400.00 600.00 800.00 1000.00 1200.00 1400.00 1600.00 1800.00 2000.00 Time (hr) 100 The respective kinetics results for the racemizations of 19-di, 112-d2117 and 10 are summarized in Table 7. Table 7: Energy barrier for racemization of 19-d?, 112-d2117 and 10. Compound k (s1) ti/2 (hours) AG* (kcal/mol) 5 l 19-d2 1.182 ± 0.021 xlO" 16.29 ±0.08 AG 344 = 27.99 ± 0.08 5 112-d2 2.626 ± 0.001 xlO" 7.33 ±0.02 AG^ = 27.44 ± 0.08 10 (experiment 1) 3.41 ±0.31xl0"7 565 ±56 AG^ss is = 31.42 ±0.07 7 : 10 (experiment 2) 4.14 ± 0.53 xlO" 466 ± 69 AG 355 is = 31.29 ±0.10 The interconversion barrier of 10 is therefore significantly higher than that of either 19-d2 or 112-d2. As a result, enantiopure 10 is clearly very stable at 25 °C and can be stored without significant interconversion between the two enantiomers. This resistance towards enantiomerization can in part be attributed to the ability of 10 to adopt a low-energy conformation where its 10-membered rings are in a [2323] diamond-lattice conformation. In toluene, the secondary amine hydrogens of 10 are likely taking part in transannular intramolecular hydrogen bonds to the bridgehead tertiary amine nitrogens. Although both 19 and 112 share similar conformational features, their nitrogen substituents clearly play a role in lowering enantiomerization barriers relative to the N-H parent case. Since enantiomerization of cross-bridged[6.6.2]tetraamines occurs by the ethylene bridge tuck as well as the net inversion of all four nitrogens, it can be reasoned that any intramolecular hydrogen bonds, as in the case of 10, will hinder such an enantiomerization process. 101 IV. Conclusions The resolution was 10 was accomplished through selective crystallization of its diastereomeric salts of L-(+)-tartaric acid. Furthermore, it was established that both enantiomers of 10 can be isolated enantiomerically pure based on which enantiomer of the chiral resolving agent is used. The absolute configuration of the resolved enantiomer of 10, from the selective crystallization of diastereomeric salts of L-(+)-tartaric acid 123, has been determined to be (S,S) at the bridgehead nitrogens. Racemization kinetics experiments on enantiopure 10 were conducted and the energy barriers of racemization for two kinetics runs were determined to be 31.42 ± 0.07 and 31.29 ± 0.10 kcal/mol. These are significantly higher than the energy barrier previously observed for 19 and 112, which augurs well for the practical applications of enantiopure 10 and its derivatives.117 102 CHAPTER 4 COMPUTATIONAL INVESTIGATION OF NITROGEN LONE PAIR ORIENTATION EFFECTS ON THE METHINE NMR PARAMETERS OF TRICYCLIC ORTHOAMIDES I. Introduction Tricyclic orthoamides 128 are a group of cyclic polyamines with three nitrogen bridgehead atoms and a central methine.204"206 A™ m(k N^lm m = 0,1 128 The ]H NMR analysis of tricyclic orthoamides 129,130 and 131 indicated a significant chemical shift variation of the methine hydrogens (C-H) in these systems.204 Compound 129 has its methine hydrogen at 2.25 ppm, which is significantly upfield from that of compound 130 and 131 for which the chemical shifts were 3.76 and 5.03 ppm, respectively. H H H / 129 130 131 This variation in chemical shifts for this series has been attributed to the change in the dihedral angle between the methine hydrogens and the three adjacent nitrogen lone pair 103 orientations.204 In 129 the nitrogen lone pairs are antiperiplanar (180°) to the methine hydrogen. On the other hand, this dihedral angle is synperiplanar for 131 and synclinal (gauche) for 130. Investigation of the *H NMR spectra of cyclic amine compounds have shown that protons antiperiplanar to a nitrogen lone pair resonate upfield from those in which a proton is synperiplanar or synclinal to the nitrogen lone pair.207 Two arguments have been made to rationalize these observations: the shielding of the antiperiplanar proton by the nitrogen lone pair,208 and hyperconjugative nitrogen lone pair derealization (n—*cr*cH)-2°9 Furthermore, a significant variation in the methine C-H 1 JCH coupling constants of these orthoamides was observed. These values are 141 and 184 Hz for 129 and 131 respectively.204 The tribenzyl analog of 130, compound 132, prepared by Stetter,210 has a 'JcHof 159 Hz. DBnM VI Bnt 132 It has not yet been confirmed whether these coupling constant variations are a result of the nitrogen lone pair derealization n-»o CH (hyperconjugation)211 or a result of a dipolar interaction (electrostatic) between the methine C-H bond dipole moment and the nitrogen lone pair dipole. These effects are illustrated in Figure 32. H H H Hyperconjugation: n-»o*CH Dipolar interaction (electrostatic) Figure 32: Hyperconjugation and dipolar interaction. 104 II. Background In a computational study, Perrin and Cuevas reported on the l Jew observed for 919 91^ tetrahydropyran conformers." "'" They concluded that the observed values for the coupling constant were in fact not the result of oxygen lone pair derealization (n-»a CH)- Their computational investigation indicated, contrary to their expectations, that '/CH values were the largest when the COCH dihedral angle was 180 ° and the ' Jen values decreased as the dihedral angle decreased (Figure 33). (T _ I C-O-C-H I H H 0° 180° Hyperconjugation: n-»o CH Dihedral angle of COCH fragments Figure 33: Tetrahydropyran. Their natural bond order (NBO) analysis214 revealed no correlation between stabilization energies due to lone pair derealization and variations in the 1 JQH- Their final conclusion was that the variation in the coupling constants must be caused by the dipolar interaction between the C-H and the dipole of the oxygen lone pairs. They reasoned that although C-H bonds are nonpolar, the electron distribution of the C-H bond may be polarized due to the electric field of the oxygen lone pair dipole moment. This was confirmed by electron density calculations, which indicated that at a 0 ° COCH dihedral angle the hydrogen was more electron rich and the 1JQH value was the smallest. Similarly, Perrin and Erdelyi have also demonstrated that the 'Jcc coupling constant variation in ethers correlate with a dipolar interaction."15 Increasing xJcc values were observed with an increase in the COCC dihedral angles. 105 III. Results and Discussion 1. Computational methodology The goal of this project was to computationally investigate and understand the cause behind the variation in one-bond C-H coupling constants (VCH) and the methine hydrogen chemical shifts for the three orthoamides 129,130 and 131. For this purpose, several computations were undertaken. The initial structures of the three cyclic systems were built and optimized in Spartan '02 using MMFF calculations.216 The structures were then exported to Gaussian 94 where their geometries were optimized using density function theory B3LYP/6-31 lG+(d,p), by which all of the following computations were i j 217,218 also done. Two sets of computations were performed. NMR calculations (using the GIAO basis set)219 at the B3LYP/6-31 lG+(d,p) level were done to calculate methine C-H coupling constants (VCH) and the chemical shifts of the protons (5H).220 These values were then used for comparison to the literature-reported experimental values. The hyperconjugation phenomenon was investigated through NBO analysis214 at the B3LYP/6-311 G+(d,p) level and the dipolar interaction was investigated through Mulliken charge results. 106 2. Computational results Optimized structures and their symmetries are indicated in Figure 34. 129 C3V 130 C3 131 C3 Figure 34: Optimized structures: B3LYP/6-31 lG+(d,p). Although this is a small data set, good agreement between the experimental and calculated ' Jen and methine proton chemical shifts (5H) was observed (Table 8). This indicated that the level of theory and basis set choice for the calculations were appropriate. Table 8: Calculated and experimental methine 'JCH and SH- 129 130 131 Calculated Experimental Calculated Experimental Calculated Experimental 8H (ppm) 2.18 2.25 3.55 3.76 4.99 5.03 '•/CH (Hz) 131 141 149 159 (for 131) 178 184 Graph 3 shows the linear relationship observed between the calculated JCH and 6H values. The apparent trend observed could be an indication of a common contributor to these two spectral properties. 107 Graph 3: Coupling constants ('JCH ) vs- niethine chemical shifts (5H). 190 -I 131(10°) 180 • X 170 • 130 (60 °) 160 • • 150 • 129(180°) X J (Hz ) 140 • 130 • X 120 • 110 • A Experimental ^Calculated inn • 0 12 3 4 5 6 5H(ppm) From the NBO analysis, the electron donor-acceptor interactions n-»a CH and thus the stabilization energies of a CH, were recorded (Table 9). As expected, 129 exhibited the greatest stabilization. When the stabilization energies were plotted against the 'JCH and the 5H values, no clear correlation was observed (Graph 4). This indicated that variation in the observed spectral data could not be solely due to the nitrogen lone pair derealization. Table 9: Stabilization energies (CT*CH ) per nitrogen lone pair. Compound 129 130 131 Stabilization kcal/mol 7.74 0.87 4.56 108 Graph 4: Stabilization energy vs. 1JQH and SH- 200 • T 6 131(10°) 180 • X 178 130 (60 °) • 4.99 160 • + 5 X 149 129(180°) 140 • X 131 + 4 120 • • 3.55 J (Hz ) 100 • + 3 3 80 • • 2.18 60 • + 2 40 • + 1 20 • Xj(Hz) Appm 0 • -+- -t- • • • * i • • • • i * -t- 3 4 5 6 7 Stabilization energy (kcal/mol) On the other hand, when the Mulliken charges of the methine hydrogens were plotted against the ' JCH and SH, a clear relationship was observed (Graph 5). The electron density on the methine proton decreased as the dihedral angle decreased from 180 ° to approximately 10 °. The electron density on the methine proton was the largest when the angle was 180 °. The Mulliken charges for the methine hydrogens were 0.166 for 129, 0.167 for 130 and 0.184 for 131. This relationship indicates that the dipolar interaction may play a significant role in ' JCH and SH values. 109 Graph 5: Mulliken charges for the methine hydrogens vs. JCH and 5H. 200 131(10°) 180 X • t 5 160 -f 130 (60 °) 129(180°) X 140 -fc X t 4 120 W100 i T 3 o- 80 60 40 20 Xj(Hz) Appm 0 • i • i * • • • i • • • • i • • • • l ' ' • ' i •+- •+- 0 0.1 0.11 0.12 0.13 0.14 0.15 0.16 0.17 0.18 0.19 Mulliken charge of the methine H Finally, the vibrational frequency computations, at the B3LYP/6-31 lG+(d,p) level, indicated that the methine C-H stretching frequency of 129 was significantly different than that of 130 and 131 (Table 10). As expected, 129 has the longest methine C-H bond due to hyperconjugation. This explains why this particular methine C-H stretch was observed at lower frequency. Table 10: Calculated stretching frequencies and bond lengths. Compound 129 130 131 Frequency (cm") 2641 3044 3046 C-H Bond length (A) 1.130 1.094 1.093 110 IV. Conclusions Similar to what Perrin and Cuevas found,212 these results indicate that the lJcu and &H variations observed are not solely a consequence of nitrogen lone pair derealization n—>a CH (hyperconjugation). A dipolar interaction appears to be a significant contributor to the observed ' JCH and 5H values. Both ' JCH and 5H values follow an angular dependence, which corresponds to a dipolar interaction between the methine C-H bond dipole moment and the nitrogen lone pair dipole moment. Ill CHAPTER 5 EXPERIMENTAL DETAILS I. General methods Melting points (mp) were obtained on a Thomas Hoover capillary melting point apparatus and were uncorrected. Infrared Spectra (IR) were run on either a Nicolet MX-1 or a Nicolet 205 FT-IR spectrometers and absorptions are reported in wavenumber (cm-1). 