Highly effective ion-pair receptors based on 2,2-bis(aminomethyl)-propionic acid

Article abstract of DOI:10.1039/c6dt02833k

Compounds 2 and 3 were designed and prepared as heteroditopic ion-pair receptors. The design features a 2,2-bis(aminomethyl)propionic acid core to connect and pre-organize binding groups. The cation binding is provided by a sodium selective N-acyl aza-18-crown-6 subunit whereas for anion complexation, two urea groups (receptor 2) or two squaramide groups (receptor 3) were introduced. Beyond acting as anion binding sites, the urea and squaramide groups were used to support sodium cation complexation through metal carbonyl oxygen lone pair interactions. The receptors were found to bind sodium salts of chloride, bromide and nitrate much more strongly than the corresponding ions accompanied by counterions that do not coordinate to the receptor. For example, chloride binding to receptor 2 enhances the strength of sodium complexation by up to 23 times. Conversely, sodium binding enhances chloride recognition by a factor of three. Receptor 3 containing squaramide units, binds sodium chloride and bromide with a similar albeit lower cooperativity. Moreover, unprecedentedly tight binding of these salts was achieved, with association constants as high as log K_a = 6.52 M^-1 for NaCl salt complexation.

Full text of DOI:10.1039/c6dt02833k

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Highly effective ion-pair receptors based on
2,2-bis(aminomethyl)-propionic acid†‡
Cite this: DOI: 10.1039/c6dt02833k
Dominika Załubiniak, Maciej Zakrzewski and Piotr Piątek*
Compounds 2 and 3 were designed and prepared as heteroditopic ion-pair receptors. The design features
a 2,2-bis(aminomethyl)propionic acid core to connect and pre-organize binding groups. The cation
binding is provided by a sodium selective N-acyl aza-18-crown-6 subunit whereas for anion complexa-
tion, two urea groups (receptor 2) or two squaramide groups (receptor 3) were introduced. Beyond acting
as anion binding sites, the urea and squaramide groups were used to support sodium cation complexation
through metal carbonyl oxygen lone pair interactions. The receptors were found to bind sodium salts of
chloride, bromide and nitrate much more strongly than the corresponding ions accompanied by counter-
ions that do not coordinate to the receptor. For example, chloride binding to receptor 2 enhances the
strength of sodium complexation by up to 23 times. Conversely, sodium binding enhances chloride
recognition by a factor of three. Receptor 3 containing squaramide units, binds sodium chloride and
bromide with a similar albeit lower cooperativity. Moreover, unprecedentedly tight binding of these salts
was achieved, with association constants as high as log Ka = 6.52 M−1 for NaCl salt complexation.
Received 18th July 2016,
Accepted 30th August 2016
DOI: 10.1039/c6dt02833k
www.rsc.org/dalton
changes in the ligand that are caused by binding of the first
species. However, the cooperativity effects are often not easy to
Introduction
The design of molecular receptors capable of simultaneously observe because the formation of an ion-pair inside the mole-
binding cations and anions (salts) is an attractive area of cular receptor is accompanied by several other solution equili-
supramolecular chemistry.1 Heteroditopic salt receptors may bria including ion-pairing outside the receptor and the
offer significant advantages with regard to binding affinity, formation of monoionic complexes.
selectivity, and salt transport ability, as compared to mono-
As pointed out above, the molecular platform that connects
topic receptors.2 Salt receptors comprise a cation binding the binding domains has a great impact on the ion-binding
site(s) and a distinct anion binding site(s) that are linked ability of the resulting heteroditopic receptors, including synergi-
together by an appropriate molecular spacer. The spatial stic effects. The most frequently used molecular platforms for con-
arrangement of these heterotopic binding domains largely struction of heteroditopic molecular receptors include calixarenes,
determines the salt receptors’ complexation properties. calixpyrroles and aza-crown ethers.1 These macrocyclic com-
Generally, when the binding sites are far from each other, pounds often require multistep synthesis, including a macrocycli-
cation and anion complexation events are independent.3 zation reaction that is often low-yielding and difficult to scale up.
