Shape-Selective Recognition of Quaternary Ammonium Chloride Ion Pairs

Article abstract of DOI:10.1021/acs.joc.8b03197

Synthetic receptors that recognize ion pairs are potentially useful for many technical applications, but to date there has been little work on selective recognition of quaternary ammonium (Q⁺) ion pairs. This study measured the affinity of a tetralactam macrocycle for 11 different Q⁺·Cl^- salts in chloroform solution. In each case, NMR spectroscopy was used to determine the association constant (K_a) and the structure of the associated complex. K_a was found to depend strongly on the molecular shape of Q⁺ and was enhanced when Q⁺ could penetrate the macrocycle cavity and engage in attractive noncovalent interactions with the macrocycle's NH residues and aromatic sidewalls. The highest measured K_a of 7.9 × 10³ M^-1 was obtained when Q⁺ was a p-CN-substituted benzylic trimethylammonium. This high-affinity Q⁺·Cl^- ion pair was used as a template to enhance the synthetic yield of macrocyclization reactions that produce the tetralactam receptor or structurally related derivatives. In addition, a permanently interlocked rotaxane was prepared by capping the end of a noncovalent complex composed of the tetralactam macrocycle threaded by a reactive benzylic cation. The synthetic method provides access to a new family of rotaxanated ion pairs that can likely act as anion sensors, molecular shuttles, or transport molecules.

Full text of DOI:10.1021/acs.joc.8b03197

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Article
Shape-Selective Recognition of Quaternary Ammonium Chloride Ion-Pairs
Dong-Hao Li, and Bradley D. Smith
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03197 • Publication Date (Web): 07 Feb 2019
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Shape-Selective Recognition of Quaternary Ammonium Chloride Ion-Pairs
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Dong-Hao Li and Bradley D. Smith*
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Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall, University of Notre
Dame, Notre Dame, IN 46556, USA
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*email correspondence: smith.115@nd.edu
Table of Contents/Abstract Graphics
ABSTRACT
Synthetic receptors that recognize ion-pairs are potentially useful for many technical
applications but to date there has been little work on selective recognition of quaternary
ammonium (Q+) ion-pairs. This study measured the affinity of a tetralactam macrocycle for eleven
different Q+•Cl- salts in chloroform solution. In each case, NMR spectroscopy was used to
determine the association constant (Ka) and the structure of the associated complex. Ka was found
to depend strongly on the molecular shape of Q+ and was enhanced when Q+ could penetrate the
macrocycle cavity and engage in attractive non-covalent interactions with the macrocycle’s NH
residues and aromatic sidewalls. The highest measured Ka of 7.9 × 103 M-1 was obtained when
Q+ was a para-CN substituted benzylic trimethylammonium. This high-affinity Q+•Cl- ion-pair was
used as a template to enhance the synthetic yield of macrocyclization reactions that produce the
tetralactam receptor or structurally related derivatives. In addition, a permanently interlocked
rotaxane was prepared by capping the end of a non-covalent complex comprised of the
tetralactam macrocycle threaded by a reactive benzylic cation. The synthetic method provides
access to a new family of rotaxanated ion-pairs that can likely act as anion sensors, molecular
shuttles, or transport molecules.
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INTRODUCTION
Synthetic receptors that recognize ion-pairs are potentially useful for many technical
applications including purification, templated synthetic chemistry, catalysis, membrane transport,
and drug delivery.1–7 To date, most of the effort has focused on receptors that recognize alkali or
alkaline metal salts as either contact or separated ion-pairs. The goal of many published studies
has been to develop heteroditopic receptors with distinct anion and cation sites, and to show that
they exhibit positive binding cooperativity.8 One example of positive cooperativity, that is relevant
to this report, is when the association constant, Ka, for anion binding to a heteroditopic receptor
is increased by simultaneous binding of a proximal cation.9 This type of positive binding
cooperativity seems intuitive since the cation and anion guests are attracted electrostatically. But
as discussed by others, ion-pair recognition in weakly polar solvents can be quite a complicated
phenomenon involving several competing equilibria.10,11
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The community focus on alkali or alkaline metal salts is understandable since they have
a high charge-to-surface ratio and a strong propensity to form ion-pairs in weakly polar solvents.
In contrast, quaternary ammonium cations have a much lower charge-to-surface ratio and are
often treated as diffuse cations that do not favor ion-pairs.12 Indeed, most studies of anion binding
in organic solvents use tetrabutylammonium (TBA+) salts with the assumption that there is
negligible interaction between the anion and the TBA+ counter cation.13 However, quaternary
ammonium salts are known to form weak ion-pairs in non-polar solvents and there are a few
published reports of receptor systems that bind quaternary ammonium or alkyl pyridinium salts
as ion-pairs.14–19 A common structural feature of these literature heteroditopic receptor molecules
is an aromatic surface to interact with the organic cation and a separate set of hydrogen donors
for anion binding.20–25 But to the best of our knowledge there has been no systematic study
showing how anion affinity can enhanced by changing the identity of a quaternary ammonium
cation.
