Tetra-urea calix[4]arenes 1,3-bridged at the narrow rim

Article abstract of DOI:10.1039/b819710e

The synthesis of special tetra-urea calix[4]arene derivatives is described. Two propyl ether groups in 1,3-position and a 5-iodo-isophthalamide bridge connecting two aminopropylether residues in 2,4-position at the narrow rim keep the molecule fixed in th

Full text of DOI:10.1039/b819710e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Tetra-urea calix[4]arenes 1,3-bridged at the narrow rim†
Ganna Podoprygorina,a Michael Bolteb and Volker Bo¨hmer*a
Received 4th November 2008, Accepted 19th December 2008
First published as an Advance Article on the web 10th February 2009
DOI: 10.1039/b819710e
The synthesis of special tetra-urea calix[4]arene derivatives is described. Two propyl ether groups in
1,3-position and a 5-iodo-isophthalamide bridge connecting two aminopropylether residues in
2,4-position at the narrow rim keep the molecule fixed in the cone conformation. The aryl urea residues
are substituted by decyloxy groups in p-position to increase the solubility in apolar solvents, while the
iodo substituent allows further functionalization. Two single crystal X-ray structures of 3 and 4 show a
strongly pinched cone conformation in which the bridged phenol units are bent outwards, while the
phenol units bearing the propyl ether groups are nearly parallel. The molecules are flexible enough,
however, to form hydrogen bonded dimeric capsules in apolar solvents. Their (time averaged) D2
conformation is confirmed by 1H NMR spectroscopy.
better. With this background we started the synthesis of tetra-urea
Introduction
calix[4]arenes bridged by a handle based on 5-iodo-isophthalic
acid, where the iodo atom should allow further functionalization
by Suzuki or Sonogashira cross-coupling and the attachment e.g.
to the cantilever of an AFM tip.
Calix[4]arenes substituted at their wide rim by four (aryl) urea
groups form dimeric capsules in aprotic, apolar solvents.1 The two
calixarenes, turned by 45◦ around their common axis relative to
each other, are held together by a seam of intermolecular hydrogen
bonds between the urea functions.
Syntheses
The stability of these dimers has been characterized in various
ways.2 Association constants cannot be obtained from equilibrium
concentrations due to their extreme values. Kinetic studies under
high dilution (0.05–0.5 mM) by fluorescence resonance energy
transfer (FRET) gave association and dissociation rates from
which association constants (up to KA = 109 M-1) have been
derived.3 Rates for the guest exchange against the solvent have
been used to characterize the (kinetic) stability with respect to the
structure of the capsule, the included guest and to the solvent.4
The rapid development of atomic force microscopy (AFM)
makes it possible meanwhile to study the mechanical strength
of covalent bonds within a molecule or even of weaker forces
between molecules. We recently described such AFM studies
with dimers of tetra-urea calix[4]arenes.5 In these experiments the
stretching forces were applied between two ether functions (one
per each calixarene of the capsular dimer). The corresponding
tetra-urea calix[4]arenes with one functionalized ether group at the
narrow rim are readily prepared, although a multistep synthesis
is required.6 Geometrically, however, this attachment has some
fundamental disadvantages. The pulling forces are not exerted
“colinear” with the molecular axis and there are two “regioiso-
meric” possibilities for the attack. The stretching of a single capsule
may involve two adjacent or two remote phenolic units in the two
calix[4]arenes.7
The synthesis requires the independent acylation of two amino
functions attached in 1,3-position at the narrow rim via propy-
lether linkers, and the acylation of the four amino groups at the
wide rim to introduce the four urea groups. Starting with the
known 1,3-phthalimido derivative 1,8 in which the calix[4]arene is
fixed already in the cone-conformation by the four ether residues,
two pathways may be envisaged for the synthesis of the target
tetra-urea calix[4]arene 11 (Fig. 1). They differ mainly by the
moment where the iodo-isophthalimide bridge is introduced.
This macrocyclization may be carried out before or after the
introduction of the urea functions.