However as the binding sites get closer, the cations and anions
Recently we showed that amino acids such as ornithine,
may form either ligand-separated or solvent-separated ion- tyrosine and arginine may serve as simple molecular scaffolds
pairs.4 In rare cases, when the recognition sites are located in for the preparation of heteroditopic receptors.6 These receptors
close proximity, in a very specific spatial arrangement, binding contain a sodium-selective binding domain (N-acyl aza-18-
of a contact ion-pair is possible.5 In these latter two scenarios, crown-6) and two anion-binding groups (amide, urea or
cooperativity may be observed, arising from the electrostatic thiourea). These amino acid-based receptors bind hydrophilic
interactions between bonded ion-pairs and/or conformational sodium salts in acetonitrile solution. Highly cooperative cation
and anion binding is observed for some anions. We demon-
strated that one of the anion-binding groups can simul-
taneously provide additional cation stabilization by bridging the
ion-pair (Fig. 1). This phenomenon is most probably respon-
sible for the observed positive cooperativity of salt binding.
Guided by this observation we designed receptors 2 and 3
whose structures allow for the interaction of two anion-
binding domains with a complexed cation (Fig. 1). Compound
Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
E-mail: ppiatek@chem.uw.edu.pl
†Dedicated to Professor Janusz Jurczak on the occasion of his 75th birthday.
‡Electronic supplementary information (ESI) available: 1H and 13C NMR spectra,
job plots, UV-vis titration spectra and resulting binding isotherms, 1HNMR titra-
tions spectra and crystallographic data. CCDC 1478315. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c6dt02833k
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Results and discussion
Receptor design and synthesis
Receptors 2 and 3 are derived from 2,2-bis(aminomethyl)-
propionic acid, a new molecular platform that allows for the
easy introduction of two anion-binding groups and one
cation binding domain. Moreover,
a methyl substituent
located at the quaternary carbon atom restricts conformational
movements and causes all three functional arms to be pointed
in the same direction, creating a more defined binding cavity
(vide infra).
Receptors 2 and 3 were synthesized in seven simple steps
from commercially available 2,2-bis(hydroxymethyl) propionic
acid (Scheme 1). Protection of the 1,3-diol functionality as iso-
propylidene ketal and subsequent HATU mediated coupling of
the carboxyl group with aza-18-crown-6 gave macrocyclic
amide 5 in 79% yield, over two steps. 1,3-diol deprotection
using a strongly acidic resin that can be removed after the reac-
tion by simple filtration circumvented the problem of isolating
very polar diol 6. Surprisingly, the conversion of this diol to
bishalogen derivative 7 proved to be the most difficult step in
the presented synthesis. However after much experimentation
it was found that the use of a SOCl2/Py system at elevated
temperature and the gradual addition of excess of SOCl2 pro-
vided the desired bischloride in 75% yield. This derivative
undergoes smooth transformation to bisazide 8, and reduction
under Staudinger conditions and treatment with trifluoro-
acetic acid gave the stable bisammonium derivative 9.
Acylation of this compound with 4-nitrophenyl-isocyanate or
1-anilino-2-ethoxycyclobutene-3,4-dione in the presence of
Et3N led to receptors 2 and 3, respectively, in yields of approxi-
mately 80%.
Fig. 1 The design of receptors 1–3.
2, containing two urea groups, was designed as a close analog
of receptor 1. In receptor 3, in turn, squaramide units are used
as anion binding domains to increase the anion binding
strength and to even further increase the possibility of brid-
ging the ion-pair. It should be noted, however, that for practi-
cal reasons the carbonyl and amino groups in our newly
designed receptors 2, and 3 are separated by two carbon
atoms, rather than one as in α-amino acids. This leaves more
space between the cation and anion binding domains there-
fore making possible binding models other than the ligand-
separated ion-pair modes, such as the contact ion-pair model.
Scheme 1 Synthetic route to receptors 2 and 3.
