Recognition, encapsulation, and selective fluorescence sensing of nitrate anion by neutral C 3-symmetric tripodal podands bearing amide functionality

Article abstract of DOI:10.1021/jo202502f

A series of neutral C₃-symmetric acyclic artificial receptors incorporating amide functionality has been designed, synthesized, and fully characterized. Upon protonation, these conformationally flexible N-bridged tripodal podands 1-5 form in situ cone shape conformation through hydrogen bonding and C-H???π interactions. The protonation-induced interior preorganized cavity is capable of entrapping nitrate anions through the amide N-H bonds to form discrete nitrate complexes (1a-5a), which were fully characterized by NMR, HRESI mass spectra, and single crystal structures. By incorporating suitable fluorophores at each branch of the tripod receptor, the resulting fluorescent receptor 5 selectively recognized nitrate anions by fluorescent quenching in a DMSO solution and displayed one of the highest binding affinities for nitrate anions reported so far in polar media. Receptor 5 represents a unique example of a neutral receptor for the recognition of nitrate anions in polar solvent media by its zwitterionic form. The possible mechanism of proton-induced preorganization of these flexible, acyclic receptors in a convergent cone conformation followed by nitrate complexation has been proposed to rationalize the effective nitrate recognition.

Full text of DOI:10.1021/jo202502f

Article
pubs.acs.org/joc
Recognition, Encapsulation, and Selective Fluorescence Sensing of
Nitrate Anion by Neutral C3-Symmetric Tripodal Podands Bearing
Amide Functionality
Ashutosh S. Singh and Shih-Sheng Sun*
Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan, Republic of China
S
* Supporting Information
ABSTRACT: A series of neutral C3-symmetric acyclic artificial receptors incorporating amide functionality has been designed,
synthesized, and fully characterized. Upon protonation, these conformationally flexible N-bridged tripodal podands 1−5 form in
situ cone shape conformation through hydrogen bonding and C−H···π interactions. The protonation-induced interior
preorganized cavity is capable of entrapping nitrate anions through the amide N−H bonds to form discrete nitrate complexes
(1a−5a), which were fully characterized by NMR, HRESI mass spectra, and single crystal structures. By incorporating suitable
fluorophores at each branch of the tripod receptor, the resulting fluorescent receptor 5 selectively recognized nitrate anions by
fluorescent quenching in a DMSO solution and displayed one of the highest binding affinities for nitrate anions reported so far in
polar media. Receptor 5 represents a unique example of a neutral receptor for the recognition of nitrate anions in polar solvent
media by its zwitterionic form. The possible mechanism of proton-induced preorganization of these flexible, acyclic receptors in a
convergent cone conformation followed by nitrate complexation has been proposed to rationalize the effective nitrate
recognition.
hydrogen bonds determine the strength of the resulting
hydrogen-bonding interaction between a receptor and an
anion. In general, an acyclic receptor without specific
complementary structure favors to interact with basic anions
via hydrogen-bonding interactions or, in some extreme cases,
neat proton transfer process.7 Inspired by biological processes
of anion recognition and transporting via amide functionality,8
many artificial receptors incorporating amide functional groups
have been reported.1c,2 Selective recognition of an anionic
substrate in the biological process occurs in a specific
hydrophobic recognition environment with complementary
induced-fit conformation, and thus, free energy lost on the
dehydration of anions upon binding is compensated by
interaction of anions with available binding sites.9 The lack of
such unique binding nature in a typical artificial system renders
selective recognition of weakly coordinating anions like nitrate
anions a highly challenging task.
INTRODUCTION
■
Selective recognition and sensing of anions by artificial
receptors are of paramount significance in chemistry, biology,
environmental science, and biomedical applications.1 Develop-
ing effective probes for nitrate recognition and sensing is highly
desirable because of its multiple sources of contamination from
nuclear waste, industrial sewage, acid rain, fertilizers, and
chemicals disposals. Because of the high hydration energy
(ΔGhyd = −300 kJ mol−1), large ionic radii (196 pm),1a and
weak basicity of nitrate anions that result in low affinity for
hydrogen-bonding interactions, it is particularly challenging to
design artificial receptors with appropriately matched comple-
mentary recognition motifs for weakly coordinating nitrate
anions. To overcome the solvation effect, attempts have been
made by using cage-typed receptors possessing a confined
interior cavity for binding nitrate anions, and their selectivities
are typically marginal in polar solvents such as DMSO.2a,d,3
Thus, the design of receptors with straightforward synthetic
procedures to achieve selective and effective recognition for
nitrate anions is highly desirable.
A variety of organic scaffolds and functional groups
containing hydrogen-bond donors have been utilized for
anion recognition, such as hydrazones,10 amides,2,11 sulfona-
Hydrogen-bonding interaction plays a crucial role in the
anion recognition process.4 The relative orientation5 and the
polarity6 of hydrogen bonds as well as the numbers of available
Received: December 6, 2011
Published: January 22, 2012
© 2012 American Chemical Society
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mides,4,12 thioamides,13 pyrroles,14 imidazolium cations,15
ureas,16 thioureas,17 and guanidinium and amidinium cati-
ons.17a,18 For weakly coordinating nitrate anions with large
hydration shells, however, even these hydrogen-bond donors
alone are sometimes not sufficient for effective binding of
nitrate anions, especially in a solution medium.2c,19 Thus, a
combination of electrostatic and hydrogen-bonding interactions
imparted on the receptor moiety would be an appropriate
choice for the selective recognition of weakly coordinating
nitrate anions.
