Synthesis of novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles

Article abstract of DOI:10.1039/c2ob25171j

A total of twelve novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles have been synthesised in quantitative yields by reacting chiral (4R,5R)- and (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazides with aromatic bis-aldehydes in a [2+2]-cyclocondensation reaction. The compounds show a dynamic behaviour in solution, which has been rationalized in terms of an unprecedented conformational interconversion between two conformers one stabilised by intramolecular hydrogen bonding and π-π stacking interactions.

Full text of DOI:10.1039/c2ob25171j

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PAPER
Synthesis of novel enantiomerically pure tetra-carbohydrazide cyclophane
macrocycles†
Hany F. Nour, Nadim Hourani and Nikolai Kuhnert*
Received 22nd January 2012, Accepted 3rd April 2012
DOI: 10.1039/c2ob25171j
A total of twelve novel enantiomerically pure tetra-carbohydrazide cyclophane macrocycles have been
synthesised in quantitative yields by reacting chiral (4R,5R)- and (4S,5S)-1,3-dioxolane-4,5-
dicarbohydrazides with aromatic bis-aldehydes in a [2 + 2]-cyclocondensation reaction. The compounds
show a dynamic behaviour in solution, which has been rationalized in terms of an unprecedented
conformational interconversion between two conformers one stabilised by intramolecular hydrogen
bonding and π–π stacking interactions.
majority of supramolecular systems employ synthetic macrocyc-
lic compounds as host molecules.
Introduction
In recent years supramolecular chemistry has emerged as one of
the most actively pursued fields of the chemical sciences. Its
implications now reach from the basis of molecular recognition
in natural systems such as protein substrate interactions to excit-
ing new applications in chemical technology and material
sciences.1–9 Molecular recognition of metal cations using non-
natural receptors has reached a high level of maturity and sophis-
tication and as a consequence is successfully applied on an
industrial scale.10–12 Molecular recognition of anions using non-
natural receptors is making rapid progress,13 whereas molecular
recognition of small to medium sized organic molecules is
somehow lingering behind mainly due to the complexity of the
scientific challenge.9,10 However, a diverse number of potentially
useful applications of molecular recognition of small organic
molecules using synthetic receptors have been suggested and are
actively pursued. Among the most promising applications of
molecular recognition are the binding and remediation of
environmental toxins from soil, water and food and the binding
and removal of undesired trace by-products from the bulk manu-
facturing of fine chemicals, which all require good water solubi-
lity of the supramolecular host.14 Moreover, chiral recognition
and resolution of enantiomers, the development of sensors and
biosensors and finally the design, development and synthesis of
nano-gadgets and molecular machines form exciting challenges
for supramolecular chemistry for the next decade.8,9 The
Certain classes of macrocyclic molecules have dominated the
field including calix[n]arenes, cyclodextrins, crown-ethers and
cucurbiturils. These macrocycles were characterised by synthetic
methods making them easily available in large quantities, func-
tional groups allowing simple transformations to access more
sophisticated structures with elaborate binding motifs, good
water solubility for cyclodextrins and cucurbiturils and their
ability to bind a large variety of important guest molecules.
In the search for an ideal class of macrocycle, we have
reported on numerous occasions on the synthesis of trianglimine
macrocycles, obtained through
a [3 + 3]-cyclocondensation
reaction.1,2,15–20 These macrocycles fulfil, from a synthetic point
of view, all the requirements for an ideal macrocycle. Since the
compounds are available in a simple synthetic procedure in
almost quantitative yields from versatile building blocks, purifi-
cation is simple, the structure of building blocks can be largely
varied to allow a modular assembly of compounds with tunable
sizes and ample functionalities and finally they are enantiomeri-
cally pure and are accessible in both enantiomeric forms.
Despite all of these synthetic advantages, we have failed in
the last decade to obtain trianglimine derivatives showing good
solubility in polar solvents and additionally reported binding
constants have on no occasion exceeded the mM range. For this
reason we decided to redesign the synthetic approach we suc-
cessfully employed in trianglimine chemistry to obtain novel
macrocycles with improved properties. Maintaining the attractive
concept of conformationally biased macrocyclisations in [n + n]-
cyclocondensation reactions, we searched for suitable novel
chiral building blocks that allow incorporation of ample func-
tionality into the macrocycle combined with improved solubility
properties. Work by Sanders and co-workers have demonstrated
on numerous occasions that the combination of hydrazides with
reactive carbonyl compounds allow an efficient construction of
School of Engineering and Science, Organic and Analytical Chemistry
Laboratory, Jacobs University Bremen, Campus ring 1, P. O. Box. 750
561, 28725 Bremen, Germany. E-mail: n.kuhnert@jacobs-university.de,
h.nour@jacobs-university.de; Fax: (+)49 421 200 3229
†Electronic supplementary information (ESI) available: 1H NMR, 13C
NMR, ESI- and APCI-MS, proposed fragmentation mechanisms of the
novel macrocycles. See DOI: 10.1039/c2ob25171j
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multifunctional macrocyclic structures.21,22 Adapting this
approach to the synthesis of novel macrocycles by [n + n]-cyclo-
condensation, meant that we investigated the reaction between a
selection of chiral dihydrazides with aromatic dicarbonyl com-
pounds. In this contribution we report on the successful syn-
thesis of novel chiral tetra-carbohydrazide cyclophane
macrocycles based on dihydrazides obtained from tartaric acid
and a selection of aromatic dialdehydes.
13C NMR spectrum showed three signals at δ 168.0, 96.8 and
77.2 ppm corresponding to (CvO), (CH2) and (CH),
respectively.