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Table 2 Association constant (Ka) values for interactions of 2 with
sodium cations in the absence and presence of one equivalent of
anionsa
Binding studies of receptor 2
Compounds 2 and 3 were assessed as receptors for cations,
anions and salts in acetonitrile through UV-vis spectroscopic
titrations. All collected titration data could be fitted to a
1 : 1 model using the HypSpec fitting program.7 The stoichio-
metry of cation and anion complexation was verified by Job
plot analysis (see the ESI‡). Anion coordination to 2 and 3 was
studied by titration of 31 μM acetonitrile solution of the recep-
tor with tetra-n-butylammonium (TBA) salts (Fig. 2). TBA salts
were used in order to minimize the anion–cation electrostatic
interactions and cation coordination to receptors. For the
Na+
3690
87 100
64 800
—
KA−/KClO
−
4
−
ClO4
Cl−
—
23.6
17.5
—
Br−
− b
NO2
a UV-vis, solvent CH3CN, temperature 293 K, [2] = 31 μM, titrant
[NaClO4] = 3.15 mM, errors <10%. b Spectral changes during the titra-
tion indicate dislodging of NO2− from the receptor 2.
−
−
same reasons, cations were used as ClO4 or PF6 salts. The
calculated association constants for the titrations of receptor 2
with anions in the absence and presence of one equivalent of
sodium cations (ClO4− salt) are listed in Table 1.
the utility of 2,2-bis(aminomethyl)-propionic acid for construc-
tion of salt receptors.
In terms of cation binding, the influence of anion coordi-
nation on sodium binding to receptor 2 was also investigated
using UV-vis titrations (Table 2). Although receptor 2 binds
Inspection of Table 1 reveals a considerable increase of
anion binding strength in the presence of pre-bound sodium
cations, compared to binding of anions as TBA salts. For
bromide anion recognition, the association constants increase
over five times. Only for the most strongly bound benzoate
anion, the influence of cations on the binding strength is neg-
ligible. A comparison of receptor 1 based on the L-ornithine
scaffold6d with receptor 2, based on 2,2-bis(aminomethyl)pro-
pionic acid (column 4 and 5 of Table 1), shows that receptor 2
binds salts with higher cooperation. This observation verifies
−
sodium (ClO4 salt) with moderate affinity, the presence of
1 equiv. of chloride or bromide anions dramatically increases
the complex stability (Fig. 3). For example, chloride binding to
receptor 2 enhances the strength of sodium complexation by
up to 23 times. The much higher cooperativity factors for
sodium binding in the presence of anions compared to anions
binding in the presence of sodium cations suggest that anion
coordination substantially preorganizes the receptor confor-
mation toward cation recognition.
Solid-state structure of 3
Slow evaporation of CH3CN solution of receptor 3 yielded a
single crystal that can be analyzed by X-ray diffraction (Fig. 4).
Unfortunately, however, the size of the measured crystal was
very small and weakly diffracting, which in combination with
the severe disorder of the molecules in the crystal lattice did
not allow reflections to be collected above 0.94 Å resolution.
The aza-crown ether fragment is disordered with atoms occu-
Fig. 2 UV-vis spectrum modulation upon the addition of TBACl to the
CH3CN solution of 2: solvent CH3CN, temperature 293 K, [2] = 31 μM,
titrant [TBACl] = 0.9 mM.
Table 1 Association constant (Ka) values for interactions of 2 with
anions in the absence and presence of one equivalent of sodium
cations.a Comparison data for receptor 1b
b
TBA+
Na+
KNa+/KTBA+
Receptor 1 KNa+/KTBA+
Cl−
Br−
NO2
18 400
770
2100
53 000
3900
5800
2.9
5.1
2.8
1.0
1.8
1.5
2.0
0.4
−
PhCOO−
242 000
25 100
Fig. 3 Plots of UV-vis titrations of 2 with NaClO4 in the presence and
absence of chloride anions: solvent CH3CN, temperature 293 K, [2] =
31 μM, titrant [NaClO4] = 3.15 mM.
a UV-vis, solvent CH3CN, temperature 293 K, [2] = 31 μM, titrant [TBAX]
= 0.9 mM, errors <10%. b Data from ref. 6d.
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Comparison of the data from Tables 1 and 3 shows, as
expected,
a tremendous increase in anion complexation
strength of receptor 3 as compared to urea derivative 2.
However, we were pleased to find that the halide affinities of 3
increase even further in the presence of hard sodium or
potassium cations. The cooperativity between cation and
anion complexation is most noteworthy for the binding of
sodium and bromide ions. The very tight (log Ka = 6.52) associ-
ation of NaCl salt to receptor 3 is an unprecedented behavior
in molecular receptor systems. Conversely, cation pre-
complexation reduces the ability of receptor 3 to bind benzoate
and nitrate anions. This phenomenon is most probably a
result of lowering of “free” benzoate or nitrate concentration
caused by partial contact ion-pair formation in solution,
outside the receptor.10 The coordination of sodium or potass-
ium cations to receptor 3 not only changes the association con-
stant values but also alters the selectivity of anion recognition.
