Electroactive anion receptor with high affinity for arsenate

Article abstract of DOI:10.1021/acs.joc.0c01206

Herein, we present the synthesis and characterization of a macrocyclic polyamide cage that incorporates redox-active 1,4-dithiin units. UV/vis titration experiments with eight anions in acetonitrile revealed high affinity for H₂AsO₄<

Full text of DOI:10.1021/acs.joc.0c01206

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Article
Electroactive Anion Receptor with High Affinity for Arsenate
Samuel I. Etkind, Douglas A. Vander Griend, and Timothy M. Swager*
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ABSTRACT: Herein, we present the synthesis and characterization of a macrocyclic polyamide cage that incorporates redox-active
+0.4
1,4-dithiin units. UV/vis titration experiments with eight anions in acetonitrile revealed high affinity for H2AsO4− (log β2 = 10.4
)
−0.4
−
+0.3
+0.03
−
+0.02
−0.03
and HCO3 (log β2 = 8.3 ) over other common anionic guests, such as Cl− (log K1:1 = 3.20
), HSO4 (log K1:1 = 3.57
),
−0.4
−0.02
+0.05
and H2PO4− (log K1:1 = 4.24
), by the selective formation of HG2 complexes. The recognition of arsenate over phosphate is rare
−0.04
among both proteins and synthetic receptors, and though the origin of selectivity is not known, exploiting the difference in the
binding stoichiometry represents an underexplored avenue toward developing receptors that can differentiate between the two
1
anions. Additional analysis by H NMR in 1:3 CD2Cl2/MeCN-d3 found a strong dependence of anion binding stoichiometry with
the solvent employed. Finally, titration experiments with cyclic voltammetry provided varying and complex responses for each anion
tested, though reaction between the anion and receptors was observed in most cases. These results implicate 1,4-dithiins as
interesting recognition moieties in the construction of supramolecular receptors.
detection of anions via chemiresistive,20 potentiometric,21,22
INTRODUCTION
■
capacitive,23 or redox-based sensing,24 due to their potential
Simple anions can often act as potent environmental
pollutants. For example, nitrate and phosphate leached from
application in the development of cost-effective devices. We
were particularly drawn to the development of redox-active
fertilizers can lead to algal blooms, depriving aquatic
receptors, as the effect of transiently creating cationic species
ecosystems of oxygen needed to sustain animal life.1 The
increasing levels of atmospheric CO2 is coupled with an
increase in oceanic bicarbonate concentration and therefore
has the potential to effectively bind anions in competitive
media, such as water.25
Electroactive anion receptors have been well described.25
ocean acidity, resulting in the degradation of CaCO3, a
Most designs involve appending a redox transducer, most
protective layer for many organisms.2 Millions in Bangladesh
commonly ferrocene,26−28 to a known anion receptor;
are at risk of arsenic poisoning, which could be mitigated by
however, other strategies have been employed, such as the
the environmental monitoring of arsenate levels.3 Typically,
use of electroactive ureas29 and mixed-valence systems.30 The
the accurate quantification and detection of anions at
change in reduction potential upon introduction of an anionic
environmentally relevant concentrations require the use of
guest is proposed to proceed via a variety of mechanisms,
costly analytical methods, such as high-performance liquid
including through-space interactions between the redox-active
chromatography (HPLC) and inductively coupled plasma
moiety and anion, as well as conformational changes of the
mass spectrometry (ICP-MS).4−7 These methods, however,
redox transducer upon anion complexation, which result in the
could be potentially supplanted by cost-effective techniques
guest binding to the oxidized host with a greater affinity than
that use supramolecular receptors to aid in the detection of
anionic species.
To apply anion receptors to the detection of anions in
Received: May 30, 2020
complex mixtures, researchers utilize a variety of methods, such
as changes in fluorescence,8−11 absorbance (i.e., colorimetric
sensors),12−14 or NMR resonance15−19 in the presence of
guests. More recently, there have been efforts by a number of
groups to employ electrochemical methodology toward the
https://dx.doi.org/10.1021/acs.joc.0c01206
© XXXX American Chemical Society
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A

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Figure 1. Previously reported polyamide cages 1 and 2 and new cage 3.
a
Scheme 1. Preparation of Receptor 3
a
Reagents and conditions: (i) S2Cl2, hexanes, 35 °C, 1 h, 40%; (ii) NaH, tetrahydrofuran (THF), 0 °C; Ts2O, 0 °C to room temperature (rt), 4 h;
(iii) Na2S·9H2O, EtOH, 1.5 h, 64% (two steps); (iv) KOH, EtOH, 50 °C, 2 h, 60%; (v) (COCl)2, cat. dimethylformamide (DMF), CH2Cl2, 2 h,
quant.; (vi) 9, Et3N, CH2Cl2, 0 °C to rt, 16 h, 80%; (vii) HCl, dioxane, 1 h, 98%; (viii) 9 (slow addition), Et3N, CHCl3 (1.5 mM), 20 h, 45 °C,
20%; and (ix) 9 (slow addition), various conditions, <5%.
to the nonoxidized host.31 The reduction potential of the
host−guest complexes may differ depending on the included
guest. Additionally, the observation of “two-wave” behavior, in
which the host and guest are in slow equilibria, could
potentially be useful in differentiating between multiple anionic
species.25
ment of pyrrole- and imine-containing Receptor 2, which
shows a stronger preference for tetrahedral anions via the
incorporation of hydrogen-bond-accepting moieties.44
Placement of the 1,4-dithiin units adjacent to the binding
site could give large electrochemical responses via both
through-space interactions between the anionic guest and
redox transducer and the conformational change of the redox-
active moiety upon oxidation. We also postulated that the
formation of a tricationic cavity upon oxidation may form
sufficiently strong interactions with anions to overcome their
large solvation energy in highly polar media.
We hypothesized that the modification of an existing anion
receptor with a carefully chosen redox transducer that is in
close proximity to the binding site could give large shifts in the
reduction potential of the host−guest complex upon oxidation.
The modification of known supramolecular receptor scaffolds,
such as in the introduction of halogen bonding,32,33 altering
distal functionalities to bias host−host34 or host−guest
interactions,35 or systematically altering the size and electronic
biases of the binding site,36−41 has been demonstrated to be an
effective approach toward designing receptors with high affinity
toward various anions, in addition to giving novel insights in
structure−property relationships. Additionally, we recognized
1,4-dithiin, a sulfur-rich heterocycle that exhibits a well-
behaved single-electron oxidation that is coupled with a
geometric change from bent to planar, as largely overlooked in
supramolecular scaffolds.42 Herein, we present our work on the
incorporation of 1,4-dithiin moieties into Receptor 1 to form
Receptor 3, which was previously reported as a nitrate-selective
receptor by Anslyn and co-workers (Figure 1).43 Notably, Kim,
Sessler, and co-workers have demonstrated the effectiveness of
systematic alterations to Anslyn’s Receptor 1 in the develop-
RESULTS AND DISCUSSION
■
Synthesis. The preparation of Receptor 3 was carried out
according to Scheme 1 (see Section S1.1 (Supporting
Information) for preparation of starting materials). The
treatment of ethyl acetoacetate (4) with disulfur dichloride
in hexane furnishes thioether 5.45 Initial efforts involved the
direct conversion of 5 to dithiin 7 via a variety of thionating
reagents, such as Lawesson’s reagent, Curphey’s reagent, and
P4S10, but such attempts resulted in the formation of complex
mixtures. Instead, 5 can be treated with sodium hydride and
Ts2O to yield vinyl tosylate 6 as a mixture of isomers.
