Selective Recognition of Chloride by a 24-Membered Macrocyclic Host with a Hydrophobic Methylenepyrene Substituent

Article abstract of DOI:10.1002/ejoc.202000662

A structure-guided design, synthesis, and characterization of neutral unclosed cryptand functionalized with a bulky and hydrophobic 1-methylene-pyrene substituent is described. The host selectively binds spherical chloride (Cl^–) over bigger and

Full text of DOI:10.1002/ejoc.202000662

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Selective recognition of chloride by a 24-membered macrocyclic
host with a hydrophobic methylenepyrene substituent
Authors: Kajetan Dąbrowa, Marcin Lindner, Sylwia Wasiłek, and
Janusz Jurczak
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000662
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1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000662
FULL PAPER
Selective recognition of chloride by a 24-membered macrocyclic
host with a hydrophobic methylenepyrene substituent
Kajetan Dąbrowa, Marcin Lindner, Sylwia Wasiłek, and Janusz Jurczak*
Dr. K. Dąbrowa, Dr. M. Lindner, Dr. S. Wasiłek, Prof. J. Jurczak
Institute of Organic Chemistry PAS
Kasprzaka 44/52, 01-224 Warsaw, Poland
E-mail: jurczak_group@icho.edu.pl
Supporting information for this article is given via a link at the end of the document.
Abstract: A structure-guided design, synthesis, and characterisation
of neutral unclosed cryptand functionalized with
a bulky and
hydrophobic 1-methylene-pyrene substituent is described. The host
-
selectively binds spherical chloride (Cl ) over bigger and more basic
-
-
-
carboxylates (MeCO
2
, PhCO
2
) and dihydrogenphosphate (H
2 4
PO ) in
a competitive DMSO-d
6
+ 0.5% H
2
O solvent mixture. The capture of
chloride is accompanied by formation of sandwich-type complex
stabilized by π-π and CH-π interactions. Step-wise addition of MeOH
triggers release of the cargo in a controllable manner.
Figure 1. Anion-binding properties of macrocyclic hosts 1 vs 2.
To gain a greater insight into the unusual chloride selectivity of
UC 1 we recently analyzed a large set of 48 reported molecular
receptors in order to elucidate the structural requirements that
allow for the selective binding of chloride over more basic
monovalent anions.8
It was found that a putative chloride-selective receptor should at
least meet the following criteria: (i) possess a rigid (preferentially
macrocyclic) scaffold; (ii) the size of binding cavity should be very
close to the radius of chloride to ensure a geometry-mismatch
with other competing anions; (iii) the chloride should be
surrounded by the receptor’s binding sites from all spatial
directions; (iv) the bound-chloride should be separated from the
accompanying counterion and solvent; (v) hydrophobic groups
located in close proximity to the binding pocket additionally
strengthen the interaction with the chloride at the expense of other
anions.
Host 1 fulfills criteria (i-iv) but likely not criterion (v) due to the
presence of a highly polarized lariat arm. We envisioned that, in
line with the above guidelines, replacement of the p-nitrophenyl
moiety by a bulkier and more hydrophobic substituent interaction
with more basic and hydrophilic anions might be further
suppressed, allowing for fine-tuning of the anti-Hofmeister binding
behavior of the host.
To validate our assumption, we designed and synthetized the
molecular host 2 containing a 1-methylene-pyrene substituent.
Implementation of this rational approach has allowed us to
construct a neutral molecular host having remarkable selectivity
for chloride ions.
Introduction
The recognition and transport of chloride anions play a vital role
in the regulation of cellular osmotic balance and flux of
1
metabolites. Mutations in the genes that code for chloride
channel proteins (ClCs) disrupt the transmembrane flux of
chloride causing a variety of diseases or ‘channelopathies’ such
as epilepsy, cystic fibrosis, and myotonia. For this reason,
considerable efforts have been directed towards the utilization of
artificial anion receptors as chloride transmembrane transporters,
with the goal to develop novel therapeutic agents able to assist or
even to replace the defective ClCs. To date, a variety of synthetic
receptors have proven effective as chloride carriers in micellar
systems and even under in vivo conditions. Most of these,
however, exhibit a conventional Hofmeister-type selectivity,
meaning that the weakly basic spherical chloride ion is bound
considerably less strongly than the abundant and more basic
phosphates, carboxylates, and bicarbonate.
coincidental change to the concentration gradients of these
interfering anions as well as transport inhibition due to binding to
lipid headgroups3d-g the ideal carrier should undoubtedly have
2
3
3c
4
To avoid
high selectivity toward chloride. Despite the enormous
development of anion supramolecular chemistry over the last 30
5
years, so far only a relatively small number of chloride-selective
6
receptors have been reported. Most of these contain complex
topology and, with the exceptions of Beer’s charged rotaxane,6d
show undesirable slow kinetics of chloride binding.
