A clip-like host that undergoes self-assembly and competitive guest-induced disassembly in water

Article abstract of DOI:10.1080/10610278.2018.1494275

Certain calix[4]arenes that are anionic and appended with a single hydrophobic substituent can self-assemble into homodimers in water. The unusual behaviours of these assemblies in water solutions are largely attributed to them being formed from like-char

Full text of DOI:10.1080/10610278.2018.1494275

Supramolecular Chemistry
ISSN: 1061-0278 (Print) 1029-0478 (Online) Journal homepage: http://www.tandfonline.com/loi/gsch20
A clip-like host that undergoes self-assembly and
competitive guest-induced disassembly in water
Meagan A. Beatty, Jil A. Busmann, Noah G. Fagen, Graham A. E. Garnett &
Fraser Hof
To cite this article: Meagan A. Beatty, Jil A. Busmann, Noah G. Fagen, Graham A. E. Garnett &
Fraser Hof (2018): A clip-like host that undergoes self-assembly and competitive guest-induced
disassembly in water, Supramolecular Chemistry, DOI: 10.1080/10610278.2018.1494275
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SUPRAMOLECULAR CHEMISTRY
https://doi.org/10.1080/10610278.2018.1494275
ARTICLE
A clip-like host that undergoes self-assembly and competitive guest-induced
disassembly in water
Meagan A. Beatty, Jil A. Busmann, Noah G. Fagen, Graham A. E. Garnett and Fraser Hof
Department of Chemistry, University of Victoria, Victoria, Canada
ABSTRACT
ARTICLE HISTORY
Received 11 May 2018
Accepted 18 June 2018
Certain calix[4]arenes that are anionic and appended with a single hydrophobic substituent can
self-assemble into homodimers in water. The unusual behaviours of these assemblies in water
solutions are largely attributed to them being formed from like-charged building blocks. We
report here a new entry into this series – a difunctionalized analog with two hydrophobic arms, a
KEYWORDS
Calixarene; host-guest
chemistry; hydrophobic
effect; self-assembly
1
net – 3 charge on each monomer, and an overall U-shaped ‘clip’ topology. We use H NMR, 1-D
DOSY and ITC to show that the new compound dimerizes in water but remains monomeric in
organic solvents. Various cationic ammonium ion guests are able to drive dimer disassembly in
favor of 1:1 host-guest complexes. The extent of competition is proportional to overall guest
hydrophobicity.
Introduction
We previously reported on a series of mono-functio-
nalized calix[4]arenes that assemble into 1:1 homodi-
mers in water. These molecules have the self-
complementary topology of a yin-yang symbol – the
hydrophobic pendant arm of each monomer binds as a
guest into the other monomer’s binding pocket (1,
Figure 1(a)). Unlike most self-assembling species, the
monomers in this family bear an overall –4 charge in
neutral water that is mutually repulsive. The assemblies’
responses to added co-solutes is largely explained by
considering their unique combination of like charges,
hydrophobic binding elements, and complementary
shapes (13). The dimers remain assembled in salty
water, mock serum and human urine. The strongest of
the series used a hydrophobic t-butylphenyl group as
the pendant arm.
Molecular clips and tweezers are important motifs for
molecular recognition in water. The combination of a
rigid, U-shaped hydrophobic surface with peripheral
solubilizing groups creates a poorly hydrated concave
surface that is predisposed to strong binding of
hydrophobic partners in water. In the most promi-
nent examples, a U-turn topology has been achieved
using glycoluril-derived structures, as pioneered by
Issacs (1–3), or norbornene-derived structures as
introduced by Klärner and Schrader (4, 5). Some of
these examples have involved self-complementary
clips that form homo- or heterodimers (6–8), while
other clips are shaped to minimize self-assembly so
they can bind guests within their hydrophobic clefts
(1, 9, 10). In some interesting examples, these two
binding modes compete with each other – individual
clips form homodimers that can be disrupted in favor
of guest binding in pure, unbuffered water (11, 12).
We converted this motif into a new structure that
has both clip-like character and symmetry. Adding a
second t-butylphenyl group to the upper rim of 1
produces a monomer with a net charge of – 3 at neutral
CONTACT Fraser Hof
fhof@uvic.ca
Department of Chemistry, University of Victoria, Victoria, Canada
Supplemental data for this article can be accessed here.
© 2018 Informa UK Limited, trading as Taylor & Francis Group