Treatment of the crude mixture with sodium sulfide gives
dithiin 7, which can then be hydrolyzed to give diacid 8. This
serves as a highly efficient methodology to form 1,4-dithiin
rings, the synthetic literature of which has been limited in
B
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Figure 2. Side (left) and top (right) views of the crystal structure of Receptor 3 with CH2Cl2 as a solvate. C−H hydrogens are omitted for clarity.
a
Table 1. Stability Constants of 3 with Various Anions
b
anion
log K1:1
log K1:2
log β2
ΔGK
ΔGK
ΔGβ
α
1:1
1:2
2
−
+0.4
+0.2
+0.4
+2
+1
+2
H2AsO4
5.0
5.4
10.4
8.3
−27
−29
−19.4
−57
−45
9
−0.3
−0.2
−0.4
−2
−1
−2
c
−
+0.06
+0.19
+0.3
−0.4
+1.7
+0.3
+2
HCO3
4.76
5.22
4.24
3.69
3.57
3.47
3.53
−26.1
−28.7
−23.3
−20.3
−19.6
−19.1
−17.6
0.25
d
−0.30
−0.05
−0.3
+0.5
−1.1
−2
d
d
d
d
OAc−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
−
+0.05
−0.10
−0.3
d
d
d
d
d
−
+0.05
+0.2
H2PO4
CN−
−
−
−0.04
−0.3
d
d
d
d
d
+0.04
+0.2
−
−
−0.03
−0.2
d
d
d
d
d
−
+0.02
+0.2
HSO4
−
−
−0.03
−0.1
d
d
d
d
d
−
+0.03
+0.2
NO3
Cl−
−
−
−
−
−0.03
−0.2
d
d
d
d
d
+0.03
+0.1
3.20
−
−
−
−
−0.02
−0.1
a
Titrations were performed at 20 °C in MeCN using the tetrabutylammonium salt of each anion. UV/vis data fitting was performed using SIVVU.
4K1:2
b
Errors are given from at least three experiments with asymmetric errors at 95% confidence intervals. Interaction parameter, defined as α =
.
K1:1
c
d
Tetraethylammonium bicarbonate was employed. Not applicable.
scope. In addition, gram-scale synthesis of diacid 8 was enabled
via this synthetic route. Conversion to diacyl chloride 9 can be
accomplished by oxalyl chloride under standard conditions.
We initially attempted the direct cyclization of acyl chloride
9 with triamine 10 to form Receptor 3; however, this resulted
primarily in the formation of oligomeric species. A more robust
approach involves molecule 13, which can be synthesized
starting with the preparation of protected amine 11, followed
by coupling with acyl chloride 9 to form 12 and deprotection
under acidic conditions.46 Use of HCl in dioxane as a
deprotecting agent was crucial as the use of trifluoroacetic acid
resulted in the formation of unidentified side products. Slow
addition of acyl chloride 9 to a dilute solution of 13 in
chloroform with gentle heating provided Receptor 3 in a 20%
yield (Section S4, Supporting Information). The structure was
confirmed by NMR, high-resolution mass spectrometry
(HRMS), and X-ray crystallography (Section S6, Supporting
Information). Notably, the X-ray structure shows all amide N−
H bonds oriented toward the cavity of the receptor, potentially
preorganizing the scaffold toward interacting with anions
(Figure 2).
analysis. As a result of the low concentration used for titration
experiments (<35 μM) and the polar solvent employed, ion-
pairing interactions were ignored.51 Binding stoichiometries
were assessed by applying various binding models in the
formation of HG and HG2 species to each experiment and
selecting the binding stoichiometry that gave the lowest error,
as is currently considered best practices.52,53 Additionally, the
simpler binding model was selected in situations where
multiple models gave a similar error. In the cases of select
−
−
−
−
anions, such as H2AsO4 , H2PO4 , HSO4 , and NO3 ,
titrations were performed at least two concentrations between
5 and 35 μM to give further support to the assigned binding
stoichiometry and determined association constant.
Cl− was bound with low affinity, a useful feature given its
−
ubiquity in environmental and biological settings. NO3 ,
HSO4 , and CN− were bound with moderate affinity, followed
−
by H2PO4 and OAc− with stronger binding affinity.
−
Additionally, when measuring the stability constants of
−
Receptor 3 with HCO3 , binding isotherms were produced
that could not be accurately fit to a 1:1 binding model, and
−
with H2AsO4 , the application of a 1:1 binding model provided
fits that were associated with higher error than our other anion
Binding Characterization. Association constants of
Receptor 3 in acetonitrile with various tetrabutylammonium
or tetraethylammonium salts were determined via UV/vis
titrations, using SIVVU for data analysis (Table 1 and Section
S2, Supporting Information).47,48 We chose a list of environ-
mentally and biologically relevant monoanionic guests to probe
the binding behavior of Receptor 3. Asymmetric errors on the
binding constant terms were calculated by bootstrapping each
data set column-wise 1000 times.49 The errors of at least three
separate titrations were then combined according to model 2
of Barlow’s paper and were reported as 95% confidence
intervals.50 The absorbance of all species, including the host,
guest, and complexes thereof, was refined as part of our data
binding experiments. Instead, it was found that the binding of
−
−
H2AsO4 and HCO3 could be more accurately fit with a 1:2
host/guest binding mode in accordance with the following
equations
H + G F HG
K1:1
HG + G F HG2 K1:2
H + 2G F HG2 β2
From the K1:1 and K1:2 values, the binding cooperativity can be
assessed by calculation of the interactivity parameter α (Table
1).53 Interestingly, while HCO3 demonstrates negative
−
C
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Figure 3. Comparison of 1:1 and 1:2 fits of Receptor 3 at (a) 28.7 μM after the addition of 5.08 equiv of TBAH2AsO4 with (b) the resulting
residuals from the application of 1:1 and 1:2 binding models and (c) 30.0 μM after the addition of 15.5 equiv of TBAH2PO4 with (d) the resulting
residuals from the application of 1:1 and 1:2 binding models. Absorbance data from 275 to 500 nm were used to determine the association constant
and absorbance of all species in solution. Full binding models for these experiments are available in the Supporting Information in Figures S81−S84
and S65−S68 for TBAH2AsO4 and TBAH2PO4, respectively.
