Boosting the salt recognition abilities of L-ornithine based multitopic molecular receptors by harnessing a double cooperative effect

Article abstract of DOI:10.1039/c4dt00576g

A family of l-ornithine based salt receptors 1a-f was synthesized, bearing a cation binding site and multiple anion binding sites (nitrophenylurea and amide groups) that may simultaneously associate with a single anion. The variation in H-bond donor abilities of one of these anion binding sites has relatively little influence on NO₂^- anion binding when the anion is accompanied by a noncoordinating TBA cation. However, in the presence of a sodium cation, which strongly coordinates with the cation binding domain of 1a-f, the increased H-bond donor abilities of the anion binding group result in a significant enhancement of NO₂^- anion binding. A direct correlation between the anion binding site H-bond donor tendencies and the binding cooperation of sodium cations and nitrite anions was also observed. Cation complexation fixes the nitrophenylurea moiety orientation and exposes that domain to bind anions. This cation and anion cooperation induces a second cooperative effect, namely the simultaneous association of a single anion with both urea and amide binding groups. Receptor 1d was found to be highly selective for NaNO₂ over sodium bromide and nitrate. A transport experiment using a bulky liquid membrane showed that this receptor can effectively transport NaNO₂ from the aqueous phase through the organic phase. the Partner Organisations 2014.

Full text of DOI:10.1039/c4dt00576g

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Boosting the salt recognition abilities of
L-ornithine based multitopic molecular receptors
by harnessing a double cooperative effect†
Cite this: Dalton Trans., 2014, 43,
8515
Piotr Piątek, Marcin Karbarz and Jan Romański*
A family of L-ornithine based salt receptors 1a–f was synthesized, bearing a cation binding site and mul-
tiple anion binding sites (nitrophenylurea and amide groups) that may simultaneously associate with a
single anion. The variation in H-bond donor abilities of one of these anion binding sites has relatively little
−
influence on NO2 anion binding when the anion is accompanied by a noncoordinating TBA cation.
However, in the presence of a sodium cation, which strongly coordinates with the cation binding domain
of 1a–f, the increased H-bond donor abilities of the anion binding group result in a significant enhance-
−
ment of NO2 anion binding. A direct correlation between the anion binding site H-bond donor
tendencies and the binding cooperation of sodium cations and nitrite anions was also observed. Cation
complexation fixes the nitrophenylurea moiety orientation and exposes that domain to bind anions. This
cation and anion cooperation induces a second cooperative effect, namely the simultaneous association
of a single anion with both urea and amide binding groups. Receptor 1d was found to be highly selective
for NaNO2 over sodium bromide and nitrate. A transport experiment using a bulky liquid membrane
showed that this receptor can effectively transport NaNO2 from the aqueous phase through the organic
phase.
Received 24th February 2014,
Accepted 21st March 2014
DOI: 10.1039/c4dt00576g
www.rsc.org/dalton
solubilization, extraction and membrane transport.4 However,
in spite of their potential applications in various fields, the
Introduction
In both cation and anion binding by monotopic molecular number of such ion pair receptors remains limited. Among
receptors, the complexed ion is accompanied by a counterion. other factors, this is due to the difficulties associated with
Thus for a receptor to associate with a target ion, it must the synthesis of heteroditopic receptors, which obviously
compete with the counterion. To overcome this problem, the must consist of at least two properly oriented heterotopic
so-called noncompeting counterions are often used in labora- binding regions. Moreover, many of the most effective salt
tory applications. However, in many real-life applications, the receptors have a multi-macrocyclic structure and their syn-
luxury of noncompetitive counterions is not available, and thesis requires the application of high-dilution techniques.3a–c,g,h,4a,5
hence inter-ion competition can be significant. The only way Therefore, fine-tuning of the structure, and concurrently
to eliminate this problem is through simultaneous binding of the binding properties, of many heteroditopic receptors is very
both the anion and cation, i.e. salt binding.1 This can be problematic. Furthermore, due to the “closed” structure of
achieved using heteroditopic receptors to simultaneously bind these receptors it is difficult to introduce an additional struc-
the anion and the cation.2 A potential advantage to be gained tural element into the system, such as a new binding domain,
by covalently linking the anion and the cation binding sites is chromophore/fluorophore or increased solubility/lipophilicity
the possibility of positive binding cooperativity, which function. Therefore the synthesis of multitopic receptors that
enhances the selectivity and efficacy of ionic species recog- can effectively recognize ion pairs and are concurrently prone
nition.3 Moreover, the complexation of both ions by a ditopic to structural modification is an important area of interest.
