Synthesis of novel chiral bis-N-substituted-hydrazinecarboxamide receptors and probing their solution-phase recognition to chiral carboxylic guests by ESI-TOF/MS and tandem ESI-MS

Article abstract of DOI:10.1016/j.tet.2013.11.002

Seven novel bis-N-substituted-hydrazinecarboxamide receptors were synthesized in good to excellent yields by reacting chiral dicarbohydrazides, obtained from commercially available tartaric acid, with substituted aromatic isocyanates. The newly synthesized hydrazinecarboxamides formed structurally unique supramolecular aggregates, which have been confirmed by ESI-TOF/MS and tandem ESI-MS. They also showed molecular recognition to a selection of chiral carboxylic guests and oligopeptides, which mimic the backbone structure of the bacterial cell wall. The structures of the novel compounds were verified by various spectroscopic techniques including FTIR, ¹H NMR, ¹³C NMR, ESI-TOF/MS, tandem ESI-MS, 2D ROESY NMR, and CD spectroscopy.

Full text of DOI:10.1016/j.tet.2013.11.002

Tetrahedron 69 (2013) 11130e11137
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of novel chiral bis-N-substituted-hydrazinecarboxamide
receptors and probing their solution-phase recognition to chiral
carboxylic guests by ESI-TOF/MS and tandem ESI-MS
a
b
b
b
ꢀ
Hany F. Nour , Agnieszka Golon , Tuhidul Islam , Marcelo Fernandez-Lahore ,
Nikolai Kuhnert b
,
*
a National Research Centre, Department of Photochemistry, El Behoose Street, PO Box 12622, Cairo, Dokki, Egypt
b School of Engineering and Science, Centre for Nano and Functional Materials (NanoFun), Jacobs University, 28759 Bremen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 May 2013
Received in revised form 21 October 2013
Accepted 4 November 2013
Available online 8 November 2013
Seven novel bis-N-substituted-hydrazinecarboxamide receptors were synthesized in good to excellent
yields by reacting chiral dicarbohydrazides, obtained from commercially available tartaric acid, with
substituted aromatic isocyanates. The newly synthesized hydrazinecarboxamides formed structurally
unique supramolecular aggregates, which have been confirmed by ESI-TOF/MS and tandem ESI-MS. They
also showed molecular recognition to a selection of chiral carboxylic guests and oligopeptides, which
mimic the backbone structure of the bacterial cell wall. The structures of the novel compounds were
verified by various spectroscopic techniques including FTIR, 1H NMR, 13C NMR, ESI-TOF/MS, tandem ESI-
MS, 2D ROESY NMR, and CD spectroscopy.
Keywords:
Hydrazinecarboxamide
Self-assembly
ESI mass spectrometry
Dicarbohydrazide
Isocyanate
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
assemble together to form a precise and extremely well ordered
double helix strand of encoded genetic information. Peptide am-
Over the past decades, molecular self-assembly (MSA) has
emerged as a stupendous field of endeavors in supramolecular
chemistry.1 MSA has a wide range of applications in biology,
nanochemistry, and material science.2 In order for molecules to
undergo self-organization, they must possess functionalities, which
aid formation of complementary structures.3 Noncovalent in-
phiphiles (PAs), which were firstly reported by Stupp and co-
workers, spontaneously formed high molecular weight cylindri-
cally nanofibers.7 Both the hydrophobicity and hydrogen bonds
participate cooperatively in the formation of the self-assembled
aggregates.7
Mass spectrometry (MS) has been extensively used in studying
noncovalent interactions.8 The detection of biological macromole-
cules, host/guest (H/G) complexes or self-assembled associations
became possible with the development of soft-ionization MS
techniques, such as electrospray ionization (ESI). An important
feature of ESI-MS is that the solution-phase information can be
retained into the gas phase. However, there are some limitations
and obstacles associated with detecting high ordered self-
assembled structures. These obstacles usually include low peak
intensities of the complexes or decomposition of the intact as-
sembled associations before reaching the detector.
teractions, such as hydrogen bonds and
pep-stacking play
a prominent role in holding and thus stabilizing the assembled
associations.4 In most cases, the self-assembled structures can
possess attractive and distinct properties, which differ entirely
from that of the non-assembled precursors.5 An example from
nature, which demonstrates the concept of MSA is the self-
assembly of the tobacco mosaic virus (TMV).6 The helical struc-
ture of TMV forms by self-assembly of a defined number of protein
subunits around a single strand of ribonucleic acid (RNA). Another
common example is the WatsoneCrick base pairing model in
deoxyribonucleic acid (DNA), in which the building blocks
Recently, we reported on the synthesis of a new class of chiral
cyclophane-type macrocycles (A) and (B) in almost quantitative
yields (Fig. 1).9 We showed that the macrocycles could be obtained
in both enantiomeric forms (R) or (S) by reacting chiral dicarbo-
hydrazides, obtained from commercially available diethyl tartrate,
with aromatic dialdehydes and diisocyanates in [2þ2]
* Corresponding author. Tel.: þ49 421 200 3120; fax: þ49 421 200 3229; e-mail
addresses: hany.nour@daad-alumni.de (H.F. Nour), n.kuhnert@jacobs-university.de
(N. Kuhnert).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.002

H.F. Nour et al. / Tetrahedron 69 (2013) 11130e11137
11131
Fig. 1. Tetra-(carbohydrazide) cyclophane (A) and tetra-(hydrazinecarboxamide) cy-
clophane (B).