−
cooperativity (α = 0.25), H2AsO4 demonstrates positive
cooperativity (α = 9), indicating that the binding of one
anionic species makes the binding of the second more
favorable. Such binding stoichiometry may be indicative of
the formation of anti-electrostatic hydrogen bonds;54−58
however, we have been able to obtain neither solution- nor
solid-state evidence for the exact binding mode of these two
anions.
phosphate is rare in both proteins and synthetic receptors, and
only a few reports are present in the literature.39,61−63
We sought to further probe the difference in binding
−
−
behavior between H2AsO4 and H2PO4 by electrospray
ionization mass spectrometry (ESI-MS) studies in acetonitrile.
Although ESI-MS studies are, by themselves, insufficient in
determining the stoichiometry of a host−guest interaction,
results of such experiments can serve as supporting evidence
for the observed binding stoichiometry from solution-phase
experiments.64,65 While experiments with TBAH2PO4 only
revealed evidence of a 1:1 complex (Section S3.2, Supporting
Information), similar experiments with TBAH2AsO4 revealed a
mass corresponding to [M + NBu4 + H2As2O7]−, which could
provide additional evidence of the formation of a 1:2 complex
(Section S3.1 and Figure 4). The preparative formation of
pyroarsenate salts requires temperatures in an excess of 150
°C, typically for several hours, and they degrade rapidly in the
presence of water.66 Given that the ESI source was held at 100
°C, it could be possible that the guest induces dehydration of
We were especially surprised to discover that the 1:2 binding
−
−
behavior in the case of H2AsO4 does not hold for H2PO4 ,
given their similar sizes and properties.59 We closely
scrutinized this behavior by subjecting several arsenate and
phosphate titrations to both 1:1 and 1:2 binding models to
assess the best fit. The absorbance and accompanying fits from
1:1 and 1:2 binding models at 292 nm are shown in Figure 3.
We found analysis of the residuals to be particularly useful in
the determination of the binding stoichiometry, and such
analysis has been demonstrated to be significantly more
informative and robust than Job’s plot analysis.52,60 As shown
in Figure 3a,b, the application of a 1:1 binding model for
−
H2AsO4 at elevated temperatures or in the gas phase, due
either to hydrogen bonding or by simply holding two guest
molecules in close proximity to one another. The formation of
pyroarsenate induced by Receptor 3 in solution, however,
could potentially explain the difference in binding energies
−
H2AsO4 results in residuals that trace a sinusoidal curve,
which has been demonstrated to be indicative of an additional
binding event.60 Additionally, a global fit of this experiment
results in extinction coefficients for the HG complex of 0 at
certain wavelengths, a nonrealistic value, and large absorbance
of the guest, an artifact not observed in the absence of the host
(Figure S81). Removing guest absorbance from the binding
model does not improve the resulting fit. Application of a 1:2
binding model, instead, provides significantly reduced residuals
and realistic extinction coefficients for all species involved (H,
G, HG, and HG2) (Figure S83). Application of the same
−
−
between H2PO4 and H2AsO4 , as computational studies
indicate that the formation of pyroarsenate is ∼20 kJ/mol less
unfavorable than the formation of pyrophosphate.67 Solution-
phase evidence to confirm or refute pyroarsenate formation,
however, is currently elusive, and we are actively investigating
the possibility of this phenomenon.
We also endeavored to further probe the binding
interactions with all anions by 1H NMR titration, as
observation of similar binding interactions at different
concentrations can serve as further evidence for assigned
binding behavior (Section S5, Supporting Information).53 As a
result of aggregation and solubility issues observed in pure
MeCN-d3 at concentrations greater than 0.25 mM, a mixed-
solvent system, 25% CD2Cl2 in MeCN-d3, was employed.
−
process to titration experiments with H2PO4 provides similar
residuals for both the 1:1 and 1:2 binding models, which is
indicative that a 1:2 binding model is not necessary to account
for the change in absorbance (Figure 3c,d). Thus, evidence
from UV/vis titration experiments indicates that phosphate
and arsenate undergo different binding events with Receptor 3
in acetonitrile (see Section S2 (Supporting Information) for
global fits of all titrations and three-dimensional (3D) plots of
residuals). Indeed, strong selectivity between arsenate and
−
A representative titration experiment with HCO3 is shown
in Figure 5. In all cases, the resonances corresponding to the
amide protons shift downfield with increasing equivalents of
D
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revealed a K1:1 that is greater than that measured in our UV/vis
titration experiments (log K1:1 ∼ 4.6), as well as a relatively
small K1:2 (log K1:2 ∼ 3.4, log β2 ∼ 8.1) (Figure S109). As
evidenced by our experiments with arsenate and bicarbonate,
the size of the binding site does not preclude the inclusion of
two anionic species, and it may be that the slightly less polar
solvent system induces further burying of the hydrophilic
−
surface area of H2PO4 , forming higher-order complexes.
Additionally, switching of the binding stoichiometry is not
uncommon upon changing the solvent polarity.64,68,69 Finally,
1H NMR titrations with CN− were inconsistent with our UV/
vis experiments, but we also observed a change in solution
color (colorless to orange), which may indicate some reaction
of cyanide with the receptor, complicating the binding model
(Figure S111). Such behavior was not observed at lower
concentrations in the case of the UV/vis experiment. See
Section S5.1 (Supporting Information) for further discussion
1
on the H NMR experiments.
The overall affinities of Receptor 3 with the anions surveyed
are surprisingly high. Although Receptor 1 demonstrates
relatively high affinity for NO3 and OAc− (log K1:1 ∼ 2.5
−
and 2.9 in 25% CD2Cl2 in MeCN-d3), the overall anion affinity
is significantly decreased compared to that of Receptor 3.43 We
speculate that this may be due to repulsive interactions
between the pyridine nitrogen and anionic guest. The sulfur
atom, on the other hand, is bent out of the plane of the amide
hydrogens, preventing such repulsive interactions, as observed
from the crystal structure and density functional theory
(DFT)-calculated geometry (Figures 2 and S169). Addition-
ally, modeling of Receptor 3 with either one or two molecules
of H2AsO4 or H2As2O7 indicated the formation of C−H
hydrogen-bonding interactions with the methyl groups on the
1,4-dithiin rings, which may enhance interactions with guests
(Figures S170−S172, Section S11, Supporting Information).
This increase in affinity is advantageous in that it could help to
overcome the large solvation energy of anions, allowing
binding in more polar solvents.
Figure 4. ESI-MS of Receptor 3 (95 μM) in the presence of 2 equiv
of TBAH2AsO4 in MeCN. The attached table shows the observed
masses and their assigned adducts.
anion, which is indicative of hydrogen-bonding interactions.
Interestingly, titration with TBAH2AsO4 resulted in exception-
ally broad receptor peaks, which may be a result of the
inclusion of quadrupolar nuclei (Figure S110). This may
implicate Receptor 3 as a probe for the presence of arsenate by
1H NMR. Due to the decreased solvent polarity, similar, but
−
2−
−
slightly higher, association constants were obtained for HSO4
(Figure S112) and NO3− (Figure S113). For experiments with
HCO3 , different values were obtained for K1:1 and K1:2 than
−
from UV/vis titration experiments, but data analysis indicated
the same binding stoichiometry and similar value for β2.
