(Thio)ureido anion receptors based on a 1,3-alternate oxacalix[2]arene[2] pyrimidine scaffold

Article abstract of DOI:10.1021/jo300004p

In pursuit of highly preorganized macrocyclic host molecules for the complexation of anions, a series of oxacalix[2]arene[2]pyrimidine-based bis(thio)ureido receptors were synthesized and fully characterized. The pincer-like 1,3-alternate conformation of the oxacalix[4]arene scaffold, essential for an efficient host-guest interaction, was visualized by single-crystal X-ray analysis and supported by variable-temperature NMR studies. The anion binding properties of the receptors were evaluated via ¹H NMR titration experiments, showing intermolecular interactions with H ₂PO₄^-, AcO^-, BzO^-, and Cl^- ions. The host molecule bearing 4-nitrophenyl substituents on the bisurea binding pocket showed association constants in the range of 200-400 M^-1 in the strongly competitive solvent mixture of DMSO/0.5% H ₂O.

Full text of DOI:10.1021/jo300004p

Article
pubs.acs.org/joc
(Thio)ureido Anion Receptors Based on a 1,3-Alternate
Oxacalix[2]arene[2]pyrimidine Scaffold
Wim Van Rossom,† Jef Caers,† Koen Robeyns,‡,§ Luc Van Meervelt,‡ Wouter Maes,*,†,⊥
and Wim Dehaen*,†
†Molecular Design and Synthesis, Department of Chemistry, Katholieke Universiteit Leuven (KU Leuven), Celestijnenlaan 200F,
3001 Leuven, Belgium
‡Biomolecular Architecture, Department of Chemistry, Katholieke Universiteit Leuven (KU Leuven), Celestijnenlaan 200F, 3001
Leuven, Belgium
§Institute of Condensed Matter and Nanosciences (IMCN), Universite
Louis Pasteur 1, bte 3, 1348 Louvain-la-Neuve, Belgium
́ ̂
Catholique de Louvain (UCL), Batiment Lavoisier, place
⊥Design & Synthesis of Organic Semiconductors (DSOS), Institute for Materials Research (IMO-IMOMEC), Hasselt University,
Agoralaan 1 − Building D, 3590 Diepenbeek, Belgium
S
* Supporting Information
ABSTRACT: In pursuit of highly preorganized macrocyclic host molecules for the
complexation of anions, a series of oxacalix[2]arene[2]pyrimidine-based bis(thio)ureido
receptors were synthesized and fully characterized. The pincer-like 1,3-alternate conformation
of the oxacalix[4]arene scaffold, essential for an efficient host−guest interaction, was visualized
by single-crystal X-ray analysis and supported by variable-temperature NMR studies. The
1
anion binding properties of the receptors were evaluated via H NMR titration experiments,
showing intermolecular interactions with H2PO4 , AcO−, BzO−, and Cl− ions. The host
−
molecule bearing 4-nitrophenyl substituents on the bisurea binding pocket showed association
constants in the range of 200−400 M−1 in the strongly competitive solvent mixture of
DMSO/0.5% H2O.
chemistry of oxacalixarenes have steadily increased.6e−g,8 Most
efforts have been directed to the development of novel syn-
INTRODUCTION
Neutral organic host molecules containing polarized N−H
■
thetic procedures and postmacrocyclization modifications of
the calixarenoid framework, although the enlarged scope of
O-bridged calix(hetero)aromatics has already triggered a few
initiatives toward supramolecular applications.8 In general, a
(distorted) 1,3-alternate solid-state conformation has been
observed for the smallest and most rigid homologues of the
series, the oxacalix[4]arenes, and this conformation has also
been proposed as the most likely one in solution (although a
very fast conformational interconversion at the NMR time scale
cannot really be excluded). The 1,3-alternate conformation makes
these systems excellent candidates as highly preorganized scaffolds
toward selective tweezer-type receptors.6e−g,8 Introduction of
porphyrinoid moieties onto the oxacalixarene periphery has
previously provided access to a bis(porphyrin) tweezer showing a
selective interaction with fullerene C70 over C60.8s Fullerene
complexation was also established with triptycene-derived oxa-
calixarenes with an expanded cavity.8o Heteroaromatic guest
molecules, such as 1,10-phenanthroline, 2,2′-pyridine, and 4,4′-
bipyridine, could be complexed by functionalized oxacalix[2]-
arene[2]triazines,8l whereas oxacalix[2]arene[2]naphthyridines
moieties are known to act as hydrogen-bond donors toward
anions and are widely used for anion recognition and sensing
purposes, which renders these receptors of great significance in
biology, medicine, catalysis, and environmental chemistry.1,2
Calixarenes are well-established as one of the most versatile
molecular platforms for supramolecular applications, due to
their highly preorganized cavity and straightforward function-
alization at both the upper and the lower rim.3,4 Several studies
have focused on either intra- or extra-annular introduction of
(thio)ureido moieties to optimize the calixarene’s binding
properties. In general, a 1,3-alternate calixarene conformation is
preferred, as this preorganization has resulted in the best
association constants for a 1:1 host−guest stoichiometry.5
Heteracalixarenes,6,7 in which heteroatoms replace the
methylene linkages of traditional calixarenes, are particularly
attractive for applications in supramolecular chemistry since the
bridging heteroatoms enable tuning the ring size, the electron
density on the arene constituents, and the host conformation
and may provide additional binding sites, resulting in an im-
proved (induced) fit of a desirable guest. Among the hetera-
calixarenes, the thia analogues have been studied most
intensively, and they are nowadays widely recognized as
effective receptors for small organic compounds and heavy/
transition metals.6b,c During the past decade, reports on the
Received: January 2, 2012
Published: February 24, 2012
© 2012 American Chemical Society
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have shown interactions with o-salicylic acid and Hg2+ metal
ions.8e,v
Although oxacalixarene macrocycles provide excellent plat-
forms for the construction of effective recognition sites, only
one group has reported on oxacalixarene-based receptors for
anions so far. Wang and co-workers observed anion com-
plexationF− and Cl−, in combination with H2Owith a
dichlorooxacalix[2]arene[2]triazine derivative via anion−π
interactions, and very recently also extended this approach to
ion-pair receptors.8g,w,9 Therefore, we envisaged synthesizing a
series of bis(thio)ureido receptors starting from a versatile
oxacalix[2]arene[2]pyrimidine scaffold and analyzing their
1
affinity for anionic guests by H NMR titration studies.