During our studies on anion recognition, we found that a
pentaamidic 24-membered unclosed cryptand (UC) bearing a
CONH-p-nitrophenyl tether (lariat arm) has a slightly increased
Results and Discussion
-
-
2
affinity towards chloride (Cl ) over the carboxylates (MeCO and
-
-). (Fig. 1)7
The host UC 2 was readily prepared from commercially available
PhCO ), but not to the dihydrogen phosphate (H PO
2
2
4
starting materials as illustrated in Scheme 1a.
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000662
FULL PAPER
-1
a
Table 1. Stability Constants K (M ) and Relative Binding Affinity (Krel) for the
Complexes of Hosts 1 and 2 with Anions a
1
2
[
b]
Anion
Cl-
V
c
[
c]
[c]
K
anion
K
rel
K
anion
K
rel
23.7
59.4
778
642
-
627
197
90
-
-
MeCO
2
0.08
-0.21
0.68
0.50
0.84
1.25
-
H
2
PO
4
62.6
1268
162
-
PhCO
2
124.8
35
1
[
2
a] determined in DMSO-d
6
+0.5% H
2
O using H titration at 303K and HypNMR
1
2
008 for non-linear curve fitting; anions added as TBA salts; estimated errors
±
10% (detailed error estimates are given in Table S1). [b] Calculated anion
3
volume in Å , see ref 8. [c] Krel = log(KCl-/Kanion-) ≥ 0 indicates preference for
chloride over other anion, data for 1 from ref 8.
‡
Scheme 1. Synthesis of chloride-selective host 2 (a) and its X-ray structure (b).
Briefly, the 2,6-dihydroxybenzoic acid was converted to the acid
chloride and then coupled with a 1-pyrenemethylamine yielding
the diphenol 3, which was subjected to double O-alkylation by
bromomethylacetate affording the ,-diester 4. Compound 4
and ,-diamine 5 (prepared previously in two-steps from 2,6-
dipyridine carboxylic acid methyl ester) were then reacted under
the established MeONa-mediated macrocyclization protocol
yielding the target host 2. All new compounds were fully
In all cases, the corresponding titration curves were consistent
with a 1:1 (host:guest) binding model as judged by the residual
analysis.11 To our delight, analysis of the titration data indicates
that host 2 has the highest affinity for the chloride ion amongst the
series of anions studied. Interestingly, in contrast to host 1, the
-
-
2
anti-Hofmeister anion binding selectivity of host 2 (Cl > MeCO >
-
-
H
2
PO
guest – the bigger anion is bound less strongly than smaller one
(cf. parameter V in Table 1). Interestingly, the selectivity for
4 2
> PhCO ) is clearly correlated with the size of the anionic
1
13
characterized by H and C NMR spectroscopy, high resolution
mass spectrometry (HRMS), and elemental analysis (see SI).
The structure of the host 2 was additionally confirmed by single
c
chloride (expressed as Krel ≥ 0, see footnote of Table 1) is much
better for host 2 than for the more rigid tren-based hexamide
cryptand developed by Bowman-James and co-workes (Krel
‡
crystal X‐ray crystallography (Scheme 1b). This analysis reveals
-
-,
the tight encapsulation of a water molecule within the macrocyclic
cavity by three NH amide protons (dN(3)···O(1) = 2.93 Å, and one
C=O moiety (dO(1)···OW1 = 2.79 Å). The NH amide protons
belonging to the macrocyclic skeleton are directed inside the
macrocyclic cavity, however, only three of them, situated near the
pyridine moiety, are involved in the binding of the guest. The
remaining NH is involved in an intramolecular hydrogen bond to
the amide O of the lariat arm (dO(1)···N(2) = 2.93 Å). The
encapsulated water molecule is covered from one side by the
pyrene substituent, while the carbonyl group of the lariat arm
reinforces the host-guest interaction. The macrocycle
conformation is further stabilized by non-covalent π-π and CH-π
interactions between adjacent pyrene moieties in the solid state.
