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H. F. Nour, A. M. Lopez-Periago and N. Kuhnert (b) Mixing equimolar quantities of dialdehydes 19 and 33 with (1R,2R)-1,2-diaminocyclohexane 1 in DCM To a stirred solution of (1R,2R)-1,2-diaminocyclohexane 1 (15.62 mg, 0.137 mmol) in DCM (182 mL) were added 3- phenoxybiphenyl-4,4′-dicarbaldehyde 19 (18.12 mg, 0.06 mmol) in DCM (182 mL) and ethyl 4-[4,4′-diformyl-(1,1′-biphenyl)-3-yl]- piperazine-1-carboxylate 33 (23.3 mg, 0.06 mmol) in DCM (182 mL). The mixture was stirred at room temperature for 46 h. Aliquots were taken at defined time intervals and a few drops of MeOH were added to the sample before it was infused into the ESI-TOF mass spectrometer. RESULTS AND DISCUSSION The formation of trianglimines constitutes a complex multistep reaction, in which six imine bonds are formed in a single one-pot reaction at relatively high concentrations of all reactants. Gawroński et al. reported that the reactions of (1R,2R)- 1,2-diaminocyclohexane 1 with terephthaldehyde 2 and isophthaldehyde 3 resulted in clean formation of the corresponding trianglimines 4 and 5 after 2–3 h of stirring at room temperature (Fig. 1). [9] We decided to study the mechanism of this reaction in detail taking advantage of the capability of ESI-MS in the positive ion mode to potentially detect all possible reaction intermediates. The reactions were conducted between 1 and 2 or 3 at a concentration of 0.1 M in DCM at room temperature. For MS analysis, aliquots of the reaction mixture were taken at different time intervals, diluted to a concentration of 0.1 mM and directly infused into the ESI-TOF mass spectrometer. Cyclocondensation mechanism of trans-(1R,2R)-1,2- diaminocyclohexane with terephthaldehyde and isophthaldehyde By monitoring the reaction between (1R,2R)-1,2-diaminocyclohexane 1 and dialdehyde 2 and 3 in real time with ESI-TOF MS, a total of eleven different reaction intermediates could be detected by the appearance of their protonated pseudomolecular ions and their structures were assigned based on their highresolution m/z values (Figs. 2 and 3). The reaction intermediates include a series of mono- topenta-imines 7–17 along with some long-chain higher polyimine oligomers (not shown in figures; for structures and ESI-TOF data, see Supplementary Information). In the course of the reaction the higher oligomers disappear at the expense of the final macrocyclization products. Interestingly, the relative intensity of the ions corresponding to the intermediates of the reaction with isophthaldehyde and terephthaldehyde are very different, suggesting that the mechanism of formation of the two geometrically distinct macrocycles is different. For terephthaldehyde 2 the intermediates with the two most intense signals correspond to monoimine 7 and bis-imine 8 bearing two terminal amino moieties. In contrast, for isophthaldehyde 3 the bis-imine 14 with two Figure 2. ESI-TOF mass spectrum in the positive ion mode recorded after 10 min from the start of the reaction of (1R,2R)-1,2-diaminocyclohexane 1 with terephthaldehyde 2; the products were detected as [M+H] + ions. 1072 Figure 3. ESI-TOF mass spectrum in the positive ion mode recorded after 10 min from the start of the reaction of (1R,2R)-1,2-diaminocyclohexane 1 with isophthaldehyde 3; the products were detected as [M+H] + ions. wileyonlinelibrary.com/journal/rcm Copyright © 2012 John Wiley & Sons, Ltd. Rapid Commun. Mass Spectrom. 2012, 26, 1070–1080
Trianglimine formation mechanism by ESI-TOF MS terminal amine moieties forms the major intermediate. Unusual tri-imine intermediates 10 and 16 bearing terminal amino and carbonyl moieties were observed as relatively stable and longlived reaction intermediates in both cyclocondensation reactions. Furthermore, the [3+3]-cyclocondensation reaction of (1R,2R)-1,2-diaminocyclohexane 1 with terephthaldehyde 2 proceeds via intermediates 7 to 12, while with isophthaldehyde 3 it proceeds via intermediates 13 to 18. Most importantly, the analysis of trianglimines by ESI-MS shows considerable promise due to the ability of this technique to provide precise mass values, high-resolution and little or almost no fragmentations. ESI-MS can also be used as a useful reaction monitoring system, identifying the maximum yield and end-point of the reaction (see Supporting Information). The reaction intermediates observed are shown in Schemes 1 and 2 and the observed masses and their assignments are shown in Tables 1 and 2. From the ESI-TOF MS data we can infer that the cyclocondensation reaction of (1R,2R)-1,2-diaminocyclohexane 1 with terephthaldehyde 2 requires 6 h for completion, while with isophthaldehyde 3 a mixture of [2+2]- and [3+3]-cyclocondensation products along with some minor impurities was observed after 12 h. It is worth noting that the intensity of the peaks corresponding to the assigned intermediates can be plotted versus reaction time to provide a visual representation of the progress of the reaction (Figs. 4(a)–4(c)). It can be inferred that the relative intensity of the [M+H] + ion for trianglimine 4 increased with time and reached a maximum value after 2 h of the reaction Scheme 1. Exact mechanism for the [3+3]-cyclocondensation reaction of terephthaldehyde 2 to yield trianglimine 4 based on real-time ESI-TOF MS measurements. Scheme 2. Exact mechanism for the [3+3]-cyclocondensation reaction of isophthaldehyde 3 to yield trianglimine 5 based on ESI-TOF MS measurements. 1073 Rapid Commun. Mass Spectrom. 2012, 26, 1070–1080 Copyright © 2012 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/rcm
