A Hexapodal Capsule for the Recognition of Anions

Article abstract of DOI:10.1021/jacs.0c12329

We herein describe the preparation, characterization, and recognition characteristics of novel hexapodal capsule 1 composed of two benzenes joined by six hydrogen bonding (HB) groups to encircle space. This barrel-shaped host was obtained by reversible imine condensation of hexakis-aldehyde 2 and hexakis-amine 3 in the presence of oxyanions or halides acting as templates. Fascinatingly, capsule 1 includes 18 HB donating (Csp2-H and N-H) and 12 HB accepting groups (C=O and C=N) surrounding a binding pocket (78 ?3). In this regard, the complexation of fluoride, chloride, carbonate, sulfate, and hydrogen phosphate was probed by NMR spectroscopy (DMSO) and X-ray diffraction analysis to disclose the adaptive nature of 1 undergoing an adjustment of its conformation to complement each anionic guest. Furthermore, the rate by which encapsulated chloride was substituted by sulfate or hydrogen phosphate was slow (>7 days) while the stability of [SO4 1]2- was greatest in the series with Ka > 107 M-1 in highly competitive DMSO. With facile access to 1, the stage is set to probe this modular, polyvalent, and novel host to further improve the extraction of tetrahedral oxyanions from waste and the environment or control their chemistry in living systems.

Full text of DOI:10.1021/jacs.0c12329

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Article
A Hexapodal Capsule for the Recognition of Anions
́
Han Xie, Tyler J. Finnegan, Vageesha W. Liyana Gunawardana, Radoslav Z. Pavlovic, Curtis E. Moore,
and Jovica D. Badjic*
́
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ABSTRACT: We herein describe the preparation, character-
ization, and recognition characteristics of novel hexapodal capsule
1 composed of two benzenes joined by six hydrogen bonding
(HB) groups to encircle space. This barrel-shaped host was
obtained by reversible imine condensation of hexakis-aldehyde 2
and hexakis-amine 3 in the presence of oxyanions or halides acting
as templates. Fascinatingly, capsule 1 includes 18 HB donating
(Csp2−H and N−H) and 12 HB accepting groups (CO and C
N) surrounding a binding pocket (78 Å3). In this regard, the
complexation of fluoride, chloride, carbonate, sulfate, and hydro-
gen phosphate was probed by NMR spectroscopy (DMSO) and X-
ray diffraction analysis to disclose the adaptive nature of 1
undergoing an adjustment of its conformation to complement each anionic guest. Furthermore, the rate by which encapsulated
chloride was substituted by sulfate or hydrogen phosphate was slow (>7 days) while the stability of [SO4⊂1]2− was greatest in the
series with Ka > 107 M−1 in highly competitive DMSO. With facile access to 1, the stage is set to probe this modular, polyvalent, and
novel host to further improve the extraction of tetrahedral oxyanions from waste and the environment or control their chemistry in
living systems.
core for stabilizing its aaaaaa conformation.14 Moreover,
INTRODUCTION
■
Ghosh and co-workers discovered15 that the corresponding
In the search for easily accessible and C3 symmetric hosts
hexa-amide receptors would overcome the steric gearing by
assuming conformations (aaaaaa, aaabbb, etc.) complemen-
tary to a range of anionic guests in the solid state. It follows
capable of sensing, sequestering, or transporting important and
biological molecules/ions,2 hexasubstituted benzenes (Figure
1A) have, to date, played an important role.3 At the
that by fastening six amides on one side of the benzene
platform (Figure 1A) a binding pocket is created isolated from
bulk solvent and rich in HB groups.16 In particular, placing an
anion within such pocket should be assisted by favorable
entropic and enthalpic contributions17 in which the release of
solvent molecules and the formation of multiple hydrogen
bonds ensue. From the results of computational studies
(Figure 1B),1 we anticipated that hexakis-aldehyde 2 and
hexakis-amine 3 could give hexakis-imine 1 under thermody-
namic control,18 with or without a template19 (Figure 1C).20
Such a polyvalent capsule with six HB-donating amides and six
HB-accepting imines, in addition to polarized Csp2−H
groups,11 lining its inner space (78 Å3)21 might complement
oxyanions22 and/or halides.2 We hereby delineate a method-
fundamental level, the arms of hexa-substituted benzene rings
tend to assume alternative ababab positions above (a) and
below (b) the ring (Figure 1A).4 The conformational bias (>3
kcal/mol),5 arising from so-called steric gearing,3 gives rise to a
preorganized molecule possessing a functionalized cleft for
hosting properly sized/shaped guests.6 In addition, such
preorganization has facilitated kinetic or thermodynamic
macrocyclizations7 for obtaining tripodal cages (Figure
1A).2,37 With such concave molecules acting as effective and
selective hosts of complementary guests/ions,2,8 we wondered
about developing a strategy for obtaining hexapodal capsules in
which six, instead of three, functional groups converge above
the benzene platform (Figure 1A).9 Will a greater number of
functional units within such capsules10 (featuring amides,
pyrroles, amines, ureas, pyridines etc.) permit an even more
effective and selective binding of anions?11 In line with the
proposition, Mislow and co-workers found4 that the aaaaaa
conformer of hexasubstituted benzene is the least stable and
more than 8 kcal/mol above the ababab form. To overcome
the bias from steric gearing,12 Allen and co-workers13
employed six primary amides to form a seam of intramolecular
N−H···OC hydrogen bonds (HBs) around the benzene
Received: December 2, 2020
Published: March 3, 2021
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© 2021 American Chemical Society
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Figure 1. (A) Hexasubstituted benzenes assume eight conformations of which ababab and aaaaaa are the most and least stable. (B) A side view of
the energy-minimized structure of 1 (Macrocycle Conformational Sampling; DFT/M06-2X:6-311++G**).1 (C) (Top) A condensation of hexakis-
aldehyde 2 and hexakis-amine 3 was anticipated, with or without a template, to give capsule 1. (Bottom) The preparation of 2 and 3 from
1
hexa(azidomethyl)benzene and H NMR yields of templated-directed syntheses of [anion⊂1]n− in DMSO (see Supporting Information (SI)).
ology for obtaining uniquely structured 1 and exemplify its
capacity to recognize oxyanions and halides.
with 4 equiv of TBAF (TBA = tetrabutylammonium) resulted
in the formation of a single set of sharp 1H NMR resonances in
addition to broad signals corresponding to oligomeric species
(Figure S1). However, adding 1 equiv of DBU as a base to the
reaction mixture improved the templation by further
minimizing oligomerizations (Figure S1). In this regard, a
RESULTS AND DISCUSSION
■
First, we synthesized hexakis(aminomethyl)benzene 314 and
then converted it into hexakis-aldehyde 2 (Figure 1C and
Scheme S1). After combining 2 and 3 in an equimolar ratio in
DMSO, the appearance of ill-defined 1H NMR signals
followed, suggesting the emergence of oligomeric species
(Figure S1). The result was hardly surprising, since 2 should,
in DMSO, assume ababab form.14 Considering the ability of
anions to reorganize six amides around the benzene ring,15 we
decided to probe fluoride23 as a template in directing the
formation of 1. Indeed, mixing equimolar 2 and 3 in DMSO
1
steady development of sharp H NMR signals over 24 h, with
the aldehyde singlet at 9.75 ppm disappearing and the imine
singlet growing at δ = 8.20 ppm (Figure S2), reflected the
reversible nature of imine condensations.19a After the product
1
purification, its H NMR spectrum (Figure 2A) suggested the
formation of a C6 symmetric molecule that we tentatively
assigned to [anionx⊂1]TBAy; the integration of 1H NMR
signals suggested that y = 2−3. In order to identify the anionic
guest, we obtained the 19F NMR spectrum of the product
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Figure 2. (A) 1H NMR spectra (600 MHz, DMSO-d6) of [CO3⊂1]2− obtained by the reaction of 2 (1.9 μmol) and 3 (1.9 μmol) in DMSO (500
μL) in the presence of (first spectrum) TBAF (7.6 μmol) and DBU (1.9 μmol) and (second spectrum) Na2CO3 (2.8 μmol). 1H NMR spectra (600
MHz) of model 4 in DMSO-d6 (third spectrum) CDCl3 (fourth spectrum). (B) Energy-minimized structure (MCMM/OPLS3e and DFT/M06-
2X:6-311++G**) of [CO3⊂1]2−. (C) ORTEP diagram (50% probability) of the solid-state structure of [CH3OH⊂1].
1
Figure 3. (A) H NMR spectrum (600 MHz, 298 K) of [SO4⊂1]TBA2 in DMSO-d6. (B) ORTEP diagram (50% probability) of the solid-state
structure of [SO4⊂1]TBA2; the back side of the image is removed for clarity (see SI). (C) Top and side views of the electrostatic potential surface
(DFT/B3LYP:6-31G*) of capsule [SO4⊂1]2−, after the sulfate anion was removed.
(Figure S3) and found a negligible quantity of the fluoride.
The results from ESI mass spectrometric measurements of
[anionx⊂1]TBAy showed (Figure S4) a signal at 1189 au
corresponding to (1+H)+ and another signal at 1249 a.u.
having the isotopic pattern commensurate with the formation
of [HCO3⊂1]−. Since basic fluorides generate hydroxide in
DMSO having adventitious water24 and DBU assisted the
“templation” (Figure 2A), we suspected that in situ formed
carbonate/bicarbonate anions from hydroxide and dissolved
carbon dioxide could be the true template. Accordingly, we
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Figure 4. (A) 1H NMR spectrum (600 MHz, 298 K) of [HPO4⊂1]TBA2 in DMSO-d6. (B) ORTEP diagram (50% probability) of the solid-state
structure of [HPO4⊂1]TMA2.
found that both Na2CO3 and NaHCO3 could act as effective
deshielding of amide HG (δ = 11.5 ppm) and aromatic HC (δ =
9.5 ppm) protons in [CO3⊂1]2− with respect to one-arm
model compound 4 (δ = 9.1/6.5 and 8.2 ppm, respectively)
evidenced their participation in host−guest HBs. When
[CO3⊂1]TBA2 was dissolved in methanol and the solution
was subjected to vapor from diethyl ether, we obtained single
crystals. X-ray diffraction analysis disclosed the formation of
[CH3OH⊂1] (Figure 2C) with two conformational stereo-
isomers of 1 (7:3 ratio) occupying the crystal lattice. In
essence, the hexapodal capsule used two host−guest N−HG···
O−CH3 and two intramolecular N−HG···OC (Figure 2B)
HBs to stabilize the complex. At the northern side, three
(1,3,5) imine C−HB protons occupied the capsule’s interior
(akin to 1 in Figure 1B). By comparing structures of
[CO3⊂1]2− and [CH3OH⊂1], one can see the capsule
assuming a conformation to complement different guests.
Importantly, the condensation of 2 and 3 in degassed
DMSO-d6 containing TBAF resulted in the formation of
oligomers (Figure S1). We infer that fluoride was a poor guest
of 1 and therefore ineffective in templating its formation. On
the other hand, TBACl acted as an effective template giving
templates25 (Figures S1 and S5) with H NMR spectrum of
1
[CO3⊂1]2− (Figure 2A) matching the spectrum of the product
obtained in the studies with TBAF/DBU (Figure 2A).
Moreover, a closer inspection of the 13C NMR spectrum of
[CO3⊂1]2− (from TBAF/DBU) and its comparison with that
of [13CO3⊂1]2− (from Na213CO3, Figure S6) further
corroborated the formation of this binary complex; for the
spectroscopic assignment of [CO3⊂1]2−, see Figures S7−S9.
Finally, the diffusion coefficient of [CO3⊂1]2− (DOSY NMR,
Figure S10) corresponded to rH = 8.1 Å, close to the computed
value of 1 (7.5 Å, Figure 1B).
On the basis of computational study of [CO3⊂1]2− (Figure
2B),1b the carbonate occupies the southern part of the capsule
by placing its three oxygens at the HB distance from N−HG (D
= 2.842−2.851 Å and Θ = 163.42°−164.84°)26 and Csp2−HC
(D = 3.048−3.321 Å and Θ = 159.99°−164.55°)27 while six
Csp2−HB protons cluster to populate the capsule’s top; indeed,
a small void at the top of carbonate, ∼30 Å3, could in principle
be populated with H2O (19 Å3). These results are in
1
agreement with H NMR observations in Figure 2A: large
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[Cl⊂1]TBA in 43% yield (Figures S1 and S20−S23). By
dissolving [Cl⊂1]TBA in CH2Cl2 and washing the solution
with water, we obtained 1apo (apo = lacking an anionic guest,
Figure S30); note that once exposed to water the hexaimino
capsule was chemically stable although not soluble in it. Upon
incremental addition of a standard solution of TBACl to 1apo
(DMSO-d6, Figure S30), a separate set of 1H NMR resonances
from [Cl⊂1]− appeared allowing us to, via integration,
determine a high association constant, Ka = 2 × 105 M−1,
corresponding to its formation.28 Indeed, the affinity of 1
toward anions is expected to drop in HB solvents (water,
CH3OH, etc.) and increase in nonpolar solvents (CH2Cl2,
CHCl3, etc.), albeit quantitative studies are still to be
completed with either this imine based host or its more
solvent compatible congeners.
To probe if tetrahedral oxyanions could template the
formation of 1, we ran condensations of 2 and 3 in the
presence of TBA salts of HPO42−and SO42− (Figure S1). Since
both templation processes were successful showing the
formation of [SO4⊂1]TBA2 (Figure 3A; Figures S10−S14)
and [HPO4⊂1]TBA2 (Figure 4A; Figures S10 and S15−S19),
we decided to further examine the recognition of these two
anions.
After addition of 1.5 mol equiv of Na2SO4 to 0.7 mM
solution of [Cl⊂1]TBA in DMSO-d6, a set of 1H NMR signals
corresponding to [SO4⊂1]2− grew over time (Figure S24).
With the anion metathesis requiring about a week (Figures S24
and 25), the constrictive binding characterizing the entrapment
of sulfate (55 Å3) is rather large29 with, supposedly, narrow
apertures in [SO4⊂1]2− (Figure 3C) hindering the entrance of
tetrahedral oxyanions; an addition of catalytic amounts of p-
toluenesulfonic acid (Figures S24 and S25) expedited the
anion metathesis by promoting the hydrolytic cleavage of
imine linkages.30 A more complete understanding of the
exchange mechanism though would require additional
computational and experimental studies. As in the case of
the carbonate complex, magnetic deshielding of the amide N−
HG and aromatic Csp2−HC nuclei in 1 (Figure 3A) implied the
formation of N−HG···O−S and Csp2−HC···O−S hydrogen
bonds. Moreover, the downfield shift of the imine Csp2−HB
protons (Figure 3A) denoted attractive Csp2−HB···O−S
interactions as well. In this regard, single crystals of
[SO4⊂1]TBA2 were obtained by vapor diffusion of diethyl
ether into its methanol solution. As expected, X-ray diffraction
analysis showed one sulfate anion per hexapodal 1 (Figure 3B).
Host−guest complexes [SO4⊂1]2− packed into columns along
the crystallographic a axis so that benzene “tops and bottoms”,
from juxtaposed capsules, resided at the π−π stacking distance
(3.6 Å). Furthermore, all six amides in 1 had their N−HG
groups pointing to the capsule’s interior for participating in six
N−HG···O−S hydrogen bonds (D = 2.77−2.91 Å and Θ =
157°−167°).26 Fascinatingly, the cluster of amides resembles
anion binding sites in proteins dubbed as nests.31 Following,
six aromatic Csp2−HC groups at the capsule’s equator formed
six Csp2−HC···O−S hydrogen bonding contacts (D = 3.06−
3.28 Å and Θ = 152°−171°).27 And finally, six imine Csp2−HB
protons grouped in the northern hemisphere to form a pocket
composed of positively polarized hydrogens for holding the S−
O− oxygen (D = 3.69−3.81 Å and Θ = 150°−168°, Figure
3B).27 The solution and solid-state data suggest that the
spherical pocket within [SO4⊂1]2− (Figure 3C) is lined with
18 positively polarized hydrogens contributing to a multitude
of HBs for holding the sulfate anion.
To probe the encapsulation of HPO42−, we added the
standard solution of HPO4(TBA)2 to [Cl⊂1]TBA in DMSO
1
and monitored the substitution by H NMR spectroscopy
(Figures S26 and 27). The displacement was slower than in the
case of sulfate to suggest a somewhat different mechanism for
the ingress/egress of similarly sized and shaped hydrogen
1
phosphate (59 Å3). The H NMR spectrum of [HPO4⊂1]2−
(Figure 4A) revealed downfield shifts of the capsule’s amide
N−HG and aromatic Csp2−HC resonances. On the basis of 2D
NOESY correlations (Figure 4A; Figure S19), the hydrogen
phosphate placed its P−OHK group in the northern hemi-
sphere and the vicinity of HB and HC. From 31P−1H HMBC
measurement, the cross correlation between N−HG and the
2−
phosphorus from the HPO4 guest (Figure 4A, Figure S19)
provided evidence for the amide HG protons hydrogen
bonding the anion’s oxygens. Single crystals of [HPO4⊂1]-
TMA2 (TMA = tetramethylammonium) were obtained by
vapor diffusion of tetrahydrofuran into its acetonitrile solution.
The anion is docked in the cavity of 1 (Figure 4B) with its
three negatively charged oxygens lodged in the amide nest
thereby resulting in six N−HG···O−P hydrogen bonds (D =
2.76−2.83 Å and Θ = 165°−168°).26 At the capsule’s equator,
there were six additional Csp2−HC···O−P hydrogen bonds (D
= 3.07−3.34 Å and Θ = 161°−168°).27 And finally, five imines
directed their Csp2−HB groups toward the HKO−PO32− (DC−O
= 3.56−3.95 Å and Θ = 155°−167°),27 while the same HKO−
PO32− formed a weak HB with one imine nitrogen (D = 3.27 Å
and Θ = 163°).26
In summary, fluxional host 1 altered its conformation to
complement different guests. Thus, when methanol occupied
the interior of 1 (Figure 2B), the host placed three imine
(CSp2−H) hydrogens inside and three outside while two
amides held onto methanol via hydrogen bonding. With the
sulfate (Figure 3B), the capsule assumed a conformation
comprising a spherical nest (Figure 3C) with 18 positively
polarized Csp2−Hδ+ and N−Hδ+ groups facing the anion. And
for hydrogen phosphate (Figure 4B), single imine nitrogen
from 1 complemented the phosphate’s hydroxyl while the
remaining HB sites stayed in the host’s interior.
CONCLUSION
■
In conclusion, barrel-shaped and easily accessible 1 (Figure
1C) encompasses 18 HB donating and 12 HB accepting
groups surrounding its binding pocket (78 Å3),11 with stronger
affinity toward anions (see below) than its acyclic analogues
akin to 2;15 i.e., hexa-amide receptors do not complex chloride
in DMSO.15 While acting as a host, polyvalent 1 tunes its
conformation to electronically and sterically complement the
occupant’s hydrogen bonding sites. The capsule accommo-
dates tetrahedral oxyanions (i.e., hydrogen phosphate and
sulfate) more effectively than chloride (Ka = 2 × 105 M−1),
fluoride, or carbonate. The stability of [SO4⊂1]2− is Ka > 107
M−1 (Figure S30) while that of [HPO4⊂1]−, on the basis of a
competing templation experiment (Figure S28), is somewhat
smaller. The high propensity of 1 for trapping sulfate in polar
DMSO32 makes it an excellent candidate for probing the
selective extraction of tetrahedral oxyanions from waste or the
environment.33 In this regard, our work sets the stage for
further broadening the scope and optimizing the characteristics
of hexapodal 1 and its congeners as novel abiotic and
multivalent anionic receptors with intriguing kinetic and
thermodynamic characteristics.34
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Peveler, W. J.; Jelfs, K. E. Amine Molecular Cages as Supramolecular
Fluorescent Explosive Sensors: A Computational Perspective. J. Phys.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12329.
■
sı
Additional experimental and computational details
(PDF)
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segregated benzenes - exploitation of sterically predisposed systems in
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and of its tricarbonylchromium, tricarbonylmolybdenum, and
dicarbonyl(triphenylphosphine)chromium complexes. J. Am. Chem.
Soc. 1981, 103, 6073−83.
Accession Codes
CCDC 2057358−2057360 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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[1,4-bis(4,4-dimethyl-3-oxopentyl)-2,3,5,6-tetraethylbenzene]-
chromium. J. Am. Chem. Soc. 1991, 113, 2332−3.
AUTHOR INFORMATION
Corresponding Author
■
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́
Jovica D. Badjic − Department of Chemistry & Biochemistry,
The Ohio State University, Columbus, Ohio 43210, United
States; orcid.org/0000-0001-7540-2387;
Email: badjic.1@osu.edu
Authors
Han Xie − Department of Chemistry & Biochemistry, The
Ohio State University, Columbus, Ohio 43210, United States
Tyler J. Finnegan − Department of Chemistry & Biochemistry,
The Ohio State University, Columbus, Ohio 43210, United
States; orcid.org/0000-0002-6002-8772
Vageesha W. Liyana Gunawardana − Department of
Chemistry & Biochemistry, The Ohio State University,
Columbus, Ohio 43210, United States; orcid.org/0000-
0001-5053-4236
́
Radoslav Z. Pavlovic − Department of Chemistry &
Biochemistry, The Ohio State University, Columbus, Ohio
43210, United States; orcid.org/0000-0003-1216-3950
Curtis E. Moore − Department of Chemistry & Biochemistry,
The Ohio State University, Columbus, Ohio 43210, United
States; orcid.org/0000-0002-3311-7155
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12329
Notes
The authors declare no competing financial interest.
(7) Jiao, T.; Chen, L.; Yang, D.; Li, X.; Wu, G.; Zeng, P.; Zhou, A.;
Yin, Q.; Pan, Y.; Wu, B.; Hong, X.; Kong, X.; Lynch, V. M.; Sessler, J.
L.; Li, H. Trapping White Phosphorus within a Purely Organic
Molecular Container Produced by Imine Condensation. Angew.
Chem., Int. Ed. 2017, 56, 14545−14550.
ACKNOWLEDGMENTS
■
This work was supported with funds from the NSF under
CHE-2002781. Generous computational resources from the
OSC are gratefully acknowledged.
(8) Voegtle, F.; Weber, E. Octopus molecules. Angew. Chem. 1974,
86, 896−8.
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