FT-IR (Fourier transform infrared spectroscopy) spectrum
showed strong absorption band at ν 1667 cm−1 corresponding to
the stretching vibration of the ν CvO. It showed also weak
absorption bands at ν 3191 and 3320 cm−1 corresponding to the
hydrazide NH moieties. ESI-TOF (electrospray ionization time-
of-flight) mass spectrum showed the expected pseudo molecular
ion peak at 403.1277 Da as the sodium adduct of two molecules
of the hydrazide (2M + Na+).
Results and discussion
It is worth noting that the novel dicarbohydrazides adopt con-
formations in which the carbonyl groups assume anti-orientation
to each other.25 These conformations are stabilised by strong n
→ π* interaction and intramolecular hydrogen bonding as
suggested by computational calculations (Fig. 1). Consequently,
the dicarbohydrazides become good candidates for macrocyclisa-
tion based on conformational bias, rather than polymerisation.
Next we turned out attention to the macrocyclisation reaction
of the obtained dihydrazides 2, 4, 5 and 6 with a selection of aro-
matic dialdehydes. The [2 + 2]-cyclocondensation reaction was
optimised in terms of stoichiometries and concentration of the
reactants. The common strategies for the synthesis of macro-
cycles involve either using external template to assist the macro-
cyclisation process or applying high dilution conditions to avoid
polymerisation.26–29 We conducted the [2 + 2]-cyclocondensa-
tion reaction in CH2Cl2 at 0.1 and 0.01 M. After 24 h we noticed
that, the macrocyclic product neither form by stirring at room
temperature nor by refluxing. However, some intermediates were
detected by ESI-TOF mass spectrometry which existed in equili-
bration over the course of the reaction (see ESI†). Following our
strategy, the [2 + 2]-cyclocondensation reaction took place
efficiently in MeOH at relatively high concentration of the reac-
tants (0.05 M or less) under reflux for 7 h in the presence of few
drops of AcOH as a catalyst. The [3 + 3]- and [4 + 4]-cyclocon-
densation products were observed along with the [2 + 2]-macro-
cycle under high dilution conditions (1 M), however the [2 + 2]-
macrocycle was the predominant product. We also found that,
the [2 + 2]-macrocycle forms selectively in analytically pure
form in case where a slightly excess of the dicarbohydrazide was
used (i.e., 1.2 to 1 M).
For the modular assembly of chiral macrocycles we decided to
investigate dihydrazides based on tartaric acid, offering the
advantage that both enantiomeric forms of a macrocycle will be
accessible. Our approach towards the synthesis of dihydrazide
building blocks involves protection of the vicinal hydroxyl
groups of commercially available (+)-diethyl L-tartrate (1) and
(−)-diethyl D-tartrate (2) with diethoxymethane in the presence
of the Lewis acid catalyst BF3(OEt)2.23
In situ condensation of the protected diesters with hydrazine
monohydrate in absolute ethanol afforded the corresponding
(4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2) and (4S,5S)-1,3-
dioxolane-4,5-dicarbohydrazide (4), which serve as the building
blocks for the novel macrocycles (Scheme 1).
Similarly, chiral dihydroxy (2R,3R)-hydrazide (5) and (2S,3S)-
hydrazide (6) were synthesised by reacting (+)-diethyl L-tartrate
(1) and (−)-diethyl D-tartrate (3) with hydrazine mono-hydrate in
absolute ethanol (Scheme 2).24 Structures of hydrazides (2), (4),
(5) and (6), were fully characterised using various spectroscopic
techniques. 1H NMR spectrum for (i.e., dicarbohydrazide 2)
showed broad signals at δ 9.42, 5.04, 4.41 and 4.32 ppm
corresponding to (NH), (CH), (CH2) and (NH2), respectively.
(4R,5R)-1,3-Dioxolane-4,5-dicarbohydrazide (2) reacted with
isophthaldehyde, terephthaldehyde, 4,4′-diformylbiphenyl, 4-(4-
formylphenoxy)-benzaldehyde and 4,4′-diformyltriphenylamine
Scheme 1 Synthetic route to chiral hydrazides (2) and (4).
Fig. 1 Bird’s-eye view for the computed structure of chiral dihydra-
zides (2) and (4). Structures were energy minimised using AM1 method
Scheme 2 Synthetic route to chiral hydrazides (5) and (6).
and a Polak–Ribiere conjugate gradient with rms < 0.01 kcal. mol−1
.
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to afford the corresponding [2 + 2]-cyclocondensation products
(7–9), (13) and (14) in quantitative yields which were suffi-
1
ciently pure as judged by H NMR and ESI-TOF mass spectra
(Schemes 3 and 4). Similarly, macrocycles (10–12), (15) and
(16) were synthesised according to the above mentioned pro-
cedure from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)
(Schemes 3 and 4).
Structures of the novel macrocycles were fully assigned on the
1
basis of H NMR, 13C NMR, 2D-NMR, VT-(variable tempera-
ture) NMR, CD-spectroscopy, ESI- or APCI-TOF (atmospheric
pressure chemical ionisation) and FT-IR. APCI-TOF mass spec-
trum for macrocycle (10) showed the expected molecular ion
peak (M + Na+) at 599.1599 Da (Fig. 2, see ESI† for ESI-mass
spectra and fragmentation mechanisms). High resolution TOF-
mass spectrometry data are given in Table 1. FT-IR spectrum for
macrocycle (10) showed the presence of a strong absorption
band at ν 1680 cm−1 corresponding to the stretching vibration of
Scheme 4 [2 + 2]-Cyclocondensation products (13–16).