'HNMR Spectra (!H NMR) were acquired on a Varian Mercury-400BB NMR spectrometer or a Varian INOVA-500 NMR spectrometer. Chemical shifts are reported in parts per million (ppm) relative to (CH3)4Si, TMS, unless otherwise noted, and coupling constants (J values) are in Hertz (Hz). 1 1 1 "CCHINMR spectra were acquired on a Varian Mercury-400BB NMR spectrometer or a Varian INOVA-500 NMR spectrometer. Chemical shifts are reported in parts per million (ppm) relative to (CH3)4Si (TMS) unless otherwise noted. High-resolution mass spectra (HRMS) were obtained from the Mass Spectrometry Facility at the University of Notre Dame. A JEOL AX505HA high resolution mass spectrometer was used by the staff at Notre Dame. Elemental analysis (CH&N) was performed by Atlantic Labs Inc., Georgia, USA. X-ray crystallography was performed in the laboratory of Arnold L. Rheingold at the University of California, San Diego, La Jolla, California, USA. 112 Electrochemical analysis was carried out by Edward H. Wong on a BAS100B electrochemical analyzer. A glassy carbon working electrode was used in combination with a Pt auxiliary electrode. Ultraviolet-visible spectra (UV-Vis) were acquired on a Varian Cary 50 spectrometer and absorptions are reported in nanometers (nm). Microwave reactions were carried out using a CEM Discover research-scale manual microwave analyzer. Optical rotation (a) was carried out using a Rudolph Autopol III automatic polarimeter. Kinetics experiments employed a Cole-Parmer Polystat constant temperature circulator water bath for temperature control. II. Solvents Acetone (ACS grade) was obtained from EMD Chemicals Inc. and was used without further purification. Absolute Ethanol (EtOH, ACS, USP grade) was obtained from Pharmco Products Inc. and was used without purification. Acetonitrile (MeCN) was obtained from EMD Chemicals Inc. and stored in a Innovative Technology Inc. Pure-Solv Solvent Purification System. Prior to use, the solvent was passed through the system's alumina column under low pressure to remove trace impurities and water. Benzene (CeH6, ACS grade) was obtained from EMD Chemicals Inc. and was used without further purification. 113 Dichloromethane (CH9CI2, ACS grade) was obtained from EMD Chemicals Inc. and was used without further purification. Chloroform (CHCU. ACS grade) was obtained from EMD Chemicals Inc. and was used without further purification. Deuterated NMR Solvents were obtained from Cambridge Isotope Laboratories and stored over 3A molecular sieves. Diethyl Ether (Et20) was obtained from EMD Chemicals Inc. and stored in a Innovative Technology Inc. Pure-Solv Solvent Purification System. Prior to use, the solvent was passed through the system's alumina column under low pressure to remove trace impurities and water. Ethanol (95% EtOH, ACS grade) was obtained from EMD Chemicals Inc. and was used without further purification. Hexane (ACS grade) was obtained from EMD Chemicals Inc. and was distilled using anhydrous calcium sulfate (DRIERITE) prior to use. Methanol (MeOH, Reagent/ACS/USP/NF grade) was from Pharmco Products Inc. and stored in a Innovative Technology Inc. Pure-Solv Solvent Purification System. Prior to use, the solvent was passed through the system's alumina column under low pressure to remove trace impurities and water. Tetrahydrofuran (THF) was obtained from EMD Chemicals Inc. and stored in a Innovative Technology Inc. Pure-Solv Solvent Purification System. Prior to use, the solvent was passed through the system's alumina column under low pressure to remove trace impurities and water. 114 Toluene (PI1CH3, ACS grade) was obtained from EMD Chemicals Inc. and stored in a Innovative Technology Inc. Pure-Solv Solvent Purification System. Prior to use, the solvent was passed through the system's alumina column under low pressure to remove trace impurities and water. III. Reagents Ally! bromide was obtained from Aldrich Chemical Company. Benzyl bromide was obtained from Alfa Aesar. 2-(Bromomethyl)naphthalene was obtained from Aldrich Chemical Company. tert-Buty\ bromoacetate was obtained from Aldrich Chemical Company. (l.S'H+yCamphorsulfonic acid was obtained from Aldrich Chemical Company. Cupric chloride dihydrate was obtained from Aldrich Chemical Company. Copper perchlorate hexahydrate was obtained from Aldrich Chemical Company. 1. 2-Diaminoethane was obtained from Acros Organics. 6S',.Sf)-(+yDibenzoyl-D-tartaric acid was obtained from Acros Organics. 1,3-Dibromopropane was obtained from Alfa Aesar. 1,3-Dichloroacetone was obtained from Fisher Scientific. 9-Borabicyclo[3.3.1 ]nonane was obtained from Acros Organics. Glyoxal (40 wt % in water) was obtained from Aldrich Chemical Company. Hydrobromic acid (47-49 % in water) was obtained from Alfa Aesar. Hydrochloric acid (12 M) was obtained from Fisher Scientific. Hydrogen peroxide (30 %) was obtained from Acros Organics. Potassium carbonate (K2CO3) was obtained from Fluka. 115 Potassium hydroxide (KOH) was obtained from Alfa Aesar. Sodium borohydride (NaBH4) was obtained from Lancaster Synthesis Inc.. Sodium cyanoborohydride (NaBHsCN) was obtained from Aldrich Chemical Company., Sodium sulfate, anhydrous (Na?SQ4) was obtained from EMD Chemicals. D-(-)-Tartaric acid was obtained from Aldrich Chemical Company. L-(+)-Tartaric acid was obtained from Aldrich Chemical Company. Trifluoroacetic acid (TFA) was obtained from Lancaster Synthesis Inc.. IV. Column Chromatography Alumina: Aluminum oxide 90 powder (Activity II-III, basic, Brockmann, 70-230 mesh) standardized for chromatographic adsorption was obtained from EM Science. Silica gel (230-400 mesh ASTM) for column chromatography was obtained EM Science. V. Experimental Procedures Note: All routine solvent evaporations were carried out on a standard rotary evaporator using water-aspirator pressure or using a Welch Dry Vacuum Pump (Model 2042) unless otherwise noted. 7VyV'-Bis(2-aminoethyI)-l,3-propanediamine (23). The compound was prepared according to the procedures of Van Alphen and Pruckmayr.100'115 A solution of 1,3- dibromopropane (365.36 g, 1.81 mol) in EtOH (586 mL) was added dropwise to a stirred solution of 1,2-diaminoethane (618.93g, 10.30 mol) in H20 (182 mL) under N? over a period of 2.5 h. The stirred solution was then heated to reflux for 2 h, and allowed to cool to room temperature. KOH pellets (508.02 g) were added to the stirred mixture over 30 116 min, and the mixture was further stirred overnight at room temperature. The reaction mixture was refluxed for 2 h at 100 °C, allowed to cool to room temperature, and the white solids were removed by suction filtration. The filtrate was distilled at aspirator pressure to remove the EtOH, H2O, and excess 1,2-diaminoethane. Additional KOH (60 g) was added to the filtrate, and the mixture was stirred at room temperature for 1 h and filtered. The filtrate was subjected to vacuum distillation at 150 mTorr with a maximum head temperature of 105 °C to give 146.73 g (50%) of 23 as a clear oil. The 'H NMR and 13C{'H} NMR spectra were consistent with that of authentic material. (Note: a fine white precipitate was visible in the clear oil upon storage. 13C{'H} NMR indicated the presence of 0.01 ± 0.01 molar equivalents of a possible carbamate species formed from the reaction of a primary or secondary amine with carbon dioxide.) m-Octahydro-lH,4H,7H-l,3a,6a,9-tetraazaphenalene (49). The compound was prepared according to the procedure reported by Handel.98 To a solution of NJV'- bis(2-aminoethyl)-l,3-propanediamine (23) (100.00 g, 0.62398 mol) in 1.56 L of absolute EtOH stirred at - 10 °C, 90.53 g of 40 wt % aq glyoxal (36.21 g, 0.6239 mol of glyoxal) was added dropwise. The addition was done over 1 h while the temperature was kept between -5 °C and -10 °C. The reaction mixture was then stirred at -5 °C for an additional 3 h. The solvent was removed under aspirator pressure at 0-4 °C to give a viscous light yellow oil. Removal of trace solvent under vacuum gave a sticky light yellow residue (128.53 g). The crude residue was recrystallized from 1.1 L hot hexane to give 76.16 g (67%) of crude product as a white sticky hygroscopic solid. The !H NMR and 13C{'H} NMR spectra were consistent with those of authentic material. *H NMR 117 indicated the presence of 3% of the trans isomer 50. This mixture of cis/trans diastereomers was separated by a second recrystallization: 35.55 g of the initial recrystallized product was recrystallized using 500 mL hot hexane to give 19.72 g of 49 as a white solid with less than 1% of the trans isomer 50 by 'H NMR. c/s-Decahydro-lH,6H-3a,5a,8a,10a-tetraazapyrene (13). A solution of 1,3- dibromopropane (45.25 g, 0.2241 mol) in 450 mL MeCN and a solution of c/s-octahydro- lH,4H,7H-l,3a,6a,9-tetraazaphenalene (49) (40.26 g, 0.2209 mmol) in 450 mL MeCN were added dropwise concurrently from separate addition funnels at approximately the same rate over approximately 3 hours to a mixture of K2CO3 (201.33 g, 1.46 mol) in 380 mL MeCN. The reaction mixture was then stirred at room temperature under N2 for 4 days, after which the reaction mixture was filtered through Celite®. The filtrate was concentrated under aspirator pressure to give a cloudy oily residue. The crude product was extracted from the oily residue by washing the residue with EtaO (3 x 600 mL). The Et20 washes were combined and concentrated under aspirator pressure to give 47.27 g (97% crude) of 13 as a viscous oil. The 'H NMR indicated the presence of 4% of the trans isomer 40. The crude material was then recrystallized from 200 mL hexanes at 6 °C to give 22.78 g (46%) of 13 as a white solid free of trans isomer by 'H NMR. The 'H NMR and ^C^H} NMR spectra were consistent with those of pure authentic material.43 cis-Decahydro-5H-2a,4a,7a,9a-tetraazacyclopenta[cd]phenalene (12). A solution of 1,2-dibromoethane (5.1296 g, 27.305 mmol) in 75 mL MeCN and a solution of c/s-octahydro-lH,4H,7H-l,3a,6a,9-tetraazaphenalene (49) (4.9737 g, 27.288 mmol) in 118 75 mL MeCN were added dropwise concurrently from separate addition funnels at approximately the same rate over 2 hours to a mixture of K2CO3 (18.66 g, 135.0 mmol) in 80 mL MeCN. The reaction mixture was stirred at 60 °C under N2 for 4 days, after which the reaction mixture was cooled to room temperature and filtered through Celite®. The filtrate was concentrated under aspirator pressure and the residue dissolved in CH2CI2 (20 mL) and filtered through a basic alumina plug. This was concentrated to give a brown oily residue. The crude residue was dissolved in hot hexane (25 mL), the hexane-soluble material was collected and concentrated down to a light yellow oil. The crude oil was purified by column chromatography (127 g basic alumina; column length 22 cm, column diameter 3 cm; CHCI3: Rf 0.17) to give 3.9011 g (69%) of 12 as a clear viscous oil. The !H NMR was consistent with pure authentic material.41'60'107 4,10-Bis(phenylmethyl)-l,4,7,10-tetraazabicyclo[5.5.2]tetradecane (17). To a stirred solution of (8bi?,8ai?)