Here we report that the Cl- binding ability of macrocyclic receptor M (Scheme 1a) in
chloroform solution depends strongly on the structural shape of the counter quaternary
ammonium cation, Q+. We first disclosed M in 2007 and showed that its macrocyclic structure is
highly preorganized with the four NH residues directed inwards towards the macrocyclic cavity
(Scheme 1b).26,27 We have previously demonstrated that M has high binding affinities for various
squaraine dyes, and more recently we discovered that M also has high affinities for several anionic
square planar coordination complexes of precious metals.28 During these projects we noted that
M binds Cl- with unusually weak affinity. Molecular modelling suggests that the bound Cl- is
perched outside the cavity of M to avoid repulsive interactions with the electron-rich cavity (which
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is lined with anthracene sidewalls) and that there is essentially no interaction of M or Cl- with the
diffuse TBA+ (Scheme 1c and 1e).
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Scheme 1. (a) Chemical structures of receptor M and the quaternary ammonium chloride
that salts were studied as guests. Cartoon representations of (b) empty M, (c) Cl-@M, and
(d) Q+•Cl-@M. (e) Energy-minimized structure (semiempirical, PM7) of TBA+•Cl-@M with
TBA+ deleted for clarity.
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We wondered if the Cl- binding ability of M could be enhanced if the TBA+ was replaced
with a quaternary ammonium cation, Q+ that had the structural shape and functionality to interact
with the internal cavity of M.29 As a starting hypothesis, we assumed that the Cl- would occupy
two of the NH residues in M and thus the remaining two NH residues and the aromatic sidewalls
of the macrocycle’s cavity would be available for non-covalent interactions with Q+ (see Scheme
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1d). The hypothesis was tested by conducting a series of NMR titration experiments that added
the eleven different Q+•Cl- salts shown in Figure 1a. The structures of the Q+ component contained
different functional groups, such as hydrogen bond acceptors and aromatic surfaces, that could
potentially interact with the functionality within the cavity of M. In some cases, there is clear
evidence that Q+ penetrates the cavity of M and induces a large increase in Cl- affinity (i.e., positive
binding cooperativity). The practical value of this finding is demonstrated by; (a) employing a high
affinity Q+•Cl- guest as an ion-pair template to greatly enhance the yields of macrocyclization
reactions that make M or structurally related derivatives, and (b) conducting a capping reaction
that creates a new type of rotaxanated ion-pair.
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RESULTS AND DISCUSSION
NMR Studies of Association
All of the following NMR studies were conducted in CDCl3 and thus an additional criterion
for choice of Q+•Cl- beyond its molecular structure was good solubility at millimolar concentration.
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The first set of H NMR studies simply acquired spectra of M in the presence of one molar
equivalent of Q+ salts. In all cases, the spectral patterns where consistent with either no
interaction, or an association process that was rapid on the NMR timescale.
In Figures 1 and 2 are spectra for different samples containing acetylcholine salts where
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Q+ = 1+ and the counter anion is Cl- or BArF (BArF = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate).
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A comparison of the spectra for free M (Figure 1a), 1+•BArF (Figure 1e) and a 1:1 mixture of M +
1+•BArF (Figure 1c) shows no change in chemical shifts indicating no interaction of M with 1+ or
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BArF . In contrast, a comparison of the spectra for free M, 1+•Cl- and a 1:1 mixture of M + 1+•Cl-
(Figure 2) shows complexation-induced changes in chemical shifts. Specifically, there are upfield
changes in chemical shift for all protons in 1+ and downfield changes in chemical shift for the NH
residues and protons B of M. These changes indicate hydrogen bonding between M and Cl- and
inclusion of 1+ inside the cavity of M. Independent confirmation that 1+ was inside the cavity of M
was gained by observing cross-relaxation peaks in the ROESY spectrum for a 1:1 mixture of M +
1+•Cl (Figure S33). The peaks indicated through space interactions between macrocycle proton
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B and several protons in 1+. A final comparison of spectra for a 1:1 mixture of M + 1+•BArF (Figure
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1c) and 1:1:1 mixture of M + 1+•BArF + TBA+•Cl- (Figure 1d) shows that the presence of the Cl-
promotes binding of 1+ inside M (indicated by the upfield changes in chemical shifts for the protons
in 1+ and downfield changes in chemical shift for the NH residues and protons B in M). Together,
this collection of spectral data suggests that the affinity of M for Cl- is enhanced when the counter
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cation (Q+) is changed from TBA+ to 1+ because M binds 1+•Cl- as an ion-pair with 1+ stabilized
inside the cavity of M.
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Figure 1. Partial 1H NMR spectra (400 MHz, CDCl3, 1 mM, 25 oC) of (a) M, (b) equimolar mixture
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of M and TBA+•Cl-, (c) equimolar mixture of M and 1+•BArF , (d) equimolar mixture of M, 1+•BArF
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and TBA+•Cl-, (e) 1+•BArF . Atom labels for M are provided in Scheme 1.
Figure 2. Partial 1H NMR spectra (400 MHz, CDCl3, 1 mM, 25 oC) of (a) M, (b) equimolar mixture
of M and 1+•Cl-, (c) 1+•Cl-. Atom labels for M are provided in Scheme 1.