2
M. A. BEATTY ET AL.
5% NaOD/DCl solutions. Isothermal calorimetery experi-
ments were conducted at 303 K in buffered water on a
MicroCal VP-ITC and fitted to include heat of dilution out-
lined in Supplementary Information (Section 2a). Mass
spectra of novel compounds were collected on an
Thermo Scientific Ultimate 3000 ESI-Orbitrap Exactive. All
UV-Vis and fluorescence spectra were collected on a
Molecular Device Spectra M5 spectrometer in NUNC 96-
well black walled plate. Infrared (IR) spectra were obtained
using a Perkin Elmer 1000 FT-IR spectrometer. Data are
represented as follows: frequency of absorption (cm–1),
intensity of absorption (s = strong, m = medium,
w = weak, br = broad). Melting points were collected on
a Gallenkamp Melting Point apparatus. Compound 2 was
purified using a Shimadzu Prominence HPLC system on a
9.4 mm × 250 mm semi-preparative Agilent Eclipse XDB-
C18 5 μm with UV detection at 280 nm.
Synthesis
5,17-dibromo-26,28-dibenzoyloxy-calix[4]arene (4).
Compound 3 (0.9 g, 1.5 mmol) was dissolved in
CHCl3 (30 mL) and Br2 (0.4 mL, 15 mmol) was added.
The mixture was stirred at room temperature for 4 h.
The mixture was then diluted with CH2Cl2, the organic
layer was washed with Na2S2O3 (5 g/100 mL) aqueous
solution, followed by water, brine and dried over
Na2SO4. The solution was decanted, reduced under
pressure to a pure yellow solid (0.99 g, 83%). Mp:
decomposed > 230 °C. FT-IR (cm−1): 3537 (br.), 1733
(m), 1706 (m), 1451 (m), 1265 (s), 1173 (s), 1023 (m),
Figure 1. (a) Previously reported dimeric monofunctionalized
calix[4]arene, 1, and (b) the new difunctionalized clip-like calix
[4]arene, 2.
pH, two similar arms, overall C2v symmetry, and an
increased hydrophobic surface area in the form of an
extended cleft (2, Figure 1(b)). Unlike prior water-solu-
ble clips and tweezers, the clip incorporates a sulfo-
nated calix[4]arene binding pocket of a type that is
generally useful for binding biological guests (14–18).
We report here our studies of the new molecule’s
homodimerization in water. We expect that molecules
like this should be promiscuous binders of hydrophobic
ammonium ions, and we were unsure of how homo-
dimerization would compete with guest binding. Unlike
our previous studies of 1, in the current work we report
the response of this homodimer to a variety of guests in
competitive buffered water solutions.
1
1056 (m), 861 (w), 754 (m), 709 (s). H NMR (300 MHz,
CDCl3): δ 8.24 (dd, J = 8.5 Hz, 1.5 Hz, 4H), 7.77 (tt,
J = 7.4 Hz 1.4 Hz, 2H), 7.62 (t, 7.9 Hz, 4H), 7.11 (s, 4H),
(m, 6H), 5.22 (s, 2H), 3.85 (d, J = 14.6 Hz, 4H), 3.53 (d,
J = 14.6 Hz, 4H). 13C NMR (125 MHz, CDCl3): δ 164.6,
152.0, 146.1, 134.0, 132.0, 131.7, 130.5, 129.8, 129.7,
129.3, 126.8, 111.8, 33.1. HR-ESI-MS ([M−H]−, m/z):
−
Calculated for C42H29Br2O6
787.03363
787.03364, Found
Materials and methods
5,17-dibromo-25,26,27,28-tetrahydroxy-calix[4]arene
(5).
General methods
1H, 13C, 1-D DOSY and variable temperature experiments
were recorded on a Bruker Avance 500 MHz spectrometer
unless otherwise indicated and processed with
MestReNova by Mestrelab Research S.L. 1-D DOSY proto-
col is outlined in Supplementary Information (Section 2c).
All reported chemical shifts were reported in ppm with
respect to an internal standard: cis-butenedioic acid at
6.2 ppm. Deuterated solvents were purchased from
Sigma Aldrich and NaH2PO4/Na2HPO4 (50 mM, pD 8.5) in
D2O were prepared in lab and the pD was adjusted with
Compound 4 (1 g, 1.25 mmol) was dissolved in MeOH
(50 mL) and NaOH (0.7 g, 18 mmol) was added. The
mixture was heated to reflux for 4 h. The product was
precipitated out of solution by the addition of 1 M HCl.
The solid was vacuum filtered and washed with hex-
anes to afford a light yellow solid (0.53 g, 72%). Mp:
decomposed > 230 °C. FT-IR (cm−1): 3141 (br), 1448 (s),
1
1209 (s), 856 (w), 828 (w), 750 (s), 665 (m) 514 (m). H
NMR (500 MHz, CDCl3): δ 10.06 (s, 4H), 7.17 (s, 4H), 7.08
(d, J = 7 Hz, 4H), 6.80 (t, J = 6.8 Hz, 2H), 4.20 (br. s, 4H),