-re/-decahydro-2a,6a-bis(phenylmethyl)-2a,4a,6a,8a- tetraazacyclopent[fg]acenaphthylenium dibromide (14) (1.0086 g, 1.8805 mmol) in 95% EtOH (46 mL) in a 100 mL round-bottom flask NaBH4 (3.5550 g, 93.968 mmol) was added in small portions over 40 minutes. An open-vessel microwave reaction was set up in a CEM Discover microwave reactor. The 100 mL flask was equipped with an air condenser topped with a water condenser and a N2 inlet. The microwave-enhanced reaction was run with an initial temperature set at 50 °C, followed by an increase in temperature at 5 °C/min to 70 °C, then 2 °C/min to 78 °C, which was maintained for 12 minutes. The reaction vessel was then cooled in an ice bath and the excess NaBfit was decomposed by the dropwise addition aq 3 M HC1 (35 mL) until the pH was 1. The 119 solvent was then removed under aspirator pressure, and the resulting white solid was dissolved in FLO (20 mL). While the solution was cooled in an ice bath, the pH was adjusted to 14 by the slow addition of KOH pellets. The resulting solution was extracted with benzene (8 x 50 mL), the combined benzene extracts were dried over anhyd Na2SC>4, filtered, and the solvent was removed under aspirator pressure to give 0.7120 g (100% yield) of 17 as a light yellow oil. The 'H NMR spectrum was consistent with that of pure authentic material.41'44 4,ll-Bis(phenyImethyl)-l,4,8,ll-tetraazabicyclo[6.5.2]pentadecane (18). To a stirred solution of (9ba,9ca)-decahydro-2a,7a-bis(phenylmethyl)-5H-4a,9a-diaza-2a,7a- diazoniacyclopenta[cd]phenalene dibromide (15) (0.7499 g, 1.3625 mmol) in 35 mL 95% EtOH in a 100 mL round-bottom flask, NaBH4 (2.5775 g, 68.1247 mmol) was added in small portions over 35 minutes. An open-vessel microwave reaction was set up in a CEM Discover microwave reactor. The 100 mL flask was fitted with an air condenser topped with a water condenser and a N2 inlet. The microwave-enhanced reaction was run with an initial temperature of 35 °C followed by an increase in temperature at 5 °C/min to 70 °C, then 2 °C/min to 78 °C, which was maintained for 16 minutes. The reaction vessel was then cooled in an ice bath and the excess NaBLLt was decomposed by dropwise addition of aq 6 M HC1 (20 mL) until the pH was 1. The solvent was then removed under aspirator pressure and the resulting white solid was dissolved in H2O (15 mL). While the solution was cooled in an ice bath, the pH was adjusted to 14 using KOH pellets. The resulting solution was extracted with benzene (6 x 50 mL), the combined benzene extracts were dried over anhyd Na2SC>4, filtered,an d the 120 solvent was removed under aspirator pressure to give 0.5248 g (98%) of 18 as a clear oil. The *H NMR spectrum was consistent with that of pure authentic material.107 4,ll-Bis(phenylmethyl)-l,4,8,ll-tetraazabicyclo[6.6.2]hexadecane (19). To a stirred solution of (1 Oboe, 10ac)-decahydro-3a,8a-bis(phenylmethyl)-1 H,6H-3a,5a,8a, 10a- tetraazapyrenium dibromide (16) (0.9677g, 1.7146 mmol) in 45 mL 95% EtOH in a 100 mL round-bottom flask, NaBH4 (3.3895 g, 89.5864 mmol) was added in small portions over 25 minutes. An open-vessel microwave reaction was set up in a CEM Discover microwave reactor. The 100 mL flask was equipped with an air condenser, topped with a water condenser and a N2 inlet. The microwave-enhanced reaction was run with an initial temperature set at 50 °C, followed by an increase in temperature at 5 °C/min to 70 °C, then 2 °C/min to 78 °C, which was maintained for 9 minutes. The reaction vessel was cooled in an ice bath and the excess NaBEL was decomposed by dropwise addition of aq 6 M HC1 (25 mL) until the pH was 1. The solvent was then removed under aspirator pressure and the resulting white solid was dissolved in a H2O (15 mL). While the solution was cooled in an ice bath, the pH was adjusted to 14 by the slow addition of KOH pellets. The resulting solution was extracted with benzene (8x50 mL), the combined benzene extracts were dried over anhyd Na?S04, filtered, and the solvent was removed under aspirator pressure to give 0.5756 g (79%) of 19 as a white solid; mp 88-92 °C (lit. mp 89- 91 °C).43'107 The 'H NMR spectrum was consistent with that of pure authentic material. Preparation of 2a,7a-(prop-2-en-l-yI)decahydro-5H-4a,9a-diaza-2a,7a- diazoniacyclopenta[cd]phenalene dibromide (54). 121 54 Allyl bromide (587.0 mg, 4.485 mmol) was added in one portion to a solution of cis- decahydro-5H-2a,4a,7a,9a-tetraazacyclopent[cd]phenalene (12) (99.0 mg, 0.4753 mmol) in 4.5 mL anhyd MeCN and the reaction mixture was stirred at room temperature for 17 days. The reaction mixture was centrifuged and the supernatant was decanted. The resulting white powder was washed with anhyd MeCN (2x2 mL) and the residual solvent was removed under vacuum to give 112.5 mg (53%) of 54 as a white powder; mp 166-172 °C (decomposition); *H NMR (MeOH-d4, 400 MHz) 5 1.87-1.96 (dm, 1H, H6eq, J= 15.2 Hz), 2.30-2.45 (m, 1H, H6ax), 2.85 (td, 1H, J= 12.2, 3.0 Hz), 3.03-3.24 (m, 3H), 3.25-3.35 (m, 2H), 3.37-3.60 (m, 4H), 3.70-3.97 (m, 4H), 4.00-4.10 (m, 1H), 4.30 (dd, 1H, J= 13.4, 6.4, NC#HCH=CH2), 4.38 (dd, 1H,J= 13.7, 7.6 Hz, NC#HCH=CH2), 4.45 (td, 1H, J= 12.6, 4.7 Hz), 4.60 (dd, 1H, J= 13.4, 7.1 Hz, NCH//CH=CH2), 4.66 (dd, 1H,J= 13.4, 8.0Hz,NCH#CH=CH2),4.94(Xof AX, 1H, J= 2.4 Hz,NC//N), 5.09 (A of AX, 1H, J= 2.4, NC//N), 5.75-5.80 (dm, 1H, J= 10.1 Hz, CH2CH=CH//E), 5.80-5.85 (dm, 1H, J= 10.1 Hz, CH2CH=CM/E), 5.86-5.94 (dm, 1H, J= 16.8 Hz, CH2CH=CHtfz), 5.95-6.02 (dm, 1H, J= 16.8 Hz, CH2CH=CH#Z), 6.08-6.24 (m, 2H, CH2C//=CH2); 13 C{'H} NMR (MeOH-d4, 125.68 MHz) 5 20.41 (C6), 43.23, 46.96, 47.80, 50.40, 51.70, 54.21, 60.74, 61.87, 61.92, 62.77, 77.20 (NCHN), 78.34 (NCHN), 124.32, 125.56, 130.01, 130.99; 'H COSY and gHSQC experiments were used for resonance assignments (see the figure above for compound numbering)]; 1R (KBr) 3460 (br), 3072, 3033, 3014, 3003, 2956, 2916, 2881, 2859, 2846, 1637, 1475, 1454, 1444, 1438, 1405, 1368, 1333, 1299, 1272, 1230, 1196, 1165, 1137, 1121, 1059, 1048,1020,993,945,901,881,869, 122 1 722 cm" ; Anal. Calcd for C17H3oN4Br2«0.45(H20): C, 44.55; H, 6.79; N, 12.22; Br, 34.87. Found C, 44.98; H, 6.67; N, 12.23; Br, 34.50. 4,ll,-Di(prop-2-en-l-yl)-l,4,8,ll-tetraazabicyclo[6.5.2]pentadecane (55). To a solution of 2a,7a-(prop-2-en-l-yl)decahydro-5H-4a,9a-diaza-2a,7a- diazoniacyclopenta[cd]phenalene dibromide (54) (80.0 mg, 0.1777 mmol) in 9 mL anhyd MeCN was added NaBH3CN (450.7 mg, 7.172 mmol) over 10 min and the reaction mixture was stirred at reflux under N2 for 2 days. Solvent was then removed under aspirator pressure to yield a white solid. [CAUTION: due to HCN generation, all operations must be carried out in a well ventilated hood.] The solid was dissolved in H2O (3 mL) and while cooling the vessel in an ice bath, the excess NaBF^CN was decomposed by the dropwise addition of aq 6 M HC1 (13 mL) until the pH was 1. The solvent was then removed under aspirator pressure and the resulting white solid was dissolved in H2O (5 mL). While the solution was cooled in an ice bath, the pH was adjusted to 14 using KOH pellets. The resulting mixture was extracted with benzene (5 x 30 mL), the combined benzene extracts were dried over anhyd Na2S04, filtered, and the solvent was removed under aspirator pressure to give a cloudy oil. The oil was dissolved in CH2CI2 (8 mL) and filtered through a silica plug with to give 40.9 mg (79%) of 55 as a yellow oil; 'H NMR (C6D6, 500 MHz) 5 1.42-1.56 (m, 2H), 2.29 (dt, 1H, J = 12.3, 4.8 Hz), 2.34-2.40 (m, 1H), 2.44-2.49 (m, 2H), 2.56-2.68 (m, 6H), 2.69-2.89 (m, 6H), 2.89- 2.96 (m, 3H), 3.07-3.13 (m, 3H), 3.16-3.22 (m, 1H), 3.63 (ddd, 1H, /= 12.3, 8.6, 5.0 Hz), 5.01-5.09 (m, 3H), 5.15(appdq, 1H,J=17.2, 1.7 Hz), 5.84 (ddt, 1H, .7=17.1, 10.2,6.2 Hz), 5.91 (dddd, 1H,J= 17.2, 10.2, 7.2, 5.5 Hz); ^C^H} NMR(C6D6, 125.68 MHz) 6 123 28.39 (NCCCN), 51.75, 53.69, 55.51, 55.64, 56.08, 56.83, 57.23, 57.47, 58.69, 58.83, 58.96,59.83, 115.94, 116.26, 137.26, 137.64; IR (Neat) 3071, 2967, 2916, 2856, 2785, 1641, 1446, 1407, 1367, 1264, 1109, 1014, 910, 799, 692 cm'1; HRFABMS (m/z): (M+H)+found 293.2720 (error +1.5 mmu/+5.2 ppm), (M+H)+ calcd for C17H33N4, 293.2705. (The NMR spectra indicated that sample was contaminated with silicone grease and mineral oil. There was also another contaminant (< 5 %) visible in the spectra, which could possibly be an adjacent-bridged mono-allyl species). CuCl2»9. A solution of 1,4,8,1 l-tetraazabicyclo[6.5.2]pentadecane (9) (0.1704 g, 0.8025 mmol) and CuCl2»2H20 (0.1230 g, 0.7215 mmol) in dry MeOH (10 mL) was stirred at 68 °C for 2 h. The resulting blue solution was filtered and the filtrate was concentrated down at aspirator pressure. The blue residue was then taken up in dry MeOH (5 mL) and put in an Et20 diffusion chamber. Blue crystalline plates were collected to give 0.2022 g (81% yield) of CuCl2'9; Anal. Calcd for CnH24N4'CuCl2«0.75(H2O):C, 36.67; H, 7.13; N, 15.55; CI, 19.68. Found C, 36.78; H, 7.22; N, 15.41; CI, 19.43; IR (KBr) 3444, 3283, 2935, 2875, 1637, 1486, 1095, 1012,624 1 1 1 cm" . UV-Vis (MeOH) X.max 579 (e = 71.5 M" cm" ); Cyclic voltammetry conducted in 0.1 N sodium acetate: reduction was irreversible with Ep= - 0.706 V(Ag/AgCl). [Cu(C104)«9](C104). A solution of 1,4,8,1 l-tetraazabicyclo[6.5.2]pentadecane (9) (0.1790g, 0.8430 mmol) and Cu(C104)2«6H20 (0.2810 g, 0.7584 mmol) in dry MeOH (10 mL) was stirred at 68 °C for 2 h. The resulting blue solution was filtered and the filtrate was placed in an Et20 diffusion chamber. Large blue plate-like crystals were 124 collected for X-ray structural analysis. Trace amounts of Et20 were removed from the remaining solids under reduced pressure to give 0.3106g (86% yield) of [Cu(C104)»9](C104); Anal. Calcd for C11H24N4»Cu(C104)2:C, 27.83; H, 5.10; N, 11.80; CI, 14.93. Found C, 27.67; H, 5.10; N, 11.51; CI, 14.66; IR (KBr) 3500 (br), 3385, 3125, 2913,2870,2311, 1659, 1638, 1480, 1459, 1357, 1318, 1276, 1101, 1084, 1044, 1016, 825, 746 cm"1. UV-Vis (MeOH) X^ 589 (e = 84.6 M"1 cm"1); Cyclic voltammetry conducted in 0.1 N sodium acetate: reduction was irreversible with Ep= - 0.731 V (Ag/AgCl). 4,ll-Bis-(carboxymethyl)-l,4,8,ll-tetraazabicyclo[6.5.2]pentadecane (58). A solution of 4,1 l-bis(carbo-tert-butoxymethyl)-l,4,8,l l-tetraazabicyclo[6.5.2]pentadecane (59) (96.0 mg, 0.2179 mmol) in trifluoroacetic acid (3.4 mL, 0.046 mol) and CH2C12 (3.4 mL) was stirred under N? for 2 days. The reaction mixture was then concentrated under aspirator pressure and residual solvent was removed under vacuum to give 0.1635 g (0.2179 mmol, 100%) of 58 as a brown oil with 3.7 equivalents of TFA by mass. 