The first strategy involves hydrazinolysis of 1 to diamine 2 (75%
yield) and subsequent acylation under high dilution conditions by
5-iodo-isophthalic acid dichloride in dichloromethane solution
in the presence of i-Pr2EtN as base.9 The bridged product
3 was isolated with 14% yield after purification by column
chromatography. ipso-Nitration of the compound 3 gave the hardly
soluble tetranitro compound 4. The structure of calixarenes 3 and
4 was confirmed by X-ray analysis. The low yield in the bridging
step and the separation difficulties of the product mixture derived
from compound 4 after hydrogenation forced us, however, to try
the second strategy.
The di-N-phthalimidopropyl calixarene 1 was ipso-nitrated
as published8 and the phthalimido groups were cleaved from
compound 5 by reflux with hydrazine–ethanol to produce the
corresponding diamine 6 in 87% yield. (The acylation of 6 by
5-iodo-isophthalic acid dichloride has been attempted, however,
the cyclic diamide 4 could not be isolated from the reaction
mixture.)
The diamine 6 was N-Boc-protected to produce compound 7
(98% yield). The replacement of the phthalimide by the Boc
protective group in steps (i) and (iv) is necessary, since urea
From this point of view, an attachment in the middle of a
bow connecting the phenolic oxygens in 1,3-position would be
aJohannes Gutenberg-Universita¨t, Duesbergweg 10–14, Mainz D-55099,
Germany. E-mail: vboehmer@uni-mainz.de; Fax: +49 (0)6131 3925419;
Tel: +49 (0)6131 3922319
bJohann Wolfgang von Goethe-Universita¨t, Marie Curie-Straße 11, Frank-
furt/Main D-60439, Germany
† CCDC reference numbers 706486 and 706487. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b819710e
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Fig. 1 (i) NH2NH2·H2O, EtOH, reflux; (ii) 5-iodo-isophthalic acid dichloride, i-Pr2EtN, CH2Cl2; (iii) HNO3–HOAc, CH2Cl2; (iv) Boc2O, THF; (v) H2,
Raney-Ni, toluene; (vi) p-nitrophenyl urethane of p-n-decyloxyaniline, i-Pr2EtN, THF; (vii) CF3COOH, CH2Cl2; (viii) 5-iodo-isophthalic acid, i-Pr2EtN,
PyBOP, DMF.
groups could be destroyed under the conditions necessary for the
phthalimide-cleavage. The resulting tetranitro 7 was hydrogenated
in toluene using Raney-Ni as catalyst (90%) and the tetraamine
8 was acylated by p-nitrophenyl urethane of p-n-decyloxyaniline
(74%).
The Boc-groups were cleaved from tetra-urea 9 by trifluoroacetic
acid (86%) and the diamino tetra-urea 10 was acylated by 5-iodo-
isophthalic acid in the presence of PyBOP in DMF to produce
compound 11, isolated in 14% yield, after purification by column
chromatography.
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Fig. 2 Parts of 1H NMR spectra of calixarene 11 (a) in DMSO-d6, rt; (b) in CDCl3, rt.
singlets in the ratio 1 : 1 : 1 : 1 for downfield shifted NH protons
of the urea groups (9.39, 9.31, 9.21 and 9.13 ppm); four pairs of
m-coupled doublets for protons of the aryl groups of the calixarene
skeleton, among them four doublets shifted upfield (6.03, 6.01 and
two signals overlapped at 5.94 ppm) and four doublets shifted
downfield (two signals overlapped at 8.18 ppm and two signals
overlapped at 7.78 ppm).
Self-organization of narrow rim-bridged tetra-urea
1
In polar solvents like DMSO, tetra-urea 11 displays a H NMR
spectrum corresponding to a C2v symmetrical molecule (Fig. 2a):
two singlets at 6.43 and 7.24 ppm for the aryl protons of the
calixarene skeleton; two pairs of doublets at 6.73, 6.84, 7.10 and
7.34 ppm for the aryl protons adjacent to the urea functions; four
singlets at 7.82, 8.17, 8.34 and 8.43 ppm in the ratio 1 : 1 : 1 : 1 for
NH protons of the urea groups; two triplets at 3.90 and 3.83 ppm
for –OCH2– protons of the decyloxy groups attached to the phenyl
rings adjacent to urea groups.