In the case of Cl−, a small K1:2 is observed (log K1:2 ∼ 1.0)
that may arise due to ion-pairing equilibria from both the
higher concentration and less polar solvent system employed
(Figure S114). 1H NMR titrations with OAc− provided a lower
association constant, but such activity is unsurprising given
It is important to note, however, that Receptor 1 was not
−
subjected to titration experiments with H2AsO4 , and its
−
−
binding selectivity for H2PO4 over H2AsO4 is unknown.
Most receptors that have been found to complex phosphate, in
fact, have not been tested with arsenate. Due to the
environmental and biological relevance of arsenate, we believe
that this anion should become a more standard guest in the
1
that OAc− has a K1:1 beyond the detection limit for H NMR
experiments (Figure S108).53 For H2PO4 , H NMR titration
−
1
1
Figure 5. (a) H NMR titration of Receptor 3 (1.02 mM) with TEAHCO3 in 25% CDCl2 in MeCN-d3 (the arrow indicates the resonance
associated with the amide proton), (b) assignment of protons in Receptor 3, and (c) derived changes in the chemical shift for nonamide hydrogens.
E
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Figure 6. Cyclic voltammograms of Receptor 3 with (a) no additive and varying equivalents of (b) TBAH2AsO4, (c) TEAHCO3, (d) TBAOAc, (e)
TBAH2PO4, (f) TBACN, (g) TBAHSO4, and (h) TBANO3. All measurements were performed in MeCN with 0.1 M TBAPF6, platinum working
(0.031 cm2) and counter electrodes, and Ag wire pseudoreference electrode at 100 mV/s and were referenced to the Fc/Fc+ redox couple.
characterization of supramolecular receptors to help establish
trends in arsenate−phosphate discrimination.
for effective dissolution. In comparison with model compound
S5, both are oxidized at similar potentials (3, E1/2 = 0.65 V vs
Fc/Fc+, S5, E1/2 = 0.71 V vs Fc/Fc+; Figure S125), but the
oxidation of Receptor 3 is kinetically slower, as indicated by
the larger shift in peak potential with the scan rate. To
determine the electron-transfer number for the oxidation of
Receptor 3, we performed chronoamperometry and cyclic
voltammetry with a microelectrode. Analysis of the data as
established by Amatore and co-workers indicated that the
oxidation event involved a degenerate or near-degenerate
transfer of three electrons (Section S7.2, Supporting
Information).70 Formation of a tricationic complex would
foster stronger interactions with guests via electrostatic
Electrochemical Characterization. 1,4-Dithiins, similar
to thianthrenes, are known to undergo a reversible, single-
electron oxidation under anhydrous conditions.42 As a result of
the proximity of the redox-active moiety to the binding site, as
well as the planarization of 1,4-dithiin moieties upon single-
electron oxidation, we hypothesized that the inclusion of
different anions could give rise to different electrochemical
responses, such as varying cathodic perturbations in the
observed E1/2 31 In a solution of 0.1 M TBAPF6 in MeCN, the
.
macrocycle undergoes a single quasi-reversible oxidation event
(Figures 6a and S124). Although Receptor 3 has limited
solubility in pure acetonitrile, the addition of TBAPF6 allows
F
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attraction, further enhancing the affinity of the oxidized
complex with each anion.
Table 2. Summary of Electrochemical Response toward
Various Anions
Next, the electrochemical behavior of Receptor 3 in the
presence of various anions was surveyed (Figure 6b−h). Due
to the relatively low oxidation potential of chloride (E1/2 = 0.52
V vs Fc/Fc+; Figure S132), it was excluded from this study.
Receptor 3 exhibits complex oxidation behavior for each
anionic guest, which we believe results from unique binding
behavior of the oxidized receptor, changes in the E1/2 and
electron-transfer kinetics upon complexation, and subsequent
reaction of the anion with Receptor 3 upon oxidation. Upon
a
b
anion
ΔEox (mV)
c
−
H2AsO4
−334
d
−
HCO3
OAc−
−235
−105
−480
−142
−118
−102
−
H2PO4
CN−
−
HSO4
−
NO3
Cl−
e
−
N/D
addition of NO3 , the oxidation wave shifts to less positive
a
b
Tetrabutylammonium salts were employed. Change in the peak
potential of the oxidation event upon the addition of 5 equiv of anion.
Two oxidation events are observed. The more cathodic peak is
reported here. Tetraethylammonium bicarbonate was employed.
potentials and becomes chemically irreversible (Figure 6h).
This can be rationalized by the oxidation of the tri-radical
cation by nitrate, a known behavior in thianthrene radical
c
d
cations.71 The addition of H2PO4 , H2AsO4 , HCO3 , CN−,
and OAc− gave irreversible redox couples as well, but analysis
of subsequent scans demonstrated varying degrees of
precipitation on the electrode surface (Figure 6b−f and
−
−
−
e
Not determined.
−
−
Section S7.4). In the case of H2PO4 (Figure S135), HCO3
constant with the oxidized receptor (Figure S173, Section S11,
Supporting Information). Interestingly, we found that
Receptor 3 exhibits a moderate association constant to the
supporting electrolyte, TBAPF6 (log K1:1 ∼ 3.7; Figures S130
and S131, Section S7.3, Supporting Information). In spite of
this, the addition of other anionic guests, even those with
comparable Ka, gave altered voltammograms. This may
indicate that binding occurs almost solely with the oxidized
host under the conditions for electrochemical measurements.
Finally, we found that after the addition of 5 equiv of
TBAHSO4, with a shift in E1/2 of 126 mV and a three-electron
process, a binding enhancement factor (BEF) of 2.5 × 106
could be estimated.31 Moreover, larger perturbations in the
peak potential of oxidation were observed with other anions,
but the lack of return waves precluded estimation of the BEFs.
Although the use of 1,4-dithiins as redox transducers may be
too sensitive for practical applications in the presence of
nucleophilic species, the incorporation of multiple redox-active
moieties adjacent to the binding site could give molecules with
sufficiently high ion affinities when oxidized to effectively bind
to anions in polar media.
(Figure S145), and CN− (Figure S139), the acquisition of
subsequent scans by cyclic voltammetry resulted in little signal,
indicating the formation of an insulating film on the electrode
−
surface. Subsequent scans, however, in the case of NO3
(Figure S141), H2AsO4 (Figure S137), and OAc− (Figure
−
S143) gave similar voltammograms but with lower current,
indicating that the fidelity of the electrode surface is
maintained, but that Receptor 3 proximate to the electrode
surface was consumed due to an irreversible chemical reaction
−
with the anionic guest. Finally, while HSO4 exhibited a
moderate association constant with the neutral receptor as
determined by UV/vis titrations, we found that the addition of
bisulfate caused dramatic changes in the shape of both the
oxidation and reduction waves while maintaining chemical
reversibility (Figures 6g and S133). Interestingly, in the case of
−
NO3 , “two-wave” behavior is observed (Figure 6h). Such
behavior is indicative of slow-exchange interactions and is
potentially useful in the differentiation of anions in a similar
fashion that has been described for slow host−guest exchange
in NMR studies.17 In other cases, such as H2AsO4 , H2PO4 ,
−
−
OAc−, HCO3 , and CN−, as many as three distinct oxidation
−
waves can be observed after the addition of various equivalents
of the anion (Figure 6b−f). Due to the irreversible nature of
these redox couples, exact analysis of the oxidation event is
difficult, and we abandoned further electrochemical experi-
ments due to the high reactivity of Receptor 3 in its oxidized
form. Additionally, more complex mechanisms, such as the loss
of degeneracy in the oxidation of Receptor 3 or the formation
of additional electroactive materials, may be at play, further
complicating the response.