1
the ν CvO and ν CvN. H NMR spectra for the novel macro-
cycles at ambient temperature in both DMSO-d6 and DMF-d7
showed broad signals suggesting conformational flexibility in
Scheme 3 [2 + 2]-Cyclocondensation products (7–12).
Fig. 2 APCI-TOF mass spectrum for macrocycle (10), from DMSO.
Table 1 High resolution TOF-mass data for the novel chiral macrocycles and isolated yields
Compound
Molecular formula
m/z
Meas. m/z
Error (ppm)
Yield (%)
2
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
C10H20N8NaO8
C10H20N8NaO8
C8H20N8NaO8
C8H20N8NaO8
2M + Na+
2M + Na+
2M + Na+
2M + Na+
M + Na+
M + H+
403.1296
403.1296
379.1296
379.1296
599.1609
577.1790
729.2475
599.1609
403.1277
403.1276
379.1285
379.1281
599.1596
577.1782
729.2508
599.1599
577.1450
727b
761.2292
933.3048
783.2113
911.3292
553.1816
553.1954
4.7
5.1
3.1
4
2.3
1.4
4.5
1.7
57
63
88
70
99
99
98
99
99
97
99
99
98
99
99
99
C
26H24N8NaO8
C26H25N8O8
C38H33N8O8
C26H24N8NaO8
M + H+
M + Na+
M + H+
C
26H25N8O8
577.1429
3.6
b
a,b
C38H31N8O8
C38H33N8O10
C50H42N10NaO8
M − H+
M + H+
761.2314
933.3079
783.2134
911.3260
553.1844
553.1941
2.9
3.4
2.6
−3.5
5
M + Na+
M + Na+
M + H+
C
38H32N8NaO10
C50H43N10O8
C24H25N8O8
C24H25N8O8
M + H+
M + H+
−2.3
a Error value could not be estimated due to poor solubility and hence low peak intensity. b APCI-MS2.
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Fig. 3 Variable temperature 1H NMR spectra for compound (13),
400 MHz, DMF-d7.
1
solution. H NMR spectrum for macrocycle (13) in DMSO-d6
showed a broad signal at δ 11.66 ppm with an integration of four
(4 × NH). It showed also four broad singlets at δ 8.34, 8.06, 7.93
and a signal at 7.71 ppm overlapping with the aromatic protons
corresponding to four non-equivalent azomethine protons (see
Fig. 3). In DMF-d7 the signal corresponding to the (NH) protons
splits into two broad signals appearing at δ 11.70 and
11.54 ppm, each signal integrated with two (4 × NH). In
addition, four broad signals appeared at δ 8.51, 8.28, 8.12 and
7.97 ppm corresponding to four non-symmetrical azomethine
protons.
Fig. 4 Graphical representation for the change of chemical shift in
In order to characterise the behaviour of the novel macrocycles
in solution, we performed VT-NMR studies for macrocycles (13)
and (14). VT-NMR was performed from 303 to 393 K in DMF-
d7. The two broad signals appearing at δ 11.70 and 11.54 ppm
corresponding to the four (NH) protons coalesced at 383 K to a
broad singlet appearing at δ 11.10 ppm (Fig. 3). Cooling the
NMR to 298 K yields the same spectrum as first recorded illus-
trating the reversibility of the process.
response to increasing temperature.
We suggest that two distinct conformational isomers could
result from intramolecular hydrogen bonding interactions
(–NH⋯OvC), whose interconversion involved fast exchange
during the 1H NMR time scale and resulted in reducing the solu-
bility of the macrocycles in common organic solvents and water.
VT-NMR spectra for macrocycle (14) is available with the
ESI.† The change in chemical shifts in response to changing
temperature can be graphically represented by plotting the values
of chemical shift (δ in ppm) versus temperature (°C) as shown in
Fig. 4.
It can be inferred that a intramolecular hydrogen bond breaks
upon heating, resulting in upfield shift of the associated (NH)
protons. Our hypothesis of conformational isomers was further
supported by 2D-NMR experiments. The 2D-ROESY spectrum
for macrocycle (14) showed through space interactions between
two (NH) protons with two azomethine protons (HCvN) and
two methine protons (CH) (Fig. 5 and 6).
The other (NH) protons interacted through space with two
azomethine protons (HCvN), while no interactions were
observed with methine protons.
Fig. 5 2D-ROESY spectrum for macrocycle (14), 400 MHz, DMF-d7.
based studies. Data from 2D-ROESY experiments were used for
subsequent structure modelling calculations. Structures of the
novel macrocycles (i.e., macrocycle 14) were optimised using
HyperChem software (Release 8).
The molecular structures were optimised at the AMBER
(assisted model building with energy refinement) and PM3
(parameterised model number 3) levels using the Polak–Ribiere
algorithm until the root mean square (RMS) gradient was
In order to further understand the nature of the intramolecular
hydrogen bonding, we performed several molecular modelling
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Fig. 6 2D-ROESY interactions for macrocycle (14).
0.01 kcal. mol−1 or less. The results of molecular modelling are
in good agreement with the structures suggested by 2D-ROESY
experiment and confirm the presence of intramolecular hydrogen
bonding interactions (Fig. 7).
In solution, macrocycle (14) can assume a minimum energy
conformation (14b) which comprises intramolecular hydrogen
bonding and π–π stacking interactions. Upon heating (14b) rapid
interconversion to the more symmetric conformation (14a)
occurs measurable on the NMR time scale.
Fig. 7 Computed structures for macrocycle (14) at the PM3 and
AMBER levels. A Polak–Ribiere conjugate gradient with rms <
0.01 kcal.mol−1 was used. Some hydrogen atoms were omitted for
clarity.