The splitting of the signals for –OCH2– protons of decyloxy
groups together with the large difference in shifts of the signals
for the aromatic protons (for singlets of calixarene skeleton Dd =
0.81 ppm) and for protons of the urea groups suggest a pinched cone
conformation of the molecule (compare also the crystal structures
of compounds 3 and 4). This is the typical conformation for
tetraethers of calix[4]arenes, which exist in solution in equilibrium
between two pinched cone conformations.
Crystal structures
Single crystals for the bridged compounds 3 and 4 were obtained
by slow evaporation of their solutions in methylene chloride–
ethylacetate–methanol and THF–methanol, respectively. In spite
of their structural difference (unpolar t-butyl vs. polar nitro
groups) and the different (and different amount of) solvent
included in the crystal lattice, the molecular conformations of
both compounds are rather similar.
Fig. 3 shows both molecules from two different perspectives.
Typical data (distances and angles) are collected in Table 1. In
both cases the molecule is found in a strongly pinched cone
conformation. The phenolic units I and III of the calix[4]arene
which are connected by the isophthalamide bridge are strongly
bent outwards and nearly perpendicular to each other in molecule
3. In compound 4 they include an angle (79.5◦) distinctly lower
than 90◦. The non connected propylphenylether units (II/IV) are
nearly parallel in 3 (including an angle of 5.4◦), while both are
bent inwards in 4, with an interplanar angle of 14.4◦. For further
details see Fig. 3, 4 and Table 2.
The formation of hydrogen bonded, dimeric capsules requires a
C4-symmetrical conformation of the two tetra-urea calix[4]arenes.
If the energy gain of their C2v-symmetrical pinched cone confor-
mation is too large, the formation of dimers may be impossible.
However, in apolar solvents the bridged 11 forms capsule-
like dimers similarly to normal “open chain” tetra-ureas. This
calix[4]arene can be classified as a tetra-urea of the ABAB-type.7
Such a dimer has D2 symmetry and is chiral only due to the
arrangement of the two achiral calixarenes. This type of chirality
may be referred to as supramolecular chirality. It is worth noting
that the directionality of the hydrogen bonded belt does not create
additional stereoisomers, but just reduces the symmetry of the
capsule to C2.
The iodo-isophthalyl fragment is practically planar in both
structures and oriented perpendicular (89.62◦) to the reference
plane in 3. In 4, however, it is considerably inclined by nearly 18◦,
most probably due to “packing effects”. No strain occurs in the
–O–C–C–C– chains connecting the bridge to the metacyclophane
skeleton, since all torsion angles are in the range of 177.5–180.0◦.
1
In its H NMR-spectrum the C2 symmetry of the assembly is
reflected by an additional splitting of the signals (Fig. 2b): four
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Table 1 Comparison of typical crystal data of compounds 3 and 4
Table 2 Summary of crystallographic data
Compound
3 (t-Bu)
4 (NO2)
Compound
3 (t-Bu)
4 (NO2)
˚
C64H83IN2O6·
CH3OH·H2O
1153.28
C48H47IN6O14·
2C4H8O·H2O
1221.04
Distance/A
O1–O2
O2–O3
O3–O4
3.334
3.247
3.211
3.187
3.597
5.373
9.454
5.606
6.582
6.018
5.712
3.062/3.063
3.131
4.024
1.178
3.189
3.612
3.018
3.633
3.682
5.632
9.848
4.544
6.553
6.192
5.763
3.127/3.127
3.256
4.057
1.217
M
T, K
Crystal system
Space group
a, A
173
173
Orthorhombic Monoclinic
O4–O1
O1a–O3a
O2–O4
P 212121
11.2099(5)
15.8759(6)
35.5340(15)
90
90
90
6323.9(5)
4
35791
P 21/n
˚
˚
˚
13.2687(5)
13.5843(4)
31.5174(12)
90
94.788(3)
90
5661.1(3)
4
58800
C15b–C35b
C25b–C45b
CBP–RP
b, A
c, A
a, ◦◦
b, ◦
g ,
C
C
BP–O2
BP–O4
O(water)–N(amide)
3
˚
V, A
Z
Reflections
Unique reflections
Final R indices [I > 2s(I)], R1, wR2
R indices (all data), R1, wR2
CCDC deposition number
O
O
(water)–CBP
(water)–RP
O(water)–BP
Angles/◦
RP–Ar1
RP–Ar3
Ar1–Ar3
RP–Ar2
RP–Ar4
Ar2–Ar4
RP–BP
11121
10402
0.0387, 0.1059
0.0411, 0.1082
706486
0.0352, 0.0918
0.0429, 0.0952
706487
133.8
135.1
88.88
88.16c
97.26
5.43
136.6
143. 9
79.48
84.01c
81.70c
14.40
72.29
89.62
a Oxygens connected by the bridge. b C-atoms in p-position of the
calixarene rings Ar1 to Ar4. c Values <90◦ indicate that the aromatic ring
is bent into the cavity. RP = reference plane (defined by the methylene
bridge carbons). BP = bow plane (defined by 6 aromatic carbons).
