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(6H, brs, OMe); d C (100 MHz, DMSO-d 6 ) 169.3, 155.7, 155.0, 133.0, 120.8, 114.3, 97.0, 77.2, 55.6; m/z 487.0 (40, MH – ), 337.8 (100%); HRMS: MH – , found 487.1588. C 21 H 24 N 6 O 8 requires 487.1583. 4.2. 2,2'-[(4R,5R)- 1,4-dioxaspiro-[4.5]-decane-2,3-dicarbonyl)- bis-(N-(4-methoxyphenyl) hydrazinecarboxamide] 8 Prepared from (2R,3R)-1,4-dioxaspiro-[4.5]-decane-2,3-di-carbohydrazide 2 and 4-methoxyphenyl isocyanate 4 (800.0 mg, 74%). After 24 h or stirring at room temperature, water was added and the solid was filtered off as a white solid precipitate (m.p. > 140 ºC); n max (solid) 3294, 1681 cm −1 ; d H (400 MHz DMSO-d 6 ) 9.99 (2H, brs, NHCO), 8.51 (2H,brs, NHCO), 8.09 (2H,brs, NHCO), 7.32 (4H, d, J 9.1 Hz, ArH), 6.76 (4H, d, J 8.7 Hz, ArH), 4.63 (2H, brs, CHCO), 3.64 (6H, brs, OMe), 1.73-1.55 (6H, m, CH 2 ), 1.53-1.49 (2H, m, CH 2 ), 1.33 (2H, m, CH 2 ); d C (100 MHz, DMSO-d 6 ) 169.6, 156.1, 155.1, 132.8, 121.0, 114.4, 113.4, 76.8, 55.5, 36.0, 25.5, 25.2, 24.1; m/z 555.0 (52, MH – ), 405.9 (100%); HRMS: MH – , found 555.2224. C 26 H 32 N 6 O 8 requires 555.2209. 4.3. 2,2'-[(4R,5R)-1,3-dioxolane-4,5-dicarbonyl)-bis-(N-(2,4-dimethoxyphenyl) hydrazinecarboxamide] 9 Prepared from (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide 1 and 2,4-dimethoxyphenyl isocyanate 5 (711.0 mg, 93%) as a white solid precipitate (m.p. > 190 ºC); n max (solid) 3299, 1685 cm −1 ; d H (400 MHz DMSO-d 6 ) 10.11 (2H, brs, NHCO), 8.48 (2H,brs, NHCO), 7.88 (2H,brs, NHCO), 7.79 (2H, d, J 8.7 Hz, ArH), 6.56 (2H, s, ArH), 6.42 (2H, dd, J 6.4 Hz, ArH), 5.16 (2H, brs, OCH 2 ), 4.63 (2H, brs, CHCO), 3.79 (6H, brs, OMe), 3.68 (6H, brs, OMe); d C (100 MHz, DMSO-d 6 ) 169.1, 155.6, 155.4, 149.7, 122.0, 120.1, 104.6, 99.2, 97.0, 77.1, 56.3, 55.7; m/z 547.0 (66, MH – ), 367.9 (100%); HRMS: MH – , found 547.1782. C 23 H 28 N 6 O 10 requires 547.1794. 4.4. 2,2'-[(4R,5R)-1,3-dioxolane-4,5-dicarbonyl)-bis-(N-(4-dimethylamino) hydrazinecarboxamide] 10 Prepared from (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide 1 and 4-dimethylaminophenyl isocyanate 6 (705.0 mg, 89%) as a violet solid precipitate (m.p. > 200 ºC); n max (solid) 3263, 1688 cm −1 ; d H (400 MHz DMSO-d 6 ) 10.04 (2H, brs, NHCO), 8.37 (2H, brs, NHCO), 7.95 (2H, brs, NHCO), 7.21 (4H, d, J 9.1 Hz, ArH), 6.62 (4H, d, J 9.1 Hz, ArH), 5.14 (2H, brs, OCH 2 ), 4.65 (2H, brs, CHCO), 2.77 (12H, brs, NMe); d C (100 MHz, DMSO-d 6 ) 169.2, 155.8, 147.0, 129.7, 121.0, 113.5, 97.0, 77.2, 41.2; m/z 513.0 (70, MH – ), 350.9 (100%); HRMS: MH – , found 513.2240. C 23 H 30 N 8 O 6 requires 513.2216. 4.5. 