'H NMR(MeCN-d3, 500 MHz) 5 1.69-1.76 (dm, 1H, J= 16.8 Hz), 2.14-2.28 (m, 1H), 2.82- 3.52 (m, 22-23H), 3.53 and 3.89 (AX, 2H, J= 17.6 Hz, NC//2C02), 3.86 and 4.05 (AB, 13 1 2H, J= 17.4 Hz, NC/f2C02), 11.64 (br s, 6H, includes all COOHpeaks); C{ H} NMR (MeCN-d4, 125.68 MHz) 5 20.94, 48.58, 50.04, 50.40, 52.25, 53.36 (br), 53.85, 55.16 (br), 55.69, 56.37, 57.59, 58.21, 58.40, 117.08 (q, Ur = 283.2 Hz, F3CCOOH), 160.67 2 (q, JCF = 37.0 Hz, F3CCOOH), 170.88, 172.99. No additional characterization was done on this compound as it was used immediately in the subsequent complexation reaction } with Cu(C104)2»6H20. ( H NMR integration from 2.82 to 3.52 ppm was slightly above 125 what was expected, there may be a small amount of an impurity present or possibly some H20). Synthesis and copper (II) complexation of 4,ll-bis-(carboxymethyI)-l,4,8,ll- tetraazabicyclo [6.5.2] pentadecane (58). N N TFA:CH N N H r N CVS< ^ ^ > CY° CU(CI04)2-6H20 .N N^Y° >LASNV° —^ASNV°-"™ — ' -ASNV° <&> N N ^0-^" y HO"^" PH8, INNaOH CT^ y l.2NaCI04 95% EtOH/Et20 Diffusion (quant) (44%) 59 58 Cu-58'2(H20>1.2(NaC104) A solution of 4,11-bis(carbo-tert-butoxymethyl)-1,4,8,11- tetraazabicyclo[6.5.2]pentadecane (59) (96.0 mg, 0.2179 mmol) in trifluoroacetic acid (3.4 mL, 0.046 mol) and CH2CI2 (3.4 mL) was stirred under N? for 2 days. The reaction mixture was then concentrated under aspirator pressure and the residual solvent was removed under vacuum to give 0.1635 g (0.2179 mmol, 100%) of 58 as a brown oil containing 3.7 equivalents of TFA by mass. To the solution of 58*3.7 TFA in 95% EtOH (15 mL) was added C^CKXb^HaO (135.5 mg, 0.3657 mmol) and the pH of the reaction mixture was adjusted to 8 with 1 M NaOH. The reaction was then refluxed under N2 for approximately 23 hours. The reaction mixture was centrifuged and the supernatant collected and concentrated down under aspirator pressure. Residual solvent was removed under vacuum to give 263.7 mg of a blue solid. The solid was dissolved in 95 % EtOH (15 mL) and the blue solution was placed in an Et20 diffusion chamber. A powdery blue solid was collected to give 55.3 mg (44%) of Cu-58»2(H20)-1.2(NaC104). Anal. Calcd for Cu(C15H26N404>2H2<>1.2NaC104: C, 31.45; H, 5.28; N, 9.78; CI, 7.43. Found C, 31.49; H, 5.14; N, 9.68; CI, 7.10; IR (KBr) 3536, 3490, 3430, 3394, 3364, 1610, 1485, 1 1437, 1397, 1320, 1098, 631cm" . UV-Vis (H20) ^max 608 (e = 32.1 VT W); Cyclic 126 voltammetry conducted in 0.1 N sodium acetate: indicated a quasi-reversible reduction with Ep= -0.950 V (Ag/AgCl). A 0.13 M solution of Cu-58-2(H20>1.2(NaC104) in 95 % EtOH was placed in an EtoO diffusion chamber. Plate-like blue crystals were collected for X-ray structural analysis, which yielded an empirical formula of Cu»58»H2ONaC104. Preparation of c«-2-methylidenedecahydro-lH,6H-3a,5a,8a,10a- tetraazapyrene (92). iL 2 J3 92 A solution of 3-chloro-2-(chloromethyl)-l-propene (4.2717 g, 34.174 mmol) in dry MeCN (200 mL) was added to a stirred solution of cfs-octahydro-lH,4H,7H-l,3a,6a,9- tetraazaphenalene (49) (6.2462 g, 34.269 mmol) and K2C03 (31.80 g, 0.1736 mol) in dry MeCN (200 mL) and the reaction mixture was stirred under N2 for 4 days. The mixture was filtered and the filtrate was concentrated under aspirator pressure to give an oil. The oil was dissolved in CH2CI2 (10 mL), filtered through a basic alumina plug, and the solvent was removed under aspirator pressure. The resulting oil was then Kugelrohr distilled from 80-100 °C (25 mTorr) to give 7.1247 g (89%) of 92 as a clear viscous oil: 'HNMRCCeDe, 500 MHz) 6 0.81-0.87 (dm, 1H, J= 13.2 Hz, H7eq), 1.89-1.96 (m, 1H), 1.99-2.10 (m, 3H, 777ax and 2 other H), 2.24-2.32 (m, 2H), 2.48-2.55 (m, 3H), 2.66-2.75 (m,2H), 2.84 (td, .7=13.4, 3.4 Hz), 3.00 (dd, 1H, .7=14.1, 1.7 Hz), 3.17 (dd, 1H, .7=11.7, 1.5 Hz), 3.23 and 3.25 (AB, 2H, J= 3.0 Hz, N2C77-C/7N2), 3.42-3.52 (m, 2H), 3.61-3.68 127 u l (m, 1H), 4.58-4.62 (m, 1H, C=CHH), 4.77-4.81 (m, 1H, C=CHR); C{ U} NMR (C6D6, 125.68 MHz) 8 20.44 (C7), 45.20, 45.83, 53.10, 54.68, 54.79, 56.49, 59.60, 61.64, 76.80 (NCN), 77.61(NCN), 109.54 (C2), 140.76 (Cn) [Note; *H COSY and gHSQC experiments were used for resonance assignments (see the figure above for compound numbering). The enantiomerization of 92 (resulting from four nitrogen inversions and two piperazine ring inversions) exchanges the two endo and exo nitrogens and is slow on the NMRtimescale]; IR (neat) 3067, 2978, 2933, 2855, 2807, 2749, 2663, 1659, 1462, 1456, 1441, 1353, 1337, 1327, 1317, 1297, 1251, 1226, 1176, 1157, 1147,1134, 1102, 1067, 1014, 963, 894, 830 cm"1; HRFABMS (m/z): (M+H)+ found 235.1941 (error +1.9 mmu/+7.9 ppm), (M+H)+ calcd for C13H23N4, 235.1923. Preparation of c/s-3a,8a-bis(phenylmethyl)-2-methylidenedecahydro-lH,6H- 5a,10a-diaza-3a,8a-diazoniapyrene dibromide (98). 2Br 98 Benzyl bromide (2.6603 g, 15.553 mmol) was added in one portion to a solution of cis-2- methylidenedecahydro-lH,6H-3a,5a,8a,10a-tetraazapyrene (92) (0.2562 g, 10.093 mmol) in 6 mL MeCN and the reaction mixture was stirred for 14 days. The precipitate was isolated by suction filtration and washed with CH2CI2 (3x2 mL). Residual solvent was removed under vacuum to give 0.6021 g (95%) of 98 as a white solid; mp 140-143 °C (decomposition); 'H NMR (D20, 500 MHz) 6 1.88-1.96 (dm, 1H, H7eq, J = 14.9 Hz), 2.18-2.35 (m, 1H, H7ax), 2.89 (td, 1H, J=12.3, 2.7 Hz), 3.18-3.23 (m, 1H), 3.27 (br d, 2H, 128 J= 13.4 Hz), 3.37-3.61 (m, 5H), 3.67 (td, 1H, J=13.5, 2.7 Hz), 3.73(br d, 1H, J= 12.8 Hz), 3.80 (td, 1H, J= 13.4, 3.5 Hz), 3.84 (br d, 1H, J= 13.2 Hz), 4.13 (td, 1H, J= 13.4, 4.1 Hz), 4.39 (td, 1H, J = 13.3, 3.9 Hz), 4.42 (br d, 1H, J= 12.7 Hz), 4.80 and 5.32 (AX, 2H, J= 13.2 Hz), 4.87 and 5.31 (AX, 2H, J = 12.9 Hz), 5.18 (br s, 1H, NC//N), 5.26 (br s, 1H, C=CHi/), 5.34, (br s, 1H, NCf/N), 5.49 (br s, 1H, C=C#H), 7.55-7.68 (m, 10H); 13 C{'H} NMR(D20, 100.525 MHz) 6 18.60 (C7), 46.65, 47.18, 47.45 , 47.48, 51.78, 57.02, 61.12, 62.50, 63.12, 65.74, 76.72 (NCN), 77.68 (NCN), 121.82 (Cn), 125.15, 125.25, 129.12 (C2), 130.12, 130.23, 132.09, 132.22, 133.86, 133.88 [Note; 'H COSY and gHSQC experiments were used for resonance assignments (see the figure above for compound numbering)]; IR (KBr) 3084, 3064, 3026, 2976, 2951, 2921, 2906, 2842, 2793,2712, 1939, 1871, 1801, 1677, 1645, 1601, 1493, 1453, 1446, 1375, 1363, 1245, 1136, 891, 730, 696 cm4; HRFABMS (m/z): (M+) found: 495.2136 (error +1.3 mmu/+2.6 + ppm), (M ) calcd for C27Ui6BrN4, 495.2107; Anal. Calcd for C^yHseB^N^HsO): C, 52.95; H, 6.58; N, 9.15; Br, 26.09. Found C, 52.72; H, 6.48; N, 9.19; Br, 25.93. Preparation of 4,ll-bis(phenylmethyl)-6-methylidene,l,4,8,ll- tetraazabicyclo [6.6.2] hexadecane (99). 13 J.NL N^ \- // // \ ^N N^ 99 To a stirred solution of cz's-3a,8a-bis(phenylmethyl)-2-methylidenedecahydro-lH,6H- 5a,10a-diaza-3a,8a-diazoniapyrene dibromide (98) (0.5868g, 1.0180 mmol) in 33 mL 95% EtOH in a 100 mL round flask, NaBH4 (1.9257 g, 50.901 mmol) was added in small 129 portions over 20 minutes. An open-vessel microwave reaction was set up in a CEM Discover microwave reactor. The flask was equipped with an air condenser topped with a water condenser and a N2 inlet. The microwave-enhanced reaction was run with an initial temperature of 50 °C followed by an increase in temperature at 5 °G/min to 70 °C, then 2 °C/min to 78 °C, which was maintained for 18 minutes. The reaction vessel was cooled in an ice bath and the excess NaBtU was decomposed by the dropwise addition of aq 6 M HC1 (8 mL) until the pH was 1. The solvent was then removed under aspirator pressure and the resulting white solid was dissolved in H2O (4 mL). While the solution was cooled in an ice bath, the pH was adjusted to 14 by the slow addition of KOH pellets. The resulting solution was extracted with benzene (5 x 50 mL), the combined benzene extracts were dried over anhyd Na2S04, filtered, and the solvent was removed under aspirator pressure to give 0.4153 g (97%) of 99 as a off-white solid: mp 48-51 °C; 1H NMR (C6D6, 500 MHz) 5 1.27-1.39 (m, 1H, Hn), 1.44-1.53 (m, 1H, Hu), 2.25-2.33 (m, 3H), 2.36-2.57 (m, 8H), 2.65-2.70 (m,-lH), 2.84 and 3.48 (AX, 2H, J= 13.8 Hz, NC/M>CH2), 2.91 (ddd, 1H,J= 15.6, 11.7, 3.9 Hz), 2.95 and 4.55 (AX, 2H, J = 13.0 Hz, NCi/2C=CH2), 3.07 and 3.70 (AX, 2H, J = 13.4 Hz, NC//2Ph) 3.23 and 3.83 (AX, 2H, J = 13.4 Hz, NC#2Ph), 3.28 (~td (ddd), 1H, J= 12.4, 3.8 Hz), 3.37 (td, 1H, J= 12.3, 3.9 Hz), 3.88 (td, 1H, J= 11.7, 4.1 Hz), 4.91-4.93 (m, 1H, OCH/f), 4.94-4.96 (m, 1H, n l C=CHfl), 7.08-7.36 (m, 10H, Ph); C{ U} NMR (C6D6, 125.680 MHz) 5 28.28 (C,3), 51.82, 54.87, 55.76, 56.30, 56.58, 57.29, 57.57, 57.73, 59.87, 60.25, 60.92, 61.26, 111.60 (C=CH2), 126.99, 127.00, 128.41, 128.43, 129.36, 129.39, 140.84, 141.14, 150.98 [Note; 'H COSY and gHSQC experiments were used for resonance assignments (see the figure above for compound numbering). NMR spectra indicated the presence of a minor 130 impurity (< 2 %) as well as silicone grease contamination]; IR (KBr) 3038, 3064, 3025, 2976, 2951, 2905, 2842, 2794, 1493, 1445, 1376, 1364, 1245, 1136, 1109, 891, 730 cm-1; HRFABMS (m/z): (M+H)+found 419.3189 (error +1.4 mmu/+3.4 ppm), calcd for C27H39N4: 419.3175. Preparation of c/s,-2-methylidine-3a-8a-bis(2-naphthylmethyl)decahydro- lH,6H-5a,10a-diaza-3a-8a-diazoniapyrene (100). 4k^N>0 2Br 100 2-(Bromomethyl)naphthalene (1.0608g, 4.7978 mmol) was added in one portion to a solution of cw-2-methylidenedecahydro-lH,6H-3a,5a,8a,10a-tetraazapyrene (92) (121.9 mg, 0.5202 mmol) in 7 mL MeCN and the reaction mixture was stirred for 18 days. The reaction mixture was then centrifuged and the supernatant decanted. Et?0 (3 mL) was added to the solids, the mixture was centrifuged, and the supernatant was decanted. The process was repeated one additional time. Residual solvent was removed under vacuum to give 299.9 mg (81%) of 100 as an off-white solid; mp 154-156 °C (decomposition); 'H NMR (MeOH-d4, 500 MHz) 5 1.81-1.91 (dm, 1H, H7eq, J = 14.2 Hz), 2.03 (s, C/fcCN), 2.18-2.34 (m, 1H, H7ax), 3.08-3.24 (m, 4H), 3.25-3.39 (m, 2H), 3.44 (dd, \U,J = 13.9, 3.7 Hz), 3.49 (dd, 1H, J= 13.8, 3.5 Hz), 3.66-3.77 (m, 4H), 3.85 (td, 1H, J= 13.2, 3.1 Hz), 4.07 (td, 1H, J= 13.1, 3.7 Hz), 4.21 (td, 1H, J= 13.2, 4.2 Hz), 4.54 (td, 1H, J = 13.0, 4.0 Hz), 4.76 (d, 1H, J= 12.9 Hz), 5.19 and 5.65 (AX, 2H, J= 12.5 Hz), 5.20 (br s, 1H, C=C//H), 5.28 and 5.60 (AX, 2H, J= 12.9 Hz), 5.39 (br s, 1H, C=CRH), 5.70 (br s, 131 1H, NCtfN), 5.92 (br s, 1H, NC//N), 7.54-7.61 (m, 4H, Ar), 7.64-7.70 (m, 2H, Ar), 7.82- 7.88 (m, 2H, Ar), 7.91 (d, 1H, J= 8.5 Hz, Ar), 7.93 (d, 1H, J= 8.5 Hz, Ar), 7.96-8.01 (m, 13 2H, Ar), 8.25 (br d, 2H, J= 10.0 Hz, Ar); C{'H} NMR (CD3OD, 100.527 MHz) 5 19.84 id), 47.09, 47.92, 47.96, 48.25, 52.40, 57.79, 61.68, 62.64, 63.27, 66.25, 77.66 (NCN), 78.64(NCN), 121.12 (C=CH2), 123.91, 124.07, 128.32, 128.35, 128.89, 128.91, 129.23, 129.30, 129.60, 129.66, 130.07, 130.11, 130.41, 130.56, 131.45 (C=CH2), 134.45, 134.52, 135.36, 135.44, 135.53, 135.63; 'H COSY and gHSQC experiments were used for resonance assignments (see the figure above for compound numbering)]; 1R (KBr) 3651, 3642, 3338, 2995, 2960, 2907, 2855, 2809, 1600, 1848, 1449, 1279, 1144, 1132, 1079, 923. 