Next, we turned our attention to assessing the reactivity of the
unprotected dicarbohydrazides towards the [2 + 2]-cycloconden-
sation reaction. (2R,3R)-hydrazide (5) and (2S,3S)-hydrazide (6)
reacted with terephthaldehyde in methanol (<0.05 M) in the
presence of few drops of catalytic AcOH to form highly C2-sym-
metrical [2 + 2]-cyclocondensation products (17) and (18) as
judged by the 1H and 13C NMR spectra (Fig. 8).
This indicated the presence of only one conformer in solution.
1H NMR spectrum for macrocycle (17) showed a broad signal at
δ 11.27 ppm (4 × NH). It also showed broad signals at δ
8.44 ppm corresponding to four azomethine protons (4 ×
HCvN). APCI-TOF mass data for macrocycles (17) and (18)
are shown in Table 1. 2D-ROESY spectrum showed through
space interactions between (NH), (HCvN) and (OH) protons
(see ESI†). In an attempt to investigate and to explain the behav-
iour of the non-protected macrocycles in solution, we performed
molecular modelling studies at the MM+ (molecular mechanics)
level based on data from 2D-ROESY experiments. Molecular
modelling showed that macrocycle (17) adopts a conformation in
which all azomethine protons (HCvN) are anti-oriented. The
free hydroxyl groups can form concerted intramolecular hydro-
gen bonding with the carbonyl groups to yield symmetrical and
stable conformers (Fig. 9).
Fig. 8 [2 + 2]-cyclocondensation products (17) and (18).
Distances (Å) between some selected atoms based on molecu-
lar modelling calculations for macrocycles (13) and (14) are
shown in Table 2.
Fig. 9 Computed structure for macrocycle (17).
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Table 2 Distances (Å) between some selected atoms for macrocycles
(13) and (14)
Macrocycle
(13) (Å)
Macrocycle
(14a) (Å)
Macrocycle
(14b) (Å)
Atoms
C2–C21
C3–C22
C4–C23
C5–C24
N6–N25
N7–N26
C8–C27
C9–C28
C12–C31
X13–X32
C14–C33
C17–C36
C18–C37
N19–N38
N20–N1
11.83
14.02
13.56
15.56
15.90
14.02
14.99
13.79
13.25
14.09
12.51
11.49
12.06
11.59
12.42
11.12
13.51
13.45
15.43
16.04
14.29
15.43
14.40
14.18
14.94
13.27
11.70
12.00
10.55
11.92
16.64
17.14
15.77
13.45
12.21
10.18
9.31
7.33
6.60
5.28
6.29
9.84
12.00
13.15
15.27
The chirality of the novel macrocycles and their precursors
was confirmed by CD-spectroscopy as shown in Fig. 10. All-R
macrocycle (14) shows for example a positive Cotton effect with
a zero intercept at around 370 nm, whereas its enantiomeric
counterpart all-S (16) shows a negative Cotton effect. Similar to
trianglimines the observed Cotton effect is a consequence of the
interaction of the two aromatic chromophores within the
macrocycle.
Conclusion
In summary, we have synthesised a novel class of chiral non-
racemic tetra-carbohydrazide macrocycles starting from commer-
cially available diethyl tartrates. After conversion of the chiral
building block to a dihydrazide, reaction with aromatic dialde-
hydes yielded the novel macrocycles. The macrocyclisation reac-
tion takes place at relatively high concentration of the reactants
in MeOH (<0.05 M) to afford, presumably under conformational
bias, selectivity the [2 + 2]-cyclocondensation products. Macro-
cycles are available in both enantiomeric forms. VT-NMR along
with 2D-NMR experiments confirmed the presence of a dynamic
behaviour in solution, which has been rationalized in terms of an
unprecedented conformational interconversion between two con-
formers one stabilised by intramolecular hydrogen bonding and
π–π stacking interactions. Further work aimed at assessing mol-
ecular recognition of the novel macrocycles in DMF and enhan-
cing solubility in other organic solvents is under investigation
and will be published in due course.
Fig. 10 CD-spectra for chiral hydrazides (2,4–6) in water and [2 + 2]-
cyclocondensation products (7,10 and 13–16) in DMSO.
B-545 melting point apparatus and are not corrected. Infrared
spectra were determined using a Vector-33 Bruker FT-IR
spectrometer.
The samples were measured directly as solids or oils; νmax
values were expressed in cm−1 and were given for the main
1
absorption bands. H NMR and 13C NMR spectra were acquired
1
on a JEOL ECX-400 spectrometer operating at 400 MHz for H
NMR and 100 MHz for 13C NMR in DMSO-d6, D2O, CDCl3 or
DMF-d7 using a 5 mm probe. The chemical shifts (δ) are
reported in parts per million and were referenced to the residual
solvent peak. The following abbreviations are used: s, singlet; m,
multiplet; br, broad signal. Mass spectra were recorded using
HCTultra and ESI- or APCI-TOF Bruker Daltonics mass spec-
trometers and samples were dissolved in DMSO, DMF and
acetonitrile or water using the positive and negative electrospray
ionisation modes. Calibration was carried out using a 0.1 M sol-
ution of sodium formate in the enhanced quadratic mode prior to
each experimental run. The results of measurements were pro-
cessed using Compass 1.3 data analysis software for a Bruker
Daltonics time-of-flight mass spectrometer (micrOTOF). Mol-
ecular modelling calculations were carried out with Hyperchem
software (Release 8.0) at the AM1, PM3, AMBER and MM+
levels in vacuo and no influence of solvents was taken into
Experimental
All the reagents used for the reactions were purchased from
Sigma-Aldrich, Applichem or Flucka (Germany) and were used
as obtained. Whenever possible the reactions were monitored by
thin layer chromatography (TLC). TLC was performed on
Macherey–Nagel aluminium-backed plates pre-coated with silica
gel 60 (UV254). Column chromatography was carried out on
silica gel 60 (0.040–0.063 mm) under flash conditions. Melting
points were determined in open capillaries using a Buechl
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account in these calculations.30,31 4,4′-Biphenyl dicarboxalde-
hyde was synthesised according to the literature.32 Circular
Dichroism measurements were carried out using Jasco-J-810
Spectropolarimeter in H2O and DMSO. We could not measure
the 13C-spectrum for macrocycles (9) due to its poor solubility
in DMSO-d6. All products were suitable for use without further
purification.