receptor enhances the salt lipophilicity, thus facilitating its
Recently, we reported the synthesis and binding of a
heteroditopic salt receptor based on the L-ornithine scaffold.6
This receptor consists of aza-18-crown-6 (cation binding
domain) and nitrophenylthiourea (anion binding domain)
appended to the carboxylic and α-amino groups of L-ornithine,
respectively. Moreover, the ornithine δ-amino group was
converted to a methacrylamide function and used for the
Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
E-mail: jarom@chem.uw.edu.pl
†Electronic supplementary information (ESI) available: Spectroscopic data for all
new compounds, as well as experimental procedures for binding and extraction
studies. See DOI: 10.1039/c4dt00576g
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preparation of copolymers containing the receptor. Further
study revealed that this receptor is susceptible to structural
Results and discussion
changes that alternate its binding propensity. For example, we Receptors 1b–f (Scheme 1 and Fig. 1) were prepared starting
found that replacing the soft sulfur atom of the nitrophenyl- from commercially available Nα-Boc-Nδ-Cbz-L-ornithine
thiourea binding domain with a hard oxygen atom (receptor or Nα-Cbz-Nγ-Boc-L-lysine. The DCC-promoted coupling of
1c) reinforced Na+ cation binding, which affected anion and starting compounds with aza-18-crown-6 leads to crown ether
salt binding.7 In particular, this modification resulted in an functionalized amino acids 2b and 2e with ∼90% yield. Sub-
decreased anion binding strength, although an immensely sequent deprotection of the Cbz group of the ornithine deriva-
increased salt binding strength and selectivity towards NaNO2 tive 2b and acylation of the δ-amine function gave compounds
were observed. Detailed solution binding studies supported by 3c, 3d and 3f. Finally, TFA-promoted cleavage of the Boc group
molecular modeling revealed that urea CvO group coordi- followed by acylation of the resulting amines with 4-nitrophe-
nation to the crown ether complexed sodium cation is respon- nylisocyanate afforded receptors 1c, 1d and 1f. The L-lysine
sible for the reinforcement of anion binding to urea NH based receptor 1e was prepared from compound 2e by depro-
protons. Moreover, we noticed that the methacrylamide group tection of the Nα-Boc group, acylation with 4-nitrophenyliso-
located on the side arm of receptor 1c provides an additional cyanate and subsequent deprotection of the side arm amine
binding domain for anion recognition and we showed that the group and its acylation with trifluoroacetyl anhydride. Recep-
strength of anion and salt binding is decreased when this tor 1a, lacking an additional binding domain, was prepared in
group is not present. Based on this observation we envisioned an analogous manner starting from N-Boc-L-leucine.
that introducing a stronger H-bond donor group to the
Since the previously reported receptor 1c is highly selective
L-ornithine side arm should increase the anion and conse- for sodium nitrite, we decided to screen the binding ability of
quently the salt association strength. Thus, here we report a receptors 1a–f for the nitrite anion and its sodium salt. The
study concerning the influence of such receptor side arm binding experiments were conducted in CD3CN using the 1H
modifications on the anion and salt binding effectiveness. For NMR titration technique. The addition of tetra-n-butylammo-
the most effective receptor, we also describe a detailed binding nium (TBA) nitrite to a 2.6 mM solution of receptor or receptor
study and preliminary extraction and membrane transport containing one equivalent of NaPF6 caused nonlinear down-
experiments.
field shifts of both urea protons and amide protons located on
Scheme 1 Synthesis of receptors 1b–f. Reagents and conditions: (a) DCC, 1-aza-18-crown-6, CH2Cl2, 0 °C to r.t., 91–92%; (b) H2, Pd/C, MeOH–
THF, r.t., quantitative; (c) 3c: methacryloyl chloride, Et3N, CH2Cl2, 0 °C to r.t., 50%; 1e and 3d: trifluoroacetyl anhydride, Et3N, CH2Cl2, 0 °C to r.t., 73
and 72%; 3f: trifluoromethanesulfonyl chloride, Et3N, CH2Cl2, 0 °C to r.t., 91%; (d) TFA–CH2Cl2 (1 : 1), r.t., quantitative; (e) 4-nitrophenyl isocyanate,
Et3N, THF, 1c: 75%, 1d: 60%, 1f: 72%, 3e: 81%.
8516 | Dalton Trans., 2014, 43, 8515–8522
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the L-leucine based receptor 1a, without an additional anion
binding domain, and receptor 1b, possessing a weak H-bond
donor HNCbz function, associate with the nitrite anion only
moderately. Increasing the hydrogen bond donor ability of the
side arm group by introducing methacrylamide 1c or even the
trifluoroacetyl group 1d did cause an enhancement in TBANO2
association, but this increase was not great, at least not quite
twofold. Unfortunately, the most acidic trifluoromethanesulfo-
−
namide group is readily deprotonated by an NO2 anion, thus
1f cannot be used for anion and salt binding studies.