RESULTS AND DISCUSSION
■
In previous work, a convenient one-pot nucleophilic aromatic
substitution (SNAr) procedure toward oxacalix[2]arene[2]-
pyrimidines has been developed (Scheme 1).8d The use of
Scheme 1. Three-Step Procedure from Pyrimidine Precursor
1 to Functionalized Oxacalix[4]arenes 5
Figure 1. Single-crystal X-ray structures for (a) bis(methylsulfanyl)-
oxacalix[4]arene 3 and (b) bis(methylsulfanyl)thiacalix[4]arene 6.
SNAr-based reaction conditions as previously optimized for
oxacalix[4]arenes.8d Similar to the oxacalix[4]arene’s structure,
a 1,3-alternate solid-state conformation was observed by X-ray
analysis (Figure 1). Fitting the centroids of the aromatic rings
onto each other revealed a large resemblance between the two
heteracalixarene structures (see Figure S3, Supporting
Information). One expects a larger enclosed cavity (assessed
by the distances between the centroids of the opposite benzene
and pyrimidine rings) for the S-bridged macrocycle, because
of the longer C−S bonds with respect to the C−O bonds
(1.771 vs 1.375 Å, respectively), and indeed, for the longer
pyrimidine−pyrimidine distance, this hypothesis holds true.
The effect of the longer bond length is, however, evened out by
the smaller C−S−C angle (<102.7°> vs <118.8°>) and the
absence of the methyl group for the thiacalix[4]arene, which
seems to direct the opposing benzene rings outward. The re-
sulting (estimated) cavity size is 5.713 Å × 6.487 Å
for thiacalix[4]arene 6 and 4.612 Å × 7.749 Å for oxacalix[4]
arene 3.
Because of the unusual high-field chemical shifts observed for
the interior protons of the electrophilic pyrimidine components
(e.g., Hpyrim 3 at δ = 5.04 ppm vs 6.30 ppm for 4,6-dimethoxy-
2-methylsulfanylpyrimidine), attributed to the proximity of the
anisotropic shielding cone of the adjacent aromatic rings, it has
been suggested that oxacalix[2]arene[2]pyrimidines adopt a
1,3-alternate conformation in solution as well.8d,h,j A basic
investigation of the most likely conformation in solution was
performed by variable-temperature NMR (VT-NMR) analysis
of parent macrocycle 3 (in CDCl3) from 223 to 323 K (see
Figure S4, Supporting Information). The proton resonances
remained sharp and consistent over the whole temperature
range, indicating the existence of either a certain conformation
at high percentage or very fast conformational interconversion
on the NMR time scale, even at low temperature.
4,6-dichloro-2-methylsulfanylpyrimidine (1) as the electrophilic
building block, resulting in oxacalix[2]arene[2]pyrimidine 3
upon [2 + 2] cyclocondensation with orcinol (5-methyl-1,3-
dihydroxybenzene), was shown to be a highly valuable tool for
further decoration of the outer perimeter via Liebeskind−Srogl
̈
or SNAr postmacrocyclization reactions (after conversion to the
methylsulfonyl analogue), providing access to a substantial
library of variously functionalized macrocycles (Scheme 1).8h
As for most heteracalix[4]arenes, oxacalix[4]arenes have
shown a high preference to adopt (solid-state) 1,3-alternate
conformations,6e−g,8 which has been ascribed to dipole−dipole
interactions among the aromatic rings and the absence of intra-
annular hydroxyl groups favoring cone-type conformations.8,10
Previous results have shown that oxacalix[2]arene[2]-
pyrimidines also afford single-crystal structures with the
oxacalix[4]arene macrocycle in a 1,3-alternate conformation.8d,h
To analyze the conformation of parent scaffold 3 in the solid
state, suitable crystals were grown by vapor diffusion of pentane
into a CHCl3 solution of 3. The single-crystal X-ray structure
showed once more a 1,3-alternate solid-state conformation
(Figure 1).