This conclusion was confirmed and quantified by conducting a series of separate NMR
titration experiments that added different salts Q+•Cl- to a solution of M in CDCl3 and measured
the Cl- affinity (Ka). As a starting point, we added aliquots of TBA+•Cl- to M and generated titration
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isotherms by plotting the changes in chemical shift for the macrocycle peaks. As shown by the
data in Figure S38, there was a large downfield change in NH chemical shift indicating hydrogen
bonding between the Cl- and the amide NH residues in M. The titration isotherms were found to
fit nicely to a 1:1 binding model and a weak Ka of 50 M-1 was determined (Figure S39). The next
NMR titration experiment added 1+•Cl- to a solution of M (Figure S40). Non-linear fitting of the
titration isotherm (Figure S41) and an independent Job’s plot (Figure S36) both indicated a 1:1
binding stoichiometry and a Ka of 890 M-1. In other words, substituting TBA+ for 1+ increased Cl-
affinity for M by 19-fold.30
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The changes in NMR chemical shifts for binding of M by 1+•Cl indicated that the acetyl-
bearing arm of 1+ penetrated deep inside the cavity of M. Computer-based molecular modeling of
the complex suggested the supramolecular complex 1+•Cl-@M that is shown in Figure 3a with the
carbonyl oxygen of 1+ hydrogen bonded with the second pair of macrocycle NH residues. To
quantify the relative importance of this internal hydrogen bonding between M and 1+ we measured
Ka for binding of two homologues of 1+•Cl- that have a similar shape as 1+ but attenuated hydrogen
bonding capacity. The two homologues were 2+•Cl- and 3+•Cl- and the measured Ka values of 950
and 930 M-1 (Figures S44–S47), respectively, were essentially the same. In each case, there was
a large complexation-induced downfield change in NMR chemical shift for macrocycle proton B
and upfield changes in chemical shift for several of the protons on the longest arm of the Q+ cation
(Figures S68–S69). Both NMR effects are consistent with deep penetration of Q+ inside the cavity
of M.
Figure 3. Energy-minimized structure (semiempirical, PM7) of (a) 1+•Cl-@M, (b) 2+•Cl-@M, and
(c) 3+•Cl-@M.
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A computer-based molecular model of 2+•Cl-@M (Figure 3b) indicated hydrogen bonding
between the ether oxygen in 2+ and the second pair of macrocycle NH residues. In the case of
3+•Cl-@M there is no heteroatom within 3+ that is available for hydrogen bonding with the
macrocycle NH residues but there is the possibility of multiple CH- interactions between the
pentyl arm of 3+ and the aromatic surfaces that line the cavity of M (Figure 3c).31
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The idea that Q+ could interact with the aromatic sidewalls of M led us to consider Q+
structures that could form – stacking interactions. Thus, we prepared chloride salts of the eight
benzylic trimethylammonium cations 4+–11+, by reacting the parent benzyl bromide with
trimethylamine (Scheme 2). The only difference between the cationic structures was the identity
of the para-substituent, R, on the benzylic arm, which ranged from strongly electron donating
para-OMe to strongly electron withdrawing para-NO2. Association of each salt with M was
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characterized using H NMR spectroscopy. In each case, there was an upfield, complexation-
induced change in chemical shift for the benzylic protons on Q+ indicating a location deep inside
the macrocycle cavity and stacked against the anthracene sidewalls of M (Figures 4, S48-S63
and S68–S75). In the case of 8+•Cl- complexation by M, a Job’s plot confirmed 1:1 binding
stoichiometry (Figure S37) and a ROESY spectrum of the complex indicated through space
interactions between macrocycle proton B and several protons in 8+ (Figure S34).
Scheme 2. Synthesis of 4+•Cl-–11+•Cl-.
Listed in Table 1 are Ka values for binding of 4+•Cl-–11+•Cl- by M, as determined by the
NMR titration experiments. To better understand the interaction of Q+ with the anthracene
sidewalls of M, the logarithm of the relative association constant (KR/KH) for 4+•Cl-–11+•Cl- was
plotted against the Hammett para-substituent parameter p (Figure 5).32 The plot exhibits a rough
linear trend (slope of +0.52 ± 0.15), with affinity for M usually increased by having electron
withdrawing para-substituents on Q+. There are likely multiple factors controlling the observed
substituent effects on binding energy, including: (a) strength of the ion-pair interactions between
Q+ and Cl-, (b) aromatic stacking interactions between Q+ and M, (c) benzylic CH– interactions
between Q+ and M, and (d) steric repulsion in the case of the relatively large para-COOCH3
substituent. The highest affinity for the series was observed with 10+•Cl- which contained a para-
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CN substituent, and the measured value of Ka = 7.9 × 103 M-1 is 160-fold higher than the Ka for
binding of TBA+•Cl- by M.
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Figure 4. (a) Energy-minimized structure (semiempirical, PM7) of 10+•Cl-@M. (b) Partial 1H NMR
spectra (500 MHz, CDCl3, 1 mM, 25 oC) of 10+•Cl- (top), M (bottom) and their equimolar mixture
(middle). Atom labels for M are provided in Scheme 1.
Table 1. Association Constants (Ka) for Guest Binding to M in CDCl3 at 25 oC. a
Guest
TBA+•Cl-
1+•Cl-
Ka (103 M-1)
0.05 ± 0.01
0.89 ± 0.03
0.95 ± 0.06
0.93 ± 0.02
2.10 ± 0.07
1.78 ± 0.13
2.95 ± 0.15
5.32 ± 0.69
3.66 ± 0.25
2.92 ± 0.18
7.86 ± 1.82
6.02 ± 0.42
ΔG (kcal•mol-1)
-2.29 ± 0.03
-4.03 ± 0.02
-4.06 ± 0.04
-4.05 ± 0.02
-4.54 ± 0.02
-4.44 ± 0.04
-4.74 ± 0.03
-5.09 ± 0.07
-4.87 ± 0.03
-4.73 ± 0.04
-5.32 ± 0.12
-5.16 ± 0.04
2+•Cl-
3+•Cl-
4+•Cl-
5+•Cl-
6+•Cl-
7+•Cl-
8+•Cl-
9+•Cl-
10+•Cl-
11+•Cl-
a Determined by 1H NMR Titration.