In our previous report, we have demonstrated the halide
functionality-dependent properties on the formation of
molecular receptors.20 We have also shown the reversible
binding of perchlorate anions by a structurally simple tripodal
podand. However, the driving force for the formation of such a
perchlorate-encapsulated dimer was mainly electrostatic inter-
actions and solid-state packing effects, and thus no particular
selectivity can be expected. In the present case, we have further
elaborated the tripodal receptors by incorporating interior
amide functionality with halide groups at the end of each
tripodal arm. An elegant example reported by Moyer’s group
suggested that a C3 symmetric arrangement of the amide
functionality is required for the effective binding of nitrate
anions.21 Amide N−H bonds are well-known to interact with
anions in both natural8 and artificial systems,1c,2,11b whereas the
halide group is expected to increase the amide N−H
polarizability via an inductive effect. We herein report a series
of highly flexible, acyclic molecular receptors 1−4 (see Scheme
1), which converge to form a cone shape conformation upon
aqueous DMSO solution. Here, the dansyl moiety serves two
functions: (i) the ionization of sulfonic acid in the dansyl
moiety helps receptor 5 transform to a cone shape
conformation in polar solvents and (ii) the rotation of the
dansyl moiety in receptor 5 around C−N bond would create a
different steric environment to the in situ formed cavity by
tripodal branches from those receptors 1−4. These two special
features of receptor 5 in its neutral form make it possible to
recognize and encapsulate nitrate anions selectively in a highly
polar aqueous DMSO solution. The crystal structures of nitrate
complexes 2a, 3a, and 4a further imply that apart from the
flexibility of the receptors, the directionality of hydrogen bonds
is equally significant for the selective recognition of weakly
coordinating oxyanions such as the nitrate anion.
RESULTS AND DISCUSSION
Synthesis and Solid State Studies. Scheme 2 summaries
the synthetic procedures for the tripodal receptors 1−5. They
■
Scheme 2. Synthetic Procedures for Receptors 1−5
Scheme 1. Schematic Representation of Receptors (Top)
and Topographical Representations of Their Nitrate
a
Complexes (Bottom)
(a) SOCl2, CHCl3, 92%. (b) p-OH-C6H4COOMe, KOH, DMSO,
78%. (c) 5 N NaOH, MeOH, dil HCl, 92%. (d) SOCl2, DCM, DMF
(cat.). (e) p-X-C6H4NH2, DCM, Et3N, 70%. (f) 5-aminonaphthalene-
1-sulfonic acid, THF, Et3N, 65%.
were synthesized from previously reported tris(2-chloroethyl)-
amine hydrochloride22 (A) by simple SN2 substitution with 4-
hydroxymethylbenzoate in DMSO followed by basic hydrolysis
to yield corresponding triacid (C). Conversion of the tracids
(C) to their corresponding acyl chlorides followed by
condensation reaction with 4-haloamines produced desired
receptors 1−5 in 65−95% yields. The nitrate complexes (1a−
5a) were prepared in 85−97% yields by dropwise addition of
10% nitric acid in aqueous methanol to the suspension of
receptors in a mixture of methanol and chloroform at room
temperature. When a suspension of receptors 1−5 in a mixture
of MeOH and CHCl3 was treated with dilute 10% nitric acid in
aqueous MeOH, the solution mixture immediately became
transparent and homogeneous. Precipitation of nitrate
complexes 2a−5a started to appear after stirring the solution
mixture for 5−10 min. The rate of precipitation depends upon
the ratio of CHCl3 and MeOH in solution mixture, which was
a
The branches of each receptor in the nitrate complex lie on the apex
of equilateral triangle.
protonation that recognizes and reversibly binds nitrate anions
by a combination of electrostatic and H-bonding interactions to
form robust nitrate complexes 1a−4a.
In addition, incorporation of fluorescent dansyl groups to the
tripodal framework effectively converts the tripodal receptor to
a selective fluorescent nitrate anion probe (receptor 5) in an
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Figure 1. Crystal structures of nitrate complexes 2a (left), 3a (middle), and 4a (right). (a−c) Formation of a discrete unit and (d−f) cavity formed
by cooperative hydrogen-bonding interactions between the protonated centrally bridged N-atom and O-atom of aliphatic arm and C−H···π
interactions among the C-terminal aromatic rings. The nitrate anions were removed for clarity, and (g−i) branches of the tripod lie at the apex of
equilateral triangle. All hydrogen atoms have been deleted for clarity except for those interacting with the nitrate anions and showing C−H···π
interactions.
speeded up by increasing the ratio of MeOH in solution. The
nitrate complex 1a was obtained after slow evaporation of the
solution mixture over a period of one week. Alternatively, the
nitrate complexes can also be prepared from other solvent
mixtures such as MeOH/CH2Cl2, MeOH/CCl4, EtOH/
three structures 2a, 3a, and 4a are C3-symmetric, and the halide
atoms of these complexes lie at the apex of isosceles (Figure
1g−i). The bridge N-atoms of the nitrate complexes are
protonated, and the O-atoms of each aliphatic branch are equal
distances from centrally bridged N-atoms, indicative of
hydrogen-bonding interactions between the proton attached
to central N-atom and O-atoms of each aliphatic branch. The
closest distance between the centrally bridged N-atom and O-
atoms of each aliphatic branch is 2.710 Å for 2a, 2.719 Å for 3a,
and 2.718 Å for 4a, respectively (Figure 1d−f).
One ortho hydrogen atom of the C-terminal aromatic ring of
each branches are connected to C-terminal aromatic ring of
neighboring arm through C−H···π interactions (Figure 1d−f)
in a tilted edge-to-face form.23 The amide N−H bonds of each
branch protrude inside toward center in plane with the nitrate
anion (Figure 1a−c). The interatomic distances between the
receptor and nitrate anions of three nitrate complexes are
summarized in Table S1 (see the Supporting Information). The
nitrate anion is bound inside the cavity by strong H-bonds
between O-atoms of the nitrate anion and three amide N−H
protons (dN−H···O 2.21 Å, θN−H···O 156.88° for 2a, dN−H···O 2.09
Å, θN−H···O 169.35° for 3a, and dN−H···O 2.21 Å, θN−H···O 154.10°
for 4a, respectively). The data are in agreement with the
reported examples.24 The crystal structure of nitrate anion
encapsulated complex through amide functional group by
organic compound is rare.3d,24 An interesting example of nitrate
anion recognition in both solid and solution state by amide-
based ditopic receptor has been reported by Smith’s group,
t
CHCl3, and BuOH/CHCl3. The identity of receptors and
their corresponding nitrate complexes have been fully
characterized by NMR and high-resolution electrospray mass
spectrometry (HRESIMS). Nitrate complexes 2a−4a were
further characterized by single crystal structures. The single
crystals of 2a, 3a, and 4a with suitable sizes for X-ray diffraction
studies were grown by slow diffusion of chloroform to a
methanolic solution of complex 2a and 3a and slow evaporation
of a THF solution of complex 4a, respectively. The formation
of nitrate salts in current cases that can be crystallized and
examined by X-ray diffraction represents an interesting concept
for the anion recognition.