There is a much more distinct increase in binding strength
with the amplified H-bond donor ability of the side arm
domain when the nitrite anion associates with 1·Na+ com-
plexes generated by the addition of one equivalent of NaPF6 to
the receptor solution. Specifically, while sodium complexes of
receptors 1a and 1b bound NO2− with association constants of
approximately 4200 M−1, the association exhibited by 1c·Na+ is
almost two times stronger, whereas the trifluoroacetyl deriva-
tive 1d·Na+ was found to bind nitrite with the remarkable
association constant value of 19 000 M−1. Therefore, increasing
the H-bond donor ability of the side arm anion-binding group
results in 4.5 times stronger binding of the NaNO2 salt.
Since the electronic effects of the side arm group of 1 play a
very significant role in salt recognition, we decided to investi-
gate how effects associated with the geometrical features of
the binding cavity influence NaNO2 binding. Therefore, we
prepared the L-lysine based receptor 1e with the increased dis-
tance between the urea and trifluoroacetamide groups. Inter-
estingly, we found that this modification did not influence the
strength of TBANO2 binding, although NaNO2 binding is
greatly diminished compared to receptor 1d. These results
make it clear that a suitable combination of electronic and
geometric factors is necessary for effective recognition of ion
pairs.
Fig. 1 The structure of amino acid based salt receptors.
Table 1 Association constants (Ka) for interactions of receptors 1a–f
−
with NO2 in the absence or presence of one equivalent of sodium
cationsa
δNHAmide
TBANO2
1 eq. NaPF6 TBANO2
KNa/KTBA
1a
1b
1c
1d
1e
1f
—
790
795
1180
1450
1400
—
4170
4250
7590
19 000
8300
—
5.3
5.3
6.4
13.1
5.9
—
5.7
6.7
7.6
7.6
7.9
a
1H NMR, solvent CD3CN, temperature 293 K, [1] = 2.6 mM, [NaPF6] =
2.6 mM, [TBANO2] < 20 mM; M−1, errors < 10%.
Positive cooperation (i.e. an enhancement of anion binding
due to the presence of a cation) can be clearly seen for all the
receptors studied, 1a–d (Table 1, Column 5). The association
constants for nitrite binding in the presence of sodium cations
considerably increase compared to the association constants
for nitrite anions accompanied by non-coordinating TBA
cations. The highest cooperativity factor was found for receptor
1d, whose association with nitrite is over 13 times stronger in
the presence of sodium cations. Moreover, inspection of
Table 1 revealed that the cooperativity in salt binding corre-
lates well with the H-bond donor tendency of the amide
Fig. 2 1H NMR titrations of receptors 1b–e with TBANO2 in the pres-
ence of 1 equivalent of NaPF6. Profiles based on the chemical shift located on the aminoacid side arm. Given that the increased
(δ, ppm) of amide protons.
H-bond donor tendency has a relatively small impact on anion
binding but a significant influence on anion binding in the
presence of sodium cations, we tentatively attributed this
the amino-acid side arm, if applicable. The association con-
stants calculated by nonlinear regression analysis of the
binding isotherms are presented in Table 1.
The receptors listed in Table 1 are arranged in the order of
increasing H-bond donor ability of the side arm group, as esti-
mated on the basis of the amide-NH chemical shift of the free
receptors (Table 1, Column 2 and Fig. 2).8 As shown in Table 1,
phenomenon to cooperative effects.
The cooperativity between sodium and nitrate recognition
of receptors 1a–d could be ascribed to coordination of the urea
oxygen atom to the crown ether complexed cation. In particu-
lar, the coordination of the urea oxygen atom to Na+ reduces
the electron density of the urea group, which is reflected in the
blue shift charge transfer band as well as the downfield shift
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Fig. 3
A tentative sketch of the binding mode in the 1d·NaNO2
complex.
Fig. 4 1H NMR titration of receptor 1d with TBANO2 in the presence
and absence of 1 equivalent of NaPF6. Open symbols refer to the titra-
tion in the absence of sodium cations; full symbols refer to the titration
in the presence of sodium cations.
of the urea N–H protons.7 We assume that this coordination
not only increases the acidity of the urea NHs but also fixes
the nitrophenylurea moiety orientation and exposes that
domain to bind anions together with the amide function
(Fig. 3). In consequence, cation and anion cooperation
induces a second cooperative effect, namely simultaneous
cooperation of both anion binding domains in complexation
of a single ion.