Having receptor 2 in hand, we began an investigation into its
values in DMSO-d
respectively).12
Notably, the affinity to chloride is only slightly lower for host 2
6
are 0.09 and 0.17 for MeCO
2
and H
2
PO
4
-1
compared to 1 (K
lower acidity of the intraannular amide NH proton in the former
case (unconjugated CH -pyrene vs -conjugated p-nitrophenyl).
The most pronounced 14-fold decrease in binding affinity is
a
= 627 vs 778 M ), despite the considerably
2
observed for the H
2
PO -
1268 M ), whereas it is only weakly bound by host 2 (K
4
guest which is strongly bound by 1 (K
a
=
-1
-
a
= 90 M
1
-1
), which corresponds to 6.5 kJmol loss in the binding free
energy (G). Both hosts have a strong preference for chloride
over benzoate which bears a negatively polarized phenyl
-1
substituent (Krel = 0.68 vs 1.25 and G = 3.9 and 7.2 kJmol for
hosts 1 and 2, respectively).
1
-
-,
O
A closer inspection of the H NMR titration data reveals that the
binding properties towards model anionic guests (Cl , MeCO
2
-
-
PhCO
2
, and H
2
PO
4
) in a competitive DMSO-d
6
+ 0.5% H
2
b
signal corresponding to the NH amide protons (H , see Fig. 1 for
solvent mixture. Taking into account the well-known emissive
properties of the pyrene unit, we initially considered employing
fluorescence titrations to determine the anion-binding properties
of host 2. We did not observe, however, a dramatic change in the
fluorescence intensities during titration with any of the evaluated
anions, plausibly due to the lack of electronic conjugation between
labels) of the resorcinol unit were shifted markedly upfield by 1.0
-
ppm after addition of Cl , whereas other studied anions caused
-
-
either small ( = 0.1 ppm for MeCO
2
and PhCO
2
) or moderate
-
( = 0.6 ppm for H
2
PO
4
) downfield shifts (Fig. 2a).
9
pyrene fluorophore and adjacent anion-binding amide group. For
the plethora of reported pyrene-derived anion receptors showing
strong fluorescence responses such conjugation is present.10
Nonetheless, the corresponding association constants (Ka’s)
1
were determined using H NMR titration experiments (Tab. 1).
Figure 2. Comparison of chemical shift changes (Δδ) for amide protons NH(b) and
NH(a) upon addition of anions (as TBA salts) to the solution of 2 in DMSO-d + 0.5%
O; fitted binding isotherms (gray lines); see Scheme 1 for labels.
6
H
2
2
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European Journal of Organic Chemistry
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FULL PAPER
In striking contrast, the signals corresponding to the other NH
amide protons (a and c) experienced a considerable downfield
shift by up to 1.1 ppm (Figs. 2b and S5). Similarly, an upfield shift
of the NH(b) amide protons was observed upon titration of 1 with
(Figs. 4a and S11a,b), even so, they are located far away from
the primary binding sites, i.e. macrocyclic amide groups (Figs.
S11b,c).
7
TBACl (Fig. 2a). As deduced from x-ray studies and solution
experiments, the binding of anions by hosts 1 and 2 initially
requires the breaking of a rather strong intramolecular hydrogen-
o
bond followed by an 180 degree rotation of the aromatic
substituent (lariat arm). This process, in turn, directs the NH(a)
amide proton toward the macrocyclic cavity and enables
participation of the NH(b) proton in the binding event. Titration
data reveals, however, only a moderate downfield shift of the
NH(b) protons during titration with anionic guests that are larger
and more basic than chloride, suggesting a rather weak
hydrogen-bond interaction (Fig. 2a). Likewise, the binding
properties of macrocyclic hosts 1 and 2 indicate that NH(b)
protons are not decisive for the recognition process, in particular
for the binding of a chloride guest. This assumption is supported
by DFT calculations, which suggest the lack of an interaction
between NH(b)’ proton and chloride, despite the favourable
geometry of the NH-donor which is directed toward the anion (Fig.