macrocyclization reactions. In this contribution, we report on the
synthesis of new bis-N-substituted-hydrazinecarboxamides with
hydrazido urea functionalities and assessment of their solution-
phase recognition to a selection of chiral carboxylic guests by
using electrospray ionization time-of-flight mass spectrometry
(ESI-TOF/MS) and tandem ESI-MS. Parallel to our work with
ꢀ
cyclophanes (A) and (B), Gawronski and co-workers reported on
the synthesis of a tetra-(carbohydrazide) cyclophane macrocycle
from
(4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dicarbohydrazide
and terephthaldehyde.10 Macrocycle (A) possesses four
acylhydrazone moieties, making it suitable for different applica-
tions in dynamic combinatorial chemistry (DCC), while macrocycle
(B) possesses more functionalities and has a higher degree of
flexibility.9,11 Similar to the case of trianglimine chemistry, macro-
cycles (A) and (B) were formed under the conformational bias of
the dicarbohydrazide precursor.12
Fig. 2. Two-armed receptors (7e13) obtained through addition of chiral dicarbohy-
drazides (1e3) to substituted aromatic isocyanates (4e6) in THF.
Table 1
ESI-TOF/MS data and yields of receptors (7e13)
Product Molecular formula Calcd m/z aFound m/z Error [ppm] Yield %
7
8
9
10
11
12
13
C
C
C
C
C
C
C
21H24N6O8
26H32N6O8
23H28N6O10
23H30N8O6
21H24N6O8
23H28N6O10
23H30N8O6
487.1583 487.1588
555.2209 555.2224
547.1794 547.1782
513.2216 513.2240
487.1583 487.1570
547.1794 547.1799
513.2216 513.2233
ꢀ1.0
ꢀ2.8
2.2
78
74
93
89
96
99
93
2. Results and discussion
2.1. Synthesis and conformational analysis
ꢀ4.8
2.7
ꢀ1.0
ꢀ3.5
In continuation to our work with cyclophane macrocycles (A) and
(B), we report on the synthesis of a new class of two-armed receptors
(7e13), which mimic the backbone structure of macrocycle (B). The
receptors of this kind were expected to show a high degree of flexi-
bility. The new receptors (7e13) were obtained from the reactions of
chiral dicarbohydrazides (1e3) with substituted aromatic isocyanate
(4e6) in anhydrous THF (Fig. 2). The structures of compounds (7e13)
were verified by various spectroscopic techniques including FTIR, 1H
NMR, 13C NMR, 2D ROESY, circular dichroism (CD) spectroscopy, ESI-
TOF/MS, and tandem MS. The 1H NMR spectrum of (7) showed three
a
Products detected as [MꢀH]ꢀ ions.
syn/syn conformer over the syn/anti or the anti/anti conformers for
receptor (7), we performed molecular modeling studies at the
Austin Model 1 (AM1) level using HyperChem software (Release
8.0.6).13 Data from the 2D ROESY NMR were used for subsequent
structure modeling calculations. Molecular modeling suggested
a spiral-like structure for (7), in which the NH moieties are syn/syn
oriented with possibility of formation of two intramolecular hy-
drogen bonds between (NH/O]C) (3)-(50) and (30)-(5). These in-
teractions stabilize the structure of (7) and reduce the electrostatic
repulsion between the C]O moieties (2)-(5) and (20)-(50) (Fig. 4).
broad signals at d 10.05, 8.54, and 8.04 ppm corresponding to the six
amidic NH protons.
The FTIR spectrum showed a strong absorption band at
n
1689 cmꢀ1, corresponding to the stretching vibration of the C]O
moieties. The ESI-TOF/MS, in the negative ion mode, showed the
expected molecular ion peak at m/z 487.1588 as [MꢀH]ꢀ. The high
resolution mass spectrometry (HRMS) data for the new receptors
are shown in Table 1.
2.2. Probing solution-phase recognition of receptors (7e13)
to chiral carboxylic guests (14e20) by using ESI-TOF/MS
The 2D ROESY spectrum of receptor (7) (Fig. 3) showed through
space interactions between HceHd and HdeHe, which suggested
a syn/syn conformation of the NH moieties. Unlike in the case of
receptor (7), the NH moieties in macrocycle (B) assume a syn/anti
conformation.9c It is worth noting that the syn/syn conformer of
macrocycle (B) has more energy than the syn/anti or the anti/anti
conformers due to the electrostatic repulsion between the C]O
moieties (6)-(9), (21)-(24), (27)-(30), and (3)-(42).9c In order to
further understand the reasons for the preferential formation of the
ESI-MS has been widely used as a versatile soft ionization
method in studying weak noncovalent interactions.8,14 The ability
of the technique to provide precise mass values, high resolution,
and little or almost no fragmentations, makes 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 the dynamic reversibility and molecular
recognition of the tetra-(carbohydrazide) cyclophane macrocycles

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H.F. Nour et al. / Tetrahedron 69 (2013) 11130e11137
Fig. 3. 2D ROESY NMR spectrum of receptor (7) (DMSO-d6).
to oligopeptides.11,15 The novel receptors (i.e., 7) formed interesting
self-assembled dimeric, trimeric, and tetrameric supramolecular
associations.