the amide group did not cause a significant increase in anion
binding strength. Interestingly, the same trend is observed for
anion binding in the presence of sodium cations, with the
notable exception of nitrite anions. For example, sodium
nitrate is bound to receptors 1c and 1d with association con-
stants 850 and 1250 M−1, respectively.7
−
After screening the receptors’ binding affinity for the NO2
anion and NaNO2 salt, the most effective receptor 1d was
+
further explored in detail. First, its affinity for K+, NH4 and
−
Na+ cations in the presence of the non-coordinating PF6
However, the binding ability of the side-arm group has a
significant impact on the salt binding selectivity. Specifically,
the highest ion pair binding cooperativity was found for
sodium nitrite, with a cooperativity factor of 13.1. The coopera-
tivity factors for bromide and nitrate anions in the presence of
hard sodium cations are similar for receptors 1d and 1c. In
consequence, the introduction of a strong H-bond donor
group into the side arm of receptor 1d not only causes great
enhancement of NaNO2 binding strength but also makes
receptor 1d more selective towards this salt. This result can be
attributed to both the spatial and electronic demand of the
binding domains of the receptor. Specifically, we assume that
the urea group mainly controls the geometry of the complexed
anion, and it is well established that this group preferentially
binds Y-shaped coplanar anions like nitrate or nitrite. More-
over, the nitrite anion has the strongest H-bond accepting
ability among the anions studied, which can be determined on
the basis of its conjugated acid pKa value.
anion was established. The addition of cations to a 2.6 mM
solution of 1d caused nonlinear downfield shifts of the crown
ether protons. The association constants calculated by non-
linear regression analysis of the binding isotherms revealed
that both NH4 and K+ cations coordinated with the receptor
+
only moderately, with association constant values of Ka = 420
and 740 M−1, respectively. As for the previously reported recep-
tor 1c, the association constant for Na+ was found to be higher
than 5 × 104, which precluded quantitative Ka determination.9
Nevertheless, these experiments proved the high selectivity
of receptor 1d for sodium cation recognition. Therefore, the
ion-pair binding experiments were carried out in the presence
of sodium cations.
The affinity of receptor 1d towards selected anions and
their sodium salts was then examined. Anion addition to 1d
solution caused nonlinear downfield shifts of both urea NH
protons and amide protons located on the side arm of the
receptor (Fig. 4). Analyzing the complexation induced shifts of
all three NH protons of 1d using the curve fitting program
HypNMR enabled the association constants listed in Table 2 to
be calculated.
Table 2 Association constants (Ka) for interactions of receptor 1d with
anions in the absence or presence of 1 equivalent of sodium cationsa
As Table 2 shows, receptor 1d associates moderately with
TBA salts of chloride and nitrite and weakly with bromide and
nitrate anions, whereas fluoride anions cause receptor depro-
tonation. Similar to nitrite anions (see Table 2), the association
constant values for other anions are only slightly higher for
receptor 1d than for receptor 1c.7 For example, nitrate is
bound to receptors 1c and 1d with association constants 110
and 150 M−1, respectively. These results further corroborate
TBA+
Na+
KNa/KTBA
b
b
F−
—
—
—
—
—
8.8
13.1
8.2
c
Cl−
3100
390
1450
150
Br−
NO2−
NO3
3450
19 000
1250
−
a
1H NMR, solvent CD3CN, temperature 293 K, [1d] = 2.6 mM, [NaPF6]
= 2.6 mM, anions added as TBA salts [TBAX] ∼20 mM; M−1, errors <
10%. b Receptor deprotonation. c Precipitation.
−
the findings from NO2 binding studies of receptors 1a–e that
even considerable enhancement of the H-bond donor ability of
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Table 3 Solid/liquid extraction experiments dataa
and anion binding domains and possesses an additional
amine group located on the side arm. This functional group
can be modified for specific purposes, and in this study we
employed it to introduce various anion binding groups with
increased H-bond donor abilities. Although enhancement of
the H-bond donor ability of the amide group has a relatively
small influence on the anion binding strength, this function
plays an important role in the salt binding process.
We showed that the increased H-bond donor abilities of
an additional anion binding group correlated well with the
enhanced NaNO2 binding strength. A similar correlation
between amide group acidities and ion binding cooperation is
also observed. Therefore, we assume that cation complexation
δNHUrea
δNHUrea
δNHAmide
1d·saltb [%]
1d
8.30
8.88
9.05
9.86
9.74
9.23
8.66
7.76
7.95
8.07
8.65
8.27
8.18
7.93
6.93
7.03
7.29
7.83
7.60
7.34
7.08
—
—
—
47.2
30.1
40.5
26.3
NH4NO2
KNO2
NaNO2
NaBr
NaNO3
NaCl
a
1H NMR, solvent CDCl3, temperature 293 K, [1d]
= 3.2 mM.
b Determined by the sodium content by atomic emission spectroscopy.