Inspired by the high current interest in selective anion
receptors, and stimulated by the likeliness of a highly pre-
organized 1,3-alternate conformation and the ease by which
postmacrocyclization SNAr functionalization reactions can be
applied on the outer rim, it was envisaged to introduce a
In an analogous way, the sulfur analogue, bis(methyl-
sulfanyl)thiacalix[2]arene[2]pyrimidine 6, was obtained in
80% yield via the combination of 4,6-dichloro-2-methylsulfa-
nylpyrimidine (1) and benzene-1,3-dithiol under the same
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number of (thio)ureido anion receptor motifs on the
oxacalix[2]arene[2]pyrimidine skeleton.11 (Thio)ureido func-
tions have previously been shown to be particularly valuable as
neutral hydrogen-donor groups,12 due to their effective and
directional hydrogen bonds. For this reason, bis(thio)ureido
tweezer-type molecules were developed, attaching the (thio)-
urea groups to the oxacalixarene platform via a short
ethylenediamine linker (Scheme 2).
platform 4 directly with priorly prepared (thio)ureido-type
linkers resulted in a mixture of mono- and disubstituted
products, which unfortunately could not be separated
efficiently. Therefore, an amended procedure was applied,
attaching the linker unit to the upper rim before the conversion
to (thio)ureido groups. An additional advantage of the latter
method is that the differentiation between the various receptors
is only made in the final step, which is also beneficial from a
practical point of view. Oxacalix[4]arene 4 and tert-butyl-2-
aminoethylcarbamate (7) (“monoprotected ethylenediamine”)
were combined in an SNAr reaction (MeCN, Et3N as a base,
65 °C, 18 h) to produce 1,3-disubstituted oxacalixarene 8 as a
white precipitate in 89% yield (Scheme 2). Prereceptor 8 was
then converted into anion receptors 10a−10f (74−95% yield)
by a quantitative deprotection with trifluoroacetic acid (TFA)
in dichloromethane and subsequent condensation with various
iso(thio)cyanates 9a−9f (Scheme 2). In many cases, the final
receptors precipitated from the reaction mixture and were
obtained in pure form without requiring chromatographic
purification.
Scheme 2. Synthesis of Oxacalix[2]arene[2]pyrimidine-
Based Bis(thio)ureido Receptors 10a−10f
Addition of electron-withdrawing groups increases the acidity
of the urea protons, which is known to be beneficial to form
stronger complexes.13 The introduction of thiourea moieties is
also recognized to enhance anion binding due to the increased
acidity of the NH protons (pKa: urea 26.9, thiourea 21.1 in
DMSO).14,15 Therefore, in our search for a strong and selective
host, a series of both urea and thiourea receptors with and
without additional electron-deficient groups were prepared. All
receptors 10a−10f showed the same upfield chemical shift for
the 5-pyrimidinyl proton (at δ ∼ 4.50 ppm), suggesting that the
1,3-alternate conformation is preserved throughout the
complete synthetic protocol.
The obtained receptors were analyzed for their anion affinity
features by 1H NMR titrations (in DMSO-d6/0.5% H2O at 400
MHz, 5 mM host solution). Initially, host molecule 10a was
titrated with various tetra-n-butylammonium salts, showing
proton resonance shifts for the NH protons (as visualized in
Scheme 2) with anionic guests H2PO4 , AcO−, BzO−, and Cl−,
−
The synthesis of precursor macrocycle 3, as previously
reported,8d could be scaled up to gram scale after slight
adjustments to the reaction conditions. An elevated reaction
temperature (100 °C) and an extended reaction time (4 days),
together with simplified purification via recrystallization from
dichloromethane (avoiding the need for column chromato-
graphic purification), resulted in the isolation of 70% of pure
cyclotetramer 3 (Scheme 1). The oxidation of 3 with m-CPBA
to obtain bis(methysulfonyl)oxacalix[4]arene 4, as described
earlier,8d,h could be performed on a gram scale as well (in 95%
yield) without further adjustments.
In initial endeavors to functionalize the outer calixarene
periphery with urea moieties directly connected to the scaffold,
a few problems were encountered. Oxacalix[4]arene 4 was
successfully converted to the 5,15-diamine derivative (5; R =
NH2, Scheme 1) according to previously described reac-
tion conditions.8h However, various attempts to react the 2-
aminopyrimidine moieties with either N,N′-carboxydiimidazole
(CDI) or phenylchloroformate failed to afford the targeted
N-carboxyimidazole or carbamate derivatives, respectively. In
addition, condensation of the diaminooxacalix[4]arene with
phenyliso(thio)cyanate did not result in the envisaged
di(thio)urea compound(s). The difficulty to insert urea groups
directly on the oxacalixarene skeleton directed us to the
introduction of a short linker between the urea moieties and the
heteracalixarene macrocycle. Initial attempts to decorate
whereas no noticeable changes in the NMR spectra were
observed upon addition of NO3 , HSO4 , or Br−. The lack of
interaction of the host with the latter anionic species might be
attributed to the lesser basic character and/or lower charge
density of the guests. Since no interaction was observed with
these species, they were not included in further studies with the
other receptors (Table 1).
−
−
The host−guest stoichiometries of the complexes formed
between receptor 10a and the different oxyanions were deter-
mined via Job plot analyses, indicating a 1:1 ratio in all cases
(Figure 2 and the Supporting Information). Despite the lack of
1
(thio)urea moieties, prereceptor 8 was also subjected to H
NMR titration studies with the selected anions. As anticipated,
no significant binding was observed, indicating that the pre-
cursor itself is not an efficient anion receptor.
