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1 Tetrahedron journal homepage: www. elsevi er.c om Synthesis, self-assembly and ESI-MS complexation studies of novel chiral bis-Nsubstituted-hydrazinecarboxamide receptors Hany F. Nour a,b , Agnieszka Golon a , Tuhidul Islam a , Marcelo Fernández-Lahore a and Nikolai Kuhnert a,* a School of Engineering and Science, Centre for Nano and Functional Materials (NanoFun), Jacobs University, 28759 Bremen, Germany. b National Research Centre, Department of Photochemistry, El Behoose Street, P.O. Box 12622, Dokki, Cairo, Egypt. ART I CLE INFO AB ST R ACT Article history: Received Received in revised form Accepted Available online Keywords: Hydrazinecarboxamide Receptors Self-assembly ESI mass spectrometry Dicarbohydrazides A total of seven novel bis-N-substituted-hydrazinecarboxamide two-armed molecular receptors were synthesized in good to excellent yields by reacting chiral dicarbohydrazides obtained from commercially available tartaric acid with aromatic isocyanates. Unlike tetra-carbohydrazide and tetra-(hydrazinecarboxamide) cyclophane macrocycles, which have recently been synthesized in our laboratory, the new receptors showed a remarkable degree of flexibility. The novel receptors showed efficient selective recognition ability in the gas phase to a selection of chiral carboxylic acids and oligopeptides with formation of structurally unique self-assembled host/guest complexes as confirmed by ESI-TOF and tandem MS. Structures of the novel receptors were fully assigned by various spectroscopic techniques such as 1 H NMR, 13 C NMR, ESI-TOF/MS, tandem MS, 2D ROESY NMR and CD spectroscopy. 2012 Elsevier Ltd. All rights reserved. 1. Introduction Over the past few decades, the synthesis of new artificial receptors has attracted considerable attention in supramolecular chemistry. 1-7 Molecular tweezers form a class of acyclic receptors bearing n-number of arms which bind a target guest molecule. 8 A central spacer unit connects the sidewalls of the tweezer and can be either flexible or rigid. The size of the spacer unit determines the shape and cavity of the tweezer. Symmetrical tweezers bear similar arms, while non-symmetrical tweezers possess different arms. 3,7,9-13 The first version of molecular tweezers recognizing aromatic guests via π-π stacking interactions was developed by Whitlock and Zimmerman. 8,14-16 Following this work, many structurally unique tweezers were synthesized and showed their promise in binding neutral and charged guests. 1-7 Molecular recognition of synthetic receptors to carboxylic and amino acids is of particular interest to supramolecular chemists due to their biological, industrial and environmental concern. An ideal receptor should have adequate solubility and should incorporate functionalities into its structural framework in order to promote its recognition ability. Both hydrogen bonding and π-π stacking interactions play significant roles in stabilizing and strengthening the binding interactions of tweezer/guest complexes. Although many receptors which bind carboxylic acids are reported in literature, only few examples such as diketopiperazine are known *Correspondence to: N. Kuhnert, email: n.kuhnert@jacobsuniversity.de Tel.: +49-421-200-3120; Fax: +49-421-200-3229. for peptide recognition. 7,17-26 Recently, we have described the synthesis of a novel class of cyclophane-type macrocycles A and B in almost quantitative yields. 27-29 We showed that the macrocycles can be obtained in both enantiomeric forms (R or S) by reacting chiral dicarbohydrazides obtained from diethyl tartrate with aromatic dialdehydes and diisocyanates in [2+2]-cyclocondensation reactions. Parallel to our work with cyclophanes A and B, Gawroński et al. reported the synthesis of a tetra-carbohydrazide cyclophane macrocycle derived from (4R,5R)-2,2-dimethyl-1,3-dioxolane- 4,5-dicarbohydrazide and terephthaldehyde. 30 Macrocycle A possesses four amide and four imine moieties making it suitable for different applications in DCC (dynamic combinatorial chemistry), while macrocycle B has more functionalities and higher degree of flexibility. 27-29,31
2 Similar to the case of trianglimine chemistry, macrocycles A and B form under conformational bias of dicarbohydrazides. 32-40 2. Results and discussion 2.1. Synthesis and molecular modeling In continuation to our work with cyclophane macrocycles A and B, we decided to synthesize a class of two-armed receptors which simulates the structural framework of macrocycle B. Receptors with such structural features are expected to be more flexible and to show improved molecular recognition abilities. Two-armed receptors 7-13 were synthesized from chiral dicarbohydrazides 1- 3 by reacting with substituted aromatic isocyanate 4-6 in anhydrous THF (Fig. 1). The sidewalls of the receptors are made of amide moieties, which function as the receptor binding motifs, while dioxolane rings constitute the spacer units. The recognition affinity of the novel receptors in the gas phase to a selection of chiral carboxylic acids and oligopeptides is demonstrated by using electrospray ionization time of flight mass spectrometry (ESI-TOF/MS) and tandem MS. Structures of the novel receptors were fully assigned by various spectroscopic techniques such as FT IR, 1 H NMR, 13 C NMR, 2D ROESY, Circular Dichroism spectroscopy (CD), ESI-TOF/MS and MS/MS. for subsequent structure modeling calculations. Structure of receptor 7 was energy-minimized using HyperChem software (Release 8.0) at the Austin Model 1 level (AM1). 