To test whether receptor 1d could be used to affect NaNO2 fixes the nitrophenylurea moiety orientation and exposes that
extraction, preliminary extraction and membrane transport domain for anion binding. This cation and anion cooperation
studies were carried out. Specifically, complete solid/liquid induces a second cooperative effect, namely simultaneous
salt extraction studies were undertaken using solutions of 1d association of a single anion with both urea and amide
in CDCl3 layered over powdered inorganic salts. Based on N–H binding groups. The highest cooperativity effect is observed for
proton chemical shifts of salt saturated 1d solutions, the rela- the trifluoroacetamide equipped receptor 1d, which interacts
tive content of 1d·salt complexes in the organic phase could be with NaNO2 with the association constant of 19 000 M−1
estimated.10
Furthermore, receptor 1d was found to be highly selective for
.
The data collected in Table 3 revealed that under interfacial NaNO2 over sodium bromide and nitrate salts. Receptor 1d
conditions, the selectivity towards cations of selected nitrite proved to be able to extract solid sodium salts of nitrite,
salts is in agreement with solution studies, namely NH4 < K+ nitrate, bromide and chloride in organic solution, exhibiting
+
< Na+. Moreover the predisposition of 1d to preferentially bind selectivity for NaNO2 similar to that seen in solution studies.
nitrite over Cl−, Br−, and NO3− was also confirmed. This result Finally, a transport experiment using a bulky liquid membrane
is further corroborated by the quantitative determination of showed that receptor 1d can effectively transport NaNO2 from
the sodium cation concentration in the organic phase by the aqueous phase through the organic phase. Thus we have
atomic emission spectroscopy. These results are in agreement demonstrated that systematic development of the structure
with those from NMR experiments, although lower selectivity and electronic properties of the binding domains of molecular
between nitrite and nitrate anions is observed.
receptors may lead to a very effective and selective salt
The ability of receptor 1d to extract and transport NaNO2 receptor.
from aqueous solutions was also tested. A 1.5 M solution of
NaNO2 in deionized water was layered onto a 14 mM solution
of 1d in CDCl3. The two layers were thoroughly mixed and
Experimental section
then separated. The 1H NMR spectrum of the organic phase
revealed that NH signals are shifted only slightly. By atomic
emission spectroscopy we demonstrated that 1d is able to
transfer sodium cations into chloroform with an extraction
efficiency of 3.1%. Encouraged by that result, we carried out a
bulky liquid membrane transport experiment.4e,11 Initially, the
source phase consisted of 2 ml of 1 M aqueous NaNO2 solution
and 3 ml of the chloroformic liquid membrane contained
receptor 1d at 40 mM. The salt concentration in the receiving
phase was determined by conductometric measurements and
Compounds 1a, 1c and 2b were prepared according to the pro-
cedure found in the literature.6,7 Other reagents and chemicals
1
were of reagent grade quality and purchased commercially. H
and 13C NMR spectroscopy as well as titration experiments
were conducted on a 200 MHz spectrometer. 1H NMR chemical
shifts δ are reported in ppm referenced to the tetramethyl-
silane (CDCl3) or protonated residual solvent signal (CD3CN).
Compound 2e
the initial flux was calculated to be 2.26 × 10−6 mol × (m−2
×
s−1). Thus extraction and transport experiments demonstrate To a solution of Nα-Cbz-Nε-Boc-L-lysine (549 mg, 1.44 mmol)
that receptor 1d is capable of transporting NaNO2 from the and 1,3-dicyclohexylocarbodiimide (326 mg, 1.58 mmol) in
solid state and more importantly from the aqueous solution.
20 ml of dry dichloromethane, 1-aza-18-crown-6 (380 mg,
1.44 mmol) at 0 °C (ice bath) was added. The reaction mixture
was stirred for 30 min and then left at room temperature over-
night. The precipitate was filtered off, washed with dichloro-
methane and the solvent was evaporated. The residue was
Conclusion
In conclusion we have found that L-ornithine can be used as a purified by silica gel column chromatography (2% methanol
convenient molecular platform for the construction of salt in chloroform) to give the title product as a colorless oil
receptors. This platform allows for the introduction of cation (820 mg, 91% yield).
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HRMS (ESI): calcd for C31H51N3O10Na [M + Na]+: 648.3472,
HRMS (ESI): calcd for C30H49N5O11Na [M + Na]+: 678.3326,
found: 678.3344.
found: 648.3458.