Figure 4. Comparison of chemical shift changes (Δδ) for selected C-HAr protons upon
addition of anions (as TBA salts) to the solution of 2 in DMSO-d + 0.5% H O (green –
6 2
chloride, red – acetate, blue – dihydrogenphosphate, black – benzoate); fitted binding
isotherms (gray lines); see Scheme 1 for labels.
At the same time, pyridine protons f and g experience strong
shielding effect which indicates occurrence of - face-to-face
stacking interactions between electron-rich pyrene and electron-
deficient 2,6-dicarbamoyl pyridine rings (Fig. 4b).
3a).
Overall, these features highlight the design aspects of chloride
receptors outlined at the beginning of this report, and give
credence to the design principles used for host 2. The steric effect
of the pyrene substituent that caps the binding pocket, allows for
remarkable control over the selectivity of chloride recognition.
Importantly, the observed fast exchange (on the NMR timescale)
indicates that the energy barrier required for the structural-
reorganization of host 2 is not too high, thereby allowing fast
chloride capture and release, possibly` on demand.
Very recently Flood and co-workers reported a triazole-based
cryptand which offers outstanding binding affinity and selectivity
towards the chloride anion.14 The rate of the guest exchange is,
however, extremely slow on the NMR timescale, and more
-
Figure 3. The energy-minimized structure of 2Cl (B3LYP-D3/def2-tzvp/CPCM-DMSO)
3
importantly, addition of AgNO is required to release the bound
-
exemplifying lack of interaction between Cl and one of NH-amide protons (a) and non-
covalent interactions between aryl substituents (b); chloride in space-fill
representation; non-acidic protons omitted for clarity.
chloride ion from the host. We assumed that in our case chloride
release could be realized upon addition of an agent less
competitive than a silver salt, but still more competitive than the
1
DMSO/water mixture used in the H NMR titration experiments.
The distance between this NH-donor and chloride (dNH(b)’Cl-
.40 Å) is evidently too long to maintain a hydrogen bond
=
We choose methanol since it is capable of completely switching
off the anion recognition of nearly all non-charged hosts solely
employing hydrogen bond donors for anion binding. As is depicted
in Fig. 5, a stepwise addition of MeOH, up to 62%, triggers the
4
interaction in combination with a second NH(b) proton which
assists in chloride binding (dNH(b)Cl- = 3.30 Å). On the other hand,
the X-ray data and computational calculations reveal that NH(b)
protons in the structure of free 2 are engaged in hydrogen bond
interactions (Scheme 1b and Fig. S15). These observations
correlate well with the observed change of proton NMR shift
during titration of 2 with TBACl.
complete dissociation of the 2Cl- complex, entailing
conformational rearrangement of the macrocycle 2.
a
In addition, theoretical calculations reveal that the entrapped
chloride is unsymmetrically bound in the macrocyclic cavity by just
four NH donors, while from one side it is capped by the flat pyrene
ring. The conformation of the complex is additionally stabilized by
π-π interactions between pyrene and pyridine rings, resembling a
sandwich-like structure (Fig. 3b). Such
a supramolecular
1
assembly is corroborated by the H NMR titration experiments
which reveals a considerable shielding (upfield shifts) of the host
C-HAr protons upon addition of TBACl, whereas TBA salts of
-
-
-
2 2 4 2
MeCO , H PO , and in particular PhCO , cause much less
prominent shift changes (see SI for further details). For example,
pyrene protons e and d experience considerable upfield shifts
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000662
FULL PAPER
Figure 5. The instant chloride release and capture by host 2 upon gradual addition and
removal of complexing agent CD
titration experiments in DMSO-d + 0.5% H
3
OH, respectively monitored by 1H-NMR assisted
6
2
O.
Likewise, evaporation of the volatile MeOH reassembles the
complex, exemplifying the reversibility of chloride binding.
Figure 6. Dependence of the type of cation on the stability constants (logK
(a) and interaction energy (Eint) for pyrene-cation complexes (b).