Fig. 4 Packing of the molecules 3 seen along the a-axis (a) and of the
molecules 4 seen along the b-axis (b).
Fig. 3 The molecular conformation of 3 (a) and of 4 (b) found in the
crystal structure of 3·H2O·MeOH and 4·H2O·2THF, respectively, seen
from two directions.
to the reference plane (defined by the methylene bridge carbon
˚
atoms of the calix[4]arene skeleton) is also very similar, 4.025 A
˚
for 3 and 4.057 A for 4, and the same is true for the distance to
˚
˚
Both crystals were obtained from non aqueous solvent mixtures,
although not under strictly anhydrous conditions. Nevertheless,
one molecule of water is incorporated in both cases, which is
hydrogen bonded by both NH-groups. Therefore the distance
between the water oxygen and both amide nitrogens is identical,
the isophthalyl plane (1.178 A and 1.217 A). Obviously this water
molecule occupies the same place, filling a gap in the crystal lattice,
which otherwise cannot be formed. Since both crystals were grown
from methanol containing solvent mixtures, it may be concluded
that the methanol molecule is already too large to be incorporated
here.
˚
˚
3.063 A for 3 and 3.127 A for 4. For both structures the distance
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was filtered off, washed with ethanol (2 ¥ 50 ml) and dried (in
high vacuum) to give the product as a 1 : 1 complex with ethanol
(4.85 g, 86%) as yellow powder which was used for the next step;
mp >165 ◦C (decomp.); dH (DMSO-d6) 7.79 (4 H, s, Ar-H), 7.51
(4 H, s, Ar-H), 4.39 (4 H, d, 2JHH 13.7 Hz, Ar-CH2-Ar), 4.04 (4 H,
Experimental
1H NMR spectra were recorded on a Bruker DRX400 Avance
instrument (at 400 MHz). FD and ESI mass spectra were
measured on a Finnigan MAT 8230 spectrometer and a Mi-
cromass Q-ToF Ultima3 instrument, respectively. Melting points
are uncorrected. Tetra-tert-butyl- and tetranitrocalix[4]arene 1,3-
dipropyl-2,4-diphthalimidopropyl ethers 2 and 5 were prepared as
described.8
3
3
t, JHH 6.8 Hz, -O-CH2-), 3.99 (4 H, t, JHH 7.3 Hz, -O-CH2-),
3.69 (4 H, d, 2JHH 13.7 Hz, Ar-CH2-Ar), 3.54–2.92 (10 H, m, -O-
CH2-CH3, N-H2), 2.71 (4 H, t 3JHH 6.6 Hz, NH2-CH2-,), 1.98–1.78
(8 H, m, -NH-CH2-CH2-, -O-CH2-CH2-), 1.05 (3 H, t, 3JHH 7.1 Hz,
-CH3), 0.96 (6 H, t, 3JHH 7.3 Hz, -CH3); for a sample obtained by
evaporation from acetone: dH (DMSO-d6) 7.95 (4 H, s, Ar-H), 7.38
(4 H, s, Ar-H), 4.36 (4 H, d, 2JHH 13.9 Hz, Ar-CH2-Ar), 4.28–3.38