1H NMR (200 MHz, CDCl3) δ: 1.28–1.51 (m, 9H + 2H),
1H NMR (200 MHz, CDCl3) δ: 1.26–1.79 (m, 9H + 6H),
1.57–1.79 (m, 2H), 1.80–2.08 (m, 2H), 3.02–3.19 (m, 2H), 2.97–3.16 (m, 2H), 3.55–3.94 (m, 24H), 4.85 (bs, 1H + 1H), 6.96
3.45–3.85 (m, 24H), 4.61–4.85 (m, 1H + 1H), 5.09 (s, 2H), 5.62 (bs, 1H), 7.39 (d, 2H, J = 9.2 Hz), 7.97 (d, 2H, J = 9 Hz), 8.35
(d, 1H, J = 8.6 Hz), 7.31–7.39 (m, 5H).
(s, 1H).
13C NMR (50 MHz, CDCl3) δ: 23.09, 28.63, 29.94, 33.06,
13C NMR (50 MHz, CDCl3) δ: 22.61, 28.63, 29.80, 33.56,
40.40, 47.08, 49.02, 50.81, 66.97, 69.64, 69.83, 70.61, 70.76, 40.20, 47.79, 49.57, 49.88, 69.14, 69.78, 70.86, 71.08, 79.39,
70.86, 71.09, 79.21, 128.22, 128.68, 136.59, 156.16, 172.43.
117.69, 125.13, 141.91, 146.05, 154.80, 156.34, 175.00.
Compound 3d
Compound 3f
To the degassed solution of 2b (4.88 g, 7.99 mmol) in 100 ml
of THF–MeOH (1 : 4) catalytic amounts of 10% Pd/C were
added. The reaction mixture was kept under a H2 atmosphere
(balloon pressure) at room temperature overnight. The catalyst
was removed by filtration through a pad of Celite and washed
with MeOH. The filtrate was concentrated under reduced
pressure to give the crude product in quantitative yield
(3.81 g). The amine was used in the next step without further
purification. To a solution of amine (2.29 g, 4.8 mmol) in
100 ml of dry dichloromethane, triethylamine (870 μl,
6.24 mmol) was added. The reaction mixture was cooled under
an argon atmosphere (0 °C, ice bath) and trifluoroacetyl anhy-
dride (734 μl, 5.28 mmol) was added dropwise. After stirring
overnight at room temperature, the reaction mixture was
diluted with water. The water layer was separated and extracted
with dichloromethane (2×). The organic layers were collected
and washed with brine, dried over MgSO4, filtered, and con-
centrated under reduced pressure. The residue was purified by
silica gel column chromatography (2% methanol in chloro-
form) to give compound 3d as a colorless oil (1.79 g, 72%
yield).
To the degassed solution of 2b (4.88 g, 7.99 mmol) in 100 ml
of THF–MeOH (1 : 4) catalytic amounts of 10% Pd/C were
added. The reaction mixture was kept under a H2 atmosphere
(balloon pressure) at room temperature overnight. The catalyst
was removed by filtration through a pad of Celite and washed
with MeOH. The filtrate was concentrated under reduced
pressure to give the crude product in a quantitative yield
(3.81 g). The amine was used in the next step without further
purification. To an amine solution (500 mg, 1.05 mmol) in
40 ml of dry dichloromethane, triethylamine (160 μl,
1.15 mmol) was added. The reaction mixture was cooled under
an argon atmosphere (0 °C, ice bath) and trifluoromethanesul-
fonyl chloride (111 μl, 1.05 mmol) was added. After stirring
overnight at room temperature, the reaction mixture was
diluted with water. The aqueous layer was separated and
extracted with dichloromethane (2×). The organic layers were
collected, dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel
column chromatography (5% methanol in chloroform) to give
compound 3f as a colorless oil (580 mg, 91% yield).
HRMS (ESI): calcd for C23H45N3O10SNa [M + Na]+: 578.2723,
found: 578.2730.
HRMS (ESI): calcd for C24H42F3N3O9Na [M + Na]+: 596.2771,
found: 596.2766.
1H NMR (200 MHz, CDCl3) δ: 1.43 (s, 9H), 1.59–1.83 (m,
4H), 3.19–3.40 (m, 2H), 3.55–4.05 (m, 24H), 4.65–4.84 (m, 1H),
5.47 (d, 1H, J = 8.8 Hz), 7.33 (d, 1H, J = 6.2 Hz).
1H NMR (200 MHz, CDCl3) δ: 1.43 (s, 9H), 1.50–1.85
(m, 4H), 3.30–3.50 (m, 2H), 3.50–3.85 (m, 24H), 4.72 (bs, 1H),
5.35–5.45 (m, 1H), 7.60 (bs, 1H).