Titration of Cl− to the different host solutions resulted in a
clear downfield shift of the (thio)urea protons (NHa and NHb)
in all cases. However, a large amount of anion was required to
saturate the binding site(s), resulting in low association con-
stants (Table 1). For both AcO− and BzO−, fewer equivalents
were needed to give complete deshielding, pointing to stronger
interaction with the guest ions (Ka between 50 and 740 M−1;
Table 1). Next to the NH protons, no other resonances of the
oxacalix[4]arene framework showed a significant shift, which
implies that the anions are bound by hydrogen bridges to the
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Table 1. Ka Values (M−1) for the Complexation of
Oxacalixarene-Based Receptors 8 and 10a−10f with Anionic
Guests (in DMSO-d6/0.5% water, 5 × 10−3 M Host Solution
e
at 298 K)
AcO−
BzO−
H2PO4
Cl−
−
receptor
a
a
a
a
8
b
10a
10b
10c
10d
10e
10f
152
133
63
94
87
131
<10
<10
<10
19
125
b
50
50
362
232
145
95
349
d
c
534
740
17
b
81
331
<10
a
b
No shift observed. NHa deprotonated, Ka calculated for NHb and
c
d
NHc. NHa deprotonated, Ka determined for NHb only. NHa and
NHb deprotonated, Ka determined for NHc only. When simultaneous
deprotonation was observed, the Ka values have to be approached with
caution.17 Determined by HypNMR with errors estimated < 15%.16
e
The stability constants were calculated based on the shifts of the
(thio)urea NH protons (NHa and NHb). The proton assignment is
indicated in Scheme 2.
Figure 3. UV−vis spectra for 10e (yellow) and 10e-H2PO4− (orange)
in DMSO (at 293 K, c = 1 × 10−5 M). Inset: visual color change upon
addition of H2PO4 (10 equiv).
−
the thioureido nitrogen atom, resulting in a clear red shift for
the low-wavelength band from 362 to 374 nm and a
hyperchromic shift for the high-wavelength band at ∼475 nm
(Figure 3).
Among the urea-based receptors, host molecule 10d, bearing
electron-withdrawing nitro groups on the phenyl entities, did
not undergo deprotonation and showed relatively strong
complexation with AcO−, BzO−, and H2PO4 (362, 232, and
−
349 M−1, respectively) and rather weak binding with Cl−
(19 M−1) (Figure 4). Compared to this, receptor 10b, lacking
Figure 2. Job plot for the complexation of receptor 10a (5 × 10−5 M)
with tetra-n-butylammonium acetate in DMSO-d6/0.5% H2O.
NH groups rather than by the electron-deficient pyrimidine
rings in the cavity and that the preorganized 1,3-alternate
conformation of the calixarene platform is likely to be
maintained throughout the titration experiment. After addition
of a first aliquot of H2PO4− to the thiourea compounds 10a and
10c and urea derivative 10f, the most acidic proton NHa
disappeared due to deprotonation. On the other hand, a clear
shift was seen for protons NHb and NHc. Receptor 10e showed
complete deprotonation of both NHa and NHb, while a
downfield shift for NHc suggests further association with the
−
anion. Besides, for H2PO4 , the most basic anion in the series,
no deprotonation was observed, except for the combination
10e-AcO−, where the NHa proton resonance also disappeared
after addition of about 1 equivalent of anion to the host
Figure 4. Variation of the chemical shift of NHb vs the number of
equivalents of tetra-n-butylammonium salt added for host molecule
10d (5 × 10−3 M in DMSO-d6/0.5% H2O, 293 K).
−
solution. In contrast to the combination 10e-H2PO4 , no shift
and hence no increased contribution of NHc was observed after
deprotonation of NHa by AcO−.17
the electron-withdrawing functionality, showed a 3 times
weaker association with the anions (Table 1). For receptor
Addition of AcO− or H2PO4 to receptor 10e resulted in a
−
−
10f, an interesting selectivity toward H2PO4 (331 M−1) over
concomitant color change from yellow to orange (Figure 3).
This suggests that a negatively charged p-nitroanilide ion was
formed, which causes a significant increase in charge density on
AcO−, BzO−, and Cl− (81, 95, and <10 M−1, respectively) was
observed, notwithstanding the deprotonation of NHa.
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scale without particular adjustments. Material identity and purity were
CONCLUSIONS
■
1
confirmed by mp, MS, and H and 13C NMR.
A series of oxacalix[2]arene[2]pyrimidine-based bis(thio)-
ureido anion receptors were synthesized via a straightforward
postmacrocyclization functionalization method. In most cases,
the need for column chromatographic purification could be
completely avoided throughout the whole synthetic sequence.
The scaffold’s 1,3-alternate preorganization, affording an
appropriate arrangement of the receptor motifs, was confirmed
by single-crystal X-ray (solid-state) and VT NMR (solution)
4,6,16,18-Tetraaza-5,17-bis(methylsulfanyl)-2,8,14,20-
tetrathiacalix[4]arene (6). A mixture of 4,6-dichloro-2-methylsulfa-
nylpyrimidine (100 mg, 0.51 mmol, 1 equiv), benzene-1,3-dithiol
(59 μL, 0.51 mmol, 1 equiv), K2CO3 (183 mg, 1.32 mmol, 2.6 equiv),
and 18-crown-6 (24 mg, 0.09 mmol, 5.6 mol %) in DMF (5 mL) was
stirred at 70 °C under an Ar atmosphere during 48 h. DMF was
removed under vacuum, and the residue was redissolved in
dichloromethane (100 mL) and washed with water (3 × 50 mL).
The organic fraction was dried over MgSO4 and filtered, and the
solvent was removed under vacuum. After column chromatographic
purification (silica, MPLC: eluent heptane−ethyl acetate, 8:2), the
desired thiacalix[4]arene 6 (109 mg, 80%) was isolated in pure form as
a white solid. mp 286.4−287.3 °C; MS (ESI+) m/z 528.8 [M + H]+;
HRMS (EI) calcd for C22H16N4S6: m/z 527.9699 [M]+; found: m/z
527.9701; 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 2H; 2-Ph), 7.54 (d,
3J = 7.9 Hz, 4H; 4,6-Ph), 7.42 (t, 3J = 7.7 Hz, 2H; 5-Ph), 5.33 (s, 2H;
1
analysis. H NMR titration studies indicated reasonably strong
molecular interactions with oxyanionic guests H2PO4 , AcO−,
−
and BzO−, and weak associations with Cl−, whereas no
noteworthy affinity was observed for NO3 , Br−, or HSO4 .