The crystallographic data and parameters for structure
refinements of crystals 2a, 3a, and 4a are collected in Table
S1 and selective bond distances and bond angles are
summarized in Table S2 (see the Supporting Information).
The homogeneous nature of crystals for these nitrate
complexes was confirmed by powder X-ray diffraction studies.
Figure 1 illustrates the crystal structures and important
structural characteristics. The single crystal X-ray diffraction
studies show 1:1 identity of all nitrate complexes. The crystal
structures of three nitrate complexes are isostructural with the
same space group (P3) and very similar cell parameters. All
̅
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1
Figure 2. Partial H NMR (400 MHz, 20 °C) titration spectra of receptor 2b (1.5 × 10−3 M) with tetrabutylammonium nitrate in an acetone-d6
solution.
where the interatomic distances between the receptor and
anion depend upon the counterion employed.24 The
encapsulated nitrate anion is not symmetrically located inside
the cavity by the reported ditopic receptor. To the best of our
knowledge, the current report represents the first example in
which a nitrate anion is symmetrically encapsulated by amide
groups bearing acyclic tripodal receptors with one of the
highest binding affinities in a polar aqueous solvent by a neutral
receptor (receptor 5, vide infra).
N−H signals in all four receptors. This observation indicates
that (i) the protonation of the centrally bridged N-atom is
mandatory to reorganize the otherwise floppy neutral receptors
to a convergent conformation via intramolecular hydrogen
bonding interaction between the protonated N−H and
aliphatic O-atoms (vide infra) and (ii) very weak binding of
1
nitrate anions in DMSO-d6 may not be observed through H
NMR titration experiment.
To meet both requirements, anion binding in solution was
conducted by addition of TBANO3 to an acetone-d6 solution of
protonated perchlorate complexes 1b−4b. The protonated
perchlorate complexes were chosen for solution binding studies
because of the large ionic radii and the lipophilic nature of
perchlorate anion, which cannot be effectively encapsulated
inside the tripodal cavity of the protonated receptors and
interfere with the subsequent binding events. These perchlorate
complexes also show better solubility in common deuterated
solvents than their parent receptors. The pKa values of
receptors 1b−4b are expected to be similar to triethylammo-
nium ion with a value near 9 in a DMSO solution.25
The distances between the N-atom of nitrate anions and the
bridged N-atom of receptors in a discrete unit are both 7.88 Å
for 2a and 4a, whereas it is 7.84 Å for 3a (Figure 1a−c). The
closest distances between the centrally bridged N-atom of the
podand and the center of nitrate anion in crystal packing are
3.59 Å for 2a and 4a and 3.52 Å for 3a. In the crystal structures
of all three complexes 2a, 3a, and 4a, there are infinite channels
along the c-axis, which are filled by solvent molecules (CHCl3
in 2a and 3a and THF in 4a). The remarkable differences
observed in the three crystal structures were that the edge of
isosceles increase from 11.87 Å of nitrate complex 2a to 12.37
Å of nitrate complex 4a (Figure 1g−i) with decreasing
electronegativity of the halide group. However, the distance
between the amide N-atom of neighboring branch of nitrate
complex 2a is 0.05 Å larger than that of nitrate complexes 3a
and 4a (Figure 1g−i).
1
A representative H NMR titration spectra of protonated
receptor 2b upon addition of nitrate anions is illustrated in
Figure 2, and the binding constants of different anions with
protonated receptors 1b−4b calculated from a 1:1 binding
stoichiometry according to the crystal structures are summar-
ized in Table 1 (see Figures S26−S40 in the Supporting
Information for all titration spectra). Although the peaks of
protonated centrally bridged amines were not observable, the
amide N−H signals of protonated receptors were consistently
downfield shifted upon addition of different anions indicative of
the presence of hydrogen-bonding interactions between the
anion and amide N−Hs. Two peaks corresponding to the
aromatic Hd and Hf also downfield shifted, which is ascribed to
the effect of through space electrostatic interaction (see Figure
Nitrate Binding in Solution and Gaseous NO2 Fixation
1
Studies. H NMR spectra recorded in DMSO-d6 for nitrate
complexes 1a−4a, prepared from CHCl3/MeOH mixture
solution, showed downfield shifted peaks for the aliphatic C−
H protons compared to those in the corresponding neutral
receptors, which suggests that the centrally bridged N-atom in
all nitrate complexes is protonated. Addition of tetrabutylam-
monium nitrate (TBANO3) to a solution of neutral receptors
1−4 in DMSO-d6 resulted in no apparent shift of the amide
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Table 1. Binding Constants (Ka, M−1) Determined by H
NMR Titrations of Perchlorate Complexes 1b−4b (1.48 ×
10−3 M) with Different Anions as Their
mixture solution for 3−5 min. The precipitate thus obtained
was simply filtered and dried in air. The identity of this isolated
solid was fully matched with the nitrate complex 2a on the basis
of a variety of characterization methods including 1H NMR, 13C
NMR, and HRESI mass spectra. HRESI mass spectra has been
successfully utilized for detection of supramolecular species in
solution.26
Despite the fact that no particular selectivity was observed for
nitrate anions by protonated receptors 1b, 2b, and 4b in
solution, the anion-binding studies by receptor 5 showed very
intriguing results. For receptor 5, anion binding studies were
performed in DMSO-d6, as the −SO3H group of the dansyl
moiety is expected to dissociate in a polar solvent like DMSO
to form a convergent cone shape conformation by its
zwitterionic form (see Figure 3), and hence anion-binding
Tetrabutylammonium Salts in an Acetone-d6 Solution
a
1b
2b
3b
4b
−
NO3
Br−
940 80
250 50
710 100
870 70
c
1120 50
870 60
1840 150
1580 20
c
1000 90
500 40
720 90
b
Cl−
−
HSO4
840 110
−
H2PO4
c
a
Complex 3b is sparingly soluble in acetone-d6, and immediate
b
precipitation appeared after addition of anions. The amide N−H peak
disappeared after addition of 1 equiv of bromide anion and hence the
binding constant determined by the changes of aromatic C−H proton
of N-terminal aromatic ring (proton “f”). Deprotonation of centrally
bridged N-atom occurred after addition of 3 equiv of H2PO4 anion.
c
−
2 for the proton labels).16b The observed data suggests that the
binding affinity for anions does not fully correlate with the
electronegativity of the halide atoms attached on the receptors.