The results of the electrochemical anion titrations are
summarized in Table 2. Although the magnitude of the change
in peak potential is similar to the more common strategy of
appending receptors with well-known redox transducers, such
as ferrocene, changes in the peak shape and degree of chemical
reversibility vary widely based on the identity of the anionic
guest. In our case, we also believe that the conformational
activity of the electroactive moiety may participate in
enhancing the response toward anions. Geometry of the triply
oxidized host, as generated from DFT calculations, indicates
that the planarization of the 1,4-dithiin moieties generates a
cationic binding site of unique size as compared to the neutral
receptor, which may aid in enhancing the change in association
CONCLUSIONS
■
In conclusion, we have synthesized and characterized an anion
receptor with novel 1,4-dithiin moieties. The receptor shows
high selectivity and affinity toward HCO3 and H2AsO4 ,
which were observed to bind in a 1:2 host/guest binding
mode. Additionally, H2AsO4 was found to undergo different
−
−
−
−
binding behavior with Receptor 3 than H2PO4 , an uncommon
characteristic given the two anions’ similar size and properties.
The origin of arsenate−phosphate discrimination, however, is
currently unknown. Further analysis by cyclic voltammetry
revealed unique responses upon the addition of anionic guests,
but due to the high reactivity of Receptor 3 when oxidized,
deconvolution of the response proved difficult in many cases.
Due to the interest in the detection and binding of arsenate
and the lack of effective strategies toward selective complex-
ation, we hope this report will encourage other researchers to
include this anion in their studies to help establish trends in
arsenate−phosphate discrimination. Future experiments in our
laboratory will involve the further synthesis and character-
ization of anion receptors with potential application in the
monitoring of environmentally relevant anion contaminants.
G
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supporting electrolyte. In the case that the oxidation was chemically
irreversible, which is the case with all anions except for TBAHSO4, the
first scan is reported. In the case of TBAHSO4, the third scan is
reported, which is similar to the first two scans.
ESI-MS Experiments. Electrospray ionization (ESI) binding
experiments were carried out on a JEOL Accu-TOF equipped with
an ESI source. All ions were observed in negative mode, with the
orifice and desolvating chambers held at 100 °C. The samples were
run via direct infusion at the specified concentration at a rate of 1.0
mL/h using a syringe pump. All experiments were run, holding the
host concentration at approximately 100 μM in acetonitrile.
Computational Studies. Theoretical calculations were carried
out with the Spartan’18 (1.4.4, Wave function Inc., Irvine CA)
software packages on a computer operating with Windows 10 OS.
Geometry optimizations were performed with density functional
theory (DFT) calculations using the B3LYP functional with the 6-
31G* basis set in the gas phase. Frequency calculations were
performed to confirm that the structures were at a local energy
minimum. Outputs were visualized with CYLview.72
EXPERIMENTAL SECTION
■
General Experimental Considerations. All reagents were
purchased from commercial sources and used without further
purification unless otherwise specified. Tetrabutylammonium dihy-
drogen arsenate was prepared according to a literature procedure.39
Anhydrous tetrahydrofuran (THF) and dichloromethane (CH2Cl2)
were purified using an Inert solvent purification system by passage
through two alumina columns and were stored in a Schlenk flask over
4 Å molecular sieves under an argon atmosphere. Tetrabutylammo-
nium hexafluorophosphate for electrochemical analysis was recrystal-
lized from EtOH three times and dried in a vacuum oven at 60 °C. All
chemical manipulations were performed under an argon atmosphere
in flame-dried glassware unless otherwise specified. The reported
reaction temperatures refer to the temperature of external water or oil
baths.
Chromatographic purifications were performed with a Biotage
Isolera using Biotage SNAP Ultra columns with the specified solvent
gradient. Typically, columns were performed with 1 column volume
of the initial solvent gradient, followed by a linear gradient over 10
column volumes to the final solvent composition, followed by an
additional 2 column volumes at the final solvent composition.
NMR spectra were recorded on either a 400 MHz Bruker Avance-
III HD Nanobay spectrometer, 500 MHz Bruker Avance Neo
spectrometer, or 600 MHz Bruker Avance Neo spectrometer.
Chemical shifts δ are reported in parts per million (ppm) downfield
from tetramethylsilane by referencing to residual solvent signals
(CDCl3: δ 1H 7.26 ppm, δ 13C 77.16 ppm; dimethyl sulfoxide
(DMSO)-d6: δ 1H 2.50 ppm, δ 13C 39.52 ppm; CD3CN: δ 1H 1.94, δ
13C 118.26). Coupling constants J are listed in hertz (Hz) with
multiplicities s (singlet), d (doublet), t (triplet), q (quartet), and m
(multiplet). Mass spectra were obtained on a JEOL Accu-TOF system
equipped with either a direct analysis in real time (DART) (DART-
MS) or ESI (ESI-MS) source or an Agilent 6545 quadrupole time-of-
flight (Q-TOF) equipped with an AJS-ESI (Q-TOF-ESI-MS) source.
Titration Experiments. All UV/vis titrations were carried out on
an Agilent Cary-4000 UV/vis spectrometer, recording from 500 to
200 nm at intervals of 0.5 nm. Tetrabutylammonium salts were stored
in a vacuum desiccator prior to titration. UV/vis titrations were
carried out in HPLC-grade MeCN in 1 cm cuvettes at the specified
host concentration. Host concentration was determined using the
Beer’s law absorbance of Receptor 3 at 292 nm, which is linearly
correlated with concentration (Figures S3, S4). Anionic guests were
dissolved in a solution of the host to keep the host concentration
constant over the course of the experiment. Guests were added using
either 10 or 50 μL syringes (Hamilton), followed by manual agitation
for 5−10 s. Association constants were then determined using SIVVU
with absorbance data from 275 to 500 nm.
Synthetic Procedures. Diethyl 2,2′-Thiobis(3-oxobutanoate)
(5). Caution: This reaction produces stoichiometric amounts of HCl
gas and must be performed in a fume hood or similarly well-vented
area. The title compound was prepared according to a modified
literature procedure.45 To a round-bottom flask open to the
atmosphere, ethyl acetoacetate (4) (10.0 mL, 78.5 mmol, 1.0
equiv) and hexanes (16 mL) were added. The mixture was then
heated to 40 °C, upon which the solution became homogeneous.