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Figure 5. Plot of relative association constants log(KR/KH) and Hammett para-substituent
parameter p. The red line is a linear best fit of the points.
Templated Macrocyclization Synthesis of M
The synthesis of macrocycle M and its close analogues can be achieved by reacting 9,10-
bis(aminomethyl)anthracene (12) with the corresponding 1,3-isophthaloyl derivative (13). Under
these conditions, a low yield (<20%) of the [2+2] macrocycle is obtained along with linear
oligomers and higher order macrocycles as impurities. A classic synthetic approach to improving
the yield of a macrocyclization process is to conduct the reaction in the presence of an inert
template molecule that has affinity for the reactive intemediate(s) produced during the reaction
and selectively promotes the desired cyclization step.33–37
Having identified 10+•Cl- as a high affinity guest for M, we investigated if it could be used
as a macrocyclization template. As summarized in Scheme 3, a series of comparative
macrocyclization reactions was conducted on the 100 mg scale, in the absence or presence of
10+•Cl-. After the completion of each reaction, the solvent was removed and the crude product
determined by integration of appropriate 1H NMR peaks. A comparison of entries 1 and 2 in Table
2 shows that the presence of 10+•Cl- in the reaction increased the crude yied of M from 19% to
50%. The ion-pair template was completely removed by extracting the crude product with
methanol, and after subsquent selective extraction steps, pure M was obtained in 46% isolated
yield without requiring column chromatography. Entries 3 and 4 in Table 2 show that the same
ion-pair template (10+•Cl-) could be used to improve the synthesis yields of two structural
analogues of M that are needed for our ongoing research efforts.38 In Scheme 3b is a mechanistic
picture of the template-promoted macrocyclization step. Attractive non-colvalent interactions
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between the penultimate reactive intermediate and the 10+•Cl- ion-pair increase the likelihood of
an intramolecular cyclization over competing intermolecular reactions.
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Scheme 3. a) Macrocyclization reactions conducted in the presence and absence of one
molar equivalent 10+•Cl-. b) Intramolecular cyclization of the penultimate reactive
intermediate is promoted by non-covalent interactions with 10+•Cl- as a reaction template.
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Table 2. Crude yields of [2+2] macrocycle product.
10+•Cl-
Template
Crude
Yield (%)
Entry
X
1
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13a
13a
13b
13c
No
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50
27
43
Yes
Yes
Yes
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Rotaxane Synthesis
The success with a templated macrocyclization prompted us to try a threaded “capping”
reaction,27,39,40 that traps a dumbbell-shaped organic cation inside M and produces a mechanically
interlocked rotaxane; an approach that is conceptually different to other literature methods of
creating rotaxanes using the anion component of an ion-pair as a template.41 As shown in Scheme
4, the benzylic ion-pair 16+•Cl-, whose structure includes a terminal alkyne group, was prepared
in straightforward fashion and then subjected to a biphasic azide/alkyne cycloaddition reaction in
the presence of M to produce the rotaxanated ion-pair M⊃17+•Cl- in low yield.42
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Scheme 4. Synthesis of rotaxane ion-pair M⊃17+•Cl-.
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The structure of M⊃17+•Cl- was characterized by a combination of mass spectrometry
(Figure S30), 1H NMR and COSY (Figure S29 and S35). In Figure 6 is a comparison of partial 1H
NMR spectra for the rotaxane and the free components in CD3OD. As expected, rotaxane
formation induced a downfield change in chemical shift for the macrocycle protons B, whereas
the axle phenylene protons 6 and 7 moved significantly upfield. Because of the unsymmetric axle,
the macrocycle protons C, D and E are not equivalent and there is a pair of peaks for each set of
protons. The macrocycle protons A, B are single peaks indicating signal averaging due to rapid
pirouetting of the macrocycle around the axle, which is consistent with the molecular dynamics
exhibited by a structurally related rotaxane with the same macrocycle M but different axle
component.43
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Figure 6. Partial 1H NMR spectra (500 MHz, 2 mM, 25 oC) of a) M in CD3OD/CDCl3 (9:1, v/v), b)
rotaxane M⊃17+•Cl- in CD3OD, and c) free axle 17+•Cl- in CD3OD. Atom labels are provided in
Scheme 4. Note that the NH signals are absent due to exchange with the CD3OD solvent.
CONCLUSIONS
The ability of tetralactam macrocyclic receptor M to bind Cl- in weakly polar chloroform
solution depends strongly on the shape of the counter quaternary ammonium cation (Q+). Values
of Ka were enhanced (i.e., positive binding cooperativity) when the shape and functionality of the
quaternary ammonium cation allowed it to penetrate the macrocycle cavity and engage in
attractive non-covalent interactions with the macrocycle’s NH resides and aromatic sidewalls. A
structure/affinity study revealed enhanced macrocycle affinity when Q+ was a benzylic
trimethylammonium cation with an electron withdrawing para-CN substituent on the benzyl ring
(i.e., 10+) which favors aromatic stacking and CH– interactions between Q+ and M. The yields of
macrocyclization reactions that make M or structurally related derivatives, were increased
substantially when 10+•Cl- was present as a stoichiometric macrocyclization template. A new type
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of rotaxanated ion-pair, M⊃17+•Cl-, was prepared by “capping” the end of a self-assembled
complex comprised of M threaded by a reactive benzylic quaternary ammonium cation (i.e., 16+).