896, 867, 823, 760, 483 cm-1; Anal. Calcd for C35H4oBr2N4'0.8(H20)'0.6(CH3CN): C, 60.76; H, 6.11; N, 9.00; Br, 22.33. Found C, 60.89; H, 6.07; N, 8.65; Br, 22.31. Preparation of 6-methylidene-4,ll-bis(2-naphthylmethyl)-l,4,8,ll- tetraazaBlcyclo [6.6.2] hexadecane (101). To a stirred solution of c/'s-2-methylidine-3a-8a-bis(2-naphthylmethyl)decahydro-lH,6H- 5a,10a-diaza-3a-8a-diazoniapyrene (100) (89.2 mg, 0.132 mmol) in 4 mL 95% EtOH in a 10 mL round-bottom flask, NaBH4 (250.0 mg, 6.608 mmol) was added in small portions over 20 minutes. An open-vessel microwave reaction was set up in a CEM Discover 132 microwave reactor. The 10 mL flask was equipped with an air condenser topped with a water condenser and a N2 inlet. The microwave-enhanced reaction was set up with an initial temperature of 50 °C followed by an increase in temperature at 5 °C/min to 70 °C, then 2 °C/min to 78 °C, which was maintained for 11 minutes. The reaction vessel was cooled in an ice bath and the excess NaBH4 was decomposed by the dropwise addition aq 6 M HC1 (3 mL) until the pH was 1. The solvent was then removed under aspirator pressure and the resulting white solid was dissolved in H2O (3 mL). While the solution was cooled in an ice bath, the pH was adjusted to 14 using KOH pellets. The resulting solution was extracted with benzene (8x10 mL), the combined benzene extracts were dried over anhyd Na2SC>4, filtered, and the solvent was removed under aspirator pressure ! to give 60.9 mg (89%) of 101 as an off-white solid; mp 108-111 °C; H NMR (C6D6, 500 MHz) 5 1.33-1.44 (m, 1H, Hl3), 1.50-1.59 (m, 1H, Hl3), 2.25-2.35 (m, 3H), 2.39-2.56 (m, 7H), 2.58-2.64 (m, 1H), 2.73-2.79 (m, 1H), 2.87 and 3.54 (AX, 2H, J= 13.9 Hz, NC//2C=CH2), 2.93-3.01 (m, 1H), 3.02 and 4.63 (AX, 2H, J= 12.8 Hz, NC#2C=CH2), 3.23 and 3.84 (AX, 2H, J= 13.3 Hz, CH2Ar), 3.35 (td, 1H, J= 12.2, 3.9 Hz), 3.38 and 3.99 (AX, 2H, J= 13.4 Hz, CH2Ar), 3.44 (td, 1H, J= 12.2, 3.0 Hz), 3.96 (td, 1H, J = 11.7, 4.1 Hz), 4.95 (br s, 1H, C=CHH), 5.01 (br s, 1H, C=CHH), 7.24-7.32 (m, 4H, Ar), 7.56 (d, 1H, J= 8.4 Hz, Ar), 7.57 (d, 1H, J= 8.4 Hz, Ar), 7.63-7.72 (m, 8H, Ar); 13C{1H} NMR (C6D6, 100.53 MHz) 5 28.27 (C13), 51.90, 54.95, 55.61, 56.30, 56.62, 57.31, 57.46, 57.80, 60.11 (CH2Ar), 60.47 (CH2Ar), 61.01 (NCH2OCH2), 61.29 (NCH2C=CH2), 111.72 (C6), 125.67 (2C), 126.14, 126.16, 127.69 (2C), 127.91 (2C), 128.03 (2C), 128.10 (2C), 128.28 (br, 2C), 133.27 (2C), 133.98 (2C), 138.43, 138.71, 133 150.89 (C=CH2) [Note; *H COSY and gHSQC experiments were used for resonance assignments (see the figure below for compound numbering). NMR spectra indicated the presence of silicon grease or mineral oil as a minor impurities.]; 1R (KBr) 3054, 3020, 2981,2947,2918,2896,2793, 1643, 1599, 1507, 1361, 1340, 1242,1107,898,859,812, 759, 476 cm"1; HRFABMS (m/z): (M+H)+found: 519.3469 (error -1.9 mmu/-3.7 ppm); (M+H)+calcd for C35H43N4: 519.3488. Preparation of cw-decahydro-lH,6H-3a,3a,10a-tetraazapyren-2-ylmethanol (104). x i y. 104 A flame dried 100 mL Schlenk flask equipped with a stir bar and N2 inlet was charged with c«-2-methylidenedecahydro-lH,6H-3a,5a,8a,10a-tetraazapyrene (92) (1.1174 g, 4.7682 mmol) and 40 mL dry THF. The solution was cooled to -78 °C and charged with 9-borabicyclo[3.3.1]nonane in THF (30 mL, 0.5 M, 0.015 mol) and stirred at -78 °C for 1.5 h. The reaction mixture was then stirred at room temperature for an additional 3.5 h. To the reaction mixture was added 11.6 mL 95% EtOH, 11.6 mL 3 M aq NaOH and 11.6 mL 30% H2O2. The reaction mixture was then stirred for 1 h at room temperature and saturated with K2CO3. The THF phase was separated and the solvent was removed under aspirator pressure. The residue was then refluxed in 40 mL 2 M aq HC1 for 1 h and continuously extracted with CH2CI2 overnight. The aqueous phase was collected and with cooling in an ice bath, the pH was adjusted to 14 with solid KOH. The resulting solution 134 was extracted with CHCI3 (6 x 100 mL) and the combined CHCI3 layers were dried over anhydrous NaiSO^ filtered and solvent was removed by rotatory evaporation to give 893.5 mg of a crude off-white solid. The crude solid was dissolved in acetone (24 mL) and filtered through a 6 g silica gel plug and the plug was washed with MeOH (30 mL). Solvent was removed from the combined eluates under aspirator pressure to give 585.3 mg (49%) of 104 as a white solid. 'H NMR indicated the major species to be 104, the axial alcohol, and 2% of a minor an tertiary alcohol was observed (product ratio -50/1). The diastereomeric mixture was separated by washing the mixture with anhyd acetone: 500.6 mg was washed with anhyd acetone (3 x 3mL) to give 409.5 mg (34%) of 104 as a white solid: mp 158-162 °C; 'HNMR (CDC13, 500 MHz) 51.19-1.27 (m, 1H, H7eq), 1.68- 1.76 (m, 1H, H2eq), 1.92-3.92 (dynamically broadened m, 18H), 3.04 and 3.12 (AX, 2H, J = 3.1 Hz, N2C//C//N2), 4.00-4.36 (dynamically broadened m, 1H), 4.15 (br s, 1H, OH); 13 C{'H} NMR (CDCI3, 100.53 MHz) 619.80 (C7), 37.80 (C2), 44.83 (dyn br), 47.86 (dyn br), 52.71 (dyn br), 53.88 (dyn br), 54.64 (dyn br, 2C), 56.04 (dyn br), 57.52 (dyn br), 65.95 (HOCH2C), 76.93 (NCHN), 77.16 (NCHN) [Note; gHSQC experiment was used to assign resonances (see the figure above for compound numbering)]; IR (KBr) 3157 (br), 2966,2913,2849,26691465, 1439, 1339, 1303, 1257,1216, 1160,1141, 1101, 1084, 1041, 964, 888, 825, 790, 762 cm"1; HRFABMS (m/z): (M+H)+found: 253.2038 (error +0.9 mmu/+3.7 ppm), (M+H)+ calcd for C3H25N4O, 253.2028. Preparation of 3a,8a-di(phenylmethyl)-2-(hydroxymethyl)decahydro-lH,6H- 5a,10a,diaza,3a,8a-diazoniapyrene dibromide (107). 135 // >\ "M' i ~M' 2 Br" OH 107 Benzyl bromide (1.0868 g, 6.354 mmol) was added in one portion to a solution of cis- decahydro-lH,6H-3a,3a,10a-tetraazapyren-2-y!methanol (104) (0.1134 g, 0.4494 mmol) in 4 mL anhyd CH2CI2 and the reaction mixture was stirred for 17 days. The reaction mixture was then centrifuged and the supernatant decanted. Et20 (4 mL) was added to the solids and the mixture was centrifuged and the supernatant decanted. This was repeated one additional time. Residual solvent was removed under vacuum to give 0.1633 g (61%) of an off-white solid. The solid was then taken up in 1.5 mL MeOH and placed in an Et90 diffusion chamber. A first crop of white solids was collected and residual solvent was removed under to give 85.2 mg (32%) of 107, mp 122-126 °C (decomposition); *H NMR(MeOH-d4, 500 MHz) 6 1.81-1.88 (dm, 1H, J= 15.0 Hz, H7eq), 2.21-2.33 (m, 2H, H2eq and H7ax), 3.02-3.17 (m, 4H), 3.24-3.39 (m, 5H), 3.47 (dd, 1H, J= 13.6, 3.4 Hz), 3.55-3.68 (m, 3H), 3.79 (dd, 1H, J= 10.8, 8.5 Hz), 3.89 (td, 1H, J= 13.2, 3.4 Hz), 4.09 (dd, 1H, J= 13.4, 5.8 Hz), 4.26 (td, 1H, J= 12.8, 3.3 Hz), 4.58 (td, 1H, J= 13.1, 4.0 Hz), 4.90 and 5.41 (AX, 2H, J= 12.9 Hz, CH2Ph), 4.92 and 5.41 (AX, 2H, J= 12.7 Hz, C//2Ph), 5.55 (br s, 1H, NC//N), 5.59 (br s, 1H, NC//N), 7.50-7.71 (m, 10H, Ph); u l C{ U} NMR (MeOH-d4, 125.68 MHz) 5 19.76 (C7), 35.01 (C2), 46.82, 48.24, 48.29, 50.17, 52.40, 53.75, 61.31, 61.56, 62.93, 63.12, 63.24, 78.28 (NCHN), 78.91 (NCHN), 127.07, 127.15, 130.65 (2C), 132.33 (2C), 134.61(2) [Note; gCOSY experiment was used to assign resonances (see the figure above for compound numbering)]; IR (KBr) 3371 136 (br), 3060, 3032, 2950, 2858, 2815, 1622, 1454, 1436, 1357, 1147, 1058, 876, 872 cm'1; Anal. Calcd for CsyHas^OB^LbO): C, 51.44; H, 6.71; N, 8.89; Br, 25.35. Found C, 51.48; H, 6.56; N, 8.94; Br 25.11. Preparation of (4,ll-bis(phenyhnethyl)-l,4,8,ll- tetraazabicyclco[6.6.2]hexadec-6-yl)methanoI dihydrobromide monohydrate (108«2HBr»H2O). 13 14|/\.12 / \ _ ;(.V): /T^\ ^N ^Ni 2HBr ( ) I I (rac) 108«2HBr>H2O To a solution of 3a,8a-di(phenylmethyl)-2-(hydroxymethyl)decahydro-lH,6H- 5a,10a,diaza,3a,8a-diazoniapyrene dibromide (107) (41.5 mg, 0.0698 mmol) in 5 mL 95% EtOH in a 25 mL round bottom flask, NaBH4 (132.6 g, 3.505 mmol) was added in small portions over 10 minutes. An open-vessel microwave reaction was set up in a CEM Discover microwave reactor. The 25 mL flask was equipped with an air condenser topped with a water condenser and a N? inlet. The microwave-enhanced reaction was run with an initial temperature of 50 °C followed by an increase in temperature at 5 °C/min to 70 °C, then 2 °C/min to 78 °C, which was maintained for 14 minutes. The reaction vessel was cooled in an ice bath and the excess NaBFL was decomposed by the dropwise addition of aq 6 M HC1 (2 mL) until the pH was 1. The solvent was then removed under aspirator pressure and the resulting white solid was dissolved in FLO (3 mL). While the solution was cooled in an ice bath, the pH was adjusted to 14 by the slow addition of KOH pellets. 137 The resulting solution was extracted with benzene (5x10 mL), the combined benzene extracts were dried over anhyd Na2S04, filtered, and the solvent was removed under aspirator pressure to give 25.7 mg of an oily residue. To the residue dissolved in EtOH (1 mL) was added 47 wt % aq HBr (13.5 uL, 9.4 mg, 0.1168 mmol of HBr). The mixture was then concentrated down to a white solid (40.4 mg) and recrystallized from EtOH (3 mL) to give a first crop of crystals (27 mg), which upon a second recrystallization from ! EtOH (1 mL) gave 24.4 mg (57%) of 108«2HBr»H2O as a white solid: mp 184-188 °C; H NMR(MeOH-d4, 500 MHz) 5 1.75-1.82 (dm, 1H, J= 16.8, Hi3eq), 2.31-2.43 (m, 1H, Hnax), 2.52-2.62 (m, 1H, H6ax), 2.69-3.11 (m, 10H), 3.12-3.27 (m, 2H), 3.46-3.70 (m, 6 H), 3.93 (td, 1H, J= 13.6, 4.5 Hz), 4.06 (t, 1H, J= 12.3 Hz), 4.23 (td, 1H, J= 12.7, 2.7 Hz), 5.08 and 5.17 (AB, 2H, J= 13.0 Hz, C//2Ph), 5.10 and 5.13 (AB, 2H, J= 13.5 Hz, l3 l CH2Ph), 7.47-7.55 (m, 6H, Ph), 7.63-7.70 (m, 4H, Ph); C{ H} NMR (MeOH-d4, 125.68 MHz) 5 18.79 (Ci3), 31.80 (C6), 44.08, 44.82, 48.99, 49.66, 52.46, 52.54, 52.88, 52.98, 55.53, 57.78, 57.99, 60.76, 61.16, 126.18, 126.21, 128.70 (4C), 129.89 (4C), 132.14, 132.19 [See the figure above for compound numbering]; IR (KBr) 3375 (br), 3130, 2962, 2941,2889, 1398, 1169, 1104, 1063, 871, 695 cm"1; Anal. Calcd for C27H42N4Br2O'l(H2O>0.1(CH3CH2OH): C, 52.60; H, 7.24; N, 9.02; Br, 25.73. Found C, 52.48; H, 7.16; N, 8.91; Br, 25.57. 4,ll-Bis(phenylmethyl)-l,4,8,ll-tetraazabicyclo[6.6.2]hexadecane (SyS)-(+)- dibenzoyl-D-tartrate (119). (5',5)-(+)-Dibenzoyl-D-tartaric acid (117) (0.1073 g, 0.2994 mmol) was added to a solution of 4,1 l-bis(phenylmethyl)-l,4,8,11- tetraazabicyclo[6.6.2]hexadecane (19) (0.1218 g, 0.2994 mmol) in 5 mL absolute ethanol 138 and the reaction mixture was stirred at 75 °C for 5 min, at which time the reaction mixture was homogeneous. The reaction mixture was then stirred at room temperature over night. The solvent was removed under aspirator pressure to give 0.2376 g (quantitative yield) of 119 as a white solid (a 1:1 diastereomeric mixture): mp 79-83 °C. 