In general, complex 2b shows higher binding affinities to anions
compared to complexes 1b and 4b. Complex 2b displays the
highest binding affinity to chloride anions, whereas complexes
1b and 4b are slightly selective for nitrate anions over chloride
and hydrogen sulfate anions. Upon titration of protonated
−
receptors 1b−4b with H2PO4 , no shift was observed for amide
−
N−H peak until the addition of 3 equiv of H2PO4 anion.
However, the peak for protons attached to C-atom adjacent to
bridged N-atom shifted upfield and splitted to a triplet and
−
remains almost unchanged after further addition of H2PO4
anions (see Figures S30, S35, and S40 in the Supporting
Information). This observation suggests that centrally bridged
−
N-atom was deprotonated after addition of 1 equiv of H2PO4
anion, and hence no encapsulation of H2PO4− anion is possible
by protonated receptors 1b−4b.
For comparative studies, the binding behavior of isostructural
trigonal planar anions such as acetate anions has also been
studied. Concentration-dependent 1H NMR spectra of the
corresponding acetate complex 4c (see Figure S41 in the
Supporting Information) showed a similar pattern to that of
free receptor 4. The inability of acetate binding is ascribed to
the weak acidity of AcOH to protonate the bridged N-atom,
and hence the formation of a preorganized interior cavity did
not effectively take place in this case. Upon titration of
perchlorate complexes 1b−4b with tetrabutylammonium
acetate, peaks corresponding to aliphatic C−H proton
remarkably shifted upfield after addition of 1 equiv of acetate
anions. The significant upfield shift of peaks corresponding to
aliphatic C−H protons suggests that the centrally bridged
protonated N-atom got deprotonated from complexes 1b−4b
in the presence of basic acetate anion, and hence, encapsulation
of acetate anions can not be expected.
Recently, a mechanism for nitric oxide in contact with water
to form nitric acid was reported by Gerber’s group.25 We
envisioned that the high affinity of receptors 1−4 to bind
nitrate anion in acidic medium renders the trapping of nitrogen
dioxide gas after water contact by these receptors highly
feasible. Therefore, the fixation of gaseous nitrogen oxide to
nitrate was explored with these receptors. Nitrogen dioxide was
prepared by treating copper turnings with concentrated nitric
acid, and the resulting reddish brown gas was bubbled through
a suspension of receptor 2 in CHCl3/MeOH (1/1 in v/v)
Figure 3. Formation of in situ preorganized interior cavity by
zwitterionic form (I, II, and III) of tripodal receptor 5 for
encapsulation of nitrate anion.
studies can be carried out in its neutral form without external
proton source. The peaks for protonated centrally bridged
amine, amide N−H, and −SO3H group of receptor 5 were all
not observable (see Figures S17 and S19 in the Supporting
1
Information) in the H NMR spectrum recorded in a DMSO-
d6 solution, possibly because of a rapid proton exchange with
the residual water in deuterated DMSO. A very minor shift
observed for peaks in titration experiment of neutral receptor 5
with chloride and bromide anions indicates very weak
interactions between receptor 5 and these two anions. On
the other hand, the peaks of aromatic protons in dansyl moiety
gradually upfield-shifted with increasing concentration of
1
nitrate anion as illustrated in the H NMR titration spectra of
neutral receptor 5 in a DMSO-d6 solution (see Figure 4). A
similar titration pattern was observed with hydrogen sulfate
anions. These observations suggest hydrogen bond formation
between the incoming anions and the amide N−H protons of
neutral receptor 5. Nonlinear regression analysis of the binding
isotherms based on the upfield shift of proton f with a 1:1
binding stoichiometry yielded binding constants of 550 40
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Figure 4. Partial H NMR spectra of receptor 5 (1.48 × 10−3 M) upon addition of nitrate anion in a DMSO-d6 solution.
M−1 and 240
respectively.27 Receptor 5 shows more than 2-fold higher
30 M−1 for NO3 and HSO4 anions,
Table 2. Effect of Solvent Polarity on the Binding Constants
−
−
1
(Ka, M−1) Determined by H NMR Titration of Receptor 5
(1.48 × 10−3 M) with Nitrate Anion in DMSO-d6 Solutions
in the Presence of Various Amounts of H2O
−
−
affinity for NO3 anion than HSO4 anion in a DMSO-d6
solution. Control experiments were also carried out in the
presence of excess innocent tetrabutylammonium perchlorate
to verify that the changes of chemical shifts observed during the
1H NMR titration experiments for nitrate recognition were not
simply due to the variation of solution ionic strength caused by
the addition of salts. The binding affinities for nitrate anion
were calculated to be 510 30 M−1 and 850 60 M−1 in the
presence of 10 and 100 equiv of tetrabutylammonium
perchlorate, respectively (see Figures S42, S43, and S53 in
the Supporting Information). These results suggest that the
changes of the chemical shifts upon addition of nitrate anions
were actually due to the binding event between receptor 5 and
the incoming nitrate anion. Moreover, the increasing ionic
strength of solution in the presence of 100 equiv of
tetrabutylammonium perchlorate results in an enhanced
ionization of the sulfonic acid in receptor 5 that further shifts
the equilibrium to a conical conformation shown in Figure 3 by
facilitating protonation of the central bridged nitrogen atom.
To the best of our knowledge, this is one of the highest binding
constants reported so far in polar solvents for nitrate anion by a
neutral acyclic receptor.
a
solvent
Ka (M−1
)
DMSO-d6 only
550 40
590 40
870 60
430 40
DMSO-d6 + 5% H2O
DMSO-d6 + 10% H2O
DMSO-d6 + 20% H2O
a
Binding constants determined with proton f of the dansyl moiety in
receptor 5.
Such enhancement in binding affinity may be attributed to a
higher degree of proton ionization in a more polar solvent
medium that results in more protonated receptor 5 with
convergent conformation to bind nitrate anion in solution (see
Figure 4). It is not surprising to see that the binding affinity
decreased upon further increasing the water content in solution
where the excess water would compete with protonated
receptor 5 for the hydrophilic nitrate anion.
1
A H NMR titration experiment of receptor 5 with basic
−
H2PO4 anion was also conducted in a DMSO-d6 solution.