This new synthetic method provides access to novel rotaxanated ion-pairs that are likely to exhibit
interesting behavior as a anion sensors, molecular shuttles or transport molecules.44–46
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EXPERIMENTAL SECTION
1
General Methods. H, 13C, COSY and ROESY NMR spectrum were recorded on 500 MHz or
400 MHz NMR spectrometer. Chemical shifts are presented in ppm and referenced by residual
solvent peak. High resolution mass spectrometry (HRMS) was performed using a time of flight
(TOF) analyzer with electron spray ionization (ESI).
Synthetic
Procedures.
2-Acetyloxy-N,N,N-trimethylethanaminium
tetrakis[3,5-
bis(trifluoromethyl)phenyl]boron (1+•BArF ). Compound 1+•Cl- (100 mg, 0.550 mmol) and sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (976 mg, 1.10 mmol) were dissolved in methanol (10
mL). The mixture was stirred at room temperature for 4 h. Solvent was removed under reduced
pressure and the residue was suspended in water (20 mL). The mixture was extracted with
dichloromethane (3 x 20 mL). The organic layers were combined and washed with water (60 mL).
Solvent was removed to afford the product as a light yellow powder (500 mg, 90%). Mp = 115 –
118 oC. 1H NMR (400 MHz, CDCl3, 25 oC)  (ppm) 7.70 – 7.69 (m, 8H), 7.56 (s, 4H), 4.40 – 4.36
(m, 2H), 3.34 – 3.32 (m, 2H), 2.90 (s, 9H), 2.10 (s, 3H). HRMS (ESI-TOF) m/z: [M]+ calcd for
-
+
C7H16NO2 146.1176; found 146.1176. [M]- calcd for C32H12BF24- 863.0645; found 863.0654.
General Synthetic Procedure for compounds 2+•Cl- and 3+•Cl-. 2-Bromoethyl ethyl ether or 1-
bromopentane (1 eq, 887 μM), trimethylamine (2 M in MeCN, 3 eq, 1.33 mL, 2.66 mM) and MeCN
(10 mL) was added to a round bottom flask with a stir bar. The mixture was stirred at 90 oC for 8
hours. After cooling the mixture to room temperature, diethyl ether (20 mL) was added to form a
white precipitate which was collected by filtration and further washed with diethyl
ether/dichloromethane (1:1, v/v) in an ultrasonic bath. The solid was dried to obtain the
corresponding bromide salt. Chloride-exchange resin (Dowex® 22 Chloride Form) (12 g) was
washed with de-ionized water and loaded on to a column which was eluted first with 5 % HCl (200
mL) and then de-ionized water until the pH of the eluted solution was neutral. The solid bromide
salt was dissolved in MeCN and loaded to the column of chloride-exchange resin. The column
was eluted with MeCN (200 mL) and the eluted solvent removed to obtain the desired chloride
salt. The presence of Cl- was confirmed and quantified by AgNO3 titration.
2-Ethoxy-N,N,N-trimethylethanaminium chloride (2+•Cl)-. white solid (140 mg, 94%). Mp = 115 –
120 oC. 1H NMR (400 MHz, CDCl3, 25 oC)  (ppm) 4.03 – 3.96 (m, 2H), 3.95 – 3.89 (m, 2H), 3.56
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(q, J = 7.0 Hz, 2H), 3.46 (s, 9H), 1.22 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3, 25 oC) 
(ppm) 67.0, 65.6, 64.5, 54.5, 15.0. HRMS (ESI-TOF) m/z: [M]+ calcd for C7H18NO+ 132.1383;
found 132.1371.
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N,N,N-trimethyl-1-pentanaminium chloride (3+•Cl-). white solid (146 mg, 99%). Mp = 145 – 148
oC. 1H NMR (400 MHz, CDCl3, 25 oC)  (ppm) 3.61 – 3.51 (m, 2H), 3.46 (s, 9H), 1.85 – 1.32 (m,
2H), 1.57 (s, 4H), 1.05 – 0.86 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3, 25 oC)  (ppm) 67.0, 53.4,
28.3, 23.0, 22.4, 13.9. HRMS (ESI-TOF) m/z: [M]+ calcd for C8H20N+ 130.1590; found 130.1578.
General Synthetic Procedure for Compounds 4+•Cl-, 5+•Cl-, 6+•Cl-, 7+•Cl-, 8+•Cl-, 9+•Cl-, 10+•Cl- and
11+•Cl-. The benzyl bromide precursor (100 mg), CH3CN (3 mL), and trimethylamine (2 M in
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MeCN, 2 mL) were added to a 20 mL vial. The mixture was stirred at 50 C for 12 hours. After
cooling to room temperature, diethyl ether (20 mL) was added to give the bromide salt product as
a precipitate. The white precipitate was collect by filtration and further washed with diethyl
ether/dichloromethane (1:1, v/v) in an ultrasonic bath. The solid bromide salt was dried and
converted to the desired chloride salt using the ion-exchange procedure described above.