13C NMR (50 MHz, CDCl3) δ: 20.26, 25.25, 28.53, 30.85,
44.04, 47.11, 49.51, 69.36, 69.45, 70.35, 70.51, 70.66, 77.44,
80.06, 123.30, 155.79, 172.57.
13C NMR (50 MHz, CDCl3) δ: 24.09, 28.51, 31.76, 40.12,
47.16, 49.31, 49.75, 69.51, 69.57, 70.49, 70.73, 70.89, 71.19,
80.06, 172.54.
Compound 3e
Receptor 1b
To the degassed solution of 2e (820 mg, 1.32 mmol) in 30 ml Compound 2b (500 mg, 0.817 mmol) was dissolved in 10 ml of
of THF–MeOH (1 : 4) catalytic amounts of 10% Pd/C were dichloromethane and 2.5 ml of trifluoroacetic acid was added.
added. The reaction mixture was kept under a H2 atmosphere The reaction mixture was stirred at room temperature until
(balloon pressure) at room temperature overnight. The catalyst the starting material was consumed (TLC monitoring). The
was removed by filtration through a pad of Celite and washed mixture was neutralized with saturated NaHCO3. The water
with MeOH. The filtrate was concentrated under reduced layer was separated and extracted with dichloromethane (2×).
pressure to give the crude product in a quantitative yield The organic layers were collected and washed with brine, dried
(648 mg). The amine was used in the next step without further over MgSO4, filtered, and concentrated under reduced
purification. To the solution of amine (610 mg, 1.24 mmol) in pressure. The obtained amine (395 mg, 95% yield) was used in
20 ml of dry THF, 4-nitrophenyl isocyanate (230 mg, 1.4 mmol) the next step without further purification. To the solution of
was added. After stirring overnight at room temperature, amine (395 mg, 0.773 mmol) in 20 ml of dry THF, 4-nitrophe-
the reaction mixture was concentrated and purified by silica nyl isocyanate (126 mg, 0.773 mmol) was added. After stirring
gel column chromatography (2% methanol in chloroform) to overnight at room temperature, the reaction mixture was con-
give compound 3e as a pale-yellow oil (660 mg, 81% yield).
centrated and purified by silica gel column chromatography
8520 | Dalton Trans., 2014, 43, 8515–8522
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(2% methanol in chloroform) to give receptor 1b as a pale- diluted with water. The water layer was separated and extracted
yellow oil (381 mg, 73% yield). with dichloromethane (2×). The organic layers were collected
HRMS (ESI): calcd for C32H45N5O11Na [M + Na]+: 698.3013, and washed with brine, dried over MgSO4, filtered, and con-
found: 698.2982.
centrated under reduced pressure. The residue was purified by
1H NMR (200 MHz, CD3CN) δ: 1.40–1.80 (m, 4H), 3.00–3.20 silica gel column chromatography (2% methanol in chloro-
(m, 2H), 3.40–3.80 (m, 24H), 4.75–4.85 (m, 1H), 5.02 (s, 2H), form) to give receptor 1e as a pale-yellow oil (480 mg, 73%
5.75–5.85 (m, 1H), 6.39 (d, 1H, J = 8.2 Hz), 7.20–7.40 (bs, 5H), yield).
7.46 (d, 2H, J = 12.4 Hz), 8.02 (d, 2H, J = 9.4 Hz), 8.06 (s, 1H).
13C NMR (50 MHz, CD3CN) δ: 26.65, 31.08, 41.35, 47.97, 674.2625, found: 674.2637.
HRMS (ESI): calcd for C27H40F3N5O10Na [M +
Na]+:
49.67, 50.62, 66.83, 69.59, 70.40, 71.14, 71.23, 71.28, 71.35,
71.45, 125.88, 128.76, 128.90, 129.51, 147.42, 155.19, 174.37.
1H NMR (200 MHz, CDCl3) δ: 1.36–1.87 (m, 6H), 3.26–3.40
(m, 2H), 3.50–4.05 (m, 24H), 4.96 (bs, 1H), 7.02 (bd, 1H), 7.29
(bt, 1H), 7.42 (d, 2H, J = 9 Hz), 78.02 (d, 2H, J = 9.4 Hz), 8.33
(s, 1H).