(10 H, m, -N-H2, -O-CH2-), 3.70 (4 H, d, 2JHH 13.9 Hz, Ar-CH2-
Calix[4]arene 3
5-Iodo-isophthalic acid (0.178 g, 0.608 mmol) and oxalyl chloride
(0.435 g, 3.42 mmol) were mixed in toluene (10 ml), 1 drop
of DMF was added and the reaction mixture was stirred for
4 h at 60 ◦C. Then it was cooled to room temperature, the
liquid was decanted and the solvent was completely removed by
evaporation in vacuum leaving an oil which slowly crystallized
in the fridge.10 The product was dissolved in dichloromethane
(200 ml). A solution of calixarene diamine 2 (0.515 g, 0.608 mmol)
and i-Pr2EtN (0.236 g, 1.82 mmol) in dichloromethane (200 ml)
was prepared. Both solutions were added dropwise with stirring to
dichloromethane (150 ml). After 24 h the solvent was evaporated
and the residue was passed through the column (silica, THF–
CH2Cl2, 1 : 30) to yield the product (0.093 g, 14%) as a white
powder; mp >290 ◦C (decomp.); dH (CDCl3) 8.53 (2 H, s, Ar-H),
8.50 (1 H, s, Ar-H), 7.58 (2 H, s, N-H), 7.13 (4 H, s, Ar-H), 6.58
(4 H, s, Ar-H), 4.38 (4 H, d, 2JHH 12.3 Hz, Ar-CH2-Ar), 4.33 (4 H,
br.t, 3JHH 7.3 Hz, -O-CH2-), 3.68 (4 H, t, 3JHH 7.5 Hz, -O-CH2-),
3
Ar), 2.88 (4 H, t, JHH 7.1 Hz, NH2-CH2-), 2.04 (4 H, m, -CH2),
3
1.91–1.78 (4 H, m, -CH2), 0.93 (6 H, t, JHH 8.1 Hz, -CH3); MS
(ESI): m/z 803.4 (M + H+, 100%), required 803.8.
Calix[4]arene 7
Boc anhydride (1.07 g, 4.91 mmol) was added to a solution
of calix[4]arene 6·ethanol (1.89 g, 2.23 mmol) in THF (30 ml)
and the reaction mixture was stirred at rt for 12 h. Then the
solvent was evaporated and the oily residue was reprecipitated
from dichloromethane–hexane to give the pure product (2.19 g,
98%) as white powder; mp >125 ◦C (decomp.); dH (DMSO-d6)
7.78 (4 H, s, Ar-H), 7.50 (4 H, s, Ar-H), 6.92 (2 H, br.t, N-H),
4.37 (4 H, d, 2JHH 13.7 Hz, Ar-CH2-Ar), 4.00 (4 H, t, 3JHH 7.6 Hz,
-O-CH2-), 3.95 (4 H, t, 3JHH 6.6 Hz, -O-CH2-), 3.68 (4 H, d, 2JHH
14.2 Hz, Ar-CH2-Ar), 3.18–3.05 (4 H, m, NH-CH2-), 2.04–1.92
(4 H, m, -NH-CH2-CH2-), 1.92–1.79 (4 H, m, -O-CH2-CH2-), 1.37
(18 H, s, -CH3), 0.94 (6 H, t, 3JHH 7.3 Hz, -CH3).
2
3.57–3.49 (4 H, m, -NH-CH2-), 3.18 (4 H, d, JHH 12.3 Hz, Ar-
CH2-Ar), 2.25–2.13 (4 H, m, -NH-CH2-CH2-), 1.89–1.79 (4 H, m,
3
-O-CH2-CH2-), 1.32 (18 H, s, -CH3), 0.88 (6 H, t, JHH 7.3 Hz,
-CH3), 0.83 (18 H, s, -CH3); MS (FD): m/z 1103.3 (M+, 100%),
Calix[4]arene 8
required 1103.3.