Fig. 4 Single-crystal X-ray structure of receptor 3. Non-donating
hydrogen atoms and solvent molecules are omitted for clarity. Note the
distorted aza-crown ether fragment and CF3 groups.
pying alternatively two or three positions. All but one CF3 Specifically, the combination of negative and positive coopera-
group are also disordered over two positions. Unidentified tive effects causes 3 to be much less selective for benzoate in
solvent molecules in the structures were modeled by partial favor of chloride.
occupancy of oxygen atoms. However, other regions of the
Interestingly, receptor 3 associates with sodium cations
structure are better defined, which reveals that all (ClO4− salt) over two times more strongly than 2 (Table 4). This
three binding domains point in one direction. Squaramide may suggest that the two squaramide carbonyl groups provide
NH’s are directed toward the crown ether unit and stronger support to crown ether cation complexation than one
interact with water molecules. One of these NH protons also carbonyl of the urea group. Therefore, 3 is the more effective
forms an intramolecular hydrogen bond with the amide cation receptor. Sodium complexation becomes much tighter
oxygen atom.
in the presence of halogen anions, as shown in Table 4.
A cooperativity factor of 12 was achieved for sodium binding in
the presence of a bromide anion. Both anion complexation
studies in the presence of metal cations and sodium binding
studies in the presence of anions of receptor 3 are consistent
and show considerable cooperativity of cation and anion
binding.
Binding studies of receptor 3
Two squaramide units were introduced into the structure of
receptor
3 in the expectation that they might provide
additional carbonyl–metal interactions and increase the co-
operativity between metal and anion binding.8 Moreover,
squaramide converged NH protons are powerful H-bond
donors and monotopic receptors possessing squaramide
groups bind TBA salts of anions very strongly.9 However, tight
binding of anions TBA salts may not benefit from metal co-
binding. In fact, we and others have observed that mainly due
to ion pair formation outside the receptor, binding of strongly
coordinated anions in the presence of a metal is considerably
weaker.6,10 With this in mind, the ability of receptor 3 to bind
anions and salts was investigated (Table 3).
To gain more insights into the cation, anion and salt
binding mode and to confirm the tight association of ions to
receptor 3, 1H NMR studies in CD3CN were undertaken. The
addition of one equivalent of sodium perchlorate to a 3.1 mM
solution of 3 caused small but significant downfield shifts of
the crown ether CH2–O, protons indicating cation coordination
to the crown ether (Fig. 5). The CH2 protons of the molecular
platform appear as a singlet in the free receptor. However, this
signal splits into two broad doublets after cation addition, evi-
dencing a restriction in receptor conformational flexibility
Table 3 Association constant (Ka) values for interactions of 3 with
anions in the absence and presence of one equivalent of sodium or
potassium cationsa
Table 4 Association constant (Ka) values for interactions of 3 with
sodium cations in the absence and presence of one equivalent of
anionsa
TBA+
Na+
KNa+/KTBA+ K+
KK+/KTBA+
Na+
7950
14 100
95 500
7080
KA−/KClO
−
4
Cl−
Br−
NO2
1 740 000 3 310 000 1.9
91 200
3 310 000 1.9
204 000 2.2
107 000 0.91
ClO4
Cl−
—
1.8
12
−
372 000 4.1
100 000 0.85
Br−
−
117 000
PhCOO− 4 360 000 3 390 000 0.78
—
—
NO2
0.9
−
a UV-vis, solvent CH3CN, temperature 293 K, [3] = 31 μM, titrant [TBAX] a UV-vis, solvent CH3CN, temperature 293 K, [3] = 31 μM, titrant
= 1 mM, errors <10%.
[NaClO4] ∼ 3.15 mM, errors <10%.
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Fig. 6 Plots of 1H NMR titrations of 3 with TBABr: solvent CD3CN,
temperature 293 K, [3] = 3.05 mM, titrant [TBABr] = 30 mM.