Fig. 5. Stacked VT NMR spectra of receptor (7) (400 MHz, DMSO-d6, 298.15e413.15 K).
Molecular modeling at the semi-empirical parameterized model
3 (PM3) level for two assembled molecules of (7) suggested that the
receptor molecules were lined up in a queue-like structure and
connected together by two intermolecular hydrogen bonds forming
between (NH/O]C) (4)-(5) and (40)-(50) (Fig. 7, A). Further prob-
able structures (BeE) were not taken into consideration because
they could not permit formation of intermolecular hydrogen bonds.
Proposed fragmentation mechanisms of the self-assembled as-
sociations of receptor (7) are shown in Fig. 8. Interestingly, the
novel receptors (i.e., 7) showed unprecedented recognition to the
carboxylic guests and oligopeptides (14e20) with formation of 1:1,
1:2, 1:3, and 2:1 complexes, which have been confirmed by ESI-
TOF/MS and MS/MS (Scheme 1 and Table 2). Up to six assembled
associations of receptor (7) were observed and unambiguously
assigned by ESI-TOF/MS and tandem ESI-MS (see the
Supplementary data). The tandem ESI-MS of the supramolecular
complex (7/14) showed a peak at m/z 1168.3, corresponding to two
The behavior of the new receptors toward increasing tempera-
ture was investigated by performing variable temperature NMR (VT
NMR) studies. The VT NMR experiment for receptor (7) was per-
formed from 313.15 to 413.15 K in DMSO-d6 (Fig. 5). By increasing
temperature, the NH moieties of receptor (7) showed significant
downfield chemical shifts. The decrease in
d
(ppm) for NHc, NHe,
and NHd is a consequence of breaking inter- or intramolecular hy-
drogen bonds (NH/O]C). Cooling the NMR to 298.15 K gave the
same spectrum as first recorded due to the re-establishment of the
hydrogen bonds. The molecular self-assembly of (7) was in-
vestigated by ESI-TOF/MS and MS/MS. The tandem ESI mass spectra
for the self-assembled associations of (7) are shown in Fig. 6(bed).
The ESI-TOF/MS of (7) (Fig. 6a) showed four peaks at m/z 511.2,
999.4, 1487.6, and 1976.8, corresponding to the sodiated molecular
ion peaks of the free receptor, dimeric, trimeric, and tetrameric self-
assembled structures, respectively.
assembled molecules of (7) with a one molecule of
D
-(ꢀ)-quinic
acid (14) (Fig. 9c). It gave upon fragmentation three peaks
appearing at m/z 487.0, 679.1, and 975.2 (base peak), which con-
firmed self-assembly in the order shown in Fig. 10a (structure S1).
Structure (S2) was excluded because its fragmentation could not
yield a peak at m/z 975 for the intermolecular bonded two mole-
cules of (7).
Another interesting example is the self-assembly of the
supramolecular complex (7/16) (for HRMS and MS/MS spectra, see
the Supplementary data). The tandem ESI mass spectrum of the H/
G complex (7/16) showed a peak at m/z 1613 for three assembled
molecules of (7) with a one molecule of
L-(þ)-tartaric acid (16). The
MS/MS of this complex gave five intense peaks appearing at m/z
1463.3,1125.2, 975.2 (base peak), 636.9, and 486.9. These fragments
were assigned to three self-assembled molecules of (7), two mol-
ecules of (7) with a one molecule of (16), two molecules of (7), a one
molecule of (7) with a one molecule of (16), and the free receptor
(7), respectively. It can be clearly understood that three molecules
of (7) were directly linked by intermolecular hydrogen bonds and
the guest,
L
-(þ)-tartaric acid (16), bound to the first member in the
assembly. The ESI-TOF/MS and MS/MS for the self-assembled ag-
gregates (7/14e20) are shown in Supplementary data.
In solution, we investigated the effect of increasing the molar
equivalency of
D
-(ꢀ)-quinic acid (14), in a mixture of (7/14), on the
Fig. 4. Computed structure of receptor (7) at the AM1 level. A PolakeRibiere conjugate
gradient with rms 0.01 kcal molꢀ1 was used.
d (ppm) of the NH and OH protons. A small upfield shift

H.F. Nour et al. / Tetrahedron 69 (2013) 11130e11137
11133
Fig. 7. Bird’s-eye view for a proposed computed structure of two assembled molecules
of (7). Structures were energy minimized at the PM3 level. A PolakeRibiere conjugate
gradient with rms 0.01 kcal molꢀ1 was used.