) for 2Cl-
a
This compromise between the strength and selectivity of chloride
binding, due to the intrinsic features of the designed host, is
crucial in terms of the prospective application of UCs in the
+
1
5
Specifically, cations bearing an odd number of CH
2
units (Me
4
N ,
domain of anion transport across cell membranes. A high speed
of chloride uptake and release is an important prerequisite for
novel artificial systems which are to be investigated for anion
transport in biological systems.
+
+
(
n-C
bearing the even number of CH
This can be attributed to the so-called "odd-even effect”.
3 7 4 5 11 4
H ) N , and (n-C H ) N ) have a lower affinity than cations
+
+
2
4 4 9 4
units (Et N and (n-C H ) N ).
1
7
Interestingly, the chloride salt of the spherical-like
+
tetraphenylphosphonium cation (Ph
4
P ) has the lowest affinity to
We further sought to examine if the accompanying cation
2
among the series which is attributed to geometrical mismatch
influences chloride recognition by cation- interactions with the
1
6
with the flat pyrene substituent. This in turn, results in smaller
number of dispersion interactions as compared to the quaternary
ammonium cations which can adopt near-flat conformations. The
DFT calculations performed for complexes of pyrene with cations
at M06-2X/def2-TVP level of theory reproduce well the observed
binding trend in solution indicating more negative interaction
energies (i.e. stronger binding) for cations bearing even number
electron rich pyrene substituent. Along this line, we performed
titration experiments with a range of quaternary ammonium salts
that vary by the length of their alkyl chains. We found a
relationship between the degree of positive charge dissipation on
a
the cation and the value of the association constant (K ) (Fig. 6).
2
of CH units (see Fig. 6, inset and Figs. S17 and S18 for details).
Conclusion
In conclusion, this work demonstrates a rational approach to the
development of the highly chloride-selective electroneutral host 2
by fine-tuning of the molecular design. Following our hypothesis,
we prepared a size-matched, 24-membered macrocyclic host
end-capped with a hydrophobic pyrene moiety. The host 2 was
characterized by single crystal X-ray analysis, while its
1
complexing properties were screened through H-NMR assisted
6 2
titration in a demanding (DMSO-d + 0.5% H O) solvent mixture
as well as through DFT calculations. Owing to the high level of
preorganization, our tailored host efficiently encapsulates chloride,
leading to remarkable selectivity over larger and more basic
-
-
-
2 4 2 2
phosphate (H PO ) and carboxylates (MeCO , PhCO ). These
results were achieved by inclusion of an adequate number of
hydrogen bond donors and steric hindrance conferred by the
pyrene entity. The low energy barrier associated with the
conformational change allows for fast chloride capture and
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000662
FULL PAPER
release which renders pyrene-terminated host 2 a promising
candidate for the selective chloride transport through membranes.
reaction medium and the solvent was removed under reduced pressure to
yield a solid residue which was purified by silica gel chromatography using
a gradient of MeOH in DCM (1:99 → 5:95, v/v) as eluent to yield the
o
1
product 2 (22 mg, 15%) as white crystals (m.p. 162-165 C). H NMR (500
MHz, DMSO-d ) δ 9.36 (t, J = 5.8 Hz, 1H), 8.96 (t, J = 6.2 Hz, 2H), 8.43
dd, J = 7.7, 5.4 Hz, 3H), 8.28 (t, J = 8.4 Hz, 3H), 8.22 (dd, J = 10.4, 8.5
6
Experimental Section
(
Hz, 2H), 8.18 – 8.11 (m, 5H), 8.06 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 8.4 Hz,
1H), 6.79 (d, J = 8.5 Hz, 2H), 5.27 (d, J = 5.8 Hz, 2H), 4.73 (s, 4H), 3.21
(q, J = 6.2 Hz, 4H), 3.12 (q, J = 6.7 Hz, 4H), 1.62 (p, J = 6.5 Hz, 4H). 13C
All starting materials and reagents were obtained from commercial
suppliers and used without further purification. TLC was performer on silica
gel 60 F254 plates; spots were detected by fluorescence quenching under
6
NMR (125 MHz, DMSO-d ) δ 168.27, 165.79, 162.86, 155.51, 148.49,
UV light at 254 nm. Column chromatography was performed on silica gel
6
139.46, 132.08, 130.79, 130.72, 130.24, 129.97, 127.85, 127.28, 126.92,
126.13, 125.96, 125.13, 125.07, 124.71, 123.99, 123.92, 123.82, 123.16,
0 (0.040–0.063mm) using reagent-grade solvents. H NMR and 13C NMR
1
spectra were recorded on Varian Mercury 400 instrument at 400 and 100
MHz. NMR signals were assigned with the help of DEPT, COSY, HMBC,
HMQC, and NOESY experiments. Proton and carbon chemical shifts are
117.18, 106.75, 67.70, 54.84, 39.83, 39.67, 39.50, 39.33, 39.17, 36.01,
+
35.58, 28.36. HRMS ESI (m/z) Calc. for C41
found: 727.2872. Elemental analysis: Calc. for C41
C 66.93, H 5.34 N 11.42 found: C 67.11, H 5.88, N 11.14.