−
After addition of 2 equiv of H2PO4 anion, the color of the
The degree of ionization for the −SO3H group is expected to
be even higher in more polar solvent media. H NMR titration
solution turned from purple to creamy yellow. The aromatic
proton h of dansyl moiety upfield shifted until the addition of 3
equiv of H2PO4− anion, and thereafter no shift in peak position
was observed (see Figure S47 in the Supporting Information).
Moreover, aromatic proton f adjacent to the amide N−H group
1
experiments were performed in DMSO-d6 solutions of receptor
5 with NO3− anion in the presence of various amounts of water.
The binding constants obtained for 1:1 stoichiometry are
summarized in Table 2. The binding affinities of receptor 5
with nitrate anion are comparable in pure DMSO-d6 and
DMSO-d6 solution with 5% water. However, a 50% enhance-
ment in binding constant was observed in the presence of 10%
water in a DMSO-d6 solution for receptor 5 with nitrate anion.
−
also upfield shifted until the addition of 3 equiv of H2PO4
anion and thereafter remained silent. This observation shows
−
that the basic H2PO4 anion interacted with the sulfonic
protons in a Bronsted acid−base fashion. The net effect upon
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Figure 5. Concentration-dependent H NMR spectra (400 MHz, DMSO-d6, 20 °C) of receptor 4 (top), receptor 4 in the presence of perchloric
acid (middle), and perchlorate complex 4b (bottom).
−
titration of receptor with H2PO4 resulted in deprotonation of
terminal aromatic ring are in close contact with the centroid of
the C-terminal aromatic ring of the neighboring branch via
intermolecular tilted edge-to-face C−H···π interactions (dC−H···d
3.235 Å and θC−H···π 177.0° for 2a, dC−H...d 3.222 Å and θC−H···π
176.3° for 3a, and dC−H···d 3.219 Å and θC−H···π 175.9° for 4a,
respectively (see Figure 1), where d is centroid of C-terminal
aromatic ring).24
−
sulfonic acid without H2PO4 anion encapsulation.
Proposed Mechanism for Nitrate Anion Encapsula-
tion. Solution binding studies suggest that the receptor would
be protonated first upon addition of dilute HNO3, thereby
increasing its solubility in a protic solvent such as MeOH. After
protonation of the centrally bridged N-atom, all three branches
of the podand converge to a conical shape by cooperative N−
H···O hydrogen bonding and C−H···π interactions to form an
interior cavity. The amide N−Hs in the protonated receptor
would be preorganized in a trigonal planar fashion and able to
extract anions from solution by a synergistic electrostatic
interaction and increasing hydrogen-bonding interactions
between the anion and amide N−Hs. In the crystal structures
of 2a, 3a, and 4a, the distances between the centrally bridged
N-atom and O-atom of aliphatic chain are 2.710 Å for 2a, 2.719
Å for 3a, and 2.718 Å for 4a, respectively, which suggest the
possible hydrogen-bonding interactions between the bridged
N−H and O-atom of the aliphatic chain (Figure 1d−f). Close
inspection of crystal structures of 2a, 3a, and 4a shows that the
ortho H-atoms with respect to the alkoxy chain of the C-
1
Concentration-dependent H NMR spectra were recorded
for receptor 4, its corresponding perchlorate complex 4b, and
receptor 4 in the presence of perchloric acid in order to further
prove that the in situ formation of an interior cavity via N−
H···O hydrogen bonds and C−H···π interactions is due to the
1
protonation effect of the centrally bridged N-atom. The H
NMR spectrum of receptor 4 showed a notable shift of all peaks
with increasing concentration of receptor 4 from 4.49 to 74.2
1
mM (Figure 5, top), whereas the concentration-dependent H
NMR spectra of complex 4b (Figure 5, bottom) and receptor 4
in the presence of perchloric acid (Figure 5, middle) showed no
shift of peaks either in aromatic or aliphatic regions. The upfield
and downfield shifts of peaks corresponding to protons Ha and
Hb, respectively, of aliphatic branches in receptor 4 as well as
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Figure 6. A schematic diagram showing proton-mediated in situ formation of the preorganized cavity via N−H···O hydrogen bonding and C−H···π
interactions, which is able to extract trigonal planar nitrate anion selectively in polar media.
the lack of changes for the same protons in its corresponding
perchlorate complex 4b signify that receptor 4 exits in a
different conformation from its protonated form (its corre-
sponding perchlorate complex 4b or receptor 4 in the presence
of perchloric acid). This result also implies that the conforma-
tional flexibility of tripodal moiety get reduced upon
protonation of centrally bridged N-atom to form the interior
cavity. These results further support the observation made in
crystal structures that although tripodal podands 1−4 are
conformationally flexible with a large degree of freedom,
encapsulation of the nitrate anion takes place by in situ
generation of a preorganized cavity via cooperative H-bonding
and C−H···π interactions in solution with reduced conforma-
tional flexibility.
Once the interior cavity is formed by protonated tripodal
receptors, rotation of N-terminal aromatic ring around C−N
bond creates an identical environment for all the halide-
substituted tripodal receptors 1b−4b, and hence no particular
selectivity is expected for anions with different size and shape.
However, steric requirement for rotation of dansyl moiety
around C−N bond in receptor 5 will allow the differentiation of
the encapsulation of only anions with appropriate size and
shape within the in situ formed cavity of the protonated
receptor. It is likely that the aromatic protons of dansyl moiety
cause steric hindrance and hence do not allow spherical anions
to bind inside the cavity of receptor 5 as effectively as nitrate
anions. Thus, although chloride is comparable to nitrate anions
in terms of its size and hydration energy, the trigonal planar
geometry and matching C3-symmetry of nitrate anions with the
receptor allows its encapsulation and selective sensing by
receptor 5. The proposed mechanism of encapsulation of
nitrate anions in solution is summarized in Figure 6. The
encapsulation of nitrate anions with neutral receptor 5 occurs
through its zwitterionic form as shown in Figure 3. The
available donor (sulfonic acid group) and acceptor (centrally
bridged N-atom) moieties in the same molecule are capable of
preorganizing its branches in a cone conformation and reduce
the molecular flexibility with the formation of the interior
cavity, which is suitably matched for encapsulation of trigonal
planar nitrate anion.