(2R,3R)-2,3-Dihydroxydicarbohydrazide (5)
Hydrazine monohydrate (3.1 mL, 116.8 mmol) was added to a
stirred solution of (+)-diethyl L-tartrate (5 mL, 29.2 mmol) in
ethanol (40 mL). The mixture was refluxed for 7 h. The precipi-
tate was filtered off, washed with methanol, diethyl ether and
dried to give the title compound (5) as a white solid (4.61 g,
88%); mp 208–209 °C; IR νmax/cm−1 3408, 3354, 3309 and
3286 (OH and NH), 1661 (CvO); 1H NMR (400 MHz, DMSO-
d6) δH 8.75 (2H, brs, NH), 5.34 (2H, brs, CH), 4.21 (6H, brs,
NH2 and OH); 13C NMR (100 MHz, DMSO-d6) δC 171.0, 72.7;
MS (ESI-MS, H2O, HCTultra) m/z (Calcd 178.1; exp. 200.7,
M + Na+, 100%), (HRMS, ESI-TOF, H2O) m/z (Calcd
379.1296; meas. 379.1285, 2M + Na+).
(4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)
To a stirred solution of (+)-diethyl L-tartrate (17.8 mL,
71.70 mmol) in isopropyl acetate (100 mL) were added
diethoxymethane (12.1 mL, 96.86 mmol) and boron trifluoride
diethyl etherate (23.8 mL, 192.84 mmol), and the mixture was
refluxed for 7 h. The reaction mixture was carefully quenched
with saturated aqueous sodium bicarbonate and the layers were
separated. The water phase was extracted with isopropyl acetate
(2 × 100 mL) and the combined organic layers were dried with
sodium sulfate, filtered and evaporated under reduced pressure.
The crude mixture (21.9 g) was dissolved without further purifi-
cation in ethanol (100 mL) and hydrazine monohydrate (6.8 mL,
213.44 mmol) was added. The reaction mixture was refluxed for
7 h. The precipitate was filtered off, washed with ethanol and
diethyl ether to give the title compound (2) as a white solid
(11.58 g, 57%); mp 210–211 °C; IR νmax/cm−1 3320, 3191
(2S,3S)-2,3-Dihydroxydicarbohydrazide (6)
Hydrazine monohydrate (3.1 mL, 116.8 mmol) was added to a
stirred solution of (−)-diethyl D-tartrate (5 mL, 29.2 mmol) in
ethanol (40 mL). The mixture was refluxed for 7 h. The precipi-
tate was filtered off, washed with methanol, diethyl ether and
dried to give the title compound (6) as a white solid (3.64 g,
70%); mp 208–209 °C; IR νmax/cm−1 3408, 3354, 3309 and
1
3286 (OH and NH), 1659 (CvO); H NMR (400 MHz, D2O)
δH 4.64 and 4.46 (2H, brs, CH); 13C NMR (100 MHz, D2O) δC
171.8, 71.9; MS (ESI-MS, H2O, HCTultra) m/z (Calcd 178.1;
exp. 200.7, M + Na+, 100%), (HRMS, ESI-TOF, H2O) m/z
(Calcd 379.1296; meas. 379.1281, 2M + Na+).
1
(NH), 1667 (CvO); H NMR (400 MHz, DMSO-d6) δH 9.42
(2H, brs, NH), 5.04 (2H, brs, CH), 4.41 (2H, brs, CH2), 4.32
(4H, brs, NH2); 13C NMR (100 MHz, DMSO-d6) δC 168.0,
96.8, 77.2; MS (ESI-MS, H2O, HCTultra) m/z (Calcd 190.1;
exp. 212.8, M + Na+, 100%), (Calcd 190.1; exp. 402.9, 2M +
Na+, 74%), (HRMS, ESI-TOF, H2O) m/z (Calcd 403.1296;
meas. 403.1277, 2M + Na+).
General procedure for the synthesis of tetra-carbohydrazide
macrocycles (7–18)
Dicarbohydrazide (2), (4), (5) or (6) (1.2 mmol) and the corre-
sponding dialdehyde (1 mmol) were mixed in MeOH (<0.05 M)
and two drops of catalytic AcOH were added. The reaction
mixture was refluxed for 7 h. The precipitate which form was
filtered off, washed with water, chloroform and dried to give the
corresponding macrocycle in a quantitative yield.
(4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)
To a stirred solution of (−)-diethyl D-tartrate (17.8 mL,
71.70 mmol) in isopropyl acetate (100 mL) were added
diethoxymethane (12.1 mL, 96.86 mmol) and boron trifluoride
diethyl etherate (23.8 mL, 192.84 mmol), and the mixture was
refluxed for 7 h. The reaction mixture was quenched with satu-
rated aqueous sodium bicarbonate and the layers were separated.
The water phase was extracted with isopropyl acetate (2 ×
100 mL), and the combined organic layers were dried with
sodium sulfate, filtered and evaporated under reduced pressure.