Disulfur dichloride (3.14 mL, 39.2 mmol, 0.5 equiv) was then added
in one portion. After 1−2 min, the solution developed a yellow color
and began to bubble vigorously. After the bubbling had subsided, the
solution was allowed to react for a further 30 min, over which a solid
precipitated. The reaction was then cooled in an ice bath, and the
white solid was collected by vacuum filtration, washed first with
hexanes and then water, and subsequently dried under vacuum at 50
°C to remove residual water. The solid was purified by
recrystallization in acetone (25 mL) to give the target compound as
1
colorless needles (4.59 g, 15.8 mmol, 40%). H NMR (500 MHz,
CDCl3) δ 13.40 (s, 2H), 4.23 (q, J = 7.1 Hz, 4H), 2.42 (s, 6H), 1.30
(t, J = 7.1 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 181.4,
172.9, 95.1, 61.4, 21.1, 14.3. HRMS (DART-MS) m/z: [M + H]+
calcd for C12H19O6S+ 291.0897; found 291.0900.
Diethyl 3,5-Dimethyl-1,4-dithiine-2,6-dicarboxylate (7). THF (50
mL) was added to a round-bottom flask containing sodium hydride
(3.31 g, 60% dispersion in mineral oil, 82.8 mmol, 3.0 equiv). The
mixture was cooled to 0 °C, and compound 5 (8.0 g, 27.6 mmol, 1.0
equiv) was added as a solution in THF (125 mL) via cannula transfer
over approximately 10 min, resulting in the evolution of H2 gas. After
completion of the addition, the mixture was allowed to stir for a
further 30 min at 0 °C, after which tosyl anhydride (19.8 g, 60.7
mmol, 2.2 equiv) was added as a solution in THF (150 mL) via
cannula transfer over approximately 10 min, during which the reaction
mixture became viscous. The reaction was then allowed to warm to
room temperature. After conversion was complete, as judged by TLC
(approximately 3 h), the reaction was quenched slowly with the
addition of water (20 mL) and then 4 M HCl (20 mL). The reaction
was concentrated under reduced pressure to a total volume of about
100 mL. The resulting mixture was then extracted with diethyl ether
(3 × 100 mL), and then the organic layers were combined, washed
with saturated NaHCO3 (100 mL) and brine (100 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure to give
approximately 15 g of a red oil containing compound 6 as a mixture of
isomers. The mixture was used without purification in the next step.
The red oil was dissolved in EtOH (125 mL), and sodium sulfide
nonahydrate (4.96 g, 20.7 mmol, 0.75 equiv) was added in one
portion, resulting in the appearance of an orange solution and the
precipitation of a solid. After 1.5 h, CH2Cl2 (125 mL) was added to
further precipitate additional salts, and the mixture was filtered
through a bed of celite, and the volatiles were removed under reduced
pressure. The dark oil was then purified by flash chromatography (1
→ 15% EtOAc in hexanes) to give the title compound as an orange oil
1H NMR titrations were performed in 25% CD2Cl2 in CD3CN.
Anionic guests were dissolved in a solution of the host to keep the
host concentration constant over the course of the titration. Solutions
of the anion were added in 5 or 25 μL aliquots using either 10 or 50
μL syringes (Hamilton) followed by manual agitation for 10−15 s
followed by immediate measurement by H NMR at the specified
field. In all cases, the spectra were referenced to residual CDHCl2 (δ =
5.32 ppm).
Electrochemical Experiments. Electrochemical experiments
were performed in a nitrogen-filled glovebox (O2 < 20 ppm, H2O <
2 ppm) with a BioLogic SP-150 potentiostat. Platinum working
electrodes (2 mm or 10 μm diameter) were polished using first
suspensions of 1.0 μm, then 0.3 μm, then 0.05 μm alumina in water
on a polishing pad followed by sonication in methanol to remove
excess alumina and then chemical polishing by cycling the electrode in
1 M H2SO4 over the potential window of water until the resulting
traces overlapped. The electrode was then rinsed with methanol and
blown-dry with nitrogen before being transferred into the glovebox. A
platinum wire was used as the counter electrode. A silver
pseudoreference electrode was used, and all measurements were
referenced to Fc/Fc+. All titration experiments were performed at 1.0
mM of the active material in MeCN, with 0.1 M TBAPF6 as a
1
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1
that solidifies upon storage at 2−5 °C (5.08 g, 17.6 mmol, 64%). H
NMR (400 MHz, CDCl3) δ 4.25 (q, J = 7.1 Hz, 4H), 2.41 (s, 6H),
1.32 (t, J = 7.2 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.9,
149.6, 122.3, 61.9, 22.7, 14.3. HRMS (DART-MS) m/z: [M + H]+
with hydrogen five times. The reaction was purged with hydrogen
several times until conversion was complete as observed by H NMR
1
(typically 3 days). After the reaction was complete, the reaction
mixture was filtered through a pad of celite. The filtrate was then
concentrated under reduced pressure, giving the title compound as a
pink solid (10.5 g, 42.1 mmol, >95%). 1H and 13C NMR spectra were
consistent with those reported in the literature.75 1H NMR (500
MHz, CDCl3) δ 3.87 (s, 6H), 2.82 (q, J = 7.5 Hz, 6H), 1.37 (s, 6H),
1.23 (t, J = 7.5 Hz, 9H). 13C{1H} NMR (126 MHz, CDCl3) δ 140.5,
137.6, 39.8, 22.7, 16.9.
+
calcd for C12H17O4S2 289.0563; found 289.0558.
3,5-Dimethyl-1,4-dithiine-2,6-dicarboxylic Acid (8). Potassium
hydroxide (85%, 2.90 g, 44.0 mmol, 2.5 equiv) pellets were crushed
using a mortar and pestle and then dissolved in EtOH (35 mL). The
ethanolic KOH was then added to compound 7 (5.08 g, 17.6 mmol,
1.0 equiv) in one portion, and the mixture was then heated to 50 °C
with strong stirring. Within 10 min, a solid had precipitated. The
reaction was allowed to proceed for a further 1.5 h, after which the
mixture was cooled to 0 °C. The solid was collected by filtration,
washed several times with EtOH, and then dissolved in water (50
mL). The product was precipitated with the addition of 4 M HCl
until the solution had a pH < 1. The product was collected by
filtration, washed with water, and dried at 60 °C under vacuum to give
the title compound as a light orange powder (2.43 g, 10.5 mmol,
60%). 1H NMR (500 MHz, DMSO-d6) δ 13.43 (s, 2H), 2.34 (s, 6H).
13C{1H} NMR (126 MHz, DMSO-d6) δ 163.7, 146.9, 123.0, 22.1.