Reversible Binding of Nitrate Anion. The reversible
binding of nitrate anions can also be easily modulated by acid−
base titration. The aliphatic C−H proton signal adjacent to the
central bridged N-atom shifted back to the original position of
receptor 2 upon treating the nitrate complex 2a with 1 equiv of
KOH in a DMSO-d6 solution. After addition of excess KOH
(4.5 equiv), the peak for amide N−H protons disappeared, and
the solution became orange, which is attributed to either the
fast proton exchange that causes a significant broadening of the
signal or partial deprotonation of the amide N−Hs (see Figure
S55 in the Supporting Information). The peak for amide N−H
protons reappeared after acidifying the same solution mixture
by trifluoroacetic acid, and the final spectrum was merged with
the original spectrum of the nitrate complex 2a, which was also
confirmed by HRESI mass spectrum.
Fluorescent Sensing of Nitrate Anion. The effective
encapsulation of nitrate anion by receptor 5 suggests the
possibility of fluorescent sensing of nitrate anion. Fluorescence
titration experiments of neutral receptor 5 with nitrate and
hydrogen sulfate anions were performed in DMSO solutions
with various amounts of water. Figure 7 shows the fluorescence
titration spectra of receptor 5 with nitrate anion in a DMSO
solution. Binding constants of different anions with receptor 5
calculated from a 1:1 binding stoichiometry are summarized in
1
Table 3. Similar to the H NMR titration studies, the binding
constants of receptor 5 derived from fluorescence titrations
showed a higher binding constant for nitrate than hydrogen
sulfate. The binding constants for nitrate anion in pure DMSO
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and all para-haloamines were commercially available and used as
received. All solvents were purified by standard procedures. NMR
spectra were recorded with a 400 MHz spectrometer. Chemical shifts
are reported on the δ scale relative to tetramethylsilane. Emission
spectra were recorded in an air-equilibrated solution according to
reported procedures.28 Single crystal data were collected with a CCD
diffractometer. CCDC-754903 and CCDC-754904 contain the
supplementary crystallographic data for nitrate complexes 2a and 4a,
respectively, and CCDC-819453 for nitrate complex 3a. These data
can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1H NMR titrations of all samples were measured on a 400 MHz
spectrometer, and deuterated solvents were used from freshly opened
bottle. Samples were prepared just prior to titration experiments, and
all anions were used in the form of tetrabutyl ammonium salts.
Titration experiments for protonated receptors 1b−4b were
performed in acetone-d6 solutions, and binding constants were
calculated from shifting of amide N−H protons (except for 4b with
tetrabutylammonium bromide, where the binding constant was
calculated from the shifting of N-terminal aromatic C−H protons, as
in this case the amide N−H proton disappears after addition of 1 equiv
of bromide anion). Titration experiments of neutral receptor 5 with
different anions were performed in DMSO-d6, and binding constants
were calculated from the shifting of aromatic (dansyl moiety) C−H
protons.
Figure 7. Fluorescent titration spectra (λex = 375 nm) of neutral
receptor 5 (2.1 × 10−6 M) with nitrate anion in a DMSO solution.
Table 3. Effect of Solution Polarity on Equilibrium
Constants (Ka, M−1) Determined by Fluorescence Titration
(λex = 375 nm) of Receptor 5 (2.1 × 10−6 M) with Anions as
Their Tetrabutylammonium Salts in DMSO Solution with
Various Amounts of Water (v/v)
General Procedures for the Synthesis of Receptors 1−5. To a
solution of 4-hydroxymethylbenzoate (16.7 g, 0.11 mol) in dry DMSO
(80 mL) was added NaOH (5.98 g, 0.15 mol), and the solution was
stirred at rt for 30 min. To the resulting solution, tris(2-chloroethyl)-
amine hydrochloride (8.0 g, 33.2 mmol) was added at once, and the
mixture was heated at 80 °C for 12 h. Thereafter, the solution was
allowed to cool to rt, diluted with distilled water (100 mL), extracted
with ethyl acetate (3 × 100 mL). The organic layer was washed three
times with 10% K2CO3 solution and then two times with cold water.
The organic layer was collected and dried over anhydrous MgSO4, and
the solvent was removed under reduced pressure. The crude product
was purified by flash column chromatography eluted with ethyl acetate
in hexane to obtain the triester B (14.3 g, 78% yield). Thereafter, 150
mL of 5 N NaOH solution was added to a suspension of triester B in
250 mL of MeOH−H2O (1:1 in v/v) mixture solution, and the
resulting solution was refluxed for overnight. After cooling to rt, the
reaction mixture was acidified with 25% HCl solution and allowed to
stand at rt for a further 6−7 h to precipitate the expected triacid C.
The milky white precipitate was filtered out, washed with Et2O, and
air-dried (12.1 g, 92% yield). This triacid C was used for next step
without further purification.
To a suspension of triacid C (5.0 g, 9.81 mmol) in dry
dichloromethane (100 mL), 4.5 equiv of thionyl chloride (3.13 mL,
44.2 mmol) was added, followed by addition of a catalytic amount of
DMF (1 mL), and the mixture was refluxed under guard tube for 6 h.
After cooling of the reaction mixture to rt, the volatile was removed
under reduced pressure to get the creamy yellow solid of
corresponding acid chloride. The acid chloride was again dissolved
in dry dichloromethane (100 mL) and transferred through cannula to
another two-necked 500 mL round-bottom flask containing 3.6 equiv
of corresponding 4-haloamine (35.3 mmol) dissolved in a 100 mL of
dry dichloromethane under nitrogen atmosphere in an ice bath. The
mixture solution was allowed to stir for 10−15 min in the ice bath, and
then 4.5 equiv of triethylamine (44.2 mmol) was added. The reaction
mixture was allowed to reach room temperature and refluxed for 8−12
h. Solvent was removed under reduced pressure, and the crude
product was purified by flash chromatography with CHCl3/MeOH
mixture solution as the eluent to get the desired receptors in 69−95%
yields. Receptor 5 was synthesized by similar procedures described
above, except THF was used instead of dichloromethane, and the
crude product was first recrystallized by hot THF followed by MeOH
to yield receptor 5 in 65% yield.