H
39
6
N O
7
[M+H] : 727.2880,
39 6 2
H N O7.5 (M+0.5H O):
reported in ppm (δ) (DMSO-d
6
, 1H NMR δ = 2.54 and 13C NMR δ = 39.52).
J coupling constants values are reported in Hz. Melting points are
uncorrected. High resolution mass spectra (HRMS) were recorded using
ESI-TOF technique. Compounds 4 and 5 were prepared according to the
previously reported procedures.7,17c,18
Titration experiments: As the source of anions, commercially available
tetraalkylamminum salts and tetraphenylphosphonium chloride (TPPCl)
were used. Distilled water was added to the commercially available
DMSO-d
concentration (DMSO-d
6
of 99.9% isotopic purity to obtain the appropriate water
/H O 99.5:0.5 v/v). The host solution was titrated
2
2
1
,6-Dihydroxy-N-(pyren-1-ylmethyl)benzamide (3): A suspension of
6
2
,6-dihydroxybenzoic acid (0.65 g, 4 mmol) and TEA (0.60 mL, 4.4 mmol,
in a NMR tube with the solution of the respective TBA/TPP salt in receptor
aliquots (details are given in Table S1). The binding constants were
calculated from the changes in chemical shifts of ligand protons which
were shifted during titration. Nonlinear curve fitting was carried out with
HypNMR 200819 (Version 4.0.71) program with fitting to the appropriate
global binding model (see Table S1).
o
.1 equiv) in DCM (40 mL) was cooled to 0 C and SOCl
2
(0.32 mL, 4.4
mmol, 1.1 eq.) was added dropwise and the reaction mixture was stirred
for 10 min. Then cooling bath was removed and stirring was continued for
60 min. Afterwards, a suspension of 1-pyrenemethylamine hydrochloride
(
1070 mg, 4 mmol) and TEA (1.2 ml, 8 mmol, 2 equiv) in DCM (10 mL)
was added dropwise over 10 min. After the reaction was stirred for 24h a
silica gel (~5 g) was added and the solvent was removed under reduced
pressure. The yellowish residue was purified by silica gel chromatography
‡
Monocrystal was obtained by a slow vapour-vapour diffusion of water
vapors into the DMSO/water solution of 2 at rt. C41 9.26, M = 766.94,
monoclinic, P-21/c, a = 11.1051(7) Å, b = 11.6400(6) Å, c = 13.3274(7) Å,
42 6
H N O
with EA in hexanes (1:1 v/v) to furnish a product 3 (0.30 g, 20.4 %) as a
1
yellowish powder. H NMR (500 MHz, DMSO-d
6
) δ 12.56 (s, 2H), 9.55 (t,
3
α = 94.114(4)◦, β = 106.905(5)◦, γ = 106.237(5)◦, V = 1560.44(15) Å , T =
J = 5.7 Hz, 1H), 8.49 (dd, J = 9.3, 1.5 Hz, 1H), 8.34 – 8.29 (m, 3H), 8.28
d, J = 1.4 Hz, 1H), 8.17 (d, J = 1.5 Hz, 2H), 8.13 – 8.07 (m, 2H), 7.17 (td,
J = 8.2, 1.4 Hz, 1H), 6.37 (dd, J = 8.2, 1.5 Hz, 2H), 5.32 (d, J = 5.8 Hz, 2H).