2,2'-[(4S,5S)-1,3-dioxolane-4,5-dicarbonyl)-bis-(N-(4-methoxyphenyl) hydrazinecarboxamide]11 Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide 3 and 4-methoxyphenyl isocyanate 4 (910.0 mg, 96%) as a pale yellow solid precipitate (m.p. 224-225 ºC); n max (solid) 3260, 1681 cm −1 ; d H (400 MHz DMSO-d 6 ) 10.05 (2H, brs, NHCO), 8.54 (2H,brs, NHCO), 8.04 (2H,brs, NHCO), 7.31 (4H, d, J 9.1 Hz, ArH), 6.79 (4H, d, J 9.1 Hz, ArH), 5.15 (2H, brs, OCH 2 ), 4.66 (2H, brs, CHCO), 3.65 (6H, brs, OMe); d C (100 MHz, DMSO-d 6 ) 169.3, 155.7, 155.0, 133.0, 120.9, 114.3, 97.0, 77.2, 55.6; m/z 486.9 (100, MH – ), 337.9 (19%); HRMS: MH – , found 487.1570. C 21 H 24 N 6 O 8 requires 487.1583. 4.6. 2,2'-[(4S,5S)-1,3-dioxolane-4,5-dicarbonyl) -bis-(N-(2,4-dimethoxyphenyl) hydrazinecarboxamide] 12 Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide 3 and 2,4-dimethoxyphenyl isocyanate 5 (735.0 mg, 99%) as a pale yellow solid precipitate (m.p. > 190 ºC); n max (solid) 3297, 1696 cm −1 ; d H (400 MHz DMSO-d 6 ) 10.13 (2H, brs, NHCO), 8.50 (2H,brs, NHCO), 7.90 (2H,brs, NHCO), 7.90 (2H, d, J 8.7 Hz, ArH), 6.57 (2H, s, ArH), 6.42 (2H, dd, J 6.4 Hz, ArH), 5.18 (2H, brs, OCH 2 ), 4.66 (2H, brs, CHCO), 3.79 (6H, brs, OMe), 3.68 (6H, brs, OMe); d C (100 MHz, DMSO-d 6 ) 169.2, 155.6, 155.4, 149.7, 121.9, 120.2, 104.6, 99.2, 97.1, 77.2, 56.2, 55.7; m/z 547.0 (39, MH – ), 367.9 (100%); HRMS: MH – , found 547.1799. C 23 H 28 N 6 O 10 requires 547.1794. 4.7. 2,2'-[(4S,5S)-1,3-dioxolane-4,5-dicarbonyl)-bis-(N-(4-dimethylamino) hydrazinecarboxamide] 13 Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide 3 and 4-dimethylaminophenyl isocyanate 6 (740.0 mg, 93%) as a violet solid precipitate (m.p. > 210 ºC); n max (solid) 3256, 1688 cm −1 ; d H (400 MHz DMSO-d 6 ) 10.04 (2H, brs, NHCO), 8.37 (2H,brs, NHCO), 7.95 (2H,brs, NHCO), 7.21 (4H, d, J 9.1 Hz, ArH), 6.61 (4H, d, J 9.1 Hz, ArH), 5.14 (2H, brs, OCH 2 ), 4.64 (2H, brs, CHCO), 2.76 (12H, brs, NMe); d C (100 MHz, DMSO-d 6 ) 169.3, 155.8, 147.0, 129.7, 121.0, 113.5, 97.0, 77.2, 41.2; m/z 513.1 (31, MH – ), 350.9 (100%); HRMS: MH – , found 513.2233. C 23 H 30 N 8 O 6 requires 513.2216. Acknowledgments H. Nour deeply thanks Deutscher Akademischer Austausch Dienst (DAAD) for financial support and Jacobs University for excellent facilities. References and notes 1. Bogaschenko, T. Y.; Lyapunov, A. Y.; Kikot’, L. S.; Mazepa, A. V.; Botoshansky, M. M.; Fonari, M. S.; Kirichenko, T. I. Tetrahedron 2012, 68, 4757. 2. Xie, T.-Z.; Guo, C.; Yu, S.-Y.; Pan, Y.-J. Angew. Chem. Int. Ed. 2012, 51, 1177. 3. Kuchelmeister, H. Y.; Schmuck, C. Chem. Eur. J. 2011, 17, 5311. 4. Zhu, Z.; Cardin, C. J.; Gan, Y.; Colquhoun, H. M. Nat. Chem. 2010, 2, 653. 5. Nishiuchi, T.; Kuwatani, Y.; Nishinaga, T.; Iyoda, M. Chem. Eur. J. 2009, 15, 6838. 6. Hayashi, N.; Ujihara, T. Tetrahedron 2009, 65, 8209. 7. Wennemers, H.; Nold, M. C.; Conza, M. M.; Kulicke, K. J.; Neuburger, M. Chem. Eur. J. 2003, 9, 442. 8. Chen, C.-W.; Whitlock, H.W. J. Am. Chem. Soc. 1978, 100, 4921. 9. Vicente, A. I.; Caio, J. M.; Sardinha J.; Moiteiro, C.; Delgado, R.; Félix, V. Tetrahedron 2012, 68, 670. 10. Barnhill, D. K.; Sargent, A. L.; Allen, W. E. Tetrahedron 2005, 61 8366. 11. Ishi-i, T.; Crego-Calama, M.; Timmerman, P.; Reinhoudt, D. N.; Shinkai, S. Angew. Chem. Int. Ed. 2002, 41, 1924. 