The crude mixture (22.63 g) was dissolved without further
purification in ethanol (100 mL) and hydrazine monohydrate
(6.5 mL, 207.6 mmol) was added to the reaction mixture. The
reaction mixture was refluxed for 7 h. The precipitate was
filtered off, washed with ethanol and diethyl ether to give the
title compound (4) as a white solid (13.11 g, 63%); mp
209–210 °C; IR νmax/cm−1 3320, 3193 (NH), 1667 (CvO);
1H NMR (400 MHz, DMSO-d6) δH 9.41 (2H, brs, NH), 5.04
(2H, brs, CH), 4.41 (2H, brs, CH2), 4.31 (4H, brs, NH2);
13C NMR (100 MHz, DMSO-d6) δC 168.0, 96.8, 77.2; MS
(ESI-MS, H2O, HCTultra) m/z (Calcd 190.1; exp. 212.8,
M + Na+, 100%), (Calcd 190.1; exp. 402.9, 2M + Na+, 67%),
(HRMS, ESI-TOF, H2O) m/z (Calcd 403.1296; meas. 403.1276,
2M + Na+).
(3R,4R,16R,17R)-Tetra-carbohydrazide cyclophane (7)
Prepared from (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)
and isophthaldehyde as a white solid precipitate (99%); mp >
315 °C (decomp.); IR νmax/cm−1 3218 (NH), 1681 (CvO,
CvN); 1H NMR (400 MHz, DMSO-d6) δH 11.78 (4H, brs,
NH), 8.40–8.19 (2H, m, CHvN), 8.08–7.96 (2H, m, CHvN),
7.88–7.12 (8H, m, ArH), 5.45 (2H, brs, CH), 5.23–5.08 (4H, m,
CH2), 4.78 (1H, brs, CH), 4.52 (1H, brs, CH); 13C NMR
(100 MHz, DMSO-d6) δC 170.4, 165.8, 148.9, 144.5, 134.7,
129.7, 97.2, 77.5; MS (ESI-MS, DMF and ACN, HCTultra) m/z
(Calcd 576.2; exp. 599.1, M + Na+, 100%), (HRMS, APCI-TOF,
DMSO) m/z (Calcd 599.1609; meas. 599.1596, M + Na+).
(3R,4R,17R,18R)-Tetra-carbohydrazide cyclophane (8)
Prepared from (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)
and terephthaldehyde as a pale yellow solid precipitate (99%);
mp > 345 °C (decomp.); IR νmax/cm−1 3206 (NH), 1672 (CvO,
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CvN); 1H NMR (400 MHz, DMSO-d6) δH 11.77 (4H, brs,
NH), 8.35 (1H, brs, CHvN), 7.95–7.87 (2H, m, CHvN),
7.74–7.11 (9H, m, CHvN and ArH), 5.38 (2H, brs, CH),
5.20–4.99 (4H, m, CH2), 4.76 (1H, brs, CH), 4.49 (1H, brs,
CH); 13C NMR (100 MHz, DMSO-d6) δC 170.5, 165.7, 148.9,
144.4, 134.3, 128.0, 97.5, 77.3; MS (ESI-MS, DMF and ACN,
HCTultra) m/z (Calcd 576.2; exp. 577.1, M + H+, 100%),
(HRMS, APCI-TOF, DMSO) m/z (Calcd 577.1790; meas.
577.1782, M + H+).
CvN); 1H NMR (400 MHz, DMSO-d6) δH 11.72 (4H, brs,
NH), 8.39 (1H, brs, CHvN), 7.94 (2H, brs, CHvN), 7.79–7.04
(17H, m, CHvN and ArH), 5.38 (2H, brs, CH), 5.19–5.02 (4H,
m, CH2), 4.75–4.32 (2H, m, CH); MS (APCI-MS2, DMSO,
HCTultra) m/z (Calcd 728.2; exp. 729.2, M + H+, 100%), (Calcd
728.2; exp. 727.2, M − H+, 100%).
(3R,4R,22R,23R)-Tetra-carbohydrazide cyclophane (13)
Prepared from (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)
and 4-(4-formylphenoxy)benzaldehyde as a white solid precipi-
tate (99%); mp > 315 °C (decomp.); IR νmax/cm−1 3220 (NH),
(3R,4R,21R,22R)-Tetra-carbohydrazide cyclophane (9)
1
Prepared from (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)
and 4,4′-diformylbiphenyl as a yellow solid precipitate (98%);
mp > 340 °C (decomp.); IR νmax/cm−1 3211 (NH), 1672 (CvO,
CvN); 1H NMR (400 MHz, DMSO-d6) δH 11.72 (4H, brs,
NH), 7.94 (2H, brs, CHvN), 7.79–7.05 (18H, m, CHvN and
ArH), 5.38–5.02 (6H, m, CH and CH2), 4.48 (1H, brs, CH),
4.33 (1H, brs, CH); MS (ESI-MS, DMSO, HCTultra) m/z (Calcd
728.2; exp. 729.2, M + H+, APCI-MS2, 100%), (HRMS,
APCI-TOF, DMSO) m/z (Calcd 729.2475; meas. 729.2508,
M + H+).