'H NMR (MeOH-d4, 400 MHz) 6 1.70-1.81 (m, 4H, CH2Ctf2CH2), 2.60-2.67 (m, 2H), 2.74-2.86 (m, 4H), 2.90-3.16 (m, 12H), 3.46-3.57 (m, 2H), 3.80 and 3.86 (AB, 4H, J =13.7 Hz, C//2Ph, br upfield peaks for overlapping AB's of diastereomers), 5.91 (s, 2H, CZ/dibenzoyl tartrate) 7.28-7.38 (m, 10H), 7.44-7.49 (m, 4H), 7.57-7.62 (m~tt, 2H), 13 ] 8.11-8.15 (m,4H); C{ H} NMR(MeOH-d4, 125.681 MHz) 5 24.96 (br), 51.30 (br), 52.82 (br), 54.36 (br), 55.37 and 55.40 (1:1 diastereomers), 58.60 and 58.64 (1:1 diastereomers), 75.21, 129.50, 129.58, 131.06, 131.31, 131.35, 134.35, 167.42, 171.58; IR(KBr) 3423, 3015, 3068, 2929, 2917, 2827, 1710, 1629, 1446, 1262, 1119, 1062, 710 1 cm' , Anal. Calcd for C44H52N4O8'0.5(H2O): C, 68.29; H, 6.90; N, 7.24. Found C, 68.24; H, 6.94; N, 7.28. 4,ll-Bis(phenylmethyI)-l,4,8,ll-tetraazabicyclo[6.6.2]hexadecaneL-(+)- tartrate (diastereomeric mixture) (120). L-(+)-Tartaric acid (118) (15.7 mg, 0.1043 mmol) was added to a solution of 4,11-bis(phenylmethyl)-l,4,8,11- tetraazabicyclo[6.6.2]hexadecane (19) (42.4 mg, 0.1043 mmol) in 2 mL absolute EtOH and the reaction mixture was stirred at room temperature for 1 h. The solvent was then removed under aspirator pressure to give 57.6 mg (99% yield) of 120 as a white solid (a 1:1 diastereomeric mixture): mp 54-58 °C. ' H NMR (MeOH-d4, 500 MHz) 6 1.69-1.84 (m, 4 H), 2.60-2.69 (m, 2H), 2.73-3.18 (m, 16H), 3.47-3.63 (m, 2H), 3.79 and 3.84 (AB, 139 13 4H, .7=13.7 Hz, Ci/2PH), 4.39 (s, 2H), 4.88 (s, 4H), 7.27-7.41 (m, 10H, Ph); C{'H} NMR (MeOH-d,, 125.680 MHz) 5 25.16, 51.50, 52.90, 54.48, 55.47, 58.68, 58.79, 74.12, 128.77, 129.55, 131.24, 137.43, 176.81; IR(KBr) 3416, 3089, 3056, 3031, 2929, 2835, 1724, 1610, 1450, 1348, 1196, 1123, 1078, 1025, 968, 890, 739, 702, 616 cm"1; Anal. Calcd for Cso^N^l.SCHsO^O^CHsCHsOH): C, 61.58; H, 8.19; N, 9.45. Found C, 61.78; H, 7.90; N, 9.44. l,4,8,ll-Tetraazabicyclo[6.6.2]hexadecane di-(lS)-(+)-camphorsulfonate (diastereomeric mixture) (121). (l ! °C. H NMR (Acetone-d6, 500 MHz) 5 0.86 (s, 6H, CH3, camphorsulfonate = CS), 1.14 (s, 6H, CH3, CS), 1.38 (ddd, 2H, J=12.6, 8.7, 3.3 Hz, CS), 1.57 (ddd, 2H, J= 14.2, 9.4, 4.7 Hz, CS), 1.68-1.76 (m, 2H), 1.88 (d, 2H, J= 18.1 Hz, CS), 1.92-2.03 (m, 4H, CS), 2.26-2.34 (m, 2H, CS), 2.32-2.45 (m, 2H), 2.59-2.67 (m, 4H, 2H for CS)), 2.67 (X of AX, 2H, J= 14.7 Hz, CS), 2.71-2.80 (m, 2H), 2.86-2.94 (m, 2H), 3.03-3.11 (m, 2H), 3.14 (A of AX, 2H, J= 14.7 Hz, CS), 3.17-3.25 (m, 2H), 3.26-3.42 (m, 6H), 3.45-3.62 (m, 4H), 13 ] 3.87 (br s, 2H), 8.88 (br s, 2H); C{ H} NMR (Acetone-d6, 125.68 MHz) 6 20.26 (CH3, CS), 20.43 (br), 20.57 (br), 20.64 (CH3, CS), 25.60 (CS), 27.52 (CS), 42.92 (br), 42.97 (br), 43.30 (CS), 43.70 (CS), 47.60, 48.09 (CS), 48.23 (CS), 50.88, 50.94, 56.30, 56.40, 58.46, 58.50, 59.30 (CS), 217.02 (CS); 1R (KBr) 3457, 3410, 3334, 3248, 2957, 2887, 140 2850, 1741, 1487, 1453, 1373, 1224, 1190, 1049, 793, 726, 618, 254, 510 cm"1; Anal. Calcd for C32H58N408S2»1.5(H20): C, 53.53; H, 8.56; N, 7.80. Found C, 53.86; H, 8.57; N, 8.08. Preparation of l,4,8,ll-tetraazabicyclo[6.6.2]hexadecane (5',5)-(+)-dibenzoyl- D-tartrate (diastereomeric mixture) (122). ,4 2 ^Y H A r^ H A ,,-N, -N« n Ph ,,-N. -N n Ph Hs[>rj7 °Y H Q^j Y e O O 122 (1:1 Diastereomeric Mixture) (5',5)-(+)-Dibenzoyl-D-tartaric acid (117) (0.1688g, 0.4711 mmol) was added to a solution of 1,4,8,11 -tetraazabicyclo[6.6.2]hexadecane (10) (0.1067g, 0.4714 mmol) in 3 mL absolute EtOH and the reaction mixture was stirred at room temperature for 1 h. The solvent was then removed under aspirator pressure to give 0.2975 g (quantitative yield) of J 122 as a white solid (a 1:1 diastereomeric mixture): mp 150-153 °C. HNMR (D20, 500 MHz) 6 1.58-1.66 (dm, 4H, H6A3eq,J = 16.8 Hz), 2.15-2.29 (m, 4H, H6ji3ax), 2.40-2.51 (m, 4H), 2.54-2.61 (m, 4H), 2.78-2.87 (m, 8H), 2.95-3.19 (m, 16H), 3.31-3.39 (m, 4H), 3.43 (tt, 4H, J= 13.1, 3.4 Hz), 5.73 (s, 4H, CHdibenzoyl tartrate), 7.55-7.61 (m, 8H), 7.70-7.74 (m, 4H), 8.12-8.15 (m, 8H); "C^H} NMR (D20, 125.680 MHz) 5 18.84, 42.32, 47.76, 49.56, 55.80, 58.21, 75.91, 129.43, 129.53, 130.46, 134.74, 168.46, 173.54; IR(KBr) 3410, 3066,2968,2837, 1712, 1629, 1489, 1452, 1360, 1329, 1261, 1115, 1 1071, 1057, 1026, 726 cm" ; Anal. Calcd for C3oH4oN4Cv0.5(H20>0.5(CH3CH2OH): C, 60.38; H, 7.19; N, 9.08. Found C, 60.22; H, 6.92; N, 9.42. 141 Preparation of l,4,8,ll-tetraazabicyclo[6.6.2]hexadecane L-(+)-tartrate (diastereomeric mixture) (123). 13 'N' tiN' 0H M. N' 0H H%NS °H H'^ OH 6 123 (1:1 Diastereomeric Mixture) L-(+)-Tartaric acid (118) (1.9673 g, 13.108 mmol) was added to a solution of 1,4,8,11- tetraazabicyclo[6.6.2]hexadecane (10) (2.9670 g, 13.108 mmol) in absolute EtOH (50 mL), and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under aspirator pressure and the resulting oil was triturated with EtaO followed by the removal of Et20 by rotary evaporation (4 x 50 mL) to give 4.9383g (quantitative yield) of 123 as a white solid (a 1:1 diastereomeric mixture): mp 48-51 °C. !H NMR (MeOH-d4, 500 MHz) 5 1.57-1.73 (m, 4 H, H6;13eq for each diastereomer), 2.19-2.34 (m, 4H.-H6.i3ax for each diastereomer), 2.45-2.64 (m, 6H), 2.70-3.48 (m, 32H), 3.61 (td, 2H, J = 12.7, 2.7 Hz), 4.44 (s, 4H, tartrate CH), 4.89 (br s, 12H); "C^H} NMR (MeOH-d4, 125.680 MHz) 5 19.96 (CCC for one diastereomer), 20.88 (CCC for one diastereomer), 42.52, 43.17, 48.07, 48.82, 50.55, 50.73, 55.18, 56.66, 59.15, 59.73, 76.25 (CH tartrate), 180.87 [Note; !H gCOSY and gHSQC experiments were used to assign resonances (see the figure above for compound numbering)]; IR (KBr) 3448, 3332, 2934, 2848, 1709, 1610, 1592, 1487, 1452, 1398, 1321, 1225, 1130, 1110, 1073, 1048,917,794,725,704 cm"1; Anal. Calcd for CieHs^N^K^O^.KCHaCHoOCHoCHj^C, 49.01; H, 8.78; N, 13.90. Found C, 48.65; H, 8.80; N, 13.96. 142 Preparation of l,4,8,ll-tetraazabicyclo[6.6.2]hexadecane D-(-)-tartrate (diastereomeric mixture) (125). i4 I2 H i HJ H r,- j H nH 'N' nN' 9 „N:, N: OH H;^; OH H^N AH 6 125 (1:1 Diastereomeric Mixture) D-(-)-Tartaric acid (126) (68.7 mg, 0.458 mmol) was added to a solution of 1,4,8,11- tetraazabicyclo[6.6.2]hexadecane (10) (103.7 mg, 0.4581 mmol) in anhyd MeOH (1 mL), and the reaction mixture was stirred at room temperature for 20 min. The solvent was removed under aspirator pressure to give 172.4 mg (quantitative yield) of 125 as a white solid (a 1:1 diastereomeric mixture): mp 77-80 °C. *H NMR (MeOH-d4, 500 MHz) 5 1.58-1.73 (2 overlapping dm, 4H, J= 16.6 and 16.4 Hz, H6,i3eqfor each diastereomer), 2.18-2.34 (m, 4H, H6,i3ax for each diastereomer), 2.46-2.63 (m, 6H), 2.70-2.79 (m, 2H), 2.82-3.49 (m, 30H), 3.62 (td, 2H, J= 12.7, 3.1 Hz), 4.43 (s, 4H, tartrate CH), 4.94 (br s, U X 10H); C{ U} NMR (MeOH-d4, 125.680 MHz) 6 19.97 (C6,n for one diastereomer), 20.77 (C6,i3 for one diastereomer), 42.53, 43.11, 48.05, 48.50, 50.56, 50.71, 55.34, 56.61, 59.12, 59.60, 76.19 (CH tartrate), 180.71 [see the figure above for compound numbering]; IR (KBr) 3408 (br), 2966, 2836, 2799, 2362, 2337, 1598, 1479, 1369, 1340, 1 1112, 1055, 732, 618 cm" ; Anal. Calcd for Ci6H32N4(V1.2(H2O>0.2(CH3OH): C, 48.10; H, 8.77; N, 13.85. Found C, 48.34; H, 8.94; N, 13.48. 143 VI. Fractional Crystallization of 123 (1:1 diastereomeric salt mixture). Fractional crystallization of 4.9040 g of 123 (1:1 diastereomeric salt) was carried out using absolute EtOH as solvent. Relevant details for each crystallization are listed in Figure 35. General procedure: the diastereomeric salt was dissolved in hot EtOH and the homogenous solution was allowed to cool to room temperature in a capped flask. The crystallization was then allowed to occur slowly at either 6 °C or -15 °C for a recorded period of time. (The temperature and time for each crystallization are indicated in Figure 35). After the recorded time period, the crystals were separated from the mother liquors by decantation, and washed with cold absolute EtOH. This wash was then added to the mother liquors. The mother liquors were then concentrated under aspirator pressure, followed by the removal of residual solvent under vacuum to give sticky solids. *H NMR spectra of both the crystals and concentrated mother liquor samples indicated the presence of EtOH from the crystallizations. To aid in the removal of excess EtOH, samples were dissolved in MeOH (amounts listed in Figure 35) and concentrated down under aspirator pressure. Each sample was then placed under vacuum at 40 °C (using a mineral oil bath) for 10-30 minutes, then at room temperature overnight. The samples were massed and their !H NMR spectra (MeOH-d4) were recorded. The diastereomeric ratios were determined as discussed in Chapter 3, by integration of the td at 3.61 ppm and the two dm resonances at 1.57-1.73 ppm. Indicated in each box of Figure 35 is: the amount (grams) of diastereomeric salt used in the crystallization, the measured diastereomeric ratio (dr), the volume (mL) of absolute EtOH used for the crystallization, the crystallization temperature (6 °C or -15 °C) and the time period (days, d) over which the crystallization occurred. 144 As described above, the crystals were separated from the mother liquor, and washed with cold absolute EtOH (amounts listed in the flowchart). This information is followed by the amount of MeOH used to aid in the removal of excess EtOH from the samples (the same volume of MeOH was used for the crystals and the concentrated mother liquor samples). The percent recovery for each crystallization is also listed below. For the resolution of 4.9040 g of a 1:1 diastereomeric mixture of 123 a maximum yield of the selectively crystallized diastereomer should be 50% of the initial mass (2.4520 g). After completion of the experiment 1.7988 g of diastereomerically pure (dr > 500 by 'H NMR; no minor diastereomer detected) 123 was collected (37 % combined recovery; 73% of theory) and indicated by the bold boxes of Figure 35. 145 123 (1:1 Diastereomenc Mixture) 4.9040 g, dr 1 Dissolved in 70 mL absolute EtOH, -15 °C, 6 d Crystals were washed with 2x10 mL cold absolute EtOH 2x50 mL of MeOH used to aid in removal of EtOH Crystals Mother liquor 1.4734 g (30%), dr>200 3.3749 g (69%), dr 2.7 Dissolved in 16 mL absolute EtOH, 6 °C, 1 d Dissolved in 35 mL absolute EtOH, 6 °C, 7 d Crystals were washed with 2x8 mL cold absolute EtOH Crystals were washed with 2x10 mL cold absolute EtOH 2 x 20 mL of MeOH used to aid in removal of EtOH 2 x 20 mL of MeOH used to aid in removal of EtOH x Crystals Mother Liquor Crystals Mother liquor 1.0170 g (69%), dr>500 0.4895 g (33%), dr 69 4 0.4096 g (12%), dr 31.8 2.9431 g(87%), dr4.5 Dissolved in 5 mL absolute EtOH, 6 °C, 7 d Dissolved in 25 mL absolute EtOH, 6 °C, 3 d, no crystallization occurred, then -15 °C, 14 d Crystals were washed with 2x10 mL cold absolute EtOH 2x10 mL of MeOH used to aid in removal of EtOH Crystals were washed with 3x3 mL cold absolute EtOH 2 x 20 mL of MeOH used to aid in removal of EtOH Crystals Mother Liquor Crystals Mother Liquor 0.2488 g (51%), dr>500 0.231 lg (47%), dr 14.6 0.1344g(5%),dr22.7 2.8000 g (95%), dr 7.0 Combined Dissolved in 5 mL absolute EtOH, 6 °C, 7 d Crystals were washed with 3x3 mL cold absolute EtOH 2x5 mL of MeOH used to aid in removal of EtOH Crystals Mother Liquor 0 3118 g (49%), dr>500 0.3298 g (51%), dr 12.5 Dissolved in 3 mL absolute EtOH, 6 °C, 3 d Crystals were washed with 3x2 mL cold absolute EtOH 3x10 mL of MeOH used to aid in removal of EtOH Crystals Mother Liquor 0.2212 g (67%), dr>500 0.1112 g (33%), dr 3.5 Figure 35: Fractional crystallization of 123 (1:1 diastereomeric salt mixture). VII. Recovery of enantiopure free base (.SySVlO and the preparation of (S,S)-4dl- bis-(carbo-fert-butoxvmethvl)-l,,4,,8,ll-tetraazabicvclo[6.6.21hexadecane (133). Enantiopure free base (S.