12. Kuchelmeister, H. Y.; Schmuck, C. Eur. J. Org. Chem. 2009, 4480. 13. Liu, S.-Y.; He, Y.-B.; Wu, J.-L.; Wei, L.-H.; Qin, H.-J.; Meng, L.- Z.; Hu, L. Org. Biomol. Chem. 2004, 2, 1582. 14. Zimmerman, S. C.; VanZyl, C. M. J. Am. Chem. Soc. 1987, 109, 7894. 15. Zimmerman, S. C.; Wu, W. J. Am. Chem. Soc. 1989, 111, 8054. 16. Zimmerman, S. C. In Topics in Current Chemistry; SpringerLink: 1993, Vol. 165/1993, 71-102, DOI: 10.1007/BFb0111281. 17. Iorio, E. J.; Still W. C. Bioorg. Med. Chem. Lett. 1996, 6, 2673. 18. Iorio, E. J.; Still W. C. Bioorg. Med. Chem. Lett. 1999, 9, 2145. 19. Chen, X.; Du, D.-M.; Hua, W.-T. Tetrahedron: Asymm. 2003, 14 999. 20. Shepherd, J.; Gale, T.; Jensen, K. B.; Kilburn, J. D. Chem. Eur. J. 2006, 12, 713. 21. Braxmeier, T.; Demarcus, M.; Fessmann, T.; McAteer, S.; Kilburn, J. D. Chem. Eur. J. 2001, 7, 1889. 22. Nestler, H. P. Mol. Divers. 1996, 2, 35. 23. Conza, M.; Wennemers, H. J. Org. Chem. 2002, 67, 2696. 24. Wennemers, H.; Bernard, J. Org. Lett. 2007, 9, 4284. 25. Wennemers, H.; Krattiger, P. Synlett 2005, 4, 706. 26. Bernard, J.; Wennemers, H. Org. Lett. 2007, 9, 4283. 7
8 27. Nour, H. F.; Hourani, N.; Kuhnert, N.; Org. Biomol. Chem. 2012, 10, 4381. 28. Nour, H. F.; Golon, A.; Le Gresley, A.; Kuhnert, N. Chem. Eur. J. 2012, submitted manuscript. 29. Nour, H. F.; Golon, A.; Islam, T.; Fernández-Lahore, M.; Kuhnert, N. Unpublished results. 30. Skowronek, P.; Kuncewicz, M.; Brzostowska, M.; Janiak, A.; Rychlewska, U.; Gawroński, J. Tetrahedron: Asymm. 2012, 23, 300. 31. Nour, H. F.; Islam, T.; Fernández-Lahore, M.; Kuhnert, N. Rapid Comm. Mass. Spectrom. 2012, accepted manuscript. 32. Gawroński, J.; Kołbon, H.; Kwit, M.; Katrusiak, A. J. Org. Chem. 2000, 65, 5768. 33. Kuhnert, N.; Rossignolo, G.; Lopez-Periago, A. Org. Biomol. Chem. 2003, 1, 1157. 34. Kuhnert, N.; Patel, C.; Jami, F. Tetrahedron Lett. 2005, 46, 7575. 35. Kuhnert, N.; Lopez-Periago, A. Tetrahedron Lett. 2002, 43, 3329. 36. Kuhnert, N.; Lopez-Periago, A.; Rossignolo, G. Org. Biomol. Chem. 2005, 3, 524. 37. Kuhnert, N.; Straßnig, C.; Lopez-Periago, A. Tetrahedron: Asymm. 2002, 13, 123. 38. Kuhnert, N.; Tang, B. Tetrahedron Lett. 2006, 47, 2985. 39. Kuhnert, N.; Marsh, D.; Nicolau, D. Tetrahedron: Asymm. 2007, 18, 1648. 40. Nour, H. F.; Matei, M. F.; Bassil, B.; Kortz, U.; Kuhnert, N. Org. Biomol. Chem. 2011, 9, 3258. 41. Molecular modeling was carried out using HyperChem software (Release 8.0). Hypercube, Inc., 1115 NW 4th Street, Gaineville, F1 32601 USA. Trial, version from http://www.hypercube.com 42. Stewart, J. J. Comput. Chem. 1989, 10, 221. 43. Alfonso, I.; Bolte, M.; Bru, M.; Burguete, M. I.; Luis, S. V.; Vicent, C. Org. Biomol. Chem. 2010, 8, 1329. 44. Schug, K.; Fryčák, P.; Maier, N. M.; Lindner, W. Anal. Chem. 2005, 77, 3660. 45. Arakawa, R.; Kobayashi, M.; Fukuo, T.; Shiraiwa, T. Rapid Comm. Mass. Spectrom.2001, 15, 685. 46. Nour, H. F.; Lopez-Periago, A.; Kuhnert, N. Rapid Comm. Mass. Spectrom.2012, 26, 1070.