(ꢀ0.0012 ppm) was observed for the three hydroxyl groups (OH3,
OH4, and OH5), while (OH1) showed a small downfield shift
(þ0.008 ppm) at a stoichiometry of 1:10 of (7/14). The NH protons
of (7) showed upfield shifts of (ꢀ0.0252 ppm), (ꢀ0.0149 ppm), and
(ꢀ0.0069 ppm) for NHc, NHe, and NHd, respectively. The (ArH)
showed upfield shifts of (ꢀ0.0131 ppm) and (ꢀ0.008 ppm) for ArHf
and ArHg, respectively. It can be inferred that the carboxylic proton
(COOH) of (14) formed an intermolecular hydrogen bond with ei-
ther C]O (2) or (5) of receptor (7), while the NH protons did not
participate directly in these interactions (for stacked 1H NMR
spectra of complex (7/14), see the Supplementary data). We per-
formed a 2D ROESY NMR experiment to investigate the exact
binding mode in complex (7/14).
Unfortunately no through space interactions were observed
between host (7) and guest (14) due to the long through space
distance between the protons. The slightly small shift of the NH
signals of (7) in response to addition of (14) could be a consequence
of the competitive recognition of the H/H and H/G assembles in
Fig. 6. Self-assembled associations of receptor (7) in the positive ion mode, (a) ESI-
TOF/MS, (bed) tandem ESI-MS of the self-assembled associations. Products detected
as [MþNa]þ ions.
Fig. 8. Proposed structure and fragmentation mechanism for self-assembled four
molecules of receptor (7).

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H.F. Nour et al. / Tetrahedron 69 (2013) 11130e11137
Scheme 1. A selection of chiral carboxylic guests and oligopeptides (14e20).
solution. It also could be attributed to the competing effect of the
solvent.
2.3. Recognition of receptors (7), (9), and (10) to oligopeptides
(18e20)
The molecular recognition of the new receptors to the chiral
carboxylic guests has inspired us to assess the interactions of
a mixture of different hosts with the oligopeptide guests (18e20).
The recognition of receptors (7), (9), and (10) to oligopeptides
(18e20), which mimic the backbone structure of the bacterial cell
wall, was investigated by ESI-TOF/MS and tandem ESI-MS. Three
experiments were conducted for equimolar mixtures of receptors
(7, 9), (7, 10), and (7, 9, and 10) with oligopeptides (18e20) (Table 3
and Fig. 11aec). Supramolecular complexes with mass peaks of 1:1,
1:2, and 2:1 stoichiometries were observed.
The ESI-TOF/MS for a mixture of (7), (9), and (18) showed H/G
peaks appearing at m/z 1076.4 and 1136.4 for complexes (7/18) and
(9/18), respectively (Fig. 11a). Two H/G mass peaks appeared at m/z
1076.4 and 1102.5 in a mixture of (7), (10), and (18) (Fig. 11b). In the
last experiment equimolar quantities of receptors (7), (9), and (10)
were mixed with guest (18). Three H/G complex peaks were ob-
served at m/z 1076.4, 1102.5, and 1136.4, corresponding to
Table 2
ESI-TOF/MS data of the H/G complexes (7/14e20)
Complex
Molecular Formula
Calcd m/z
Meas. m/z
Error [ppm]
7H/14a,G
7H/14b,G
7H/14c,G
7H/15d,G
7H/15e,G
7H/16a,G
7H/16b,G
7H/16c,G
7H/17a,G
7H/18d,G
7H/19d,G
7H/19e,G
7H/20d,G
7H/20f,G
C28H36N6O14
C49H60N12O22
C70H84N18O30
679.2217
1167.3872
1655.5528
796.2566
1284.4222
637.1747
1125.3403
1613.5058
620.1958
1076.4643
1005.4272
1493.5928
876.3846
1263.5964
679.2248
1167.3888
1655.5529
796.2573
1284.4226
637.1777
1125.3447
1613.5082
620.1976
1076.4673
1005.4289
1493.5875
876.3864
1263.5964
ꢀ4.6
ꢀ1.3
ꢀ0.1
ꢀ0.8
ꢀ0.3
ꢀ4.6
ꢀ3.9
ꢀ1.5
ꢀ2.9
ꢀ2.8
ꢀ1.7
3.6
Fig. 9. Self-assembled supramolecular complex (7/14), (a) ESI-TOF/MS, (b and c) tan-
dem ESI-MS for the assembled associations of (7/14). Product detected as [MꢀH]ꢀ ions.
C31H41N9O14
S
C52H65N15O22
C25H30N6O14
C46H54N12O22
C67H78N18O30
C25H31N7O12
C45H65N13O18
C42H60N12O17
C63H84N18O25
C37H53N11O14
C53H82N16O20
S
complexes (7/18), (10/18), and (9/18), respectively (Fig. 11c). The
peak intensities of the complexes don’t reflect the actual distribu-
tion of the complexes in solution or correlate with their stabilities,
since the ionization efficiency in ESI-MS is still dependent on the
desolvation energies of the individual complexes. Interestingly, we
observed mass peaks for stable H/G complexes of two different
receptors binding with a one molecule of the oligopeptide guests.
The ESI-TOF/MS for a mixture of (7), (9), and (19) showed a peak at
m/z 1553.6, corresponding to the supramolecular complex (7/9/19).
It gave upon dissociation two peaks at m/z 1003.2 (7/19) and 515.1
ꢀ2.0
0
Products detected as (a) [(MHþMG)ꢀH]ꢀ, (b) [(2MHþMG)ꢀH]ꢀ, (c) [(3MHþMG)ꢀH]ꢀ,
(d) [(MHþMG)þH]þ, (e) [(2MHþMG)þH]þ, and (f) [(MHþ2MG)þH]þ
.