Receptor 1d
Compound 3d (1.4 g, 2.44 mmol) was dissolved in 50 ml of
13C NMR (50 MHz, CDCl3) δ: 22.83, 28.58, 33.11, 39.82,
dichloromethane and 10 ml of trifluoroacetic acid was added. 47.78, 49.53, 49.73, 68.96, 69.67, 70.66, 70.81, 70.89, 71.16,
The reaction mixture was stirred at room temperature until the 117.76, 125.55, 142.01, 145.94, 154.82, 157.40, 158.13, 174.87.
starting material was consumed (TLC monitoring). The
mixture was evaporated in vacuo to yield the crude product as
Receptor 1f
the trifluoroacetate salt in a quantitative yield (1.3 g). The
ammonium salt was used in the next step without further puri-
fication. To a solution of ammonium salt (1.3 g, 2.44 mmol) in
50 ml of dry THF under an argon atmosphere, triethylamine
(850 μl, 6.1 mmol) and 4-nitrophenyl isocyanate (400 mg,
2.44 mmol) were added. After stirring overnight at room temp-
erature, the reaction mixture was concentrated and the residue
was partitioned between dichloromethane and water. The
aqueous layer was separated and extracted with dichloro-
methane (2×). The organic layers were collected and dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The crude material was purified by silica gel column
chromatography (5% methanol in chloroform) to give receptor
1d as a pale-yellow oil (860 mg, 60% yield).
Compound 3f (488 mg, 0.8 mmol) was dissolved in 20 ml of
dichloromethane and 5 ml of trifluoroacetic acid was added.
The reaction mixture was stirred at room temperature until the
starting material was consumed (TLC monitoring). The
mixture was evaporated in vacuo to yield the crude product as a
trifluoroacetate salt in quantitative yield (498 mg). The
ammonium salt was used in the next step without further puri-
fication. Next, to the solution of ammonium salt (498 mg,
0.8 mmol) in 50 ml of dry THF under an argon atmosphere,
triethylamine (279 μl, 2 mmol) and 4-nitrophenyl isocyanate
(131 mg, 2.44 mmol) were added. After stirring overnight at
room temperature, the reaction mixture was concentrated and
the residue was partitioned between dichloromethane and
water. The water layer was separated and extracted with
dichloromethane (2×). The organic layers were collected and
dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The crude material was purified by silica gel
column chromatography (2% methanol in chloroform) to give
receptor 1f as a pale-yellow oil (390 mg, 72% yield).
HRMS (ESI): calcd for
660.2468, found: 660.2454.
C26H38F3N5O10Na [M +
Na]+:
1H NMR (200 MHz, CDCl3) δ: 1.62–1.95 (m, 4H), 3.25–3.47
(m, 2H), 3.50–4.12 (m, 24H), 5.04 (bs, 1H), 7.05 (bs, 1H), 7.47
(d, 2H, J = 9 Hz), 7.81 (bs, 1H), 8.05 (d, 2H, J = 9.2 Hz), 8.37
(s, 1H).
13C NMR (50 MHz, CDCl3) δ: 25.07, 31.28, 39.98, 47.92,
49.41, 49.94, 68.84, 69.61, 70.72, 70.82, 71.19, 117.79, 125.19,
142.05, 145.92, 154.70, 174.67.
HRMS (ESI): calcd for C25H38F3N5O11SNa [M + Na]+:
696.2138, found: 696.2144.
1H NMR (200 MHz, CDCl3) δ: 1.63–2.05 (m, 4H), 3.22–3.43
(m, 2H), 3.45–4.10 (m, 24H), 5.02 (bs, 1H), 7.11 (bd, 1H, J =
7 Hz), 7.31 (bt, 1H), 7.42 (d, 2H, J = 9 Hz), 8.03 (d, 2H, J =
9 Hz), 8.27 (s, 1H).
Receptor 1e
Compound 3e (660 mg, 1.01 mmol) was dissolved in 10 ml of
dichloromethane and 2 ml of trifluoroacetic acid was added.
The reaction mixture was stirred at room temperature until the
starting material was consumed (TLC monitoring). The
mixture was evaporated in vacuo to yield the crude product as a
trifluoroacetate salt in a quantitative yield (675 mg). The
ammonium salt was used in the next step without further
purification. Next, to a solution of amine (675 mg, 1.01 mmol)
in 20 ml of dry dichloromethane, triethylamine (349 μl,
13C NMR (50 MHz, CDCl3) δ: 26.10, 30.16, 43.98, 47.85,
50.07, 68.96, 70.48, 70.69, 71.12, 117.87, 125.12, 142.09,
145.73, 154.88, 174.63.
Acknowledgements
2.5 mmol) was added. The reaction mixture was cooled under This work was supported by grant no. DEC-2013/09/B/ST5/
an argon atmosphere (0 °C, ice bath) and trifluoroacetyl anhy- 00988 from the Polish National Science Center and by a
dride (167 μl, 1.2 mmol) was added dropwise. After stirring Iuventus grant no. IP2012050572 from the Polish Ministry of
overnight at room temperature, the reaction mixture was Science and Higher Education.
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Dalton Transactions
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8522 | Dalton Trans., 2014, 43, 8515–8522
This journal is © The Royal Society of Chemistry 2014