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The Development of Novel Antibiotic
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Declaration of Authorship I, Hany N
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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
Page 17 and 18: Introduction following protonation.
Page 19 and 20: Introduction Lehn and co-workers re
Page 21 and 22: Introduction Figure 1.8 Generation
Page 23 and 24: Introduction Figure 1.11 Synthetic
Page 25 and 26: Introduction Figure 1.13 Generation
Page 27 and 28: Introduction 1.3.11 Boronic ester e
Page 29 and 30: Introduction References 1. E. Mouli
Page 31 and 32: Introduction 51. B. Shi, M. F. Grea
Page 33 and 34: Introduction Figure 2.2 shows compu
Page 35 and 36: Introduction incorporate β-cyclode
Page 37 and 38: Introduction Trianglamine-Zn(R) 2 c
Page 39 and 40: Introduction 24. J. Gajewy, J. Gawr
Page 41 and 42: Scope of Work Scope of Work In this
Page 43 and 44: Scope of Work can be obtained from
Page 45 and 46: Scope of Work Figure 3.4 Structures
Page 47 and 48: Scope of Work References 1. G. Wrig
Page 49 and 50: Organic & Biomolecular Chemistry Ci
Page 51 and 52: Downloaded by Jacobs University Bre
Page 53 and 54: View Online Downloaded by Jacobs Un
Page 63 and 64: Paper 2 Rapid Commun. Mass Spectrom
Page 65: Trianglimine formation mechanism by
Page 69 and 70: Trianglimine formation mechanism by
Page 75 and 76: Paper 3 Org. Biomol. Chem., 2012, 1
Page 81 and 82: View Online Table 2 Distances (Å)
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
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FULL PAPER Synthesis and ESI-MS Com
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ability of the technique to provide
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aimed at assessing molecular recogn
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Paper 7 manuscript Synthesis, self-
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2 Similar to the case of trianglimi
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4 Receptor 7 showed enhanced recogn
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6 The newly synthesized receptors s
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8 27. Nour, H. F.; Hourani, N.; Kuh
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120| P a g e Appendix
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Supplementary Information: Suppleme
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Supplementary Material (ESI) for Or
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Monitoring the [3+3]-cyclocondensat
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Monitoring the cyclocondensation re
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Product ions appeared as [M+H] + Fi
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Scheme 1. Assigned higher oligomers
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Supplementary Information: Synthesi
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Scheme 4. Proposed fragmentation me
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DMSO Figure 1. 1 H-NMR spectrum for
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Figure 6. 13 C-NMR spectrum for (4S
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Intens. 7 x10 1.5 200.7 1.0 0.5 0.0
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Intens. 7 x10 200.7 1.5 1.0 0.5 0.0
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Intens. 4 x10 577.2 2.0 1.5 1.0 451
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HN N O O R R NH O O N N HN R O O O
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Intens. 5 x10 727.2 2.0 1.5 1.0 O O
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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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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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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
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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
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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
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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
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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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