H.F. Nour et al. / Tetrahedron 69 (2013) 11130e11137
11135
Fig. 10. Proposed assembly and fragmentation mechanism of the supramolecular
complex (7/14).
(19). The order of assembly can accordingly be (9/7/19) or (7/19/9).
Both structures can dissociate to give the H/G complex (7/19) (see
the Supplementary data). Macrocycle (B), which has a similar
backbone structure to (7), cannot form complex structures in this
order.16 ESI-TOF/MS for higher molecular weight assembles are
shown in Supplementary data.
The chirality of the novel compounds (7e13) was confirmed by
CD spectroscopy (Fig. 12). The CD spectrum of receptor (7) showed
a bisignate Cotton effect with a negative sign at around 250 nm and
a positive sign at around 255 nm, which indicated a strong exci-
tation coupling between the chromophores. Also, receptor (7)
showed larger molar ellipticity in comparison with its
stereoisomer (11).
3. Conclusion
In summary, a novel class of chiral non-racemic two-armed re-
ceptors has been synthesized from the addition reactions of chiral
dioxolane dicarbohydrazides to substituted aromatic isocyanates.
The receptors adopt a syn/syn conformation in solution, which is
stabilized by intramolecular hydrogen bonds. They exhibited mo-
lecular self-assembly and formed unprecedented queue-like ag-
gregates with
a selection of chiral carboxylic guests and
oligopeptides. To the best of our knowledge, assembly in this order
has never been reported in the Literature. The formed supramo-
lecular assemblies were stabilized by intermolecular hydrogen
bonds. The receptors showed a remarkable degree of flexibility in
comparison with macrocycles (A) and (B). Furthermore, the new
dioxolanes can be obtained in good yields as analytically and
enantiomerically pure products. We expect applications of these
receptors in understanding noncovalent interactions, binding with
metal ions or developing new chemical sensors.
Fig. 11. ESI-TOF/MS for recognition of receptors (7), (9), and (10) to oligopeptide (18),
(a) (7/9/18), (b) (7/10/18)‚ and (c) (7/9/10/18).
4. Experimental section
4.1. General
All the reagents used for the reactions were purchased from
SigmaeAldrich, Applichem or Flucka (Germany), and were used as
Table 3
ESI-TOF/MS data for recognition of receptors (7), (9), and (10) to oligopeptide (18)
H/G complex
Molecular Formula
C45H65N13O18
Product ionsa
Calcd m/z
Found m/z
Error [ppm]
(7 and 9/18)
[(M7þM18)þH]þ
1076.4643
1097.3807
1136.4855
1175.5903
1684.6721
1076.4673
1175.5904
1102.5238
1076.4681
1136.4855
1102.5310
1175.5908
1650.7193
1684.6791
1076.4659
1097.3828
1136.4868
1175.5890
1684.6755
1076.4643
1175.5903
1102.5276
1076.4643
1136.4900
1102.5276
1175.5903
1650.7143
1684.6721
ꢀ1.5
ꢀ1.9
ꢀ1.2
1.0
ꢀ2.0
ꢀ2.7
ꢀ0.1
3.4
ꢀ3.5
ꢀ4.0
ꢀ3.1
ꢀ0.5
3.1
C46H56N12O20
C47H69N13O20
C48H82N14O20
C70H97N19O30
C45H65N13O18
C48H82N14O20
C47H71N15O16
C45H65N13O18
C47H69N13O20
C47H71N15O16
C48H82N14O20
C70H99N21O26
C70H97N19O30
[(2M9)þH]þ
[(M9þM18)þH]þ
[2M18þH]þ
[2M9þM18þH]þ
[(M7þM18)þH]þ
[2M18þH]þ
(7 and 10/18)
[(M10þM18)þH]þ
[(M7þM18)þH]þ
[(M9þM18)þH]þ
[(M10þM18)þH]þ
[2M18þH]þ
(7, 9, and 10/18)
[(M9þM10þM18)þH]þ
[(2M9þM18)þH]þ
ꢀ4.1
a
ESI-TOF/MS were recorded in the positive ion mode.

11136
H.F. Nour et al. / Tetrahedron 69 (2013) 11130e11137
Circular dichroism measurements were carried out using Jasco-J-
810 Spectropolarimeter in H2O and DMSO. Pre-loaded Wang resin,
DIEA (N,N-diisopropylethylamine), HOBt [O-(benzotriazol-1-yl)-
hydroxybenzotriazole], HBTU (N,N,N’,N’-tetramethyluranium hexa-
fluorophosphate), 1-Fmoc (9-fluorenylmethoxycarbonyl)amino acid
derivatives, DMF, NMP (N-methylpyrrolidone), TFA (trifluoroacetic
acid), EDT (1,2-ethanedithiol) and other chemicals required for
peptide synthesis were bought from Iris Biotech GmbH (Mark-
tredwitz, Germany). Peptides were synthesized with a standard solid
phase peptide synthesis technique and it was carried out on an au-
tomated peptide synthesizer (ABI-433A, Applied Biosystems, Foster
City, USA). Fmoc protected pre-loaded resin was used to grow pep-
tide chain on it. In detail, deprotection of the N-terminal of the resin
bound amino acid was performed by 20% piperidine in NMP and the
C-terminal of other protected amino acid was activated using HBTU/
HOBt/DIEA (1:1:2) in DMF for coupling with the free N-terminal of
the resin bound amino acid. A mixture of 82.5% TFA, 5% phenol, 5%
H2O, 5% thioanisole, and 2.5% EDT was used to separate the peptide
from resin as well as to remove the side chain protecting groups.