Conclusions
In conclusion, ion pair receptors 2 and 3 based on a
2,2-bis(aminomethyl)propionic acid molecular platform were
designed and synthesized in seven simple and efficient steps.
These receptors comprise a sodium-selective binding domain
(N-acyl aza-18-crown-6) and two anion-binding domains (urea
or squaramide, for receptors 2 and 3, respectively). As evi-
denced by single-crystal X-ray diffraction analysis of 3, the
methyl group of the molecular platform ensures that all three
binding domains point in one direction, thus creating a more
pre-organized host for salt binding. UV-vis spectroscopic titra-
tions showed that receptor 2 binds sodium salts of chloride,
bromide and nitrate much more strongly than the corres-
ponding ions accompanied by counterions that do not coordi-
nate to the receptor. For example, chloride binding to receptor
2 enhances the strength of sodium complexation by up to 23
times. Conversely, sodium binding enhances chloride recog-
nition by a factor of three. Receptor 3 containing squaramide
units binds sodium chloride and bromide with a similar albeit
lower cooperativity. However, very tight binding of these salts
was achieved, with log Ka = 6.52 M−1 for NaCl complexation.
These results reveal receptor 3 to be a strong yet cooperative
ion-pair receptor.
Fig. 5 Partial 1H NMR spectra of (a) receptor 3; (b) 3 + 1 eq. of NaClO4;
(c) 3 + 1 eq. of TBABr; (d) 3 + 1 eq. of NaClO4 + 1 eq. of TBABr.
including anion binding domains. Furthermore both aromatic
protons Ho and Hp undergo complexation induced downfield
shifts, which implies a lowering of the electron density at the
aromatic rings and consequently squaramide units. As NH
protons do not undergo any significant shifts during sodium
addition, this electron density diminishment can be rational-
ized in terms of the participation of squaramide oxygens in
complex formation.
Upon addition of bromide anions (TBA salt), large down-
field shifts in all four NH protons were observed, which indi-
cate the formation of strong hydrogen bonds between the
anions and receptor 3. Interestingly CH2 protons are split
further than in the case of cation complexation. This
suggests that conformational rigidification of the receptor is
more pronounced during anion binding than cation
binding. This finding is consistent with our observation that
cation complexation in the presence of a pre-bound anion is
more synergistic than anion binding in the presence of a
cation.
Experimental section
The 1H NMR titrations of receptor 3 with TBABr in the
absence and presence of sodium cations as well as titrations
with NaClO4 in the absence and presence of bromide anions
produced isotherms that reached a plateau before adding one
equivalent of ions suggesting that the binding is too strong to
be accurately determined by 1H NMR titrations (Fig. 6).
Indeed, all attempts to calculate association constants failed.
Nevertheless, these results confirmed strong binding of
cations, anions and salts by receptor 3.
All commercial-grade chemicals were used without further
purification. The anion TBA and cation ClO4 salts were dried
1
under high vacuum at 30–45 °C prior to use. H and 13C NMR
spectra as well as titrations experiments were recorded on a
300 MHz spectrometer. 1H NMR chemical shifts δ are reported
in ppm referenced to the tetramethylsilane (CDCl3) or proto-
nated residual solvent signal (CD3CN). 3-(3,5-Bis(trifluoro-
methyl)phenylamino)-4-ethoxycyclobut-3-ene-1,2-dione
prepared analogously to the literature procedure.11
was
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2,2,5-Trimethyl-1,3-dioxane-5-carboxylic acid (4)
checked by TLC analysis (10% MeOH–CHCl3). The TLC plate
was visualized in a solution of Bromocresol Green, product
spot (Rf = 0.45). The resin was filtered through a pad of Celite
and the filtrate was evaporated to dryness to give 3.5 g of
product 6 as a yellowish oil in 88% of yield. Rf (10% MeOH/
DCM) = 0.45; H NMR (300 MHz, CDCl3, δppm): 3.71 (m, 24H,
crown-CH2–O), 3.83 (d, J = 11,7 Hz, 2H, –CH2), 3.7 (d, J = 11,7
Hz, 2H, –CH2), 1.12 (s, 3H, CH3); 13C NMR (300 MHz, CDCl3,
To a solution of 4 g of 2,2-bis (hydroxymethyl) propionic acid
(30 mmol) in 30 mL of acetone, 2,2-dimethoxypropane (4,16 g,
40 mmol) and a catalytic amount of p-toluenesulfonic acid
monohydrate (30 mg) were added. The resulting mixture was
stirred at room temperature for 12 hours. The reaction was
ended by addition of solid sodium bicarbonate and stirring
was continued for another 20 minutes. Acetone was removed
under vacuum and the solid residue was taken up in a mixture
of water–diethyl ether. The layers were separated. The organic
layer was then washed with a solution of sodium bicarbonate
and twice with distilled water. The organic phase was dried
over MgSO4, filtered, and the solvent was removed in vacuo.