A solution of calix[4]arene 7 (1.86 g, 1.85 mmol) in toluene
(100 ml) was vigorously stirred under hydrogen at rt in the
presence of a catalytic amount of Raney-Ni for 5–6 hours (the
conversion was controlled by TLC). Then the catalyst was filtered
off and the solvent was removed in vacuum. The oily residue
was reprecipitated from chloroform–hexane to give the tetraamino
product (1.49 g, 90%) in appropriate purity as white powder; mp
>125 ◦C (decomp.); dH (DMSO-d6) 6.78 (2 H, br.t, N-H), 5.97
(4 H, s, Ar-H), 5.92 (4 H, s, Ar-H), 4.34–4.03 (12 H, m, N-H2,
Ar-CH2-Ar), 3.80–3.53 (8 H, m, -O-CH2-), 3.13–2.96 (4 H, m,
Calix[4]arene 4
Glacial acetic acid (1.0 ml) and fuming nitric acid (1.6 ml)
were added to a solution of the bridged calixarene 3 (0.132 g,
0.120 mmol) in dichloromethane (25 ml). The mixture was stirred
for 2 h, then quenched by the addition of water. A precipitate
was formed and the water layer was decanted. The suspension
in dichloromethane was washed additionally with water (3 ¥
100 ml). Finally, the solvent was evaporated from the suspension
and the residue was dried by azeotropic distillation of added
toluene. Recrystallization of the residue in dichloromethane gave
the product (0.050 g, 39%) as yellowish powder; mp >240 ◦C
(decomp.); dH (DMSO-d6) 8.45 (4 H, s, Ar-H), 8.21 (2 H, s, N-
H), 8.12 (2 H, s, Ar-H), 8.07 (1 H, s, Ar-H), 6.89 (4 H, s, Ar-H),
4.55–4.42 (4 H, m, -O-CH2-), 4.35 (4 H, d, 2JHH 13.6 Hz, Ar-CH2-
Ar), 3.76–3.59 (8 H, m, -O-CH2-, Ar-CH2-Ar), 3.43–3.33 (4 H, m,
-NH-CH2-), 1.87–1.73 (4 H, m, -NH-CH2-CH2-), 1.67–1.54 (4 H,
m, -O-CH2-CH2-), 0.74 (6 H, t, 3JHH 7.3 Hz, -CH3).
2
NH-CH2-), 2.77 (4 H, d, JHH 12.7 Hz, Ar-CH2-Ar), 2.12–1.70
(8 H, m, -NH-CH2-CH2-, -O-CH2-CH2-), 1.38 (18 H, s, -CH3),
3
0.89 (6 H, t, JHH 7.3 Hz, -CH3); dH (CDCl3) 6.22 (4 H, s, Ar-
H), 5.87 (4 H, s, Ar-H), 5.00 (2 H, br.s, N-H), 4.24 (4 H, d, 2JHH
13.3 Hz, Ar-CH2-Ar), 3.84 (4 H, t, -O-CH2-), 3.63 (4 H, br.t,
-O-CH2-), 3.28–3.10 (4 H, m, NH-CH2-), 2.77 (12 H, m, N-H2,
Ar-CH2-Ar), 2.06 (4 H, br.s, -NH-CH2-CH2-), 1.90–1.69 (4 H, m,
3
-O-CH2-CH2-), 1.44 (18 H, s, -CH3), 0.95 (6 H, t, JHH 7.3 Hz,
-CH3); MS (FD): m/z 882.7 (M+, 100%), required 883.1.