Subsequently, the peptide was isolated through precipitation in cold
(ꢀ20 ꢁC) Et2O and lyophilized by Christ freeze dryers (Martin Christ
Gefriertrocknungsanlagen GmbH, Osterode am Harz, Germany).
Peptides were purified by HPLC (high performance liquid chroma-
tography) and analyzed by HRMS. The dicarbohydrazides (1e3) were
synthesized according to the Literature.9a,b
4.2. General procedure for preparation of chiral receptors
(7e13)
To a stirred solution of the corresponding aryl isocyanates (4e6)
(2 mmol) in anhydrous THF (6 mL) were added dicarbohydrazides
(1e3) (1.1 mmol) in anhydrous THF (6 mL). The mixture was stirred at
room temperature for 24 h. The solid was filtered, washed successively
with H2O, Et2O, and dried to give the chiral dioxolane receptors (7e13).
4.2.1. 2,20-((4R,5R)-1,3-Dioxolane-4,5-dicarbonyl)bis(N-(4-
methoxyphenyl)hydrazinecarboxamide) (7). Prepared from (4R,5R)-
1,3-dioxolane-4,5-dicarbohydrazide (1) and 4-methoxyphenyl iso-
cyanate (4) (740 mg, 78%) as a white solid precipitate (mp 227e228);
nmax (solid) 3271, 1689 cmꢀ1
; d (400 MHz, DMSO-d6) 10.05 (2H, br s,
NHCO), 8.54 (2H, br s, NHCO), 8.04 (2H, br s, NHCO), 7.31 (4H, m,
ArH), 6.79 (4H, m, ArH), 5.14 (2H, br s, OCH2), 4.65 (2H, br s, CHCO),
Fig. 12. CD spectra of the chiral receptors (7e13), samples were measured in DMSO.
3.65 (6H, br s, OMe) ppm; d (100 MHz, DMSO-d6) 169.3, 155.7, 155.0,
obtained. Whenever possible the reactions were monitored by thin
layer chromatography (TLC). TLC was performed on Macher-
eyeNagel aluminum backed plates pre-coated with silica gel 60
(UV254). Melting points were determined in open capillaries using
a Buechl B-545 melting point apparatus and are not corrected. In-
frared spectra were determined using a Vector-33 Bruker FTIR
spectrometer. The samples were measured directly as solids or oils;
nmax values were expressed in cmꢀ1 and were given for the main
absorption bands. 1H NMR, 13C NMR, and 2D ROESY spectra were
acquired on a JEOL ECX-400 spectrometer operating at 400 MHz for
1H NMR and 100 MHz for 13C NMR in DMSO-d6 using a 5 mm probe.
133.0, 120.8, 114.3, 97.0, 77.2, 55.6 ppm; m/z 487.0 (40, MHꢀ), 337.8
(100%); HRMS: MHꢀ, found 487.1588. C21H24N6O8 requires 487.1583.
4.2.2. 2,20-((2R,3R)-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-dicarbohydrazide (2) and 4-
methoxyphenyl isocyanate (4) (800 mg, 74%). After 24 h of stirring
at room temperature, H2O was added and the solid was filtered as
a
white solid precipitate (mp>140 ꢁC); nmax (solid) 3294,
1681 cmꢀ1
;
d
(400 MHz, DMSO-d6) 9.99 (2H, br s, NHCO), 8.51 (2H,
br s, NHCO), 8.09 (2H, br s, NHCO), 7.32 (4H, m, ArH), 6.76 (4H, m,
ArH), 4.63 (2H, br s, CHCO), 3.64 (6H, br s, OMe), 1.73e1.55 (6H, m,
The chemical shifts (d) are reported in parts per million (ppm) and
were referenced to the residual solvent peak. The following abbre-
viations are used: s, singlet; m, multiplet; br, broad signal. Mass
spectra were recorded using HCTultra and ESI-TOF Bruker Daltonics
mass spectrometers and samples were dissolved in DMF, CH3CN, and
H2O using the ESI/þMS and ESI/ꢀMS modes. Calibration was carried
out using a 0.1 M solution of sodium formate in the enhanced qua-
dratic mode prior to each experimental run. The results of mea-
surements were processed using Compass 1.3 data analysis software
for a Bruker Daltonics time-of-flight mass spectrometer (micrOTOF).
Molecular modeling calculations were carried out with HyperChem
software (Release 8.0.6) at the AM1 and PM3 levels in vacuo and no
influence of solvents was taken into account in these calculations.13
CH2), 1.53e1.49 (2H, m, CH2), 1.33 (2H, m, CH2) ppm;
d (100 MHz,
DMSO-d6) 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 ppm; m/z 555.0 (52, MHꢀ), 405.9 (100%);
HRMS: MHꢀ, found 555.2224. C26H32N6O8 requires 555.2209.