4-Methoxy-N,N,N-trimethyl-benzenemethanaminium chloride (4+•Cl-). white solid (100 mg, 92%).
Mp = 35 – 38 oC. 1H NMR (500 MHz, CDCl3, 25 oC)  (ppm) 7.51 (d, J = 8.7 Hz, 2H), 6.85 (d, J =
8.7 Hz, 2H), 4.89 (s, 2H), 3.75 (s, 3H), 3.30 (s, 9H).13C{1H} NMR (125 MHz, CDCl3, 25 oC)  (ppm)
161.3, 134.5, 119.6, 114.5, 68.6, 55.4, 52.3. HRMS (ESI-TOF) m/z: [M]+ calcd for C11H18NO+
180.1383; found 180.1375.
N,N,N-trimethyl-benzenemethanaminium chloride (5+•Cl-). white solid (108 mg, 99%). Mp = 205
– 208 oC. 1H NMR (500 MHz, CDCl3, 25 oC)  (ppm) 7.64 (d, J = 8.5 Hz, 2H), 7.49 – 7.44 (m, 1H),
o
7.44 – 7.39 (m, 2H), 5.02 (s, 2H), 3.40 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3, 25 C)  (ppm)
133.2, 130.9, 129.3, 127.7, 69.1, 52.8. HRMS (ESI-TOF) m/z: [M]+ calcd for C10H16N+ 150.1277;
found 150.1260.
4-Fluoro-N,N,N-trimethyl-benzenemethanaminium chloride (6+•Cl-). white solid (106 mg, 99%).
Mp = 206 – 209 oC. 1H NMR (500 MHz, CDCl3, 25 oC)  (ppm) 7.69 (dd, J = 8.6, 5.3Hz, 2H), 7.14
o
(dd, J = 8.6 Hz, 2H), 5.08 (s, 2H), 3.37 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3, 25 C)  (ppm)
135.4, 135.3, 116.7, 116.5, 68.1, 52.7. HRMS (ESI-TOF) m/z: [M]+ calcd for C10H15FN+ 168.1183;
found 168.1163.
4-Chloro-N,N,N-trimethyl-benzenemethanaminium chloride (7+•Cl-). white solid (103 mg, 96%).
Mp = 184 – 187 oC. 1H NMR (500 MHz, CDCl3, 25 oC)  (ppm) 7.65 (d, J = 8.4 Hz, 2H), 7.40 (d,
J = 8.4 Hz, 2H), 5.12 (s, 2H), 3.39 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3, 25 oC)  (ppm) 137.4,
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134.6, 129.6, 126.2, 67.9, 52.8. HRMS (ESI-TOF) m/z: [M]+ calcd for C10H15ClN+ 184.0888; found
184.0865.
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4-Bromo-N,N,N-trimethyl-benzenemethanaminium chloride (8+•Cl-). white solid (105 mg, 99%).
Mp = 170 – 172 oC. 1H NMR (500 MHz, CDCl3, 25 oC)  (ppm) 7.57 (m, 4H), 5.12 (s, 2H), 3.39 (s,
9H).13C{1H} NMR (125 MHz, CDCl3, 25 oC)  (ppm) 134.8, 132.7, 126.7, 125.9, 68.0, 52.8. HRMS
(ESI-TOF) m/z: [M]+ calcd for C10H15BrN+ 228.0382; found 228.0355.
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4-(Methoxycarbonyl)-N,N,N-trimethyl-benzenemethanaminium chloride (9+•Cl-). white solid (100
mg, 91%). Mp = 175 – 180 oC. 1H NMR (500 MHz, CDCl3, 25 oC)  (ppm) 8.06 (d, J = 8.2 Hz, 2H),
7.79 (d, J = 8.2 Hz, 2H), 5.23 (s, 2H), 3.93 (s, 3H), 3.43 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3,
o
25 C)  (ppm) 166.2, 133.4, 132.5, 132.3, 130.3, 68.0, 53.0, 52.7. HRMS (ESI-TOF) m/z: [M]+
+
calcd for C12H18NO2 208.1332; found 208.1306.
4-Cyano-N,N,N-trimethyl-benzenemethanaminium chloride (10+•Cl-). white solid (107 mg, 99%).
Mp = 228 – 230 oC. 1H NMR (500 MHz, CDCl3, 25 oC)  (ppm) 7.93 (d, J = 8.2 Hz, 2H), 7.78 (d,
o
J = 8.2 Hz, 2H), 5.36 (s, 2H), 3.44 (s, 9H). 13C{1H} NMR (125 MHz, DMSO-d6, 25 C)  (ppm)
133.84, 133.72, 132.73, 118.34, 112.96, 66.33, 51.91. HRMS (ESI-TOF) m/z: [M]+ calcd for
+
C11H15N2 175.1230; found 175.1203.
4-Nitro-N,N,N-trimethyl-benzenemethanaminium chloride (11+•Cl-). white solid (106 mg, 99%).
Mp = 170 – 172 oC. 1H NMR (500 MHz, CDCl3, 25 oC)  (ppm) 8.33 (d, J = 8.6 Hz, 2H), 8.00 (d,
J = 8.6 Hz, 2H), 5.36 (s, 2H), 3.41 (s, 9H). ). 13C{1H} NMR (125 MHz, DMSO-d6, 25 oC)  (ppm)
+
148.6, 135.5, 134.4, 123.8, 66.0, 52.0. HRMS (ESI-TOF) m/z: [M]+ calcd for C10H15N2O2
195.1128; found 195.1105.