The introduction of thiourea groups in combination with
electron-withdrawing moieties resulted in deprotonation of the
most acidic protons and visible formation of a p-nitroanilide
ion. For the bisurea receptor with nitrophenyl end groups, for
which no complication due to deprotonation occurred,
reasonable association constants (200−400 M−1 in the highly
competitive solvent mixture DMSO/0.5% H2O) were observed,
showing the potential of this class of receptor molecules to act
as neutral hydrogen-bonding anion hosts in polar media.18
−
−
5-pyrim), 2.56 (s, 6H; SCH3); 13C NMR (75 MHz, CDCl3) δ 172.8
(C; 4,6-pyrim), 171.7 (C; 2-pyrim), 143.7 (CH; 2-Ph), 138.4 (CH;
4,6-Ph), 131.2 (CH; 5-Ph), 130.1 (C; 1,3-Ph), 106.2 (CH; 5-pyrim),
14.4 (CH3); IR (ATR) νmax (cm−1) 2920, 2851, 1491, 1394, 1359,
1249, 1106, 1073, 812, 687.
tert-Butyl-2-aminoethylcarbamate (7). This compound has been
prepared before.20 Material identity and purity were confirmed by mp,
1
MS, and H and 13C NMR.
EXPERIMENTAL SECTION
4,6,16,18-Tetraaza-11,23-dimethyl-5,17-bis[tert-butyl-(2-
aminoethyl)carbamoyl]-2,8,14,20-tetraoxacalix[4]arene (8). A mix-
ture of bis(methylsulfonyl)oxacalix[2]arene[2]pyrimidine 4 (1.016 g,
1.82 mmol, 1 equiv), tert-butyl-(2-aminoethyl)carbamate (7) (731 mg,
4.56 mmol, 2.5 equiv), and triethylamine (1.3 mL, 9.34 mmol, 5.1
equiv) in dry MeCN (20 mL) was stirred at 65 °C under an Ar
atmosphere during 18 h. The white precipitate was filtered off, washed
with MeCN, and dried under vacuum at 40 °C. Yield 89% (1.161 g);
mp 235.3−236.3 °C; MS (ESI+) m/z 717.4 [M + H]+; HRMS (ESI+)
calcd for C36H45N8O8: m/z 717.3360 [M + H]+; found: m/z 717.3369;
1H NMR (600 MHz, DMSO-d6) δ 7.40 (sbr, 2H; NH), 6.91 (s, 4H;
4,6-orc), 6.87−6.84 (m, 4H; 2-orc, NH); 4.51 (s, 2H; 5-pyrim), 3.35−
3.25 (m, 4H; CH2), 3.15−3.05 (m, 4H; CH2), 2.27 (s, 6H; CH3), 1.38
(s, 18H; t-Bu); 13C NMR (150 MHz, DMSO-d6) δ 172.7/172.1 (C;
4,6-pyrim), 162.6 (C; 2-pyrim), 155.8 (C; CO), 152.7 (C; 1,3-orc),
142.7 (C; 5-orc), 119.8 (CH; 4,6-orc), 112.4 (CH; 2-orc), 77.8 (CH;
5-pyrim), 76.6 (C), 40.7 (CH2), 40.0 (CH2), 28.3 (CH3; t-Bu), 20.7
(CH3; Me); IR (ATR) νmax (cm−1) 3276 (NH), 3147 (NH), 2975,
1709 (CO), 1584, 1543, 1458, 1339, 1304, 1162, 789.
■
General Experimental Methods. NMR spectra were acquired on
commercial instruments, and chemical shifts (δ) are reported in parts
per million (ppm) referenced to tetramethylsilane (1H) or the internal
(NMR) solvent signals (13C).19 NMR peak assignments were
performed based on standard 2D NMR methods (COSY, HMQC,
and HMBC) and the knowledge previously gained from analogous
oxacalix[2]arene[2]pyrimidine macrocycles.8d,h,j Exact mass measure-
ments were acquired in the EI (at a resolution of 10 000) or ESI (at a
resolution of 60 000) mode. IR spectra were recorded on an FT-IR
spectrometer with a universal sampling module. UV−vis spectra were
measured with a quartz cuvette (path length of 1 cm) at 293 K in
DMSO. Melting points were determined by using a Reichert
Thermovar apparatus and were not corrected. For column
chromatography, 70−230 mesh silica 60 was used as the stationary
phase. MPLC flash chromatography was performed using a Buchi
̈
Sepacore Flash apparatus. Chemicals received from commercial
sources were used without further purification. Reaction solvents
(DMF, CHCl3, THF; 99.5+ %) were dried on molecular sieves (4 Å)
or distilled prior to use (CH2Cl2). Tetra-n-butylammonium salts were
4,6,16,18-Tetraaza-11,23-dimethyl-5,17-bis[(2-(N′-(2-
chlorophenyl)thioureido)ethyl)amino]-2,8,14,20-tetraoxacalix[4]-
arene (10a) (General Procedure 1). A solution of oxacalix[4]arene 8
(200 mg, 0.28 mmol, 1 equiv) in CH2Cl2/TFA (4/2 mL) was stirred
at rt under an Ar atmosphere during 3 h, after which the volatiles were
removed under reduced pressure. The residue was redissolved in
chloroform (5 mL), stirred with triethylamine (1.2 mL, 8.6 mmol, 30
equiv), and 2-chlorophenylisothiocyanate (9a) (110 μL, 0.84 mmol, 3
equiv) was added. The reaction was then continued at 50 °C under an
Ar atmosphere during 18 h. The precipitate was filtered off, washed
with chloroform, and dried under vacuum at 40 °C to obtain the
desired oxacalix[4]arene 10a (222 mg, 92%) as a pure white solid. mp
159.9−160.9 °C; MS (ESI+) m/z 856.1 [M + H]+; HRMS (ESI+)
calcd for C40H37N10O4S2Cl2 [M + H]+: m/z 855.1818; found: m/z
855.1826; 1H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 2H; NHa), 8.04
1
dried overnight under vacuum at 40 °C prior to use. All H NMR
titrations to study anion complexation were performed using 500 μL
of the host solution with an initial concentration of 5 × 10−3 M in
DMSO-d6/0.5 v% H2O, to which guest solutions with concentrations
of 5 × 10−1 M (prepared with host solution) were added gradually,
and the chemical shifts of the relevant N−H protons were recorded
following each addition.