4.2.3. 2,20-((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 mg, 93%) as
a
white solid precipitate
(400 MHz, DMSO-d6)
(mp>190 ꢁC); nmax (solid) 3299, 1685 cmꢀ1
;
d
10.11 (2H, br s, NHCO), 8.48 (2H, br s, NHCO), 7.88 (2H, br s, NHCO), 7.79
(2H, m, ArH), 6.56 (2H, s, ArH), 6.42 (2H, m, ArH), 5.16 (2H, br s, OCH2),

H.F. Nour et al. / Tetrahedron 69 (2013) 11130e11137
11137
4.63 (2H, br s, CHCO), 3.79 (6H, br s, OMe), 3.68 (6H, br s, OMe) ppm;
Supplementary data
d
(100 MHz, DMSO-d6) 169.1, 155.6, 155.4, 149.7, 122.0, 120.1, 104.6,
99.2, 97.0, 77.1, 56.3, 55.7 ppm; m/z 547.0 (66, MHꢀ), 367.9 (100%);
1H NMR, 13C NMR, ESI-TOF/MS, MS/MS, proposed fragmentation
mechanisms, and assembled structures of the new receptors with
the carboxylic guests and oligopeptides. Supplementary data asso-
ciated with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2013.11.002. These data include MOL file
and InChiKey of the most important compound described in this
article.
HRMS: MHꢀ, found 547.1782. C23H28N6O10 requires 547.1794.
4.2.4. 2,20-((4R,5R)-1,3-Dioxolane-4,5-dicarbonyl)bis(N-(4-
(dimethylamino)phenyl)hydrazinecarboxamide) (10). Prepared from
(4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (1) and 4-dimethyla
minophenyl isocyanate (6) (705 mg, 89%) as a violet solid pre-
cipitate (mp>200 ꢁC); nmax (solid) 3263, 1688 cmꢀ1
; d (400 MHz,
DMSO-d6) 10.04 (2H, br s, NHCO), 8.37 (2H, br s, NHCO), 7.95 (2H, br s,
NHCO), 7.21 (4H, d, J 9.1 Hz, ArH), 6.62 (4H, d, J 9.1 Hz, ArH), 5.14 (2H,
br s, OCH2), 4.65 (2H, br s, CHCO), 2.77 (12H, br s, NMe) ppm;
References and notes
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Seto, C. T.; Mathias, J. P.; Whitesides, G. M. J. Am. Chem. Soc. 1993, 115,
1321.
d
(100 MHz, DMSO-d6) 169.2,155.8,147.0,129.7, 121.0,113.5, 97.0, 77.2,
41.2 ppm; m/z 513.0 (70, MHꢀ), 350.9 (100%); HRMS: MHꢀ, found
513.2240. C23H30N8O6 requires 513.2216.
2. (a) Zhang, S. Biotechnol. Adv. 2002, 20, 321; (b) Zhang, S. Nat. Biotechnol.
2003, 21, 1171; (c) Reches, M.; Gazit, E. Curr. Nanosci. 2006, 2, 105; (d)
Whitesides, G. M.; Mathias, J. P.; Seto, C. T. Science 1991, 254, 1312; (e)
Gazit, E. Nat. Nanotechnol. 2008, 3, 8; (f) Weiß, T.; Schierbaum, K. D.;
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26-27, 203.
4.2.5. 2,20-((4S,5S)-1,3-Dioxolane-4,5-dicarbonyl)bis(N-(4-methoxy-
phenyl)hydrazinecarboxamide) (11). Prepared from (4S,5S)-1,3-
dioxolane-4,5-dicarbohydrazide (3) and 4-methoxyphenyl iso-
cyanate (4) (910 mg, 96%) as a pale yellow solid precipitate (mp
€
224e225 ꢁC); nmax (solid) 3260, 1681 cmꢀ1
; d (400 MHz, DMSO-d6)
3. Beijer, F. H.; Kooijman, H.; Spek, A. L.; Sijbesma, R. P.; Meijer, E. W. Angew. Chem.,
Int. Ed. 1998, 37, 75.
10.05 (2H, br s, NHCO), 8.54 (2H, br s, NHCO), 8.04 (2H, br s, NHCO),
4. Lee, H.-Y.; Olasz, A.; Pink, M.; Park, H.; Lee, D. Chem. Commun. 2011, 481.
5. Ariga, K.; Hill, J. P.; Lee, M. V.; Vinu, A.; Charvet, R.; Acharya, S. Sci. Technol. Adv.
Mater. 2008, 9, 014109.
7.31 (4H, d, J 9.1 Hz, ArH), 6.79 (4H, d, J 9.1 Hz, ArH), 5.15 (2H, br s,
OCH2), 4.66 (2H, br s, CHCO), 3.65 (6H, br s, OMe) ppm; d (100 MHz,
6. (a) Caspar, D. L. D.; Namba, K. Adv. Biophys. 1990, 26, 157; (b) Klug, A. Philos.
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DMSO-d6) 169.3,155.7,155.0,133.0,120.9,114.3, 97.0, 77.2, 55.6 ppm;
m/z 486.9 (100, MHꢀ), 337.9 (19%); HRMS: MHꢀ, found 487.1570.