1681 (CvO, CvN); H NMR (400 MHz, DMSO-d6) δH 11.66
(4H, brs, NH), 8.34 (1H, brs, CHvN), 8.06 (1H, brs, CHvN),
7.93 (1H, brs, CHvN), 7.71–7.43 (9H, m, CHvN and ArH),
7.09–6.65 (8H, m, ArH), 5.42 (2H, brs, CH), 5.42–5.10 (4H,
1
brs, CH2), 4.75 (1H, brs, CH), 4.54 (1H, brs, CH); H NMR
(400 MHz, DMF-d7) δH 11.70 (2H, brs, NH), 11.54 (2H, brs,
NH), 8.51 (1H, brs, CHvN), 8.28 (1H, brs, CHvN), 8.12 (1H,
brs, CHvN), 8.00–7.94 (1H, m, CHvN), 7.76 (7H, m, ArH),
7.57 (1H, brs, ArH), 7.14–6.83 (8H, m, ArH), 5.65 (1H, brs,
CH), 5.59 (1H, brs, CH), 5.35–5.23 (4H, m, CH2), 4.90 (1H,
brs, CH), 4.78 (1H, brs, CH); 13C NMR (100 MHz, DMSO-d6)
170.3, 165.6, 157.7, 148.8, 144.4, 129.7, 119.5, 97.2, 77.5; 13C
NMR (100 MHz, DMF-d7) 170.2, 165.7, 158.4, 148.6, 144.2,
129.4, 119.2, 97.4, 78.0; MS (ESI-MS, DMF and ACN, HCTul-
tra) m/z (Calcd 760.2; exp. 761.3, M + H+, 100%), (HRMS,
APCI-TOF, DMSO) m/z (Calcd 761.2314; meas. 761.2292,
M + H+).
(3S,4S,16S,17S)-Tetra-carbohydrazide cyclophane (10)
Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)
and isophthaldehyde as a white solid precipitate (99%); mp >
323 °C (decomp.); IR νmax/cm−1 3223 (NH), 1680 (CvO,
CvN); 1H NMR (400 MHz, DMSO-d6) δH 11.78 (4H, brs,
NH), 8.40 (1H, brs, CHvN), 8.07–7.96 (2H, m, CHvN),
7.88–7.14 (9H, m, CHvN and ArH), 5.46–5.40 (2H, m, CH),
5.23–5.08 (4H, m, CH2), 4.86–4.79 (1H, brs, CH), 4.52 (1H,
brs, CH); 13C NMR (100 MHz, DMSO-d6) δC 170.4, 165.8,
148.9, 144.5, 134.4, 129.7, 97.3, 77.5; MS (ESI-MS, DMF and
ACN, HCTultra) m/z (Calcd 576.2; exp. 599.1, M + Na+, 100%),
(HRMS, APCI-TOF, DMSO) m/z (Calcd 599.1609; meas.
599.1599, M + Na+).
(3R,4R,22R,23R)-Tetra-carbohydrazide cyclophane (14)
Prepared from (4R,5R)-1,3-dioxolane-4,5-dicarbohydrazide (2)
and 4,4′-diformyltriphenylamine as a yellow solid precipitate
(99%); mp > 224 °C (decomp.); IR νmax/cm−1 3214 (NH), 1681
1
(CvO, CvN); H NMR (400 MHz, DMF-d7) δH 11.38 (2H,
brs, NH), 11.22 (2H, brs, NH), 8.20 (1H, brs, CHvN), 7.92
(1H, brs, CHvN), 7.80 (1H, brs, CHvN), 7.74 (1H, brs,
CHvN), 7.49–7.22 (6H, m, ArH), 7.22–6.98 (6H, m, ArH),
6.91–6.77 (6H, m, ArH), 6.77–6.49 (8H, m, ArH); 5.32 (2H,
brs, CH), 5.06–4.94 (4H, m, CH2), 4.62 (1H, brs, CH), 4.46
(1H, brs, CH); 13C NMR (100 MHz, DMSO-d6) 170.3, 165.4,
148.3, 146.3, 144.4, 130.4, 129.1, 126.0, 125.2, 123.5, 97.1,
77.5; MS (ESI-MS, DMF and ACN, HCTultra) m/z (Calcd
910.3; exp. 911.5, M + H+, 100%), (HRMS, APCI-TOF,
DMSO) m/z (Calcd 933.3079 ; meas. 933.3048, M + Na+).
(3S,4S,17S,18S)-Tetra-carbohydrazide cyclophane (11)
Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)
and terephthaldehyde as a pale yellow solid precipitate (99%);
mp > 346 °C (decomp.); IR νmax/cm−1 3206 (NH), 1671 (CvO,
CvN); 1H NMR (400 MHz, DMSO-d6) δH 11.77 (2H, brs,
NH), 11.62 (2H, brs, NH), 8.36 (1H, brs, CHvN), 7.92–7.87
(2H, m, CHvN), 7.80–7.18 (9H, m, CHvN and ArH),
5.37–5.00 (6H, m, CH and CH2), 4.76 (1H, brs, CH), 4.22 (1H,
brs, CH); 13C NMR (100 MHz, DMSO-d6) δC 170.7, 165.4,
146.1, 144.2, 135.3, 128.0, 97.0, 77.8; MS (ESI-MS, DMF and
ACN, HCTultra) m/z (Calcd 576.2; exp. 577.1, M + H+, 100%),
(HRMS, APCI-TOF, DMSO) m/z (Calcd 577.1429; meas.
577.1450, M + H+).