13C NMR (125 MHz, DMSO-d
) δ 169.9, 160.2, 133.6, 132.1, 130.8, 130.3,
30.2, 128.0, 127.9, 127.4, 127.2, 126.4, 126.4, 125.4, 125.3, 124.9, 124.1,
23.9, 123.0, 107.3, 102.6. HRMS ESI (m/z) Calc. for C24
00(2) K, Z = 2, µ(Mo-Kα) = 0.097 mm−1, 66503 collected reflexes, 15452
1
(
unique (Rint = 0.048). CCDC deposition number: 1954968.
6
1
1
3
Acknowledgements
H16NO :
3
-
67.1207 [M-H] , found: 367.1199.
This work was supported by 2014/15/B/ST5/05038 (J.J.) and
UMO-2016/23/D/ST5/03301 (K.D.) projects funded by Poland’s
National Science Centre (NCN).
Dimethyl-2,2’-{2-[((pyren-1-ylmethyl)carbamoyl)-1,3-phenylene]
(
bisoxy)}diacetate (4): To the vigorously stirred solution of diphenol 3
(
140 mg, 0.38 mmol) in acetone (20 mL) were added finely powdered
2 3
anhydrous K CO (110 mg, 0.78 mmol, 2.05 equiv) and the catalytic
Keywords: macrocyclic receptor • anti-Hofmeister anion
selectivity • chloride selective • unclosed cryptand • anion
recognition
amount of KI (10 mg, 0.038 mmol, 10% mol). After 15 min the methyl 2-
bromoacetate (70 µL, 0.76 mmol, 2 equiv) was slowly added dropwise and
the reaction mixture was stirred at reflux for 48 h. The reaction was cooled
to rt and inorganic salts were filtered through a plug of Celite, washed with
acetone (~50 mL), and the solvent was removed under reduced pressure.
The resulting residue was purified by silica gel chromatography using a
gradient of EA in hexanes (3:7 → 1:1, v/v) as eluent to yield the product 4
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6
o
1
(
120 mg, 58.6%) as a yellowish powder (m.p. 102 C). H NMR (500 MHz,
2
DMSO-d ) δ 8.74 (t, J = 5.8 Hz, 1H), 8.45 (d, J = 9.2 Hz, 1H), 8.32 – 8.23
6
(m, 5H), 8.18 – 8.13 (m, 2H), 8.08 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 8.4 Hz,
1
(
H), 6.64 (d, J = 8.5 Hz, 2H), 5.17 (d, J = 5.9 Hz, 2H), 4.80 (s, 4H), 3.67
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6
) δ 169.03, 164.02, 155.41, 132.78,
1
1
5
5
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25.02, 124.98, 124.75, 123.89, 123.87, 123.20, 117.78, 106.16, 65.53,
5
+
1.74. HRMS ESI (m/z) Calc. for C30
12.1714.
H26NO
7
[M+H] : 512.1709, found:
2
Macrocyclic chloride-selective host (2): The product was prepared
according to previously described procedures.7,17c,18 To the solution of
α,ω-diester 4 (100mg, 0.2 mmol) and α,ω-diamine 5 (80 mg, 0.2 mmol) in
anhydrous MeOH (40 mL) was added a freshly prepared MeONa (0.4
mmol) in MeOH (100 mL) and the reaction mixture was stirred for 7 days
under ambient conditions. Afterward, silica gel (~2 g) was added to the
2
019, 5, 429–444; f) X. Wu, L. W. Judd, E. N. Howe, A. M.
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4
5
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European Journal of Organic Chemistry
10.1002/ejoc.202000662
FULL PAPER
[
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-
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6
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European Journal of Organic Chemistry
10.1002/ejoc.202000662
FULL PAPER
Entry for the Table of Contents
Insert graphic for Table of Contents here.
Insert text for Table of Contents here.
Small steps make big changes: structure-guided optimization of existing macrocyclic platform for anions allows synthesis of novel
neutral receptor with extraordinary anti-Hofmeister type selectivity for chloride. A drawing discloses X-ray structure of the free receptor
and its DFT-calculated complex with chloride. The hydrophobic interactions are crucial for achieving selectivity for this spherical guest.
The capture and release of cargo is controlled by the hydrogen-bonding power of solvent in a controllable manner.
7
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