Di-tert-butyl ((5-((((Benzyloxy)carbonyl)amino)methyl)-2,4,6-
triethyl-1,3-phenylene)bis(methylene))dicarbamate (S4). The title
compound was prepared according to a modified literature
procedure.46 Compound 10 (4.00 g, 16.0 mmol, 1.0 equiv) and
sodium hydroxide (960 mg, 24.0 mmol, 1.5 equiv) were added to a
round-bottom flask and dissolved in dioxane (80 mL) and water (80
mL), and the solution was cooled to 0 °C. Benzylchloroformate (3.87
mL, 27.2 mmol, 1.7 equiv) and di-tert-butyl dicarbonate (11.0 g, 50.5
mmol, 3.15 equiv) were dissolved in a minimal amount of dioxane to
give a total volume of 20 mL and added over 4 h via a syringe pump.
After the addition was complete, the reaction was allowed to come to
room temperature and stirred for a further 2 h. The dioxane was then
removed under reduced pressure, and the resulting aqueous layer was
extracted with CH2Cl2 (3 × 50 mL). The organic layers were
combined, washed with brine (100 mL), filtered, and concentrated
under reduced pressure to give an orange oil, which is then purified by
flash chromatography (5 → 30% EtOAc in hexanes with 1% v/v
Et3N) to give the title compound as a white solid (2.42 g, 4.14 mmol,
−
HRMS (Q-TOF-ESI-MS) m/z: [M − H]− calcd for C8H7O4S2
230.9791; found 230.9793.
3,5-Dimethyl-1,4-dithiine-2,6-dicarbonyl Dichloride (9). General
Procedure. A round-bottom flask was charged with compound 8 (1.0
equiv) and CH2Cl2 (0.2 M), giving a suspension. DMF (one to two
drops) and oxalyl chloride (2.5 equiv) were then added, resulting in
the evolution of gas. After 2 h, the solution became homogeneous,
and the volatiles were removed under reduced pressure, giving an
orange solid. For all transformations, the conversion of diacid to acyl
chloride was assumed to be quantitative. Diacyl chloride 9 was
1
26%). H and 13C NMR spectra were consistent with those reported
in the literature.46 1H NMR (500 MHz, DMSO-d6) δ 7.40−7.24 (m,
5H), 7.16 (t, J = 4.8 Hz, 1H), 6.53 (t, J = 4.8 Hz, 2H), 5.04 (s, 2H),
4.25 (d, J = 4.9 Hz, 2H), 4.18 (d, J = 4.9 Hz, 2H), 2.72−2.61 (m,
6H), 1.38 (s, 18H), 1.05 (t, J = 7.4 Hz, 9H). 13C{1H} NMR (126
MHz, DMSO-d6) δ 155.8, 155.2, 143.0, 142.7, 137.2, 132.2, 131.80,
128.3, 127.7, 127.6, 77.7, 65.3, 38.7, 38.1, 28.3, 22.5, 22.4, 16.2, 16.1.
Di-tert-butyl ((5-(Aminomethyl)-2,4,6-triethyl-1,3-phenylene)bis-
(methylene)) Dicarbamate (11). The title compound was prepared
according to a modified literature procedure.46 A round-bottom flask
was charged with 5% palladium on carbon (172 mg) and MeOH (40
mL). The reaction vessel was then evacuated and refilled with
hydrogen five times. A solution of compound S4 (2.27 g, 3.89 mmol,
1.0 equiv) in MeOH (40 mL) was added, and the vessel was then
evacuated and refilled with hydrogen five times. The reaction was
repeatedly purged with hydrogen until conversion was complete, as
observed by 1H NMR (around 2.5 h). After the reaction was
complete, the reaction was filtered through a pad of celite. The filtrate
was then concentrated under reduced pressure, giving the title
1
prepared from diacid 8 directly when needed. H NMR (500 MHz,
CDCl3) δ 2.46 (s, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 163.0,
156.9, 125.3, 23.3.
1,3,5-Tris(bromomethyl)-2,4,6-triethylbenzene (S2). The title
compound was prepared in accordance with a literature procedure.73
1,3,5-Triethylbenzene (S1) (10.0 mL, 53.1 mmol, 1.00 equiv) and
paraformaldehyde (16.8 g, 560 mmol, 10 equiv) were dissolved in a
solution of 30% HBr in HOAc (100 mL). Zinc bromide (19.8 g, 87.8
mmol, 1.65 equiv) was added, and the reaction was then brought to
90 °C and stirred overnight. The mixture was cooled to room
temperature, and the solid was collected by vacuum filtration and
washed with water to give the title compound as an off-white powder
1
(21.1 g, 47.8, 90%). H and 13C NMR spectra were consistent with
those reported in the literature.73 1H NMR (500 MHz,CDCl3) δ 4.58
(s, 6H), 2.95 (q, J = 7.6 Hz, 6H), 1.34 (t, J = 7.6 Hz, 9H). 13C{1H}
NMR (126 MHz, CDCl3) δ 145.2, 132.8, 28.7, 22.9, 15.8.
1,3,5-Tris(azidomethyl)-2,4,6-triethylbenzene (S3). Caution:
Azides are potentially explosive. While we never experienced any
explosions with the title compound, appropriate hazards should be
observed when preparing and working with it. The title compound
was prepared according to a modified literature procedure.74
Compound S2 (21.1 g, 47.8 mmol, 1.0 equiv) was dissolved in
DMF (100 mL). Sodium azide (10.3 g, 158 mmol, 3.3 equiv) was
then added in one portion, and the solution became homogeneous
over the course of 10 min. After 2 days, water (50 mL) was added,
and the mixture was extracted with Et2O (3 × 100 mL). The organic
layers were combined, washed with water (4 × 50 mL) and brine
(100 mL), dried with MgSO4, filtered, and concentrated under
reduced pressure to give the title compound as a white powder (14.8
1
compound as a white solid (1.75 g, 3.89 mmol, quant.). H and 13C
NMR spectra were consistent with those reported in the literature.46
1H NMR (500 MHz, DMSO-d6) δ 6.61 (t, J = 4.8 Hz, 2H), 4.17 (d, J
= 4.8 Hz, 4H), 3.70 (s, 2H), 2.71 (q, J = 7.5 Hz, 4H), 2.64 (q, J = 7.5
Hz, 2H), 1.38 (s, 18H), 1.10 (t, J = 7.5 Hz, 6H), 1.06 (t, J = 7.3 Hz,
3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 155.2, 141.9, 141.8,
136.9, 132.0, 77.6, 38.2, 28.3, 22.4, 22.1, 16.5, 16.3.