41,42 Molecular modeling calculations are in good agreement with data from 2D ROESY NMR and suggests a spiral-like structure for receptor 7 in which the NH moieties are syn/syn oriented. Structures of receptors 7-13 are stabilized by intramolecular hydrogen bonds as shown in Figure 3. Table 1. High resolution ESI-TOF/MS data for receptors 7-13 Entry Molecular formula Calcd. m/z a Meas. m/z Error [ppm] Yield % 7 C 21H 24N 6O 8 487.1583 487.1588 –1.0 78 8 C 26H 32N 6O 8 555.2209 555.2224 –2.8 74 9 C 23H 28N 6O 10 547.1794 547.1782 2.2 93 10 C 23H 30N 8O 6 513.2216 513.2240 –4.8 89 11 C 21H 24N 6O 8 487.1583 487.1570 2.7 96 12 C 23H 28N 6O 10 547.1794 547.1799 –1.0 99 13 C 23H 30N 8O 6 513.2216 513.2233 –3.5 93 a Product ions appeared as [M – H] – Fig. 2 2D ROESY NMR spectrum for receptor 7 (DMSO-d 6). 2.2. Molecular recognition and self-assembly in the gas phase Fig. 1 Two-armed receptors 7-13, which were synthesized from chiral dicarbohydrazides 1-3 and substituted aromatic isocyanates 4-6. 1 H NMR spectrum for (i.e., chiral receptor 7) showed three broad signals at 10.05, 8.54 and 8.04 ppm corresponding to the amide NH protons. FT IR spectrum showed a strong absorption band at ν 1689 cm −1 corresponding to the stretching vibration of the ν C=O. ESI-TOF/MS showed the expected pseudo-molecular ion peak at m/z 487.1588 [M–H] – in the negative ion mode. High resolution mass spectrometry (HRMS) data for the new receptors are shown in table 1. 2D ROESY spectrum for receptor 7 (Fig. 2) showed through space interactions between H d -H c and H d -H e , which suggests a syn/syn conformation of the NH moieties. Unlike receptor 7, the NH moieties in macrocycle B assume a syn/anti conformation. 29 Data from 2D ROESY NMR were used Electrospray ionization (ESI-MS) has been widely used as a versatile soft ionization method in studying weak non-covalent interactions and molecular recognition in the gas phase. 43-45 The ability of the technique to provide precise mass values, high resolution and little or almost no fragmentations make it an indispensable tool in supramolecular analysis. Recently, we reported on the use of ESI-TOF/MS in probing the mechanism of trianglimine formation in real-time and studying dynamic reversibility and molecular recognition of tetra-carbohydrazide cyclophanes in the gas phase to oligopeptides. 31,46 Two-armed receptor 7 showed interesting molecular self-assembly both in solution and in the gas phase to form dimeric, trimeric and tetrameric supramolecular associations. Molecular self-assembly has been confirmed in solution by variable temperature NMR (VT NMR) and in the gas phase by ESI-TOF and tandem MS. VT NMR was performed from 313 to 413 K in DMSO-d 6 . A downfield in chemical shift (δ) for NH c , NH e and NH d , with increasing temperature, has been observed (Fig. 4). The decrease in δ is an indication of breaking inter- and intramolecular hydrogen bonding interactions (NH…O=C) for the associated receptor molecules. Cooling the NMR to 298 K yields the same spectrum as first recorded as a consequent of re-establishment of the hydrogen bonds. Tandem
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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
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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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Page 73 and 74: Trianglimine formation mechanism by
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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
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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
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Page 113 and 114: [2] WHO World health report 2003. h
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Page 121 and 122: aimed at assessing molecular recogn
Page 123: Paper 7 manuscript Synthesis, self-
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Page 131 and 132: 8 27. Nour, H. F.; Hourani, N.; Kuh
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
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Page 165 and 166: DMSO Figure 1. 1 H-NMR spectrum for
Page 167 and 168: Figure 6. 13 C-NMR spectrum for (4S
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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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