Page 1 and 2:
The Development of Novel Antibiotic
Page 3 and 4:
Declaration of Authorship I, Hany N
Page 5 and 6:
Abstract Over the past few decades,
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Chapter 2 Trianglimine Chemistry
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Figure 2.4 Trianglimines 10-12 with
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Abbreviations ACN AcOH Ala Acetonit
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RMS ROESY SjGST TFA THF TLC TMS TOC
Page 15 and 16:
Introduction complete remodel of th
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Introduction following protonation.
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Introduction Lehn and co-workers re
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Introduction Figure 1.8 Generation
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Introduction Figure 1.11 Synthetic
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Introduction Figure 1.13 Generation
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Introduction 1.3.11 Boronic ester e
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Introduction References 1. E. Mouli
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Introduction 51. B. Shi, M. F. Grea
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Introduction Figure 2.2 shows compu
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Introduction incorporate β-cyclode
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Introduction Trianglamine-Zn(R) 2 c
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Introduction 24. J. Gajewy, J. Gawr
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Scope of Work Scope of Work In this
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Scope of Work can be obtained from
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Scope of Work Figure 3.4 Structures
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Scope of Work References 1. G. Wrig
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Organic & Biomolecular Chemistry Ci
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Downloaded by Jacobs University Bre
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View Online Downloaded by Jacobs Un
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Paper 2 Rapid Commun. Mass Spectrom
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Trianglimine formation mechanism by
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Paper 3 Org. Biomol. Chem., 2012, 1
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Page 81 and 82: View Online Table 2 Distances (Å)
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Page 85 and 86: Paper 4 Chem. Eur. J., 2012, submit
Page 87 and 88: (4R,5R)- and (4S,5S)-dimethyl-2,2-d
Page 89 and 90: that two distinct conformational is
Page 91 and 92: the thimble was recharged with fres
Page 93 and 94: Paper 5 Rapid Commu. Mass Spectrom.