^-IO was recovered from diastereomerically pure 123 obtained from the fractional crystallization of a 1:1 diastereomeric mixture of 123 (Scheme 68). Diastereomerically pure 123 (1.0213 g, 2.7123 mmol) was dissolved in 5 mL H2O and the solution was basified to pH 14 using solid KOH. The basic solution was then extracted with benzene (4x15 mL), the combined benzene extracts were dried over anhydrous NaaSO^ filtered and concentrated under aspirator pressure. The resulting viscous oil was placed under vacuum overnight to give 0.5768 g (94%) of enantiopure (S,S)-10 as an off-white solid. The 'H NMR was consistent with that of authentic material.43 c::ftH rji^- ^ cNiHN) ,,,1^ ';N OH CSHS NH''N H ^J (940/0) L^J Diastereomerically pure 123 Enantiopure (S,S)-ld Scheme 68: Recovery of enantiopure (S,S)-10. The preparation of (5',5)-4,ll-bis-(carbo-te/*f-butoxymethyl)-l,4,8,ll- tetraazabicyclo[6.6.2]hexadecane (133) (Scheme 69).60 I I I 1 o I I Jo ' * o I I Jo SH'-N^ MeCN,Na2C03 >l XjN '"N^ U,JON "N^ f J rt, 4 d L j * ^1 j Enantiopure (S,S)-10 133 Enantiopure BFC: H2-CB-TE2A 20 Scheme 69: Preparation of enantiopure 133. 147 Anhydrous sodium carbonate (350.0 mg, 3.3022 mmol) and ^-butyl bromoacetate (303.8 mg, 1.5577 mmol) was added to a solution of enantiopure (5,5)-1,4,8,11- tetraazabicyclo[6.6.2]hexadecane (10) (1171.1 mg, 0.5173 mmol) in anhydrous MeCN (4 mL).60 The reaction mixture was stirred at room temperature for 4 days, after which the mixture was filtered through Celite®. The filtrate was concentrated under aspirator pressure to give a viscous yellow oil. The oil was dissolved in cold 20 % aqueous NaOH (3 mL) and extracted with cold toluene (4x10 mL), the combined toluene extracts were dried over anhydrous NaiSO^ filtered and concentrated under aspirator pressure. Residual solvent was then removed under vacuum to give 286.1 mg of a viscous yellow oil. The !H NMR of this crude material indicated the presence of the desired 133 as well as several other signals corresponding to minor impurities. It was thought that these could be excess alkylating agent and a small amount of protonated 133. In order to remove these impurities the oil was dissolved in cold H2O (4 mL) and extracted with cold toluene (4x10 mL). The aqueous layer was then basified with cooling to pH 14 using KOH pellets and this solution was extracted with toluene (5x10 mL), the combined extracts were dried over anhydrous Na?S04, filtered and concentrated under aspirator pressure. The material recovered from this base extraction (20.1 mg, 0.0442 mmol, 8.5 %) was consistent with the desired material by 'H NMR, with no evidence of any impurities. Since this yield was extremely low, the toluene extracts recovered from the previous neutral extraction were then concentrated under aspirator pressure to give a yellow oil (230.4 mg). This was dissolved in H?0 (4 mL), this solution was acidified to pH 1 with 6 M HC1 with cooling, and extracted with toluene (3x5 mL). The acidic aqueous solution was then basified to pH 14 with solid KOH and extracted with toluene (4x10 mL). The 148 combined toluene extracts from the base extraction were dried over anhydrous NaoSO^ filtered and concentrated under aspirator pressure to give a yellow oil (160.0 mg). The 'H NMR of this material was consistent with the desired product, however there were still several minor impurities visible in the [H NMR spectrum. A final acid/base extraction was done by dissolving the material in H2O (2 mL), acidifying to pH 1 with 1 M HC1 with cooling, and extracting with toluene (4x15 mL). The acidic solution was then basified to pH 14 with solid KOH. This basic solution was extracted with toluene (4x15 mL) and the combined extracts were dried over anhydrous Na2S04, filtered and concentrated under aspirator pressure to give a yellow oil (80.4 mg, 0.1768 mmol, 34%). The 'H NMR of this material indicated the major species to be consistent with the desired material, however there were still several minor signals that corresponded to an impurity. Alternative purification must be considered to recover more pure product from this reaction, probably column chromatography. The difficulty in purifying this material could be due to the fact that 3 equivalents of /'-butyl bromoacetate were used for the alkylation reaction. To avoid difficulty in purification a smaller amount of alkylating agent should be considered (2 equivalents).60 The deprotection of enantiopure 133 with 6263 TFA will generate an enantiopure BFC, H2-CB-TE2A 20. 149 VIII. Optical rotation of CS.SVcross-bridged cyclam (10). The optical rotation of resolved enantiopure (S,S)-10 was determined using an Rudolph Autopol III Automatic Polarimeter (angle encoding accuracy ± 0.002°), at the sodium (589 nm) wavelength. The optical rotation was measured in toluene, which was first dried over activated 3 A molecular sieves (from EM Science). The anhydrous toluene was then freeze-pump-thawed using nitrogen three times to remove CO2. Enantiopure (S,S)-10 (576.8 mg, 0.2548 mmol) was dissolved in anhydrous toluene (5 mL) in a 5 mL volumetric flask. The optical rotation was measured in a 10.00 mm QS optical cell from Fischer Scientific. The temperature of the polarimeter chamber was determined to be 24 ± 1 °C using a VWR Thermo-Hygro electronic thermometer placed within the polarimeter chamber. Ten measurements were taken for the toluene blank and for the optically active sample (Table 11). The average of these was calculated along with the 95 % confidence interval obtained using Equations 7 and 8. The mean optical rotation of the blank measurement was calculated to be 0:001° and the mean optical rotation of the optical active sample was calculated to be 0.461 ± 0.004° (95% confidence), (optical rotation - blank = 0.462° - 0.001°). Xj -Xj Zi -1 N-l (Equation 7) S = standard deviation N = number of measurements, (N = 10) X=mean v+ tS (Equation 8) t = student t value, (at 95 % t = 2.262) [x = confidence interval (95 %) 150 Table 11: Optical rotation measurements. Toluene blank Enantiopure (.S^-IO in toluene 1 0.002 1 0.450 2 0.002 2 0.457 3 0.002 3 0.461 4 0.002 4 0.464 5 0.002 5 0.464 6 -0.001 6 0.469 7 0.002 7 0.464 8 0.002 8 0.465 9 0.000 9 0.465 10 0.000 10 0.465 Mean 0.001 Mean 0.462 Standard Deviation 0.001 Standard Deviation 0.005 95% Confidence limit 0.001 95% Confidence limit 0.004 The specific rotation of (S^-IO was then determined to be + 40.0 ± 0.3, using Equation 9. °c a (Equation 9) [«r- l(dm)*c(g/ml) where: a = recorded optical rotation A, = wavelength (sodium D-line (589 nm) ° C = temperature / = length of the optical cell c = sample concentration 151 IX. Kinetics of racemization of cross-bridged cyclam (10). Kinetics experiments were conducted using toluene as solvent. Toluene was first dried over activated 3 A molecular sieves (obtained from EM Science), then freeze- pump-thawed three times using nitrogen to remove any CO2. Run 1: A solution of enantiopure (S,S)-10 (67.1 mg, 0.2964 mmol) in anhydrous toluene (8 mL) was prepared and transferred to a 15 mL, 150 psi pressure tube (part no. 8684) with a back seal polytetrafluoroethylene (PTFE) plug (part no. 5845) obtained from Ace Glass. The tube was partially submerged into a Cole-Parmer Polystat constant temperature water bath with all of the solution in the tube below the level of the water. The temperature of the bath was measured to be 82 ± 1 °C using a calibrated thermometer. The temperature was recorded prior to and after each data point. Small aliquots (~ 0.5 mL) were collected at recorded time intervals after first cooling the pressure tube in an ice-water bath for 20-30 minutes, then allowing it to reach ambient temperature. Each aliquot was concentrated under aspirator pressure without heating and residual solvent was further removed under vacuum. The material was then massed, reacted with one equivalent of L-(+)-tartaric acid (118) in absolute EtOH, and stirred at room temperature for 2 hour, after which time the reaction mixture was concentrated under aspirator pressure. Residual solvent was removed under vacuum. 'H NMR spectra were obtained using MeOH-d4 as solvent. Each acquired NMR FID was Fourier transformed, phased, integrated and baseline corrected ten separate times. The td integrals at 3.61 ppm and the two dm integrals at 1.57-1.73 ppm were recorded and used to determine the enantiomeric excess (ee) as described in Chapter 3 (Table 12). The mean ee was calculated for each data point and a 95 % confidence 152 interval was obtained using Equations 7 and 8 above. Table 12: Percent enantiomeric excess (%ee) as a function of time at 82 ± 1 °C (kinetics run no. 1). Time (hours) %ee 95% Confidence limits 0.00 100.00 0.00 111.33 76.60 1.19 162.13 76.14 0.94 267.30 57.51 2.68 363.27 53.96 2.16 467.80 44.21 2.16 576.18 47.43 0.25 675.90 38.32 2.17 896.12 31.83 1.56 A linear plot of In ee (fractional) vs. time (Graph 1) was obtained where the rate constant of racemization krac was determined by the slope, and the error propagation for the slope was done using the linear least-squares fit. The uncertainty in In ee, (oee), was determined using a weighted least-squares analysis (oee~= \i~lee~)~~ where \i = 95% confidence limits (Equation 8). These data are shown in Table 13. Table 13: Uncertainty in In (ee). Time (hours) In ee (fractional) aee = u, lee 0.00 0.0000 0.0000 111.33 -0.2665 0.0156 162.13 -0.2726 0.0123 267.30 -0.5533 0.0466 363.27 -0.6169 0.0297 467.80 -0.8162 0.0489 576.18 -0.7460 0.0053 675.90 -0.9593 0.0567 896.12 -1.1382 0.0372 Run 2: A second run of the kinetics experiment was repeated under the same conditions as described above. A solution of 10 (97.7% ee) (65.0 mg, 0.2872 mmol) in anhydrous toluene (5 mL) was prepared and transferred to the pressure tube. The kinetic 153 experiment was done at 82 ± 1 °C and the collected data are shown in Table 14. All data and error analysis were done as described for the first run. Table 14: Collective data for kinetics run no. 2. Time (hours) %ee 95% Confidence limits In ee (fractional) 2 2/ oee = \x le 0.00 97.70 1.63 -0.0232 0.0167 234.52 66.65 0.72 -0.4058 0.0108 377.32 52.55 0.43 -0.6434 0.0083 809.87 30.31 0.48 -1.1936 0.0160 880.85 22.90 1.36 -1.4739 0.0594 1145.52 10.99 1.10 -2.2085 0.1002 1291.78 8.43 2.74 -2.4736 0.3255 1849.51 8.88 0.77 -2.4218 0.0871 Run 3: A third kinetics run was conducted under the same conditions as described above. A solution of 10 (91.8% ee) (226.3 mg, 0.9997 mmol) in anhydrous toluene (5 niL) was prepared and transferred to a pressure tube as describe above. However this time the pressure tube was equipped with a front seal PTFE plug (part no. 5844). The same procedures were followed and the collected data are shown in Table 15. This kinetics run was terminated after collecting only five data points as some water from the water bath was present in the bottom of the pressure tube and the toluene solution was cloudy. The *H NMR spectrum of the pressure tube contents confirmed the presence of water. It is possible that the front seal plug did not seal the pressure tube properly. Any water in the toluene solution would lead to the inside protonation of 10, which would prevent the desire enantiomerization from occurring. All data and error analysis were done as described for kinetics run no. 1. 