4,6,16,18-Tetraaza-11,23-dimethyl-5,17-bis(methylsulfanyl)-
2,8,14,20-tetraoxacalix[4]arene (3). This compound has been
prepared before.8d The synthesis could be scaled up to (multi)gram
scale after slight adjustments to the reaction conditions. A mixture of
4,6-dichloro-2-methylsulfanylpyrimidine (5.00 g, 25.6 mmol, 1 equiv),
orcinol (3.18 g, 25.6 mmol, 1 equiv), K2CO3 (9.05 g, 65.5 mmol, 2.5
equiv), and 18-crown-6 (660 mg, 2.5 mmol, 10 mol %) in DMF (250
mL) was stirred at 100 °C under an Ar atmosphere during 4 days.
DMF was removed under vacuum, and the residue was redissolved in
ethyl acetate and washed with water. The organic fraction was dried
over MgSO4 and filtered, and the solvent was removed under vacuum.
After recrystallization from CH2Cl2, the desired oxacalix[4]arene (8.84 g,
70%) was obtained in pure form as a white solid. Material identity and
3
(sbr, 2H; NHb), 7.65 (sbr, 2H; NHc), 7.58−7.45 (dd, J = 7.5 Hz, 4H;
3
3
3,6-Ph), 7.31 (t, J = 7.7 Hz, 2H; 4/5-Ph), 7.18 (t, J = 6.6 Hz, 2H;
4/5-Ph), 6.93 (s, 4H; 4,6-orc), 6.84 (s, 2H; 2-orc), 4.53 (s, 2H; 5-pyrim),
3.69 (sbr, 4H; CH2), 3.49 (sbr, 4H; CH2), 2.28 (s, 6H; CH3); 13C NMR
(75 MHz, DMSO-d6) δ 181.5 (C; CS), 172.7/172.1 (C; 4,6-pyrim),
162.7 (C; 2-pyrim), 152.6 (C; 1,3-orc), 142.8 (C; 5-orc), 136.0
(C; Ph), 129.5 (CH; Ph), 129.1 (CH; Ph), 127.3 (CH; Ph), 119.8
(CH; 4,6-orc), 112.3 (CH; 2-orc), 76.7 (CH; 5-pyrim), 43.4 (CH2),
40.0 (CH2), 20.7 (CH3); IR (ATR) νmax (cm−1) 3251 (NH), 3133 (NH),
2930, 1610 (CS), 1585, 1545, 1472, 1347, 1297, 1163, 792, 748, 682.
8d
purity were confirmed by mp, MS, and H and 13C NMR.
4,6,16,18-Tetraaza-11,23-dimethyl-5,17-bis(methylsulfonyl)-
2,8,14,20-tetraoxacalix[4]arene (4). This compound has been
prepared before.8h The procedure could be scaled up to (multi)gram
1
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4,6,16,18-Tetraaza-11,23-dimethyl-5,17-bis[(2-(N′-phenylureido)-
ethyl)amino]-2,8,14,20-tetraoxacalix[4]arene (10b). Synthesis ac-
cording to general procedure 1: phenylisocyanate (9b) (91 μL, 0.84
mmol, 3 equiv). After the reaction, the solvent was evaporated and the
crude residue was purified by column chromatography (silica, MPLC:
eluent ethyl acetate−methanol, 95:5) to obtain the desired
oxacalix[4]arene 10b (170 mg, 81%) as a pure white solid. mp
184.7−185.7 °C; MS (ESI+) m/z 755.7 [M + H]+; HRMS (ESI+)
calcd for C40H39N10O6 [M + H]+: m/z 755.3054; found: m/z
755.3060; 1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 2H; NHa), 7.50
(t, 3J = 4.9 Hz, 2H; NHb), 7.39 (d, 3J = 7.9 Hz, 4H; o-Ph), 7.20 (t, 3J =
ethyl acetate, gradient 8:2 to 0:10) to obtain the desired oxacalix[4]-
arene 10e (232 mg, 95%) as a yellow solid. mp 162.1−163.1 °C; MS
(ESI+) m/z 877.7 [M + H]+; HRMS (ESI+) calcd for C40H37N12O8S2
[M + H]+: m/z 877.2299; found: m/z 877.2321; 1H NMR (300 MHz,
DMSO-d6) δ 10.23 (s, 2H; NHa), 8.39 (s, 2H; NHb), 8.17 (d, 3J = 8.8
3
Hz, 4H; Ph), 7.81 (d, J = 8.8 Hz, 4H; Ph), 7.58 (sbr, 2H; NHc), 6.91
(s, 4H; 4,6-orc), 6.83 (s, 2H; 2-orc), 4.54 (s, 2H; 5-pyrim), 3.80−3.65
(m, 4H; CH2-urea), 3.60−3.45 (m, 4H; CH2-pyrim), 2.27 (s, 6H;
CH3); 13C NMR (75 MHz, DMSO-d6) δ 180.3 (CS), 172.6/172.0
(C; 4,6-pyrim), 162.6 (C; 2-pyrim), 152.5 (C; 1,3-orc), 146.2 (C; ipso-
NO2-Ph), 142.7 (C; 5-orc), 141.8 (C; ipso-Ph), 124.5 (CH; Ph), 120.4
(CH; Ph), 119.7 (CH; 4,6-orc), 112.3 (CH; 2-orc), 76.7 (CH; 5-
pyrim), 43.5 (CH2), 39.6 (CH2), 20.7 (CH3); IR (ATR) νmax (cm−1)
3249 (NH), 2971, 2923, 2853, 1580, 1536, 1505, 1459, 1325, 1297,
1250, 1160, 1109, 1033, 849, 788, 680; UV−vis (DMSO) λmax (log ε)
362 (4.79), 477 (4.13).