Page 95 and 96: INTRODUCTION No single class of dru
Page 97 and 98: EXPERIMENTAL All the solvents and r
Page 99 and 100: (b) Refluxing macrocycles 5, 6 and
Page 101 and 102: Scheme 1. Graphical representation
Page 103 and 104: Figure 1. A plot of relative intens
Page 105 and 106: In contrast, formation of library m
Page 107 and 108: Figure 5. Generated dynamic library
Page 109 and 110: macrocycle 32 from the dynamic libr
Page 111 and 112: The polar carbamate group participa
Page 113 and 114: [2] WHO World health report 2003. h
Page 115 and 116: [32] B. Lienard, N. Selevsek, N. Ol
Page 117 and 118: FULL PAPER Synthesis and ESI-MS Com
Page 119 and 120: ability of the technique to provide
Page 121 and 122: aimed at assessing molecular recogn
Page 123 and 124: Paper 7 manuscript Synthesis, self-
Page 125 and 126: 2 Similar to the case of trianglimi
Page 127 and 128: 4 Receptor 7 showed enhanced recogn
Page 129: 6 The newly synthesized receptors s
Page 133 and 134: 120| P a g e Appendix
Page 135 and 136: Supplementary Information: Suppleme
Page 137 and 138: Supplementary Material (ESI) for Or
Page 153 and 154: Monitoring the [3+3]-cyclocondensat
Page 155 and 156: Monitoring the cyclocondensation re
Page 157 and 158: Product ions appeared as [M+H] + Fi
Page 159 and 160: Scheme 1. Assigned higher oligomers
Page 161 and 162: Supplementary Information: Synthesi
Page 163 and 164: Scheme 4. Proposed fragmentation me
Page 165 and 166: DMSO Figure 1. 1 H-NMR spectrum for
Page 167 and 168: Figure 6. 13 C-NMR spectrum for (4S
Page 169 and 170: Intens. 7 x10 1.5 200.7 1.0 0.5 0.0
Page 171 and 172: Intens. 7 x10 200.7 1.5 1.0 0.5 0.0
Page 173 and 174: Intens. 4 x10 577.2 2.0 1.5 1.0 451
Page 175 and 176: HN N O O R R NH O O N N HN R O O O
Page 177 and 178: Intens. 5 x10 727.2 2.0 1.5 1.0 O O
Page 179 and 180: Intens. 5 x10 697.1 1.5 1.0 728.2 0
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O O O O HN N O O NH N HN N O O NH N
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Figure 38. 1 H-NMR spectrum for mac
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Intens. 5000 276.8 4000 3000 2000 1
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Intens. 7 x10 599.1 1.5 1.0 0.5 0.0
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(a) HN N O O NH O O N (b) HN N O NH
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Scheme 11. Proposed fragmentation m
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Page 195 and 196:
Scheme 14. Proposed fragmentation m
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Intens. 4 x10 550.9 3 2 1 0 500 100
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Figure 68. 2D-ROESY spectrum for ma
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Supplementary Information: Novel sy
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Intens. 6 x10 0.8 0.6 0.4 240.9 459
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Figure 9. 1 H-NMR spectrum for macr
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Page 209 and 210:
Intens. 5 x10 1.5 968.1 1.0 0.5 813
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Intens. 5 x10 897.4 4 2 335.3 707.3
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Scheme 3. Suggested fragmentation m
Page 215 and 216:
Page 217 and 218:
Molecular modelling data for the co
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Figure 1. 1 H NMR spectrum for dica
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Intens. 2000 1493.6091 Host-Guest 1
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Intens. [%] 100 775.3 80 388.1 60 4
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Intens. 600 N HN O O 467.1916 400 O
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Intens. 6000 5000 HN N O O O O NH N
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Table 1. High resolution ESI-TOF da
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i Figure 1. 1 H NMR spectrum for ma
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i Figure 5. 1 H NMR spectrum for ma
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i j Figure 9. 1 H NMR spectrum for
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i Figure 13. DEPT-135 spectrum for
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Scheme 1. General mechanism of frag
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Intens. [%] 100 80 60 40 20 0 O H N
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Intens. [%] 100 1131.3 80 60 40 20
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Intens. 1500 1528.6088 1000 500 150
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Intens. [%] 100 80 60 40 Free guest
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Intens. 4 x10 1085.3575 1.25 1.00 0
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Intens. [%] 100 80 Free guest 586.1
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Synthesis, self-assembly and ESI-MS
Page 255 and 256:
O O HN NH HN O O NH HN O 11 O NH O
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O O HN NH HN O O NH HN O 9 O NH O O
Page 259 and 260:
H 2 O DMSO DMSO Figure 6. 1 H-NMR a
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Intens. 5 x10 5 -MS 487.1588 4 3 2
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Intens. -MS 6 x10 0.8 0.6 0.4 0.2 1
Page 265 and 266:
Intens. -MS 6 x10 O O 350.9 1.5 1.0
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Intens. [%] 100 -MS 486.9 Exact str
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Intens. [%] -MS 100 486.9 80 60 975
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Intens. [%] +MS 100 80 517.2 Exact
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Intens. [%] 100 80 60 +MS 388.1 775
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Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 80 +MS 1031.4939 7
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Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 -MS 2 586.1 80 60 4
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Intens. [%] 100 -MS 2 875.2 Exact s
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Table 1. High resolution ESI-TOF/MS
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274 | P a g e
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276 | P a g e
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4. H. Nour, A. López-Periago, N. K
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