C21H24N6O8 requires 487.1583.
7. Hartgerink, J. D.; Beniash, E.; Stupp, S. I. Science 2001, 294, 1684.
ꢀ
8. (a) Engeser, M.; Rang, A.; Ferrer, M.; Gutierrez, A.; Tarik Baytekin, T.; Schalley,
4.2.6. 2,20-((4S,5S)-1,3-Dioxolane-4,5-dicarbonyl)bis(N-(2,4-dimeth-
oxyphenyl)hydrazinecarboxamide) (12). Prepared from (4S,5S)-1,3-
dioxolane-4,5-dicarbohydrazide (3) and 2,4-dimethoxyphenyl iso-
cyanate (5) (735 mg, 99%) as a pale yellow solid precipitate
C. A. Int. J. Mass Spectrom. 2006, 255e256, 185; (b) Schalley, C. A. Int. J. Mass
Spectrom. 2000, 194, 11; (c) Schalley, C. A.; Castellano, R. K.; Brody, M. S.;
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(d) Schalley, C. A.; Muller, T.; Linnartz, P.; Witt, M.; Schafer, M.; Lutzen, A.
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dermann, F.; Kalberer, M.; Scherman, O. A. Org. Biomol. Chem. 2012, 10, 2447;
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€
€
€
(mp>190 ꢁC); nmax (solid) 3297, 1696 cmꢀ1
; d (400 MHz, DMSO-d6)
10.13 (2H, br s, NHCO), 8.50(2H, brs,NHCO), 7.90 (2H, br s, NHCO), 7.90
(2H, m, ArH), 6.57 (2H, s, ArH), 6.42 (2H, m, ArH), 5.18 (2H, br s, OCH2),
4.66 (2H, br s, CHCO), 3.79 (6H, br s, OMe), 3.68 (6H, br s, OMe) ppm;
d
(100 MHz, DMSO-d6) 169.2, 155.6, 155.4, 149.7, 121.9, 120.2, 104.6,
99.2, 97.1, 77.2, 56.2, 55.7 ppm; m/z 547.0 (39, MHꢀ), 367.9 (100%);
HRMS: MHꢀ, found 547.1799. C23H28N6O10 requires 547.1794.
10. Skowronek, P.; Kuncewicz, M.; Brzostowska, M.; Janiak, A.; Rychlewska, U.;
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Gawronski, J. Tetrahedron: Asymmetry 2012, 23, 300.
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11. Nour, H. F.; Islam, T.; Fernandez-Lahore, M.; Kuhnert, N. Rapid Commun. Mass
4.2.7. 2,20-((4S,5S)-1,3-Dioxolane-4,5-dicarbonyl)bis(N-(4-
(dimethylamino)phenyl)hydrazinecarboxamide) (13). Prepared from
(4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (3) and 4-dimethyla-
minophenyl isocyanate (6) (740 mg, 93%) as a violet solid pre-
Spectrom. 2012, 26, 2865.
ꢀ
12. (a) Gawronski, J.; Ko1bon, H.; Kwit, M.; Katrusiak, A. J. Org. Chem. 2000,
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ꢀ
hedron Lett. 2005, 46, 7575; (d) Kuhnert, N.; Lopez-Periago, A. M. Tet-
cipitate (mp>210 ꢁC); nmax (solid) 3256, 1688 cmꢀ1
; d (400 MHz,
ꢀ
rahedron Lett. 2002, 43, 3329; (e) Kuhnert, N.; Lopez-Periago, A. M.;
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DMSO-d6) 10.04 (2H, br s, NHCO), 8.37 (2H, br s, NHCO), 7.95 (2H, br
s, NHCO), 7.21 (4H, d, J 9.1 Hz, ArH), 6.61 (4H, d, J 9.1 Hz, ArH), 5.14
(2H, br s, OCH2), 4.64 (2H, br s, CHCO), 2.76 (12H, br s, NMe) ppm;
ꢀ
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Nour, H. F.; Matei, M. F.; Bassil, B. S.; Kortz, U.; Kuhnert, N. Org. Biomol.
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d
(100 MHz, DMSO-d6) 169.3, 155.8, 147.0, 129.7, 121.0, 113.5, 97.0,
77.2, 41.2 ppm; m/z 513.1 (31, MHꢀ), 350.9 (100%); HRMS: MHꢀ,
13. (a) Molecular Modeling Was Carried Out Using HyperChem Software (Release
8.0.6). Hypercube: 1115 NW 4th Street, Gainesville, F1orida 32601 USA. Trial
version from http://www.hypercube.com‚ 1995e2008. (b) Stewart, J. J. P. J.
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found 513.2233. C23H30N8O6 requires 513.2216.
14. (a) Alfonso, I.; Bolte, M.; Bru, M.; Burguete, M. I.; Luis, S. V.; Vicent, C. Org. Bi-
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T. Rapid Commun. Mass Spectrom. 2001, 15, 685.
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Acknowledgements
ꢀ
H.N. thanks Deutscher Akademischer Austausch Dienst (DAAD)
2012, 26, 1070.
for financial support and Jacobs University for excellent facilities.
16. Nour, H. F.; Golon, A.; Kuhnert, N. Unpublished results.