3
7.7 Hz, 4H; m-Ph), 6.91 (s, 4H; 4,6-orc), 6.88 (t, J = 7.4 Hz, 2H;
p-Ph), 6.81 (s, 2H; 2-orc), 6.24 (t, 3J = 5.3 Hz, 2H; NHc), 4.50 (s, 2H;
3
5-pyrim), 3.40−3.31 (sbr, 4H; CH2), 3.30 (t, J = 5.3 Hz, 4H; CH2),
2.27 (s, 6H; CH3); 13C NMR (75 MHz, DMSO-d6) δ 172.7/172.0
(C; 4,6-pyrim), 162.7 (C; 2-pyrim), 155.4 (C; CO), 152.5 (C; 1,3-orc),
142.7 (C; 5-orc), 140.4 (C; ipso-Ph), 128.6 (CH; Ph), 121.0 (CH; p-Ph),
119.7 (CH; 4,6-orc), 117.6 (CH; Ph), 112.3 (CH; 2-orc), 76.4 (CH;
5-pyrim), 41.2 (CH2), 38.6 (CH2), 20.6 (CH3); IR (ATR) νmax (cm−1)
3374 (NH), 3344 (NH), 2957, 1662 (CO), 1613, 1574, 1541, 1359,
1341, 1309, 1162, 1038, 755, 687.
4,6,16,18-Tetraaza-11,23-dimethyl-5,17-bis[(2-(N′-(3,5-di-
(trifluoromethyl)phenyl)ureido)-ethyl)amino]-2,8,14,20-
tetraoxacalix[4]arene (10f). Synthesis according to general procedure
1: 3,5-di(trifluoromethyl)phenylisocyanate (9f) (121 μL, 0.84 mmol, 3
equiv); The white precipitate formed during the reaction was filtered
off, washed with chloroform, and dried under vacuum at 40 °C to
obtain the desired oxacalix[4]arene 10f (213 mg, 74%). mp 294.6−
295.6 °C; MS (ESI+) m/z 1027.2 [M + H]+; HRMS (ESI+) calcd for
C44H35N10O6F12 [M + H]+: m/z 1027.2549; found: m/z 1027.2573;
1H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 2H; NHa), 8.09 (s, 4H;
4,6,16,18-Tetraaza-11,23-dimethyl-5,17-bis[(2-(N′-
phenylthioureido)ethyl)amino]-2,8,14,20-tetraoxacalix[4]arene
(10c). Synthesis according to general procedure 1: phenylisothiocya-
nate (9c) (100 μL, 0.837 mmol, 3 equiv); reaction time 2 h. The
precipitate formed during the reaction was filtered off, washed with
dichloromethane, and dried under vacuum at 40 °C to obtain the
desired oxacalixarene 10c (185 mg, 84%) as a pure white solid. mp
171.3−172.3 °C; MS (ESI+) m/z 787.6 [M + H]+; HRMS (ESI+)
calcd for C40H39N10O4S2 [M + H]+: m/z 787.2597; found: m/z
787.2613; 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 2H; NHa), 7.82
o-Ph), 7.53 (s, 2H; p-Ph), 7.51 (t, 3J = 5.4 Hz, 2H; NHb), 6.88 (d, 3J =
3
7.3 Hz, 4H; 4,6-orc), 6.81 (s, 2H; 2-orc), 6.59 (t, J = 5.3 Hz, 2H;
NHc), 4.50 (s, 2H; 5-pyrim), 3.45−3.40 (m, 4H; CH2), 3.40−3.30 (m,
4H; CH2), 2.27 (s, 6H; CH3); 13C NMR (100 MHz, DMSO-d6) δ
172.7/172.1 (C; 4,6-pyrim), 162.8 (C; 2-pyrim), 155.0 (CO), 152.6
(C; 1,3-orc), 142.6 (C; 5-orc), 131.3/130.9/130.4/130.0 (q; Ci-CF3,
3
3
(sbr, 2H; NHb), 7.53 (t, J = 4.9 Hz, 2H; NHc), 7.39 (d, J = 7.5 Hz,
4H; o-Ph), 7.31 (t, 3J = 7.5 Hz, 4H; m-Ph), 7.10 (t, 3J = 7.2 Hz, 2H; p-
Ph), 6.92 (s, 4H; 4,6-orc), 6.81 (s, 2H; 2-orc), 4.52 (s, 2H; 5-pyrim),
1
2JCF = 43 Hz), 128.8/125.2/121.6/118.0 (q; CF3, JCF = 361 Hz),
119.8 (CH; 4,6-orc), 117.3 (CH; o-Ph), 113.5 (CH; p-Ph), 112.4
(CH; 2-orc), 76.5 (CH; 5-pyrim), 40.8 (CH2), 39.0 (CH2), 20.7
(CH3); IR (ATR) νmax (cm−1) 3365 (NH), 3104 (NH), 2971, 1678
(CO), 1613, 1576, 1543, 1474, 1387, 1341, 1273, 1162, 1038, 887,
790, 680.