154 Table 15: Collective data for kinetics run no. 3. 2 2 2 Time (hours) %ee 95% Confidence limits In ee (fractional) aee = \i /ee 0.00 91.80 1.68 -0.0856 0.0183 66.67 77.85 0.77 -0.2504 0.0099 154.08 71.26 1.72 -0.3389 0.0241 243.93 75.73 0.86 -0.2780 0.0114 349.95 50.62 0.46 -0.6808 0.0092 The results for all three kinetics runs are summarized in Table 16. Linear plots of In ee vs. time were obtained for each experiment. The rate constants for the racemizations krac were obtained from the slopes and the half-lives were determined by ti/2 = ln2/krac. The energy barrier (AG+) for the racemization of 10 was determined using Equation 5. Table 16: Results from the three kinetics runs. 1 Run k (s ) t1/2 (hours) AG^ss.is (kcal/mol) 1 3.70 ± 0.40 xlO"7 520 ±62 31.43 ±0.07 2 4.14 ± 0.53 xlO"7 466 ±69 31.29 ±0.10 3 3.90 ± 1.14 x 10"' 493 ± 203 31.33 ± 0.24 155 APPENDIX A SPECTRAL INDEX 156 a. o o n in i m o x—z +z— (D in o }". • o in n m in o |_ - g 157 o LZZ'ti — 8S6-9f 86f« — O E0f8* — 9I9-8f 0£8'8S Eto'ec 9S3-6? 69*"6* 589-6t o 96E'0S— EOfTS 90J-5S - / Off09- *18-T9 — - i!6 I9 o JtfJ9 - 00 SOZ'LL- 6E£-8£ -- o o O ZZi'fZZ - 9SS-SST— OTO'OEI 986'OET O 158 159 & O j o in ^ o c -—, « u in m ^ o m o in in in [H 160 8. a. o BfL'XS- 889-£9 STS'SS O 6E9'SS- in 9LCT9S EE8-9S LZZ'LS- »69-8S r vo i- 8E8-8S 9S6-89 SC8-6S- o r » o o o t*6-STI— I9S'9It o J i- CN LZ8-LZ1- 0E6-LZ1 8T0"8ZT 9Z1-SZ1- o TTJ-8JT ITE"8ZT S9Z-1ET- £t9-i£T- 161 33ue:n!wsueji% 162 100 - • : /I A ft \ ^ii II il ' 7 ! |i | ! " • ,; | ON anc e n c 3 C ! E ! CO N HN |j I C r ^ J-CUCI2 ; 3~- NH N \ / v • ' CuCl2»9 f KB i \ 1 ^—i P—_.-i 1—— ,—»•,.....•».•,.. _—» 1 1—-H 1 -H -"--• 1 - t t i >--—-H> i t —-H H t— 1i — —-— —(. t •••• i 4000 3500 3000 2500 2000 1500 1000 500 Wavenumbers (cm-1) a3uejjiuisueji% 164 0H rGcY HO 58 MeCN-d3 CD2HCN central peak set at 1.94 'Wul".. " r_ 12 11 10 ppm 1.00 23.38 5.98 -0.00 2.07 0.97 1.02 I TE8' 0 04 £16'•o - 966'•o - 180' I T9T' 1 - iZE'' I Z6P' I 899'' I - ?££ •I- SI8 •T- o Z*6 •oz 61.5 •8t S£0 •OS 01*''0 9 o *9I •zs TiE '£S 198 •ES 691 '99 OOi •99 o *iE 99 *69 •is 813 •89 16E '89 o 00 I t o o 888-911- 88I'8IT- o E»E-8II-- CO CO o Z99-09I?i -fg 8W09T- •'/ »H'T9T — O H LL&'QLX - r o o CO O Q I- O U 166 o o •tn a o o o ' O m «• o *-. £ *** ot4 0 *• ««• L * a p- s£ Q 3 1 0 C 3 *fn; > 0 *• * Q 4-B i D o a - -4 ••»- -r , . -{ . -, ••» -r- "+ • ».^—'?« s- —4" ^* "*" ""* '~l—*" —^ ~~_,—j _ D8 OS a/. OS DS Df oe 167 o o o o o in 168 I o to o ZOZ'St — 8Z8-S*— 1 o in 660"CS— 6L9'fS- 98i-»S--', 68f9S— o 869'6S— J ££9-T9-- E08'9i EI9-ti O CO o en fs Q Q-&- ON ^ o u o O 0t8-tKT- 6Z6-LZX TCQ-8gT- 8£T-8ZI- 3Z3-8JT- TZ£-8JT o WfOH 169 170 .GiiCXJ 2Br 98 D20 MeCN central peak set at 2.06 111 '» »Vi WW*, «J fitjiu 5 4 3 2 ppm JL l J J i.ri 41^ ', - ^H r ' -,- •"- r -' - 2.99.94 4.71 1.00 5.09 0.99 0.92 1.00 0.93 1.02 2.04 4.14 3.05 1.02 0.99 o o ?S9-9? - 9tf« -^_^_ Lif Lt- J/ 18? "i»—' j in UfTS — EZO"iS EIT'19 - "-I I 66fZ9 •-—- 9II-E9- I [ S»fS9—y 8Tf9i- 089'ti O t-- CO o en O o I- 018"TIT u »SI"SST- -\ - t- o 6?S SZT—, \ r-« 90T-63T - \ 3JI-0EI- \ ^ TEC'OET — S60'JET- 1 EJ3"JET - ————— E98-EET ^7 ti8-££I— 172 33UeffllUSUBJJ.% 173 in -^ in o in in in in «3 174 o iZS' IS — 898' ?s - 9Sf ss - I- O JOE' 9S- "1 E8S''9 S — 067*'G — ~ (.95 "tS -— - OEZ.""i.b~ — — - i98 •69 — =— \- ° 9*Z- 09 - EZ6' 09 - 093' 19 - o o 00 o o o 009'TIT 886°9ZI EOO'iZI ZZ8-LIT SJ6'iZT ST0"8Zt 6II-8ZT O iOZ-8Zt £0E'8ZT 80?'8ZT O 68f8ZI *T9-8ZT 9fS-8ZT 98T'6ZT O SS£-6ZT T6f6ZI 0*8- OH — SH'Ifl — o in 175 #- a *=~ •>-<»__ ^".'."••l «=i. i 8 o m a m ~x J^- ?=• ^4^ 1 > a ,-, r>4 E s- CD ;;;;;;;< ^ >=sg-; '—Z Z—' 7) tevenumt O 8 8 CO ^ i —3 I [t. 3 C 3 C3 C3 c3 C3 C3 O -» 8 S 3 f 3 5 3 r i § 3 *» P aouej}iaisueJi% 176 ^N^IsT 2Br 100 MeOH-cL -J -J t. A ' i " 8 6 5 4 3 2 ppm 1.96 2.02 2.00 0.97 2.00 0.93 10.38 1.01 1.01 4.20 13.16 1.04 1.00 2.11.97 4.11 1.00 0.941.98 1.04 1.03 1.07 2.33 4.21 2.48 000-0 - 8T8 0 0< 9£8-6T -. i80'if— " TZ6'« — £96 'Li OS2'8t — 60* '8* —. TZ9-8*- - O S69-8*— efi-8t — S9i-8t—* 6E8-8»- £68'8* f © 996-8t— £86'8? - - TS0 6? - o 0ZX-6f- 0T3'6* - C9J-6* - o *9£-6* 9i»-6» 0SS'6P o 889-6? E9f6f OOfZS 88i"LS o *89-I9 0*9-Z9 T£Z-£9 6*Z"99 o 03 9S9'ti EW8t — O ST6-£3T— fLO'iZT- 0ZE-8ZT-- - o SSE 8ZT — o 888-8ZT EEZ-631 - L6Z-6Z1— 66S-6ZT - 899-63t - ZiO'OET- HI-OET- 90»*0EI — S9S-0EI - ° iWTET— r w TSi'feT— o ozs-tet = {•9E-9ET— 8EfS£T — *ES-SEI o 6Z9-SET— 178 aouen!UJSueJi% 179 101 00 C6D6 o if. I, '.hi it i i, !« Ill) I ppm .50 4.36 1.00 1.01 0.97 0.92 1.01 0.96 1.03 2.8 -0.00 1.98 1.71 1.00 1.98 0.971.97 1.98 0.95 7.26 S9Z-SI I O 868TS- EI9-SS- S0E-9S- o IT) SZ9'9S TlfiS- S9*'(.S- fOB'LS 1 I- O 0II-09- 69f09- iOO-T9 68Z'T9- o 00 © Q ^ u o at o o OZi'TTI TI9-SJT- 8ET93T O 8ST9H- S69-i5I \6f LZ1- E86'£ST- *ECT8JT- S0T'8ZT SiT-8Zt- 8£3-8ZI- O 89Z-E£I 6i6-EEI- I£*-8EX- ZTt'8EI- O 688'OSI- in 181 00 2500 2000 Wavenumbers (cm-1) I ft o o3 I ±+ o "* III So o o in o in 183 o o PI o ) 7 o X in o o o o T/LL-9L 6Zf9L Z60-LL- 6SZ-LL O 60V LL 00 184 33uen!iusueji% 185 I 3 "s - CM O ^—•z. +-Z.—J •°S§ 186 EICTSE — TZ8-9* u o CO £»Z"8* 66Z-8S 6ZS'8* 001'8? o T18-8S ZW6* Z8E;6? :nr> o in S18-6* 19fOS 66£-JS ZSl'Eg S63-T9 J99-T9- 6Z6'Z9- 60f£9 -• 8£Z-E9 - SBZ-BL-- 906-81 — ~ O 00 o o X o o 2° o 190-1ZT-- LiX- LZX- o 0S9-0EI--— TEE'ZET- 3 £T9"*ET 1] 187 188 a. O CQ -o X o So 189 B 0, i08'TE— ft *£0-** •- *38'**- ST8-9*— S86-9* - o LZO-Lf- SEO-;.*- £*0"£* -. Z80-£* — 060-£*— o 901"i* > 9SI-t»-- 861'Li— »i!'i»—' o 333'Li— in 0£3-£* — 8E3-£*— 9*3"£* — *S3-i*-' o 69J-Li -• S8ZMLi -• 9ZZ' Li — 9i£- Li — *8E-i*— 36E'£* -' 00* •£»-•' 80*•Li - iZi'Li — Stt'If - o SS»'i»- - 00 L6i'Li — 019"it— 899mLi—' 08ft* - o iE8- £*-- O 3S6-Li- 686'8*— 099-6*- ' X o S9*-3S— o i*9'39— III o [I ]| go 9t8-3Slit il 386-3S-JJ 3£S-9S-ji5, , ., |HI SLL i.5 T+p 2 166'iS-f' »9£"09-t-' 8SI-T9—! 993'33I— o E8T-93T— SI3-93I - t0i-83I—,' *68-63T— t*T-3£t 06I-3ET—^ j t 190 § o § 8 «2 .8 - \ O I | 1 ip*! f S .. ! ) y ? ? 1 s\ -* / o S ffl Wave r A /" i—i— i B \ / / 00 * (N :: wl 5 :: f\^•^ I . g 1 .R in -*— iK"-"*. #^ 1j c D C 3 C3 C3 C "3- t 0 (J3 U? s 2 F3 S* ^ 331jeniuis u 191 r cs L o ho o=< o 3 O o H o=( o -:^ 192 04 JE9 •a* 001 '8? 898 •8f E*0 •6f ITS 6* 9ZE •6i o 6£E m6\ •w •w sss •6f 96Z-TS- o *o *Z8-Z9- 6SE-?S -/ fiE'SS-/ SOfSS— S09-8S -•' # : o 00 LOZ'SL o o SS8-8JI— O - f0S 62I- N I8S-65T 390'TEI — HE'TET—' ESE-IEI— o SSE'SET -' o vo IJ?-£9T Z8S-TLZ o oo o o cs * h- 193 33uen!iusueji% 194 o o oi o CVJ o o o X "O o o CVJ o * + z Z +1 CD 195 eoo-o 8(W 81 — 8LB'B* - OSO'6?— 8TZ'6» ZEE-6S- 06£-6*— *0S•6* - T9S-6* - 9L9'6f -^ ~SKTJS 6EZ-TET- 196 . ' 1 0 ft V J V ! \ l ^ 1 if \ I 1 J^ A I 1 f w1 1 f Bn _ N^f OH co + .^\ OH c CAO -o2c^- =- u 1.0 -o2c^- °2- ^pY OH R>-.,^ 6H ^ ^ s> ,_ 120 KBr i~— >•' •••••» 4 1 h~—H |___H >•"—— 1 1 Ht ••••< - •< _—_h - -'"* • « 1 \ —..—.. H——-( h—-1 h—— -—-H >—' > —"- K-—4—- ( 4000 3500 3000 2500 2000 1500 1000 500 Wavenumbers (crrt-1) a, -_ Ol O > h A-A o < > r- » I- 198 a. o CM I S»S'•6 J 569 '6J X6f 61 o CM 058 65 9»fi •fi?; SOO OC ZOI 0€ o 9SI OC o to o o o o CM o o to o 00 o o CM 199 04 £ 33UejJ!UJSUEJi% 200 o o H Oft M PhA0 ,N: N: Ph-^o Ph CAO tvcV^'+ CAN' ON' •o.c'V 9 002" C> Ph ..-N. ,N T o o 122 D20 MeCN central peak set at 2.06 O fe.4jL.i_iAj_.__J ppm V V V 7.52 7.82 7.96 7.95 3.99 10.18 1.74 3.85 8 16.03 3.98 3.95 4.00 N:H O^M PhAn > Ph^o Ph ! N: N: 9 co CVJ -0,0V°" * (SVJ t^V 2 H%J V H%J Y" o o 122 D20 » H 4 • in *wtii*iii#^ r-\ ~T ^! T 7- n - n-p-'-rn T |-I -I n -\ rn -•-, rnjTn^T 200 180 160 140 120 100 80 60 40 20 0 ppm ujjflk* 5 a 3 C -z +z'—^/ -J \—/ x + OH - 12 3 o u H x s x >"° o-< oC M o \ / \ ^z +z^ 204 - a J96-61- 8i8"0Z- *Z9-J5—, 991"£5 Y S90-8» - . \ STS"8t- 0 W SS8''8 » — V'' L_ O LZO •6i — ., \ 66V '65 — 19C65 6£S"65 tts-os-y o »E1'0S--',; BLfSS—i',' 099- 9S - -'/ ESI-6S-' O CO ' CVJ 9W6S- o ZSJ-9Z.- •o X O O •!o• o o € - >) TI- o O O X X o o o o o I- \ / \ t 518"081 00 o o 205 4000 2500 2000 1500 Wavenumbers (cm-11 ft. o o -Z + Z- I- o -z +z'-/ -f ^—/ x IS ffi 1 m + 'c\i O 2o 207 S96-6T 69fOJ—, 90T-E*- **0-8*- 00S-8* 0T0-6? I8T-6*— TSE-65 9TfOS- '/, 809'9S—•/ TJT-6S-,' I9-6S- -' O 88T-9£ o o O O—( o o ^2 +-Z.—I 208 o c: *=: N^---" 1 p-R l^TiSii s a 6 °. T ... i s * o H £ p £2 3 x) ft 2 +2 / £ + c* CQ (N k> ... O (J CM O O I S x)- ^—z +z ZJ Z """1 - 8 en D ^r c3 S3 C3 £3 C 1 f 2 c3 C2 F 33U6JJIU 209 APPENDIX B COMPOUND INDEX 210 COMPOUND INDEX Compound Structure Experimental Spectra 23 HpN^^^NH, 116 49 rN+N^ in H H H 13 III 118 CD Bn 17 C \ D 119 N N Bn r\Bn 18 f \ ^ 12° N N Bn'\ 211 n,Bn 19 (YD 121 54 121 157 55 CO 123 160 ^ N N ^^\ / N HN CuCl2«9 (^ |^ J-CuCI2 124 163 NH N 1^1 N HN cio - [Cu(C104)'9](C104) |^ ^ J -Cu(CIO) 4 124 164 NH N 4 OcYOH 58 r 125 165 9 L I J ° -3.7TFA .Cic^ •Cu+2 Cu'58 o o 126 167 II CV OV. > 2H20 0^N--'\ / 1.2NaCIO„ 212 92 127 168 i3r~w 98 TO r 128 171 2Br 99 129 174 100 \-/^^N^^TN ^ 131 177 2Bf 101 132 180 Pi 104 134 183 OH Njin ^ 107 ^X0 135 186 \=/^ Is^J 2 Br- OH 213 20 .N <~V/ < x\-_-. 2HBr 13? OH N Ph Bn r S > ° N-^- A 138 V^ y Bn I^TJ O Ph o ^-^ Y o QH Bn rv^ > 4- OH Bn 1J;| CH'J OH Hn>N ;N^ ^ ; \^ Bn iH'J OH 140 f^l H A ^\ ° H ,N' N' Ph^-o f -It] H II >;. V ^V** + £ | +^ i s co, ldl H 2C CH'J 0_Ph H,N "V ° VI HI r^iH ,N' N' OH " -K, N' QH HW 6H HLf'^J"02< OH 142 \^ H H' I OH C^IH N N: OH i .n, H H 2 TH-J OH :N 'N^ i 143 \^ H Q^ OH 214 (S,S)-10 N.^HN 145 NH''N 133 o r"»OCY] i o Y 145 215 REFERENCES Bosnich, B.; Poon, C. K.; Tobe, M. L., Inorg. Chem. 1965, 4 (8), 1102-1108. Hancock, R. D.; Darling, E. A.; Hodgson, R. H.; Ganesh, K., Inorg. Chim. Acta 1984, 90 (3), 83-84. Kimura, E., Tetrahedron 1992, 48 (30), 6175-6217. Kaden, T. A., Top. Curr. Chem. 1984,121 (Host Guest Complex Chem. 3), 157- 179. Kaden, T. A., Crown Compounds. Wiley-VCH: New York, 1992. Wainwright, K. P., Coord. Chem. Rev. 1997,166, 35-90. Beletskaya, I. P.; Artamkina, G. A.; Ivushkin, V. A.; Guilard, R., Tetrahedron Lett. 2000,47(3), 313-316. Davies, P. J.; Taylor, M. R.; Wainwright, K. R., Chem. Commun. 1998, (7), 827- 828. Tripier, R.; Lagrange, J.-M.; Espinosa, E.; Denat, F.; Guilard, R., Chem. Commun. 2001, (24), 2728-2729. Mishra, A. 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