General Templated Synthesis of [2+2] Macrocycle. A member of the compound class 13 (0.320
mmol) was dissolved in a solution containing anhydrous chloroform (10 mL). Compound 9,10-
anthracenedimethanamine 12 (82.9 mg, 0.320 mmol) was dissolved in a solution of anhydrous
chloroform (10 mL) with trimethylamine (0.5 mL). Both aliquots were added over 12 hours by dual
syringe pump into a stirring solution of 10+•Cl- (67.2 mg, 0.320 mmol) in anhydrous chloroform
(20 mL). The mixture was stirred at room temperature for additional 24 h after injection. The
mixture was washed with 5% HCl (50 mL), water (50 mL), brine (50 mL) and dried over Na2SO4.
The solvent was evaporated and crude yield was measured by integration of 1H NMR peaks using
pyrazine as an added internal standard. In the specific case of reactant 13a, the crude product
containing M was suspended in MeOH (80 mL) and sonicated for 2 h at room temperature to
remove the 10+•Cl- template. The mixture was filtered, the solid was suspended in CHCl3 (10 mL)
and filtered through a Celite pad. Hexane (100 mL) was added to the filtrate to precipitate M, and
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the mixture was cooled in a -30 C freezer for 30 minutes. The solid was collected by filtration,
washed with acetone (10 mL) and dried to afford M as a yellow solid (63 mg, 46% isolated yield)
whose structure and high purity was confirmed by 1H NMR (Figure S22).
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4-(Bromomethyl)-N-2-propyn-1-yl-benzamide (14). Compound 4-(bromomethyl)benzoic acid
(1.00 g, 4.65 mmol) was suspended in DCM (20 mL), and oxalyl chloride (2.36 g, 18.6 mmol) was
added to the suspension followed by two drops of N,N-dimethylformamide. The mixture was
stirred under argon atmosphere until the solid was completely dissolved. The solvent was
removed to and the residue was dissolved in dry CHCl3 (50 mL). After cooling the solution with
an ice bath, a solution of propargylamine (0.298 mL, 4.65 mmol) and diisopropyl ethylamine (3.84
mL, 23.3 mmol) in 20 mL dry CHCl3 was added dropwise. The mixture was stirred, with ice bath
cooling, for 5 h after addition. The solvent was removed and the residue purified by column
chromatography (SiO2, 20-60% ethyl acetate in hexane) to afford the product as a yellow solid
(560 mg, 48%). Mp = 131 – 135 oC. 1H NMR (500 MHz, CDCl3, 25 oC)  (ppm) 7.78 (d, J = 8.2
Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 6.38 (br s, 1H), 4.61 (s, 2H), 4.25 (dd, J = 5.2, 2.6 Hz, 2H), 2.29
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(t, J = 2.6 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3, 25 C)  (ppm) 166.7, 141.4, 129.5, 129.0,
127.7, 79.6, 72.2, 45.5, 30.1. HRMS (ESI-TOF) m/z: [M+H]+calcd for C11H11BrNO+ 252.0019,
found 251.9994.
4-[(Dimethylamino)methyl]-N-2-propyn-1-yl-benzamide (15). A mixture of compound 14 (300 mg,
1.19 mmol), dimethylamine (2 M in THF, 5.95 mL, 11.9 mmol) and K2CO3 (493 mg, 3.57 mmol)
in dry THF (10 mL) was stirred overnight. Water (50 mL) was added, and the mixture was
extracted with CHCl3 (3 × 30 mL). The organic layers were combined, dried over Na2SO4, then
evaporated to afford the product as a yellow solid (257 mg, 99%). Mp = 65 – 68 oC. 1H NMR (500
MHz, CDCl3, 25 oC)  (ppm) 7.73 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.61 (t, J = 5.2 Hz,
1H), 4.22 (dd, J = 5.2, 2.5 Hz, 2H), 3.43 (s, 2H), 2.25 (t, J = 2.5 Hz, 1H), 2.21 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3, 25 oC)  (ppm) 167.3, 143.2, 132.7, 129.4, 127.3, 79.8, 72.0, 64.1, 45.6,
29.9. HRMS (ESI-TOF) m/z: [M+H]+ calcd for C13H17N2O+ 217.1335, found 217.1316.
Compound 16+•Cl-. A solution of compound 15 (100 mg, 0.462 mmol) and 3,5-di-tert-
butylbenzylbromide (144 mg, 0.509 mmol) in CH3CN (20 mL) was stirred at 90 oC for 12 hours.
The resulting mixture was allowed to cool to room temperature and diethyl ether (20 mL) was
added to form a white precipitate. The precipitate was collect by filtration, further washed with
diethyl ether in ultrasonic bath, then dried to give the corresponding bromide salt which was
converted to the chloride salt using the ion-exchange procedure described above. The desired
product was obtained as a yellow solid (210 mg, 99%). Mp = 202 – 205 oC. 1H NMR (500 MHz,
CDCl3, 25 oC)  (ppm) 9.03 (t, J = 5.5 Hz, 1H), 7.96 (d, J = 7.6 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H),
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7.51 (t, J = 1.8 Hz, 1H), 7.31 (d, J = 1.8 Hz, 2H), 5.27 (s, 2H), 4.80 (s, 2H), 4.22 (dd, J = 5.5, 2.5
Hz, 2H), 3.06 (s, 6H), 2.24 (s, 1H), 1.29 (s, 18H). 13C{1H} NMR (125 MHz, CDCl3, 25 oC)  (ppm)
167.0, 152.3, 136.5, 133.6, 130.9, 128.6, 127.7, 126.4, 124.8, 80.7, 71.1, 68.7, 67.8, 48.5, 35.1,
31.6, 29.7. HRMS (ESI-TOF) m/z: [M]+ calcd for C28H39N2O+ 419.3057; found 419.3054.