4.4 g of product 4 in the form of a white powder was obtained
1
δppm): 175.8 (–C
̲
̲H2–O–), 70.1 (–N–C̲H2–), 69.1
(–CH2–), 48.0 (–C
̲
̲
̲
1,3-Dichloro-2-(carboxyaza-18-crown-6)-2-methyl-propane (7)
Diol 6 (2 g, 5 mmol) was dissolved in 30 ml of pyridine. To this
mixture, 5 ml of thionyl chloride was added and the mixture
was heated at 60 °C for 1 h. Then an additional portion (2 mL)
of thionyl chloride was added and heating was continued. This
operation was repeated four times. After the last addition, the
reaction mixture was heated overnight at 60 °C. The reaction
was then cooled to room temperature. Neutralization of pyri-
dine was conducted by careful addition of 2 M hydrochloric
acid. The resulting aqueous solution was extracted three times
with chloroform (3 × 100 ml). Purification by silica gel chrom-
atography (2% MeOH/CHCl3) gave dichloride 7 (1.9 g, 88%) as
a pale yellow oil. Rf (10% MeOH/DCM) = 0.65, 1H NMR
(300 MHz, CDCl3, δppm): 3.84 (d, J = 11,7 Hz, 2H, –CH2), 3.74
(d, J = 11,7 Hz, 2H, –CH2), 3.53 (m, 24H, crown-CH2–O), 1.34
1
(86% yield). H NMR (300 MHz, CDCl3, δppm): 4.16 (d, J = 12
Hz, 2H), 3.63 (d, J = 12 Hz, 2H), 1.41 (s, 3H), 1.38 (s, 3H), 1.19
(s, 3H); 13C NMR (300 MHz, CDCl3, δppm): 180.2 (–C
̲
(–C
25.0 (C
̲
̲
̲
̲
̲
̲
2,2,5-Trimethyl-1,3-dioxane-5-(carboxyaza-18-crown-6) (5)
Compound 4 (2 g, 11.5 mmol) was dissolved in 20 ml of anhy-
drous DMF. To this solution 1.1 eq. of the coupling reagent
HATU (4.8 g, 12.65 mmol) and 3 eq. of triethylamine (5 mL,
35 mmol) were added. The resulting mixture was stirred under
argon at room temperature for one hour. After this the solu-
tion became orange. The resulting mixture was then cooled to
5 °C in an ice/water bath and a solution of 3 g (1 eq.,
11.5 mmol) of 1-aza-18-crown-6 in 5 ml of DMF was added
(s, 3H, CH3); 13C NMR (300 MHz, CDCl3, δppm): 171.3 (–C
70.5 (crown-CH2–O), 69.2 (–N–CH2–), 48.8 (–C(CH3)), 48.3
(–CH2–), 19.6 (C
H3–); MS(ESI):[M + Na]+ = 438.14.
̲O),
̲
̲
̲
̲
̲
dropwise. The reaction was then stirred overnight at room 1,3-Diazide-2-(carboxyaza-18-crown-6)-2-methyl-propane (8)
temperature under argon (the solution became dark brown).
To the solution of dichloride 7 (1.88 g, 4.5 mmol) in 50 mL of
anhydrous DMF, 3 g (45 mmol) of sodium azide was added.