DMSO only
10% H2O in DMSO
20% H2O in DMSO
−
NO3
550 40
100 30
570 20
140 30
290 70
40 10
−
HSO4
solution and DMSO solution with 10% water are comparable
within the experimental error. Upon further increasing the
water content in DMSO solution to 20%, the binding affinity
for nitrate decreased nearly to half. This result is in full
agreement with the observation in 1H NMR titration
experiments. The very minor difference observed for binding
constants in DMSO and 10% water in DMSO may be
attributed to the dilution effect in typical fluorescence
experiments where receptor 5 might have dissociated well at
concentration of 2.1 × 10−6 M even in absence of water.
CONCLUSION
■
In summary, we have disclosed the protonation-induced in situ
formation of an interior cavity by highly flexible and
unpreorganized tripodal receptors, which selectively recognize
and encapsulate the trigonal planar and C3-symmetry nitrate
anion. Apart from physical characterization, crystal structures of
2a, 3a, and 4a confirmed the formation of discrete nitrate anion
complexes. Receptor 5 represents a unique example of neutral
receptor for encapsulation of highly hydrated and weakly
coordinated nitrate anion in polar solvent media. Since these
receptors do not have preorganized structural framework and
the degree of freedom was much larger than previously
reported examples of bicyclic receptors, selective recognition
and sensing may be attributed to a combination of electrostatic
attraction and optimal directionality of multiple hydrogen
bonding interactions. Moreover, effective trapping of nitrogen
oxide upon hydrolysis in aqueous solution by these receptors
provides a proof-of-concept method for monitoring the
environmental concern of atmosphere smog. Current work is
underway to prepare abiotic receptors to enhance the
fluorescence signal after binding with nitrate anions.
EXPERIMENTAL SECTION
Materials and General Procedures. 4-Hydroxybenzoic acid, 5-
aminonaphthalene-1-sulfonic acid, triethanolamine, thionyl chloride,
Receptor 1. Creamy yellow solid (5.34 g, yield 69%, mp 195−197
■
1
3
°C): H NMR (400 MHz, DMSO-d6, 20 °C) δ 3.12 (t, J = 5.6 Hz,
6H), 4.18 (t, 3J = 5.6 Hz, 6H), 7.04 (d, 3J = 8.8 Hz, 6H), 7.16 (t, 3J =
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3
3
8.8 Hz, 6H), 7.76 (dd, J = 8.8 Hz, 6H), 7.93 (dd, J = 8.8 Hz, 6H),
10.13 (s, 3H); 13C NMR (100 MHz, DMSO-d6, 20 °C) δ 53.6, 66.9,
114.2, 115.0, 115.3, 122.2, 126.8, 129.6, 135.7, 161.3, 164.9;
HRFABMS m/z calcd for [M + H+] 789.2900, found 789.2892;
Elemental analysis calcd (%) for C45H39F3N4O6·1.5H2O C 66.25, H
5.19, N 6.87, found C 66.52, H 5.08, N 6.89.
115.2, 122.3, 127.4, 129.7, 131.4, 138.6, 160.2, 164.8; HRESIMS m/z
calcd for [M − H]− 1034.0257, found 1034.0310; Elemental analysis
calcd (%) for C45H40Br3N5O9·3H2O C 49.65, H 4.26, N 6.43, found C
49.58, H 4.19, N 6.38.
Nitrate Complex 4a. Creamy yellow solid (1.00 g, yield 85%, 162−
164 °C): 1H NMR (400 MHz, DMSO-d6, 20 °C) δ 3.89 (s, 6H), 4.54
(s, 6H), 7.10 (d, 3J = 8.4 Hz, 6H), 7.61 (d, 3J = 8.4 Hz, 6H), 7.68 (d, 3J
1
Receptor 2. White solid (7.74 g, yield 94%, mp 250−252 °C): H
3
= 8.4 Hz, 6H), 7.98 (d, J = 8.4 Hz, 6H), 10.18 (s, 3H); 13C NMR
NMR (400 MHz, DMSO-d6, 20 °C) δ 3.12 (t, 3J = 5.6 Hz), 4.18 (t, 3J
3
3
(100 MHz, DMSO-d6, 20 °C) δ 53.3, 79.2, 87.1, 114.3, 122.5, 127.5,
129.7, 137.2, 139.1, 160.2, 164.7; HRESIMS m/z calcd for [M − H]−
1173.9882, found 1173.9889; Elemental analysis calcd (%) for
C45H40I3N5O9·3H2O C 43.96, H 3.77, N 5.70, found C 43.74, H
3.73, N 5.93.
Nitrate Complex 5a. Pale yellow solid (1.03 g, yield 87%, mp 170−
172 °C): 1H NMR (400 MHz, DMSO-d6, 20 °C) δ 3.86 (s, 6H), 4.53
(s, 6H), 7.04 (d, 3J = 8.0 Hz, 6H), 7.56−7.62 (m, 3H), 7.91 (d, 3J = 8.0
Hz, 3H), 7.98 (d, 3J = 8.4 Hz, 6H), 8.06−8.07 (m, 6H), 8.86−8.87 (m,
6H); 13C NMR (100 MHz, DMSO-d6, 20 °C) δ 53.3, 62.6, 114.6,
119.9, 123.1, 123.8, 125.3, 125.5, 125.7, 126.8, 127.5, 128.5, 129.7,
131.4, 144.2, 161.0, 166.9; HRESIMS m/z calcd for [M − H]−
1188.2268, found 1188.2300; Elemental analysis calcd (%) for
C57H49N5O18S3·H2O C 56.76, H 4.26, N 5.81, S 7.97, found C
56.80, H 4.23, N 5.78, S 8.01.
= 5.6 Hz, 6H), 7.04 (d, J = 8.8 Hz, 6H), 7.38 (d, J = 8.8 Hz, 6H),
7.80 (d, 3J = 8.8 Hz, 6H), 7.94 (d, 3J = 8.8 Hz, 6H), 10.19 (s, 3H); 13
C
NMR (100 MHz, DMSO-d6, 20 °C) δ 53.5, 66.9, 114.2, 121.8, 126.6,
127.0, 128.5, 129.7, 138.3, 161.3, 165.0; HRFABMS m/z calcd for [M
+ H+] 837.2013, found 837.2017; Elemental analysis calcd (%) for
C45H39Cl3N4O6 C 64.48, H 4.69, N 6.68, found C 64.21, H 4.68, N
6.59.