Rotaxane M⊃17+•Cl- and Free Axle 17+•Cl-. The ion-pair 16+•Cl- (10.0 mg, 22.0 μmol), 3,5-di-tert-
butylbenzylazide (10.8 mg, 44.0 μmol), M (37.5 mg, 44.0 μmol) were dissolved in CHCl3 (5 mL)
and H2O (1 mL). CuSO4•5H2O (2.74 mg, 11.0 μmol) and sodium ascorbate (4.35 mg, 22.0 μmol)
were added, the mixture was stirred at room temperature for 48 h. The solvent was removed and
the residue was purified by column chromatography (SiO2, 0-10% MeOH in CHCl3) followed by
Dowex® 22 column, the crude product was washed with diethyl ether/hexane (1:1, v/v) to afford
M⊃17+•Cl- and 17+•Cl-.
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Rotaxane M⊃17+•Cl-. Yellow solid (2.50 mg, 8%).1H NMR (500 MHz, CD3OD, 25 oC)  (ppm) 8.30
(d, J = 1.5 Hz, 4H), 8.11 (t, J = 1.5 Hz, 2H), 8.02 (dd, J = 6.9, 3.3 Hz, 4H), 7.85 (dd, J = 6.9, 3.3
Hz, 4H), 7.70 (t, J = 1.8 Hz, 1H), 7.59 (t, J = 1.8 Hz, 1H), 7.49 (d, J = 1.8 Hz, 2H), 7.45 (d, J = 1.8
Hz, 2H), 6.98 – 6.95 (m, 5H), 6.90 (dd, J = 6.9, 3.3 Hz, 4H), 6.61 (d, J = 8.0 Hz, 2H), 5.93 (d, J =
8.0 Hz, 2H), 5.51 – 5.48 (m, 6H), 5.12 (d, J = 14.9 Hz, 4H), 4.43 (s, 2H), 4.32 (s, 2H), 3.63 (s,
2H), 2.74 (s, 6H), 1.47 (s, 18H), 1.40 (s, 18H), 1.39 (s, 18H). The amount of 17+•Cl- is not enough
for 13C NMR measurement. HRMS (ESI-TOF) m/z: [M]+ calcd for C99H114N9O5 1508.8937; found
+
1508.8963.
Free Axle 17+•Cl-. Purple solid (11.0 mg, 71%). Mp = 145 – 148 oC. 1H NMR (500 MHz, CDCl3,
25 oC)  (ppm) 8.19 (br s, 1H), 7.89 (d, J = 7.3 Hz, 2H), 7.70 (m, 3H), 7.54 (s, 1H), 7.40 (s, 1H),
7.32 (d, J = 1.8 Hz, 2H), 7.11 (d, J = 1.9 Hz, 2H), 5.48 (s, 2H), 5.29 (s, 2H), 4.81 (s, 2H), 4.72 (d,
J = 5.1 Hz, 2H), 3.09 (s, 6H), 1.32 (s, 18H), 1.28 (s, 18H). 13C{1H} NMR (125 MHz, CD3CN, 25
oC)  (ppm) 166.0, 159.0, 152.2, 151.8, 136.6, 135.5, 133.6, 130.6, 128.0, 127.6, 126.6, 125.0,
122.8, 122.7, 122.6, 69.0, 68.2, 54.1, 49.0, 35.3, 34.8, 34.7, 30.8, 30.7. HRMS (ESI-TOF) m/z:
[M]+ calcd for C43H62N5O+ 664.4949; found 664.4972.
NMR Titration experiments. All experiments were conducted at 25 °C and used CDCl3 as the
solvent (the only exceptions were the stock solutions of 6+•Cl-,10+•Cl- and 11+•Cl- which contained
1% CD3CN). Aliquots from a stock solution containing the appropriate chloride salt were added
1
sequentially to an NMR tube containing the macrocyclic host and a H NMR spectrum was
acquired after each addition. The titration isotherms were fitted to a 1:1 binding model using
Thordarson’s equation.47 A standard non-linear squares method within OriginPro 2018 software
was used for determining binding constant (Ka). All of the titrations were independently duplicated
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and a representative titration isotherm for each experiment is provided in the Supporting
Information.
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Molecular Modeling. The starting coordinates of M for the computer modeling were obtained
from the X-ray crystal structures.48 In each case, ion-pair guest was added to the cavity, then the
host-guest complex was optimized by the semiempirical method at the PM7 level using the
MOPAC program.49
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1021/.
Copies of spectra for all new compounds; titration data, NMR spectra for complexes and
rotaxane, molecular modeling (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: smith.115@nd.edu
ORCID
Dong-Hao Li: 0000-0003-2556-1624
Bradley D. Smith: 0000-0003-4120-3210
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by grants from the NSF (CHE1708240). We thank Dr. Evgenii Kovrigin
(University of Notre Dame) for help with NMR experiments.
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