The reaction mixture was carefully heated overnight at 80 °C
(oil bath). Then the solvent was evaporated. The solid residue
was taken up in mixture of water/chloroform and after phase
separation the aqueous phase was extracted three times with
chloroform. The combined organic phases were washed with
distilled water then dried over MgSO4, filtered, and the solvent
was evaporated. The product 8 was purified by filtration
through a pad of silica gel (3% MeOH/CHCl3) to give 1.6 g
(82%) of diazide 8. Rf (10% MeOH/DCM) = 0.7; 1H NMR
(300 MHz, CDCl3, δppm): 3.64 (m, 26H, crown-CH2–O and
–CH2–), 3.56 (d, J = 12 Hz, 2H, –CH2–), 1.29 (s, 3H, CH3);
TLC analysis in 10% MeOH/DCM confirmed the formation of
the desired product. The TLC plate was visualized in a solution
of Bromocresol Green, product spot (Rf = 0.83) tinged blue.
Then, the solvent was evaporated and the residue (dark oil)
was re-dissolved in 80 ml of CHCl3 and washed three times
with distilled water. The combined aqueous phases were back-
extracted with CHCl3 (2 × 20 mL). The organic phases were
combined and dried over MgSO4, filtered, and the solvent was
evaporated. The dark brown oil obtained was purified by
column chromatography with 2% methanol/chloroform to give
4.4 g of product 5 as an oil in 92% of yield. Rf (10% MeOH/
1
DCM) = 0.83; H NMR (300 MHz, CDCl3, δppm): 3.55 (m, 24H,
crown-CH2–O), 4.05 (d, J = 11,7 Hz, 2H, –CH2), 3.60 (d, J = 11,7
13C NMR (300 MHz, CDCl3, δppm): 172.2 (–C
H2–O–), 69.4 (–N–CH2–), 56.2 (N3–CH2–), 47.7 (–C
(C
H3–); MS (ESI): [M + Na]+ = 452.2.
̲
Hz, 2H), 1.45 (s, 3H, CH3), 1.39 (s, 6H); 13C NMR (300 MHz,
C̲
̲
̲
̲
CDCl3, δppm): 173.8 (–C
O), 69.6 (–N–CH2–), 66.6 (–O–C
(CH3–CCH3–O–), 20.3 (CH3–CCH3–O–), 18.8 (C
(ESI): [M + Na]+ = 442.2.
̲
̲
̲
̲
̲
̲
̲
̲
To the solution of diazide 8 (1.6 g, 3.7 mmol) in 50 mL of THF,
3.9 g of triphenylphosphine (14.8 mmol) and approximately
1 mL of water were added. The reaction mixture was stirred
1,3-Dihydroxy-2-(carboxyaza-18-crown-6)-2-methyl-propane (6)
Compound 5 (4.4 g, 10.5 mmol) was dissolved in 100 mL of overnight at room temperature. The resulting amine was iso-
methanol. To this solution the DOWEX 50 WX2 resin (1/2 tea- lated from the solution in the form of trifluoroacetic salt.
spoon) was added. The reaction mixture was stirred at room Thus, 2.2 eq. of trifluoroacetic acid (0.6 mL, 8.1 mmol) was
temperature for 12 hours. The formation of the product was added to the solution and THF was evaporated. The solid
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residue was taken up in a water/DCM mixture. The aqueous 115.6 (ArC
̲
̲(CH3), 49.3
layer was extracted five times with DCM. The aqueous layer (–NH–C
̲
̲
was evaporated under vacuum to give product 9 (1.2 g) as tri- [M + Na]+ (calc. for C41H41F12N5Na1O10: 1014.2559).
fluoroacetic salt in 58% of yield. Rf (10% MeOH/DCM) = 0.0;
1H NMR (300 MHz, DMSO-d6, δppm): 3.54 (m, 24H, crown-CH2–
UV-vis titration experiments
O), 3.31 (d, J = 11,7, 2H, –CH2–), 3.07 (d, J = 11,7, 2H, –CH2–),
1.42 (s, 3H, –CH3); 13C NMR (300 MHz, DMSO-d6, δppm): 171.0
UV-vis titrations were performed on a Thermo Spectronic
Unicam UV500 spectrophotometer, at 298 K, in CH3CN solu-
tion. In each case, 2.5 mL of 3.1 × 10−5 M solution of the
studied receptor was added to a 10 mm cuvette. Where appli-
cable the solution also contained 1 mol equiv. of sodium per-
chlorate (or tetra-n-butylammonium anion salt). Aliquots of
the anion (cation) solution, containing the receptor in the
same concentration as in the cuvette, were then added. The
sample was mixed thoroughly, left for 3 minutes and a spec-
trum was acquired after each addition. The resulting titration
data were analysed by the HypSpec computer program to
obtain the association constant (Ka).