Tetra-tert-butyl (((((3,5-Dimethyl-1,4-dithiine-2,6-dicarbonyl)bis-
(azanediyl))bis(methylene))bis(2,4,6-triethylbenzene-5,1,3-triyl))-
tetrakis(methylene))tetracarbamate (12). A round-bottom flask
containing compound 11 (1.75 g, 3.89 mmol, 2.1 equiv) and
triethylamine (0.65 mL, 4.6 mmol, 2.5 equiv) in CH2Cl2 (10 mL) was
cooled to 0 °C. In a separate flask, diacyl chloride 9 that was freshly
prepared from diacid 8 (430 mg, 1.85 mmol, 1.0 equiv) was dissolved
in CH2Cl2 (10 mL) and added dropwise to the solution of compound
11. After the addition was complete, the reaction was allowed to come
to room temperature and was stirred overnight. The solution was then
poured into 1 M HCl (40 mL), and the layers were separated. The
aqueous layer was further extracted with CH2Cl2 (2 × 40 mL), and
the organic layers were combined, washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure to give an
orange residue, which was purified by flash chromatography (0 → 3%
MeOH in CH2Cl2) to give the title compound as an orange solid
1
g, 45.2 mmol, 95%). H and 13C NMR spectra were consistent with
those reported in the literature.74 1H NMR (400 MHz, CDCl3) δ 4.49
(s, 6H), 2.85 (q, J = 7.6 Hz, 6H), 1.24 (t, J = 7.6 Hz, 9H). 13C{1H}
NMR (101 MHz, CDCl3) δ 145.1, 130.1, 48.1, 23.3, 15.9.
(2,4,6-Triethylbenzene-1,3,5-triyl)trimethanamine (10). The title
compound was prepared according to a modified literature
procedure.75 A round-bottom flask was charged with 5% palladium
on carbon (1.07 g) and MeOH (100 mL). The reaction vessel was
then evacuated and refilled with hydrogen five times. A suspension of
compound S3 (14.8 g, 45.2 mmol, 1.0 equiv) in MeOH (100 mL)
was added, and the vessel was subsequently evacuated and refilled
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(1.62 g, 1.48 mmol, 80%). 1H NMR (500 MHz, MeCN-d3) δ 6.62 (t,
J = 4.8 Hz, 2H), 5.18 (s, 4H), 4.43 (d, J = 4.8 Hz, 4H), 4.29 (d, J =
5.0 Hz, 8H), 2.74 (q, J = 7.5 Hz, 4H), 2.69 (q, J = 7.5 Hz, 8H), 2.26
(s, 6H), 1.41 (s, 36H), 1.15 (t, J = 7.4 Hz, 6H), 1.10 (t, J = 7.4 Hz,
12H). 13C{1H} NMR (126 MHz, MeCN-d3) δ 164.0, 156.5, 144.8,
144.5, 133.7, 132.3, 125.1, 79.4, 39.4, 39.0, 28.6, 23.6, 21.9, 16.6.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01206.
■
sı
Synthesis of starting materials, binding characterization,
electrochemical characterization, computational studies,
and NMR spectra (PDF)
Coordinates from computational studies (PDF)
Crystallographic data for Receptor 3 in CIF format
(CIF)
+
HRMS (Q-TOF-ESI-MS) m/z: [M + H]+ calcd for C58H91N6O10S2
1095.6233; found 1095.6210.
N2,N6-Bis(3,5-bis(aminomethyl)-2,4,6-triethylbenzyl)-3,5-dimeth-
yl-1,4-dithiine-2,6-dicarboxamide·4HCl (13). Compound 12 (1.553
g, 1.42 mmol, 1.0 equiv) was dissolved in 4 M HCl in dioxane (12
mL), resulting in the formation of an orange precipitate. The reaction
was allowed to stir for 2 h, after which isopropanol was added to
dissolve all materials, and the volatiles were removed under reduced
pressure, giving the title compound as a light orange powder (1.18 g,
AUTHOR INFORMATION
Corresponding Author
■
1
1.40 mmol, 98%). H NMR (600 MHz, DMSO-d6) δ 8.40 (s, 12H),
Timothy M. Swager − Department of Chemistry, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139,
United States; orcid.org/0000-0002-3577-0510;
Email: tswager@mit.edu
8.30 (t, J = 4.9 Hz, 2H), 4.39 (d, J = 4.5 Hz, 4H), 4.03 (s, 8H), 2.78
(q, J = 6.9 Hz, 12H), 2.14 (s, 6H), 1.11 (t, J = 7.3 Hz, 18H). 13C{1H}
NMR (151 MHz, DMSO-d6) δ 163.3, 145.3, 144.4, 139.3, 132.3,
128.8, 125.0, 37.5, 36.0, 23.2, 22.8, 21.6, 15.9, 15.9. HRMS (Q-TOF-
+
ESI-MS) m/z: [M + H]+ calcd for C38H59N6O2S2 695.4135; found
Authors
695.4135.
Samuel I. Etkind − Department of Chemistry, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139,
United States; orcid.org/0000-0002-9596-4616
Douglas A. Vander Griend − Department of Chemistry and
Biochemistry, Calvin University, Grand Rapids, Michigan
49546, United States; orcid.org/0000-0002-8828-1112
Receptor 3. In a 1 L round-bottom flask, compound 13 (400 mg,
0.476 mmol, 1.0 equiv) was dissolved in CHCl3 (300 mL) and
triethylamine (0.67 mL, 4.8 mmol, 10 equiv), and the mixture was
brought to 45 °C. Diacyl chloride 9 was prepared according to the
general procedure using diacid 8 (221 mg, 0.951 mmol, 2.0 equiv)
and was then dissolved in CHCl3 (25 mL) and taken up into a glass
syringe. Diacyl chloride 9 was added to the reaction mixture over 8 h
via a syringe pump. After the addition was complete, the reaction was
stirred for a further 20 h and was then allowed to cool to room
temperature. The volume of the reaction was reduced to
approximately 50 mL under reduced pressure, and the solution was
washed with 1 M HCl (50 mL). The aqueous layer was then extracted
with CH2Cl2 (2 × 50 mL), and the organic layers were combined and
washed with 10% NaOH (100 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure to give an orange solid. The
residue was then purified by flash chromatography (15 → 25%
acetone in PhMe, then 0 → 100% EtOAc in hexanes) to give the title
compound as a solvate. To remove the residual solvent, the
compound was sonicated in PhMe (5 mL), and the PhMe was
removed under reduced pressure. This procedure was repeated five
times to give the title compound as a pale yellow solid (104 mg,
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01206
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the U.S. Army Engineer Research
and Development Center Environmental Quality Technology
Program under contract W912HZ-17-2-0027 and the National
Science Foundation through the Division of Chemistry
(2004005). The authors are also grateful to the Camille and
Henry Dreyfus Foundation for supporting D. Vander Griend as
a Henry Dreyfus Teacher-Scholar. The authors would like to
thank Drs. B. Qiao and N. A. Romero for their insightful
comments and discussions.
1
0.0956 mmol, 20%). H NMR (600 MHz, CDCl3) δ 6.22 (t, J = 4.8
Hz, 6H), 4.53 (d, J = 4.9 Hz, 12H), 2.66 (q, J = 7.5 Hz, 12H), 2.59 (s,
18H), 1.21 (t, J = 7.5 Hz, 18H). 13C{1H} NMR (151 MHz, CDCl3) δ
162.6, 149.6, 145.6, 131.7, 119.7, 39.0, 23.6, 23.4, 15.9. HRMS (ESI-
−
MS) m/z: [M + H]+ calcd for C54H65N6O6S6 1085.3295; found
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