Calix[4]arene 6
Calix[4]arene 9
Hydrazine hydrate (60 ml) was added to a stirred suspension
of calix[4]arene 5 (7.47 g, 7.03 mmol) in ethanol (240 ml). The
reaction mixture was refluxed for 2 hours, then cooled to room
temperature and left for 2 hours in the fridge. The precipitate
A solution of tetraamine 8 (0.515 g, 0.580 mmol) and i-Pr2EtN
(0.315 g, 2.44 mmol) in THF (10 ml) was added to the solu-
tion of N-(p-decyloxyphenyl) p-nitrophenyl carbamate (1.02 g,
2.44 mmol) in THF (10 ml). The reaction mixture was stirred at
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rt for 12 h, acetonitrile (60 ml) was added, and the stirring was
continued for further 12 h. During this time a solid precipitated
which was filtered off and washed thoroughly with acetonitrile◦to
give the product (0.856 g, 74%) as a beige powder; mp >170 C
(decomp.); dH (DMSO-d6) 8.26–7.95 (8 H, m, N-H), 7.31–7.12
(8 H, m, Ar-H), 6.95–6.64 (18 H, m, N-H, Ar-H), 4.32 (4 H, d, 2JHH
12.2 Hz, Ar-CH2-Ar), 3.99–3.65 (16 H, m, -O-CH2-), 3.18–2.97
(8 H, m, -NH-CH2-, Ar-CH2-Ar), 2.05 (4 H, m, -NH-CH2-CH2-),
1.98–1.82 (4 H, m, -CH2-), 1.74–1.57 (8 H, m, -O-CH2-CH2-),
m, 2JHH 12.6 Hz, -O-CH2-, Ar-CH2-Ar), 3.90 (4 H, t, 3JHH 6.3 Hz,
-O-CH2-), 3.83 (4 H, t, 3JHH 6.5 Hz, -O-CH2-), 3.54 (4 H, t, 3JHH
7.3 Hz, -O-CH2-), 3.46–3.35 (4 H, m, -NH-CH2-), 3.08 (4 H, d,
2JHH 11.9 Hz, Ar-CH2-Ar), 2.02–1.88 (4 H, m, -NH-CH2-CH2-),
1.74–1.53 (12 H, m, -O-CH2-CH2-), 1.46–1.12 (56 H, m, -CH2-),
3
0.92–0.77 (12 H, m, -CH3), 0.67 (6 H, t, JHH 7.5 Hz, -CH3);
MS (ESI): m/z 2063.2 (M + Na+, 100%), required 2063.5; 1043.1
(M + 2Na+, 36%), required 1043.1.
3
1.49–1.13 (74 H, m, -CH3, -CH2-), 0.95 (6 H, t, JHH 7.3 Hz,
Single-crystal X-ray diffraction
-CH3), 0.85 (12 H, br.t, -CH3); MS (ESI): m/z 2007.4 (M + Na+,
Data were collected on a STOE-IPDS-II two-circle diffrac-
69%), required 2007.7.
tometer employing graphite-monochromated MoKa radiation
˚
(0.71073 A). Data reduction was performed with the X-AREA
Calix[4]arene 10
software.11 An empirical absorption correction was done with the
PLATON program.12 Structures were solved by direct methods
with SHELXS-9013 and refined by full-matrix least-squares tech-
niques with SHELXL-97.13
Trifluoroacetic acid (3 ml) was added to a solution of tetra-urea 9
(0.303 g, 0.153 mmol) in dichloromethane (10 ml) and the mixture
was stirred at rt for 2 h. Then the solvent was removed in vacuum
and the salt was dissolved in dichloromethane and washed with
an aqueous solution of sodium hydrocarbonate. The diamine was
extracted with dichloromethane, the solution was dried (MgSO4)
and finally the solvent was removed under reduced pressure. The
oily residue was triturated with methanol; the solid was filtered off
and washed thoroughly with methanol to give the product (0.236 g,
86%) as beige powder; mp >205 ◦C (decomp.); dH (DMSO-d6) 8.30
(2 H, s, N-H), 8.23 (4 H, s, N-H), 8.13 (2 H, s, N-H), 7.23 (4 H, d,
All non-H atoms were refined with anisotropic displacement
parameters. Hydrogen atoms bonded were included at calculated
positions and allowed to ride on their parent atoms. The H atoms
bonded to N and O in 4 were freely refined. The two propyl groups
and the THF molecule in 4 are disordered over two positions
with a ratio of the site occupation factors of 0.54(1)/0.46(1),
0.59(2)/0.41(2) and 0.62(2)/0.38(2), respectively. The absolute
structure of 3 has been determined by the Flack-parameter x =
-0.01(1).