(–C
44.5 (NH2–C
̲
̲
̲H2–), 47.8 (–C̲(CH3)),
̲
Receptor 2
Trifluoroacetic salt 9 (400 mg, 0.7 mmol) was dissolved in a
mixture of 10 mL of THF and 1 mL of triethylamine (6 mmol).
After complete dissolution of the substrate, 320 mg of p-nitro-
phenyl isocyanate (1.8 mmol) was added. The reaction was
stirred overnight at room temperature. Solvents were evapor-
ated and the solid residue was taken up in a DCM/water
mixture and after phase separation, the aqueous phase was
extracted three times with DCM (3 × 50 mL). The organic 1H NMR titration experiments
phases were combined and evaporated. Receptor 2 was puri-
1H NMR titrations were performed on a 300 MHz Bruker
fied by column chromatography in 80% ethyl acetate–hexane.
To remove any inorganic salts absorbed during the work-up,
receptor 2 was dissolved in chloroform and washed with dis-
tilled water. Evaporation of the solvent (without drying) gave
260 mg (62%) of the product as a yellow powder. Rf (5%
MeOH/CHCl3) = 0.45; m.p. = 94.6–96.5; 1H NMR (300 MHz,
CDCl3, δppm): 8.58 (s, 2H), 8.07 (d, J = 9 Hz, 4H), 7.53 (d, J = 9
Hz, 4H), 6.48 (s, 2H), 3.71 (m, 26H), 3.37 (d, J = 10,5 Hz, 2H),
Avance spectrometer, at 298 K in CD3CN. In each case, 500 μL
of a freshly prepared 3.1 mM solution of receptor 3 was added
to a 5 mm NMR tube. Where applicable the solution also con-
tained 1 mol equiv. of sodium perchlorate (or tetrabutyl-
ammonium bromide salt). Small aliquots of ∼20 mM solution
of tetrabutylammonium bromide (or sodium perchlorate), con-
taining 3 at a 3.1 mM concentration, were added, and a spec-
trum was acquired after each addition.
1.26 (s, 3H); 13C NMR (300 MHz, CDCl3, δppm): 174.8 (–C
̲
amide), 155.6 (–C
125.1 (ArC–Hm), 117.6 (ArC
49.0 (–NH–C
̲
̲
̲
̲
̲
Acknowledgements
H2–), 19.1 (C
H3–)). HR-MS (ESI): m/z = 728.2867
[M + Na]+ (calc. for C31H43N7Na1O12: 728.2862).
This work was supported by Grant no. DEC-2013/09/B/ST5/
00988 from the Polish National Science Center and by
BST-1730-42 from the Ministry of Science and Higher
Education, Republic of Poland.
Receptor 3
Trifluoroacetic salt 9 (500 mg, 0.86 mmol) was dissolved in a
mixture of 20 mL of THF and 5 mL of triethylamine
(35 mmol). To the reaction mixture 3-(3,5-bis(trifluoromethyl)
phenylamino)-4-ethoxycyclobut-3-ene-1,2-dione
(300
mg,
Notes and references
0.86 mmol) was added. The reaction mixture was stirred over-
night at room temperature. Solvents were evaporated and the
solid residue was taken up in a DCM/water mixture and after
phase separation the aqueous phase was extracted three times
with DCM (3 × 50 mL). The organic phases were combined
and evaporated. Receptor 3 was purified by column chromato-
graphy in 90% ethyl acetate–hexane. To remove any inorganic
salts absorbed during the work-up, receptor 3 was dissolved in
chloroform and washed with distilled water. Evaporation of
the solvent (without drying) gave 810 mg (82%) of the product
as powder. Rf (5% MeOH/CHCl3) = 0.35; m.p. = 168.2–170.2;
1H NMR (300 MHz, CD3CN, δppm): 9.21 (s, 2H), 7.97 (s, 4H),
7.51 (s, 2H), 7.22 (s, 2H), 4.15 (m, 2H), 3.94 (m, 4H), 3.55 (m,
24H), 1.39 (s, 3H); 13C NMR (300 MHz, CD3CN, δppm): 185.1
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