1
Receptor 3. White solid (9.05 g, yield 95%, mp 258−260 °C): H
NMR (400 MHz, DMSO-d6, 20 °C) δ 3.12 (t, 3J = 5.6 Hz, 6H), 4.18
3
3
3
(t, J = 5.6 Hz, 6H), 7.04 (d, J = 8.8 Hz, 6H), 7.50 (d, J = 8.4 Hz,
3
3
6H), 7.74 (d, J = 8.4 Hz, 6H), 7.93 (d, J = 8.8 Hz, 6H), 10.18 (s,
3H); 13C NMR (100 MHz, DMSO-d6, 20 °C) δ 53.5, 66.8, 114.1,
115.0, 122.2, 126.6, 129.6, 131.3, 138.7, 161.3, 164.9; HRFABMS m/z
calcd for [M + H+] 971.0478, found 971.0431; Elemental analysis
calcd (%) for C45H39Br3N4O6·H2O C 54.62, H 4.18, N 5.66, found C
54.62, H 4.03, N, 5.72.
Receptor 4. Creamy white solid (9.83 g, yield 90%, mp 266−268
ASSOCIATED CONTENT
■
1
°C): H NMR (400 MHz, DMSO-d6, 20 °C) δ 3.11 (s, 6H), 4.18 (s,
S
* Supporting Information
6H), 7.05 (s, 6H), 7.64 (m, 12H), 7.94 (s, 6H), 10.17 (s, 3H); 13C
NMR (100 MHz, DMSO-d6, 20 °C) δ 53.4, 87.1, 114.2, 122.5, 129.7,
137.2, 139.2, 164.9; HRFABMS m/z calcd for [M + H+] 1113.0082,
found 1113.0095; Elemental analysis calcd (%) for C45H39I3N4O6 C
48.58, H 3.53, N 5.04, found C 48.74, H 3.57, N, 5.02.
1H and 13C NMR spectra, titration spectra, and CIF files for
crystal structures of 2a, 3a, and 4a. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sssun@chem.sinica.edu.tw.
Notes
Receptor 5. Pale violet solid (7.18 g, yield 65%, mp 245−247 °C):
■
3
1H NMR (400 MHz, DMSO-d6, 20 °C) δ 3.83 (s, 6H), 4.59 (t, J =
4.8 Hz, 6H), 7.05 (d, 3J = 8.2 Hz, 6H), 7.54−7.61 (m, 6H), 7.71 (d, 3J
= 8.8 Hz, 3H), 7.90 (d, 3J = 8.8 Hz, 6H), 8.06−8.09 (m, 6H), 8.87 (d,
3J = 8.8 Hz, 3H); 13C NMR (100 MHz, DMSO-d6, 20 °C) δ 52.8,
62.6, 114.6, 120.0, 123.6, 123.8, 125.2, 125.4, 125.5, 127.1, 127.4,
128.7, 129.8, 131.4, 144.2, 161.1, 166.9; HRFABMS m/z calcd for [M
− H]−: 1123.2200, found 1123.2201; Elemental analysis calcd (%) for
C57H48N4O15S3·3H2O C 58.05, H 4.62, N 4.75, S 8.16, found C 57.89,
H 4.52, N 4.71, S 7.96.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Council of Taiwan (Grant No 100-
2113-M-001-024-MY3) and Academia Sinica for support of this
research. A.S.S. thanks the postdoctoral fellowship sponsored
by the National Science Council of Taiwan (Grant No 100-
2811-M-001-090). Mass spectrometry analyses were performed
by Mass Spectrometry facility of the Institute of Chemistry,
Academia Sinica. Mr. Ting-Shen Kuo at National Taiwan
Normal University is acknowledged for assistance with X-ray
crystallography.
General Procedures for the Synthesis of Nitrate Complexes
1a−5a. To a mixture solution of the corresponding compounds 1−5
(1 mmol in 15 mL of CHCl3/MeOH, v/v in 1:1 ratio) was added 9
drops of dilute HNO3 (10%), and the resulting solution was stirred at
room temperature for 20 min and filtered. The residue obtained was
air-dried for 24 h to yield the desired nitrate complexes 1a−5a.
Nitrate Complex 1a. Creamy yellow solid (0.61 g, yield 72%, mp
160−162 °C): 1H NMR (400 MHz, DMSO-d6, 20 °C) δ 3.90 (s, 6H),
3
3
3
4.55 (d, J = 4.4 Hz, 6H), 7.11 (d, J = 8.8 Hz, 6H), 7.18 (t, J = 8.8
3
3
Hz, 6H), 7.77 (dd, J = 8.8 Hz, 6H), 7.99 (d, J = 8.8 Hz, 6H), 10.16
(s, 3H); 13C NMR (100 MHz, DMSO-d6, 20 °C) δ 53.4, 62.6, 114.3,
115.1, 122.2, 127.6, 129.6, 135.5, 160.1, 164.6, 206.4; HRESIMS m/z
calcd for [M − H]− 850.2700, found 850.2703; Elemental analysis
calcd (%) for C45H40F3N5O9·2H2O C 60.88, H 5.00, N 7.89, found C
61.14, H 4.80, N 8.13.
REFERENCES
■
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183 °C): 1H NMR (400 MHz, DMSO-d6, 20 °C) δ 3.90 (s, 6H), 4.56
(s, 6H), 7.11 (d, 3J = 8.8 Hz, 6H), 7.39 (d, 3J = 8.8 Hz, 6H), 7.80 (d, 3J
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= 8.8 Hz, 6H), 7.99 (d, J = 8.8 Hz, 6H), 10.24 (s, 3H); 13C NMR
(100 MHz, DMSO-d6, 20 °C) δ 53.4, 62.6, 114.3, 121.9, 127.1, 127.5,
128.5, 129.7, 138.2, 160.2, 164.8; HRESIMS m/z calcd for [M − H]−
898.1813, found 898.1823; Elemental analysis calcd (%) for
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7.65.
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1
130 °C, decomposition): H NMR (100 MHz, DMSO-d6, 20 °C) δ
3.90 (s, 6H), 4.56 (s, 6H), 7.11 (d, 3J = 8.4 Hz, 6H), 7.52 (d, 3J = 8.4
Hz, 6H), 7.75 (d, 3J = 8.4 Hz, 6H), 7.99 (d, 3J = 8.4 Hz, 6H), 10.23 (s,
3H); 13C NMR (100 MHz, DMSO-d6, 20 °C) δ 53.4, 62.7, 114.3,
1889
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