3
3JHH 8.5 Hz, Ar-H), 7.19 (4 H, d, JHH 8.5 Hz, Ar-H), 6.90–6.63
(16 H, m, Ar-H), 4.31 (4 H, d, 2JHH 12.3 Hz, Ar-CH2-Ar), 3.99–
3.72 (16 H, m, -O-CH2-), 3.08 (4 H, d, 2JHH 12.6 Hz, Ar-CH2-Ar),
2.82 (4 H, br.t, NH2-CH2-), 2.03 (4 H, m, -NH-CH2-CH2-), 1.98–
1.82 (4 H, m, -CH2-), 1.74–1.57 (8 H, m, -O-CH2-CH2-), 1.46–1.13
Conclusions and outlook
We have developed
a multistep synthesis for tetra-urea
3
calix[4]arenes, in which two opposite phenolic units are connected
by a macrocyclic ether bridge containing a 5-iodo-isophthalamide
structure. Although the single molecules assume the expected
pinched cone conformation they readily form hydrogen bonded
dimers in apolar solvents. The symmetrically placed iodo atom
may be converted to further functions to allow attachment to
a cantilever in an AFM setup. Thus, the mechanical strength
of the hydrogen bonded belt of such dimers may be measured,
using symmetrical stretching forces. This will improve former
experiments where the stretching of the dimer occurred between
single ether residues in a necessarily non symmetric way.5 We are
presently trying to improve the yield of the single reaction steps,
especially for the cyclisation.
(56 H, m, -CH2-), 0.95 (6 H, t, JHH 7.2 Hz, -CH3), 0.84 (12 H,
br.t, -CH3); MS (ESI): m/z 1785.2 (M + H+, 100%), required
1785.5.
Calix[4]arene 11
Trifluoroacetic acid (4 ml) was added to a solution of tetra-urea
9 (0.170 g, 0.0856 mmol) in dichloromethane (10 ml) and the
reaction mixture was stirred at rt for 2 h. The solvent was removed
in vacuum and the salt was dissolved in THF (10 ml). An excess
of Et3N (1 ml) was added to convert the salt into the appropriate
amine 10, and the solvent was evaporated to dryness. The residual
amine was dissolved in DMF (100 ml). 5-Iodo-isophthalic acid
(0.025 g, 0.086 mmol) was mixed with PyBOP (0.089 g, 0.17 mmol)
in DMF (100 ml) and the mixture was stirred for 20 min under
nitrogen. Both solutions were simultaneously added dropwise with
stirring to 50 ml DMF. The reaction mixture was stirred under
nitrogen for a further 24 h, the solvent was removed under reduced
pressure and water (100 ml) was added to the residue to precipitate
the products. The precipitate was filtered off, washed with water
and methanol. The target product (0.025 g, 14%) was isolated by
column chromatography (silica, THF–hexane, 1 : 2, followed by
3 : 4) as white powder; mp >220 ◦C (decomp.); dH (DMSO-d6) 8.43
(2 H, s, N-H), 8.43 (2 H, s, N-H), 8.34 (2 H, s, N-H), 8.17 (2 H,
br.t, N-H), 8.12 (3 H, s, Ar-H), 7.88 (2 H, s, N-H), 7.82 (2 H, s,
N-H), 7.34 (4 H, d, 3JHH 8.9 Hz, Ar-H), 7.24 (4 H, s, Ar-H), 7.10
(4 H, d, 3JHH 9.2 Hz, Ar-H), 6.84 (4 H, d, 3JHH 9.2 Hz, Ar-H), 6.73
(4 H, d, 3JHH 8.9 Hz, Ar-H), 6.43 (4 H, s, Ar-H), 4.47–4.22 (8 H,
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft (SFB
625) is gratefully acknowledged.
Notes and references
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1598 | Org. Biomol. Chem., 2009, 7, 1592–1598
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The Royal Society of Chemistry 2009
©