(3S,4S,22S,23S)-Tetra-carbohydrazide cyclophane (15)
Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)
and 4-(4-formylphenoxy)benzaldehyde as a white solid precipi-
tate (98%); mp > 305 °C (decomp.); IR νmax/cm−1 3219 (NH),
1
1681 (CvO, CvN); H NMR (400 MHz, DMSO-d6) δH 11.65
(4H, brs, NH), 8.35 (1H, brs, CHvN), 8.07 (1H, brs, CHvN),
7.93 (1H, brs, CHvN), 7.71–7.52 (8H, m, CHvN and ArH),
7.43 (1H, brs, ArH) 7.10–6.66 (8H, m, ArH), 5.42 (2H, brs,
CH), 5.22–5.05 (4H, brs, CH2), 4.75 (1H, brs, CH), 4.54 (1H,
brs, CH); 13C NMR (100 MHz, DMSO-d6) 170.3, 165.6, 157.7,
(3S,4S,21S,22S)-Tetra-carbohydrazide cyclophane (12)
Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)
and 4,4′-diformylbiphenyl as a yellow solid precipitate (97%);
mp > 340 °C (decomp.); IR νmax/cm−1 3210 (NH), 1673 (CvO,
Org. Biomol. Chem.
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148.8, 144.4, 129.7, 119.5, 97.2, 77.5; MS (ESI-MS, DMF and
ACN, HCTultra) m/z (Calcd 760.2; exp. 761.3, M + H+, 100%),
(HRMS, APCI-TOF, DMSO) m/z (Calcd 783.2134; meas.
783.2113, M + Na+).
Indrajit Ghosh for assistant with Circular Dichroism measure-
ments and Mrs Anja Müller for excellent technical assistant.
Notes and references
(3S,4S,22S,23S)-Tetra-carbohydrazide cyclophane (16)
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chester, 1st ed., 2000.
Prepared from (4S,5S)-1,3-dioxolane-4,5-dicarbohydrazide (4)
and 4,4′-diformyltriphenylamine as a yellow solid precipitate
(99%); mp > 220 °C (decomp.); IR νmax/cm−1 3214 (NH), 1681
1
(CvO, CvN); H NMR (400 MHz, DMSO-d6) δH 11.59 (4H,
brs, NH), 8.28 (1H, brs, CHvN), 7.96 (1H, brs, CHvN), 7.85
(1H, brs, CHvN), 7.67–7.57 (2H, m, CHvN, ArH), 7.46–7.28
(7H, m, ArH), 7.22–6.96 (8H, m, ArH), 6.94–6.56 (10H, m,
ArH), 5.35 (2H, brs, CH), 5.19–5.05 (4H, m, CH2), 4.71 (1H,
brs, CH), 4.45 (1H, brs, CH); 13C NMR (100 MHz, DMSO-d6)
170.3, 165.4, 148.3, 146.3, 144.3, 130.4, 129.1, 126.1, 125.1,
123.5, 97.1, 77.5; MS (ESI-MS, DMF and ACN, HCTultra) m/z
(Calcd 910.3; exp. 911.5, M + H+, 100%), (HRMS, APCI-TOF,
DMSO) m/z (Calcd 911.3260; meas. 911.3292, M + H+).
10 G. Gokel and Y. Inoue, Cation Binding by Macrocycles, Marcel Dekker,
New York and Basel, 1990.
11 A. Danil de Namor, R. Cleverley and M. Zapata-Ormachea, Chem. Rev.,
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12 P. Beer, P. Gale and A. Philip, Angew. Chem., Int. Ed., 2001, 40,
486.
(3R,4R,17R,18R)-Tetra-carbohydrazide cyclophane (17)
Prepared from (2R,3R)-2,3-dihydroxy dicarbohydrazide (5) and
terephthaldehyde as a white solid precipitate, (99%); mp >
295 °C (decomp.); IR νmax/cm−1 3268 (broad absorption band,
OH and NH), 1668 (CvO, CvN); 1H NMR (400 MHz,
DMSO-d6) δH 11.27 (4H, brs, NH), 8.44 (4H, brs, CHvN),
7.70 (8H, brs, ArH) 5.91 (4H, brs, OH), 4.49 (4H, brs, CH); 13C
NMR (100 MHz, DMSO-d6) δC 168.9, 147.6, 136.2, 127.9,
73.4; MS (APCI-MS2, DMSO, HCTultra) m/z (Calcd 552.2;
exp. 553.0, M + H+, 100%), (Calcd 552.2; exp. 551, M − H+,
100%), (HRMS, APCI-TOF, DMSO) m/z (Calcd 553.1844;
meas. 553.1816, M + H+).
13 V. Balzani, A. Credi, F. Raymo and J. Stoddart, Angew. Chem., Int. Ed.,
2000, 39, 3348.
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(3S,4S,17S,18S)-Tetra-carbohydrazide cyclophane (18)
Prepared from (2S,3S)-2,3-dihydroxy dicarbohydrazide (6) and
terephthaldehyde as a pale yellow solid precipitate, (99%); mp >
295 °C (decomp.); IR νmax/cm−1 3263 (broad absorption band,
OH and NH), 1667 (CvO, CvN); 1H NMR (400 MHz,
DMSO-d6) δH 11.27 (4H, brs, NH), 8.43 (4H, brs, CHvN),
7.70 (8H, brs, ArH) 5.94 (4H, brs, OH), 4.49 (4H, brs, CH); 13
C
NMR (100 MHz, DMSO-d6) δC 169.0, 147.7, 136.2, 127.9,
73.4; MS (APCI-MS2, DMSO, HCTultra) m/z (Calcd 552.2;
exp. 553.0, M + H+, 100%), (Calcd 552.2; exp. 550.9, M − H+,
100%), (HRMS, APCI-TOF, DMSO) m/z (Calcd 553.1941;
meas. 553.1954, M + H+).
29 B.-Y. Lu, G.-J. Sun, J.-B. Lin, X.-K. Jiang, X. Zhao and Z.-T. Li, Tetrahe-
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Acknowledgements
Financial support from Deutscher Akademischer Austausch
Dienst (DAAD) is gratefully acknowledged. We thank Mr
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem.