Stabilization and Extraction of Fluoride Anion Using a Tetralactam Receptor

Article abstract of DOI:10.1021/acs.joc.9b00042

A neutral tetralactam macrocycle was prepared in a few minutes in one pot and at high concentration using commercially available starting materials. NMR titration studies in DMSO revealed an anion affinity order of F^- > AcO^- > Cl^- > Br^-. The receptor affinity for F^- is very high due in part to formation of a self-complementary dimer comprised of two "saddle shaped" complexes. An X-ray crystal structure showed that the two F^- ions within the dimer are separated by 3.39 ?. The electrostatic penalty for this close proximity is compensated by attractive interactions provided by the surrounding tetralactam molecules. Reactivity experiments showed that stabilization of F^- as a supramolecular complex abrogated its capacity to induce elimination and substitution chemistry. This finding raises the idea of using tetralactam macrocycles to stabilize fluoride-containing liquid electrolytes within redox devices such as room-temperature fluoride-ion batteries. A lipophilic version of the tetralactam macrocycle was prepared and used to extract F^- from water into a chloroform layer with high efficiency. The favorable extraction is due to the architecture of the extracted dimeric complex, with all the polarity located within the core of the self-associated dimer and all the nonpolar functionality on the exterior surface.

Full text of DOI:10.1021/acs.joc.9b00042

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Article
Stabilization and Extraction of Fluoride Anion Using a Tetralactam Receptor
Wenqi Liu, Allen G. Oliver, and Bradley D. Smith
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00042 • Publication Date (Web): 04 Mar 2019
Downloaded from http://pubs.acs.org on March 4, 2019
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Stabilization and Extraction of Fluoride Anion Using a Tetralactam Receptor
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Wenqi Liu, Allen G. Oliver, Bradley D. Smith*
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Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall, University of Notre Dame, Notre
Dame, Indiana 46556, USA
*smith.115@nd.edu
O
O
O
O
F-
F-
NH HN
NH HN
Abstract
A neutral tetralactam macrocycle was prepared in a few minutes in one pot and at high concentration
using commercially available starting materials. NMR titration studies in DMSO revealed an anion
affinity order of F- > AcO- > Cl- > Br-. Receptor affinity for F- is very high due in part to formation of a
self-complementary dimer comprised of two “saddle shaped” complexes. An X-ray crystal structure
showed that the two F- ions within the dimer are separated by 3.39 Å. The electrostatic penalty for this
close proximity is compensated by attractive interactions provided by the surrounding tetralactam
molecules. Reactivity experiments showed that stabilization of F- as a supramolecular complex
abrogated its capacity to induce elimination and substitution chemistry. This finding raises the idea of
using tetralactam macrocycles to stabilize fluoride-containing liquid electrolytes within redox devices
such as room-temperature fluoride-ion batteries. A lipophilic version of the tetralactam macrocycle
was prepared and used to extract F- from water into a chloroform layer with high efficiency. The
favorable extraction is due to the architecture of the extracted dimeric complex, with all the polarity
located within the core of the self-associated dimer and all the non-polar functionality on the exterior
surface.
Introduction
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Although anion recognition was studied early in the history of synthetic supramolecular
chemistry, the early community focus was predominantly on cation recognition. But over last two
decades, anion recognition has emerged as a major research sub-discipline with many potential
applications in biomedicine, energy, and environmental science1–4 One of the classic problems in anion
recognition is design of synthetic receptors that selectively associate with only one of the halides.
Fluoride is the smallest halide and its strong basicity and high charge-to-surface-area ratio make it a
relatively easy target for selective recognition in aprotic solvents. High fluoride affinity is much harder
to achieve in protic solvents where the synthetic receptors have to overcome a much higher solvation
energy.5 One way to circumvent this thermodynamic barrier is to develop synthetic receptors that
incorporate Lewis acid centers such as boron, antimony or tin.6–9 While Lewis acid receptors for
fluoride have many attractive properties, they may not be the best choice in circumstances that require
long term stability or high biocompatibility. In these situations, it may be more effective to use
synthetic receptors that utilize hydrogen bonding interactions via NH and OH residues.
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Despite the extensive and growing literature on fluoride recognition chemistry,10–15 very few
synthetic hydrogen bonding receptors have been shown to capture or recognize fluoride in an aqueous
environment.4,16,17 In short, it is very challenging to design a hydrogen bonding system that can
compete with the very high enthalpy of fluoride hydration (504 kJ mol-1).18,19 This point is highlighted
by the scarcity of synthetic hydrogen bonding receptors that can extract fluoride from water.6,7,20,21 But
the need for fluoride extractors is very high since fluoride is a known pollutant that must be monitored
and removed from various types of aqueous reservoirs such as polluted lakes.22 A very different
motivation to develop supramolecular receptors for fluoride is to improve the efficiency and lifetime of
fluoride-containing electrolytes within redox devices such as fluoride-ion batteries which have high
potential as next-generation electrochemical storage devices.23 A key requirement for this technology
is a conducting, anhydrous fluoride ion electrolyte that does not decompose through elimination
chemistry.24 An unexplored potential solution is a liquid electrolyte containing a soluble receptor that
stabilizes the fluoride while still allowing high ionic conductivity. The mass scale of these two future
applications (aqueous fluoride extraction and fluoride ion batteries) is enormous and thus any practical
solution based on a synthetic fluoride receptor must be cost effective.
Our programmatic interest in supramolecular chemistry using tetralactam macrocycles25,26 led
us to consider the anion receptors reported by Jurczak and coworkers. They have systematically
explored a range of tetralactams linked by flexible alkyl chains, and observed anion binding in highly
competitive DMSO solution.27–30 Studies of 18-membered tetralactams were quite limited because the
compounds exhibited poor solubility. One of these tetralactam receptors (Scheme 1) was sufficently
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soluble in DMSO for anion titration studies and Ka for fluoride was determined to be 830 M-1.27 It
occurred to us that tetralactam 1 might be a more soluble receptor with a highly preorganized
macrocyclic structure. A literature review revealed that structural analogues of 1 have been prepared
before but they were only studied as scaffolds for copper cation binding.31–33 Here we describe the
synthesis and molecular structure of tetralactam 1 and we characterize its anion recognition ability in
solution and in the solid state. We also report the analogue 2 with an appended lipophilic chain that
enables extraction of fluoride from aqueous solution.
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Ot-Bu
O
Ot-Bu
t-BuO
O
O
t-Bu
O
O
O
A
O
O
O
O
O
O
O
O
N
HN
A'
O
C
B
NH HN
NH HN
NH HN
D
O
O
O
NH HN
N
B'
B
NH
NH
HN
HN
D
t-Bu
C
O
A
1
Jurczak’s Receptor
2
t-Bu
Scheme 1. Jurzcak’s receptor and new receptors 1 and 2 with relevant atom labels.
Result and Discussion
Synthesis
Receptor 1 was synthesized by a simple procedure that reacted 1,2-diaminobenzene with an
equal molar equivalent of 4-tert-butylisophthaloyl dichloride (Scheme 2). The reactions were
conducted in CH2Cl2 using submolar concentrations of reactants and a short reaction time (10 min at
room temperature) and the pure macrocycle product 1 was obtained in 26 % isolated yield. During the
reaction optimization studies it was found that the purification process was facilitated if
tetrabutylammonium chloride (TBA+•Cl-) was included in the reaction because it formed a soluble
complex with 1. It is likely that Cl- also promoted the desired reaction by acting as a macrocyclization
template.34 The asymmetric macrocycle 2 was prepared in two steps via intermediate bisamine 4. The
first round of reactions provided enough material for all studies and no attempt was made to optimize
the synthetic yield. But if the synthesis was to be repeated, it is likely that the yield of the second
macrocyclization step could be increased by employing literature modifications.32
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t-Bu
TBACl, Et3N
r.t., CH2Cl2, 10 min
NH2
NH2
3
4
+
O
O
1
26%
Cl
Cl
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Cl
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1.
Ot-Bu
O
O
O
Ot-Bu
t-BuO
Cl
Cl
O
O
r.t., Et3N, CH2Cl2, 5 min
NH2
O
Ot-Bu
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O
O
O
Ot-Bu
t-BuO
2.
O
O
NH
10 min
O
NH2
12%
O
O
O
O
O
NH2
NH HN
3
NH2 H2N
4
t-Bu
O
O
Cl
Cl
r.t., TBACl, Et3N, CH2Cl2, 30 min
2
15%
Scheme 2. Synthesis of 1 and 2
X-Ray Crystal Structures.
The X-ray crystal structure of empty 1 was obtained by slow diffusion of diethyl ether into a
solution of 1 dissolved in a mixture of CHCl3 and DMSO at room temperature. As shown in Figure 1,
the macrocycle adopts a closed conformation with two intramolecular hydrogen bonds.28 In Figure 2
are crystal structures of 1•Cl-, and 1•AcO-, which were obtained by slow diffusion of diethyl ether into
a solution of 1 and excess TBA+ salt in CHCl3/DMSO at 5 ˚C. In both structures, the macrocycle
adopts a relatively flat conformation with the anion perched above the central cavity. Hirshfeld surface
analysis35 (Figure S8-S10) of the diffraction data indicates that the Cl- forms hydrogen bonds with all
four amide NH residues (average NH•••Cl distance 2.56 Å) and the two isophthalamide CH protons
(average CH•••Cl distance 2.64 Å) of 1, while the anisotropic AcO- bridges the two pair of amide NH
residues (average NH•••O distance 1.98 Å) and interacts less strongly with the two isophthalamide CH
protons (average CH•••O distance 2.82 Å).
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t-Bu
H
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N
O
HN
O
O
NH
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H
t-Bu
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Figure 1. (left) X-ray crystal structure of empty 1, (right) chemical structure highlighting the closed
conformation with dashed lines indicating intramolecular hydrogen bonds. Lattice DMSO molecules
are omitted for clarity.
(a)
(b)
Figure 2. Side and top views of X-ray crystal structures of, (a) 1•TBA+•Cl-, and (b) 1•TBA+•AcO-. For
clarity, the TBA+ cation is omitted in each case, so is a lattice CHCl3 molecule in (b).
A single crystal of 1•F- was obtained by slow diffusion of pentane into a solution of 1 and
excess TBA+•F- in CHCl3/DMSO at 5 ˚C. X-ray diffraction analysis of the crystal showed that the F- is
buried in the cavity and forms hydrogen bonds with all four amide NH residues (average NH•••F
distance 1.86 Å) and the two isophthalamide CH protons (average CH•••Cl distance 2.31 Å). Unlike
the relatively flat structures of 1•TBA+•Cl- and 1•TBA+•AcO-, the structure of 1•TBA+•F- adopts a
“saddle shape” with each pair of opposing aromatic rings in 1 oriented at angles of 34.24 and 54.44°.
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In Figure 3a is a view of the crystal for 1•TBA+•F- that highlights the lattice packing as a series of
homodimers, i.e., [1•TBA+•F-]2 that are created by complementary head-to-head stacking of two
saddle-shaped complexes. Reduced Density Gradient (RDG) analysis36,37 analysis (Figure S11-S12)
reveals a large dimer interface for attractive π-π stacking and van der Waals interactions between the
two macrocycle surfaces. These attractive interactions stabilize the repulsions caused by the
dehydrated F-•••F- distance of 3.39 Å. The two counter TBA+ cations contact opposing exterior
surfaces of the dimer and form CH•••π interactions (Figure 3b). Similar CH•••π interactions were also
observed in the crystal structures of 1•TBA+•Cl and 1•TBA+•AcO-.
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(a)
(b)
Figure 3. Side and top views of the X-ray crystal structure for 1•TBA+•F-. The views in (a) highlight
the self-complementary stacking of two saddle-shaped complexes to form a solid-state homodimer
[1•F-]2, and the views in (b) show how the two TBA+ counter cations (purple) contact the opposing
exterior surfaces of the dimer. A lattice CHCl3 molecule is omitted for clarity.
Solution-State Association Studies
Anion affinities for 1 were evaluated by conducting 1H NMR titration experiments in DMSO-d6
that added the anions as TBA+ salts (Figure S13-S20). As expected, peaks for the macrocycle amide
NH protons and isophthalamide protons B moved incrementally downfield as the titration progressed
indicating that anion complexation was rapid on the NMR time scale. In each case, the chemical shift
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for the isophthalamide protons B was plotted against anion concentration and the titration isotherms
were fit to standard binding models using nonlinear computer methods. The curves for Cl- and Br-
fitted well to a simple 1:1 binding model, whereas the isotherms for F- or AcO- required a binding
model that formed a mixture of 1:1 and 2:1 macrocycle:anion complexes.29,38 Listed in Table 1 are the
derived associations, K1 and K2. As expected, the values of K1 for the anions decreased in the order of
F- > Cl- > Br-. It is notable that the affinity of tetralactam 1 for F- in DMSO-d6 is sixty times higher than
Jurczak’s receptor in Scheme 1,27 five times higher than a structurally similar tetrathiolactam reported
by Kanbara and Yamamoto,39a and twenty times higher than a related 16-membered tetralactam
reported by Lin.39b In Figure 4 is a comparison of the 1H spectra for free 1 and the spectra for 1 after
adding a large molar excess of each TBA+ salt. There is a consistent trend of higher K1 correlating with
a larger downfield change in NH chemical shift. Another distinctive feature of the NMR spectra is the
difference in peaks widths. Most of the peaks for solutions of 1 saturated with Cl- or Br- in a 1:1
stoichiometry are narrow. In comparison, most of the peaks for the solutions of 1 saturated with F- or
AcO- are slightly broadened because the complexes are an exchanging mixture of 1:1 and 2:1
stoichiometries.
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Table 1. Association constants for 1 in DMSO-d6 at 25 ˚C.
Guesta
F-
K1 (M-1)
K2 (M-1)
(5.3±0.8) × 104 (3.1±0.7) × 103
Cl-
(363±5)
(23±1)
N.A.
N.A.
Br-
AcO-
(1.2±0.1) × 104
445±15
a TBA+ salt
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A
D
3
4
C
NH
B
(e)
1+TBAOAc
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A
D
C
B
NH
(d)
(c)
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A
NH
D
C
C
B
1+TBABr
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D
B
(b)
(a)
1+TBACl
NH
A
D
B
C
1
Figure 4. Partial 1H NMR spectra (600 MHz, DMSO-d6, 25 ˚C) of: (a) free receptor 1. Receptor 1
mixed with: (b) 11 molar equiv. of TBA+•Cl-, (c) 16 molar equiv. of TBA+•Br-, (d) 1.8 molar equiv. of
TBA+•F-, and (e) 3.5 molar equiv. of TBA+•AcO-.
Mass spectrometric analysis (Figure 5, S1-S3) of separate chloroform samples containing 1
mixed with TBA+ salts of F-, Cl-, Br-, or AcO- produced observable 1:1 complexes, and in the cases of
F- and AcO- there were also peaks for the 2:1 complexes (i.e., [12•F-] and [12•AcO-]). Interestingly, the
mass spectrum of 1 mixed with TBA•F- also showed a strong peak for the dimeric complex
[12•(F-)2•TBA+]- (Figure 5), further suggesting that the dimer is an abundant species in solution.
[12·(F)]-
100
1195.5453
80
[12·(F2)(TBA)]-
60
1456.8286
R
e
l
.
I
n
t
.
(
%
)
40
20
1400
1500
1200
1300
m/z
Figure 5. Negative ion HRMS (ESI) of 1•TBA+•F- in CHCl3.
Computational Studies of Fluoride Association
Supramolecular complexes that contain clusters of multiple anions are rare but increasingly
known.40 In the case of complexes with multiple F-, there are examples of single receptor molecules
containing multiple F- and also [receptor•F-] complexes that self-associate to form aggregates.40 Most
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of the F- clusters are hydrated but when there is no hydration the F-•••F- distance is in the range of
2.91-3.26 Å.11,41 The dehydrated F-•••F- pair in dimeric [1•F-]2 is separated by 3.39 Å which is a
comparatively long distance and suggests that the surrounding pair of macrocycles prevent closer
approach and provide stability. As shown in Figure 6, a DFT energy calculation of two F- ions
separated by 3.39 Å in the gas phase produces an unfavorable binding energy of +95.5 kcal/mol. A
calculated electrostatic potential map of the saddle shaped tetralactam 1 reveals a strongly positive
potential at the macrocycle core (Figure S21). The binding energy is reduced to +50.6 kcal/mol when a
copy of 1 is associated with one of the two separated F- ions, and further reduced to +46.3 kcal/mol
when a second copy of 1 is associated with the other F- ion. Obviously, these binding energies would
be further relieved if the counter TBA+ cations and solvent were included in the model. Stabilization of
anion dimers by a surrounding pair of cofacially-stacked macrocycle receptors has been reported
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- 42
before for other anions such as HSO4 .
(a)
ΔE = + 95.5 kcal/mol
+
(b)
ΔE = + 50.6 kcal/mol
+
(c)
ΔE = + 46.3 kcal/mol
+
Figure 6. DFT calculation of 2 [1•F-] dimerization at B3LYP-6-31G+** level.
Non-Covalent Stabilization of F- and Attenuation of F- Reactivity.
F- can react as a base or as a nucleophile, and often induces a mixture of competing elimination
and substitution chemistry.43 Recent reports have shown how hydrogen-bonding F- receptors can be
used to favor one specific reaction pathway (usually substitution) and thus produce a desired synthetic
outcome.10,11,13 But to the best of our knowledge, a hydrogen-bonding receptor has not been shown to
eliminate all F- reactivity, a circumstance that is needed when F- is employed as a stable electrolyte in
redox devices.23,24 We reasoned that the capability of tetralactam 1 to stabilize F- inside self-associated
dimers would lead to strong attenuation of F- reactivity. To prove this concept, we conducted the two
comparative reactions shown in Scheme 3. The first reaction used a microwave to heat a mixture of (3-
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bromopropyl)benzene and TBA+•F- in CD3CN at 90 ˚C for 10 minutes. After heating, the reaction
solution was light yellow (Figure S22) and 1H NMR analysis of the solution (Figure S23) showed that
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40% of the (3-bromopropyl)benzene had been converted into the expected elimination and substitution
products (1:1 product ratio), along with some base promote hydrolysis and degradation of the TBA+.
The second reaction employed the same reagents and heating conditions but also included one molar
equivalent of tetralactam 1 as an additive. In this case, the solution remained colorless and 1H NMR
analysis (Figure S24) showed that there was no reaction. Thus, the results clearly show that
tetralactams, such as 1, have excellent ability to abrogate F- reactivity.
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CD3CN
Br
Br
F
TBA+•F-
TBA+•F-
+
+
+
µW, 90 °C,
10 mins
20%
20%
CD3CN
no reaction
1 (one equiv.)
µW, 90 °C,
10 mins
Scheme 3. Effect of tetralactam 1 on F- reactivity.
Fluoride extraction from water
Extracting fluoride from water is important for water purification1 and 18F radiolabeling
technology.14 The modified macrocycle 2 has high solubility in common organic solvents and therefore
was used for fluoride extraction experiments. First, a biphasic extraction was performed by mixing the
solution of 2 (3 mM) in CDCl3 (1 mL) with a solution of TBA+•F- (12 mM) in D2O (1 mL). The
extracted CDCl3 layer was separated and analyzed by 19F and 1H NMR spectroscopy. A single 19F peak
was observed at 39 ppm, greatly down-field from the signal at -126 ppm for a control sample of
TBA+•F- in CDCl3 (Figure 7). A control extraction experiment showed that in the absence of 2 there
was no 19F signal in the extracted CDCl3 layer. Thus, the 19F NMR data indicated that tetralactam 2
extracted TBA+•F- out of water and into CDCl3 by forming a complex. In Figure 8a is the 1H NMR
spectrum for the extracted CDCl3 layer. Peak integration revealed a 2:1 stoichiometry between 2 and
TBA+, indicating the extracted complex to have the formula [22•F-•TBA+] which is consistent with the
gas phase species [12•F-] identified by mass spectrometry in Figure 5. Furthermore, the 1H NMR peaks
for the TBA+ cation within the extracted [22•F-•TBA+] complex were up-field of the signals for free
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TBA+•F- in CDCl3 (Figure S25) suggesting that the TBA+ was associated with the exterior aromatic
surface of [22•F-]. Independent evidence for this conclusion was gained by acquiring a 1H ROESY
spectrum (Figure S26) of the extracted CDCl3 solution and observing cross-relaxation between the
TBA+ protons and protons A and A’ on receptor 2 (atom labeling in Scheme 1).
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Figure 7. 19F NMR (470 MHz) spectra (4-fluorobenzaldehyde as external reference) for two separate
samples: (bottom) free TBA+•F- in CDCl3, (top) CDCl3 layer containing 2•TBA+•F- after biphasic
extraction experiment.
The same biphasic extraction experiment was conducted using 2 and TBA+•Cl-. As shown by
the 1H NMR spectra in Figures 8b and S27 there was a 1:1 stoichiometry between 2 and TBA+,
indicating the extracted complex to have the formula [2•Cl-•TBA+] which is consistent with all the
other data for this complex. A final experiment was a biphasic competitive extraction using 2 and an
equimolar mixture of TBA+•F- and TBA+•Cl-. Combined 1H and 19F NMR analyses of the extracted
CDCl3 layer indicated that 4% of the extracted complex contained F- and 96% contained Cl- (Figure
S28-S29) This result is not surprising considering the strong Hofmeister bias for Cl- over F- due to the
large difference hydration energies. The inability to selectively extract F- over Cl- might be a limitation
for environmental purification where high Cl- is a common occurrence, but this scenario is less likely
to arise in 18F radiolabeling technology.14
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Figure 8. Partial 1H NMR (500 MHz) of CDCl3 layer after biphasic extraction experiment. (a)
extracted complex with the formula [22•TBA+•F-], (b) extracted complex with the formula
[2•TBA+•Cl-]. The complete NMR spectra and associated analysis are provided in the Supporting
Information.
Conclusion
Macrocyclic tetralactam 1 can be prepared in one pot and high mass scale from commercially
available starting materials. It has moderate solubility in organic solvents, especially when it is
complexed with TBA+ salts. In DMSO solution it exhibits the complexation affinity order of F- >
AcO- > Cl- > Br-. The very high affinity for F- is noteworthy and in DMSO solution the 1•F-
complexation stoichiometry is a mixture of 1:1 and 2:1. An X-ray crystal structure of 1•TBA+•F-
reveals lattice packing of two “saddle shaped” complexes as a self-complementary dimer. The two F-
ions within the dimer are separated by only 3.39 Å and the electrostatic penalty for this close proximity
is overcome by attractive interactions provided by the two surrounding receptor molecules. Because of
its capability to stabilize F- inside self-associated dimers, tetralactam 1 can eliminate the propensity of
F- to induce elimination and substitution chemistry. This finding raises the intriguing idea of
employing tetralactam receptors, such as 1, to stabilize fluoride-containing electrolytes within redox
devices such as room-temperature fluoride-ion batteries.23 Future investigations are needed to ascertain
if tetralactams can stabilize F- in solution while still allowing rapid F- conduction and capture/release at
metal fluoride electrodes.24
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The unsymmetric tetralactam 2 with appended lipophilic groups can be prepared in two simple
steps and has very high solubility in organic solvents. Biphasic extraction experiments with 2 in the
organic layer and an aqueous layer containing low millimolar concentration of TBA+•F- produced
saturation of 2 as a fluoride complex. The extraction efficiency is much better than most other reported
examples of fluoride extraction using an uncharged hydrogen bonding receptor. Typically, 60%-80%
of receptor saturation has been obtained when the starting water layer contained molar or submolar
concentrations of fluoride. 6,20,21,44–46 The high extraction efficiency is due in large part to the core-shell
architecture of the extracted dimeric complexes that contain one or two F- ions surrounded by two
copies of self-associated 2. All of the polar functional groups are buried within the dimer core, whereas
non-polar functionality dominates the exterior surface. If needed, the stability of the dimeric F-
encapsulation process can likely be enhanced by using covalently linked versions of 2 that can act as
“clam shell” receptors,16 or alternatively 2 can be grafted onto a polymeric backbone to create an
immobilized extraction agent.20
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Experimental
General
1H, 13C and 19F NMR spectra were recorded on 400, 500, or 600 MHz spectrometers at 25 ˚C. Chemical
shift is presented in ppm and referenced by residual solvent peak. Mass spectrometry (MS) was
performed using a time-of-flight spectrometer with electrospray ionization (ESI). Commercially
available solvents and chemicals were used without further purification unless otherwise stated. Water
was de-ionized and micro filtered. Flash column chromatography was performed using silica gel as the
stationary phase. 5-(tert-Butyl)isophthaloyl dichloride and compound 3 were synthesized according to
reported procedures.47
Synthesis and Characterization
Tetralactam 1. 5-(tert-butyl)isophthaloyl dichloride (200 mg, 0.77 mmol) in dried CH2Cl2 (5 mL) was
added dropwise over two minutes to a dried CH2Cl2 solution (5 mL) of 1,2-diaminobenzene (83 mg,
0.77 mmol), tetrabutylammonium chloride (1.1 g, 3.85 mmol) and Et3N (0.5 mL, 3.6 mmol), and the
reaction mixture was stirred at room temperature for a total of 10 minutes. The solvent was removed
and the residue was purified by column chromatography using 10% acetone/CHCl3 to elute 1 as a
white solid (60 mg, 26% yield). (Note: eluted fractions containing pure 1 gradually form a precipitate
during the column chromatography process). m.p. >260 ˚C. 1H NMR (500 MHz, DMSO-d6) δ 10.23
(s, 4H), 8.58 – 8.48 (m, 2H), 8.21 (d, J = 1.5 Hz, 4H), 7.88 (dd, J = 6.0, 3.5 Hz, 4H), 7.34 (dd, J = 6.0,
3.5 Hz, 4H), 1.38 (s, 18H). 13C {1H} NMR (126 MHz, DMSO-d6) δ 165.8, 152.7, 135.2, 131.5, 128.3,
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+
126.5, 125.8, 124.4, 35.6, 31.6. HRMS (ESI-TOF) m/z: (M + Na]+ Calcd for C36H36N4NaO4
611.2629; Found; 611.2606.
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Bis(amine) 4. A solution of compound 3 (1.00 g, 1.98 mmol) in dry CH2Cl2 (15 mL) was added drop
wise over 2 min to a solution of 1,3,5-benzenetricarbonyl trichloride (0.525 g, 1.98 mmol) in dry
CH2Cl2 (20 mL) at room temperature. Et3N (3.8 mL,19.8 mol) was then added drop wise to the
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reaction and the mixture stirred for 5 min. Benzene-1,2-diamine (0.43g, 3.96 mmol) in dry CH2Cl2 was
added to the reaction mixture and stirred for 10 min. The solvent was removed and the residue was
purified by column chromatography using 10% acetone in CHCl3 to elute the product 4 as yellow
viscous liquid (220 mg, 12% yield). (Note: This compound was isolated with moderate purity and used
for the next step without further purification). 1H NMR (600 MHz CDCl3) δ 8.96 (d, J = 3.3 Hz, 2H),
8.66 (s, 1H), 8.44 (s, 2H), 7.23 – 7.16 (m, 2H), 7.04 (td, J = 7.7, 1.5 Hz, 2H), 6.84 (s, 1H), 6.81 – 6.71
(m, 4H), 3.82 (d, J = 4.6 Hz, 6H), 3.67 (t, J = 6.0 Hz, 6H), 2.44 (t, J = 6.0 Hz, 10H), 1.34 (s, 27H). 13C
{1H} NMR (151 MHz, CDCl3) δ 171.4, 166.3, 164.4, 141.4, 136.1, 134.9, 134.5, 129.9, 129.0, 127.4,
125.9, 125.8, 123.9, 119.2, 118.1, 80.8, 68.9, 67.1, 60.6, 36.4, 28.1. HRMS (ESI-TOF) m/z: (M + H]+
Calcd for C46H64N5O12+ 878.4546; Found; 878.4565.
Macrocycle 2. 5-(tert-Butyl)isophthaloyl dichloride (64.9 mg, 0.25 mM) in dried CH2Cl2 (5 mL) was
added over 2 min to a mixture of 4 (220 mg, 0.25 mM), TBA+•Cl- (69 mg, 0.25 mM) and Et3N
(0.17mL, 1.25 mM) in dried CH2Cl2 (5 mL) and stirred at room temperature for 30 min. The reaction
mixture was purified by column chromatography using 10 % acetone/CH2Cl2 to elute pure 2 as an off-
white solid (41 mg, 15% yield). M.P. >260 ˚C. 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 2H), 9.72 (s,
2H), 8.78 – 8.69 (m, 2H), 8.57 (s, 1H), 8.44 – 8.28 (m, 3H), 7.50 (d, J = 8.0 Hz, 4H), 6.95 (s, 1H), 6.92
– 6.73 (m, 4H), 3.93 (s, 6H), 3.76 (t, J = 6.0 Hz, 6H), 2.49 (t, J = 6.0 Hz, 6H), 1.54 (s, 9H), 1.33 (s,
27H). 13C {1H} NMR (101 MHz, CDCl3) δ 171.6, 166.4, 165.8, 165.5, 153.2, 137.2, 135.4, 134.5,
131.3, 130.2, 129.8, 129.5, 128.3, 126.8, 126.1, 125.8, 123.9, 81.1, 69.4, 67.4, 60.9, 36.7, 31.6, 28.3.
HRMS (ESI-TOF) m/z: (M + Na]+ Calcd for C58H73N5O14Na+ 1086.5046; Found; 1086.5084.
General Procedure for NMR Titration
Association constants between host 1 and different guest anions were determined by standard 1H NMR
titration methods that added TBA+ salts in DMSO-d6 (D, 99.9%) at 25˚C. The same titration procedure
was used for each replicate and reproducibility was excellent. Standard precautions were used to
exclude water although it is likely that a small amount was absorbed by the hygroscopic solvent. The
concentration of the host was between 1 mM and 3 mM. The stock solution concentration of anion
guest was between 20 mM and 200 mM. The guest solution was prepared using host solution which
ensured that the concentration of host did not change over the whole titration process. Aliquots from
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guest stock solution were added sequentially to an NMR tube containing 1 and 1H NMR spectrum was
acquired after each addition. The chemical shift of host proton B (atom labels in Scheme 1) was fitted
to a 1:1 or 2:1 association model as described further in the Supporting Information.
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Molecular Modeling
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The coordinates for 1 were directly extracted from the X-ray crystal structure of 1•TBA+•F- and the t-
Bu groups were replaced with H to reduce the calculation time. The single point energy for each state
of separated F- ions in Figure 6 was calculated by Gaussian 09 at B3LYP/6-31+G** level without
structural optimization, and frequency calculations were not performed. The binding energy is the
difference between the single point energy of the state and the sum of single point energies for the
individual components. The structures were visualized using Mercury 3.5.1.
Reactivity Experiments
A stock solution (1 mL) of (3-bromopropyl)benzene (40 mM) was prepared in CD3CN. A stock
solution (1 mL) of TBA+•F-•3H2O (40 mM) was prepared in CD3CN, and the concentration was
further calibrated by 1H NMR peak integration using (3-bromopropyl)benzene as internal standard.
Two reaction solutions were prepared and compared. The first solution (solution A) (1 mL) was
prepared as a mixture of (3-bromopropyl)benzene (2 mM) and TBA+•F- (2.7 mM). The second solution
(solution B) was prepared as a mixture of (3-bromopropyl)benzene (2 mM), TBA+•F- (2.7 mM) and 1
(2.7 mM) (note that 1 is only soluble in CD3CN when TBA+•F- is present). Both solutions were heated
in sealed vessels at 90 ˚C for 10 min using a microwave reactor. 1H NMR spectra were acquired after
the reaction and the product yields determined by peak integration.
General Procedure for Anion Extraction
A solution of 2 (3 mM, 1 mL) in CDCl3 was mixed with the solution of TBA+•F- (12 mM, 1 mL) in
D2O and the solution was vortexed for 3 minutes. The mixture was allowed to sit for 1 hour to ensure
clean separation of the layers. The organic layer was separated and analyzed by 1H and 19F NMR. The
same procedure was used for TBA+•Cl- (12 mM, 1 mL) extraction, and also for the biphasic
competitive extraction of TBA+•F- (12 mM, 1 mL) and TBA+•Cl- (12 mM, 1mL) with 2.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS publications website at DOI:
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NMR spectra, Mass spectra, X-ray crystallography data, Hirshfeld surface analysis, RDG calculation,
computational data, NMR titration data, fluoride reactivity, and fluoride extraction data (pdf).
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AUTHOR INFORMATION
Corresponding Author
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*E-mail: smith.115@nd.edu
ORCID
Wenqi Liu: 0000-0001-6408-0204
Bradley D. Smith: 0000-0003-4120-3210
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by a grant from the NSF (CHE1708240).
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