3.70 (sbr, 4H; CH2), 3.47−3.44 (sbr, 4H; CH2), 2.28 (s, 6H; CH3); 13
C
NMR (75 MHz, DMSO-d6) δ 180.6 (CS), 172.7/172.2 (C; 4,6-
pyrim), 162.7 (C; 2-pyrim), 152.6 (C; 1,3-orc), 142.9 (C; 5-orc),
139.1 (C; ipso-Ph), 128.8 (CH; Ph), 124.4 (CH; Ph), 123.3 (CH;
p-Ph), 119.9 (CH; 4,6-orc), 112.4 (CH; 2-orc), 76.7 (CH; 5-pyrim),
43.4 (CH2), 40.2 (CH2), 20.8 (CH3); IR (ATR) νmax (cm−1) 3252
(NH), 3142 (NH), 2980, 1667, 1608, 1586, 1539, 1463, 1343, 1299,
1161, 1125, 791, 682.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra, X-ray crystallographic data and
figures for heteracalixarenes 3 and 6, VT-NMR data for 3, and
additional details on the anion titration experiments. This
material is available free of charge via the Internet at http://
pubs.acs.org.
4,6,16,18-Tetraaza-11,23-dimethyl-5,17-bis[(2-(N′-(4-
nitrophenyl)ureido)ethyl)amino]-2,8,14,20-tetraoxacalix[4]arene
(10d). Synthesis according to general procedure 1: 4-nitrophenyliso-
cyanate (9d) (138 mg, 0.84 mmol, 3 equiv). After the reaction,
the solvent was evaporated and the crude residue was purified by
column chromatography (silica, MPLC: eluent ethyl acetate−
methanol, gradient 10:0 to 9:1) to obtain the desired oxacalix[4]arene
10d (217 mg, 93%) as a pale yellow solid. mp 176.7−177.7 °C; MS
(ESI+) m/z 845.8 [M + H]+; HRMS (ESI+) calcd for C40H37N12O10
[M + H]+: m/z 845.2756; found: m/z 845.2750; 1H NMR (300 MHz,
DMSO-d6) δ 9.37 (s, 2H; NHa), 8.14 (d, 3J = 9.0 Hz, 4H; Ph), 7.63 (d,
3J = 9.2 Hz, 4H; Ph), 7.54 (t, 3J = 5.1 Hz, 2H; NHc), 6.90 (d, 3J = 4.1
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wim.dehaen@chem.kuleuven.be (W.D.), wouter.maes@
uhasselt.be (W.M.).
Notes
3
Hz, 4H; 4,6-orc), 6.83 (s, 2H; 2-orc), 6.56 (t, J = 4.9 Hz, 2H; NHb),
The authors declare no competing financial interest.
4.50 (s, 2H; 5-pyrim), 3.41−3.38 (m, 4H; CH2), 3.37−3.34 (m, 2H;
CH2), 2.27 (s, 6H; CH3); 13C NMR (75 MHz, DMSO-d6) δ 172.6/
172.0 (C; 4,6-pyrim), 162.7 (C; 2-pyrim), 154.6 (CO), 152.5 (C;
1,3-orc), 147.2 (C; ipso-NO2-Ph), 142.6 (C; 5-orc), 140.3 (C; ipso-
Ph), 125.1 (CH; Ph), 119.7 (CH; 4,6-orc), 116.8 (CH; Ph), 112.3
(CH; 2-orc), 76.5 (CH; 5-pyrim), 40.8 (CH2), 38.8 (CH2), 20.6
(CH3); IR (ATR) νmax (cm−1) 3270 (NH), 2954, 2922, 2853, 1684
(CO), 1541, 1500, 1459, 1326, 1298, 1221, 1160, 1106, 849, 789,
750, 680.
4,6,16,18-Tetraaza-11,23-dimethyl-5,17-bis[(2-(N′-(4-
nitrophenyl)thioureido)ethyl)amino]-2,8,14,20-tetraoxacalix[4]-
arene (10e). Synthesis according to general procedure 1: 4-
nitrophenylisothiocyanate (9e) (151 mg, 0.84 mmol, 3 equiv). After
the reaction, the solvent was evaporated and the crude residue was
purified by column chromatography (silica, MPLC: eluent heptane−
ACKNOWLEDGMENTS
■
We thank the FWO (Fund for Scientific Research − Flanders),
the KU Leuven, and the Ministerie voor Wetenschapsbeleid for
continuing financial support.
REFERENCES
■
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