SUPRAMOLECULAR CHEMISTRY
3
3.52 (br. s., 4H). 13C (125 MHz, CDCl3): δ 148.8, 147.9,
Calculated
423.12712.
for
C48H46O10S22−423.12717,
Found
131.6, 130.2, 129.3, 127.5, 122.52, 114.0, 31.5. HR-ESI-MS
([M−H]−, m/z): Calculated for C28H21Br2O4 578.98121,
−
Found 578.98106.
Results and discussion
5,17-dibromo-25,26,27,28-tetrahydroxy-11,23-
disulfonatocalix[4]arene (6).
The synthesis of 2 is achieved through selective upper-
rim functionalization reactions. It starts with the selec-
tive dibromination of 1,3-dibenzoyl calix[4]arene (3)
(19) which occurs selectively at the two positions para
to unprotected phenols to give 4. The benzoyl groups
are removed (5) and the newly exposed phenols are
para sulfonated along the upper rim upon treatment
with H2SO4 to yield the key precursor 6. The final
compound, 2, is obtained by a double Suzuki coupling
with t-butylphenyl boronic acid and obtained in 40%
yield after HPLC purification. Compound 2 is most solu-
ble in slightly basic water, at which it is expected to
have a net charge of – 3 due to the low pKa for the first
phenol deprotonation in calix[4]arenes (20).
Dimerization of 2 was apparent when comparing the
1H NMR spectra in CD3OD and D2O. In CD3OD, the
pendant phenyl and t-butyl resonances were found as
sharp peaks at 7.45 ppm, 7.40 ppm and 1.32 ppm, as
expected for an unaggregated monomeric state. In
D2O both the phenyl and t-butyl resonances broadened
and shifted upfield to 7.25 ppm, 7.0 ppm and 0.33 ppm,
respectively (Figure S2). This pattern of upfield shifts is
diagnostic for encapsulation of a t-butylphenyl substi-
tuent within a calix[4]arene’s electron-rich pocket (13).
The fact that this is not observed in pure CD3OD (or
even upon addition of small amounts of
CD3OD) indicates that the dimerization is primarily dri-
ven by the hydrophobic effect.
Compound 5 (50 mg, 86 μmol) was dissolved in
CH2Cl2 (2 mL) followed with conc. H2SO4 (100 μL). The
reaction was heated to reflux for 24 h to afford a
residue. The CH2Cl2 was decanted, and the residue
was rinsed with fresh CH2Cl2. The solid was suspended
in EtOAc, transferred into a conical tube and diluted
with cold Et2O. The suspension was centrifuged to a
pellet, the supernatant was decanted and the resuspen-
sion/centrifugation/decanting process was repeated
three times. The pellet was left to air dry overnight to
afford a gray solid (51 mg, 81%). Mp: decomposed
> 178 °C. IR (KBr disc) (cm−1): 2408 (br), 3221 (br),
2961 (w), 1651 (m), 1204 (m), 1163 (m), 1036 (m), 625
(m). 1H NMR (500 MHz, d6-DMSO): δ 9.62 (br. s, 7H), 7.43
(s, 4H), 7.28 (s, 4H), 3.89 (br. s, 8H). 13C NMR (125 MHz,
d6-DMSO): δ 151.6, 149.8, 140.0, 131.5, 131.3, 127.6,
127.0, 112.3, 41.0, 30.6. HR-ESI-MS ([M−2H]2−, m/z):
2−
Calculated for C28H20Br2O10S2
368.94376.
368.94378, Found
5,17-di(4-t-butylphenyl)-25,26,27,28-tetrahydroxy-
11,23-disulfonatocalix[4]arene (2).
Compound 6 (50 mg, 67 μmol), t-butyl-phenylboronic
acid (26 mg, 148 μmol), K2CO3 (74 mg, 0.51 mmol) and
Pd(OAc)2 (5 mg, 22 μmol) were dissolved in a micro-
wave vial with 3 mL of 1:1 EtOH:deionized water. The
reaction was irradiated to a temperature of 150 °C for
5 minutes with cooling air and stirring on (Biotage
Initiator Microwave Reactor). After, thiourea (1 M,
0.5 mL) was added and the reaction stirred at 90°C for
1 h. The solution was filtered through a PDVF syringe
filer (0.45 μm), and concentrated until solution became
cloudy. The slurry was re-dissolved with small amounts
of CH3CN and purified by HPLC purification with a
gradient running from 90% H2O (+ 0.1% TFA)/10%
CH3CN (+ 0.1% TFA) to 40% H2O (+ 0.1% TFA)/60%
CH3CN (+ 0.1% TFA) over 18 minutes. Lyophilization of
collected fractions afforded a white powder in 40%
yield (22 mg). Mp: decomposed > 190 °C. FT-IR (cm−1):
3398 (br), 2962 (m), 2874 (w), 1456 (m), 1268 (m), 1153
(m), 1038 (s), 822/32 (m), 750 (s), 629 (s), 542 (s). 1H NMR
(500 MHz, CD3OD): δ 7.69 (s, 4H), 7.44 (s, J = 7.4 Hz, 4H),
7.41 (s, 4H), 7.39 (d, J = 7.4 Hz, 4H), 4.07 (br. s, 8H), 1.31
(s, 18H). 13C NMR (125 MHz, d6-DMSO): δ 151.0, 149.52,
149.50, 140.2, 137.5, 133.7, 129.2, 128.3, 127.5, 126.9,
126.4, 125.9, 34.6, 31.6, 31.1. HR-MS ([M−2H]2−, m/z):
The existence of dimer in solution was confirmed by
DOSY. The diffusion coefficient of monomeric 2 was
obtained by 1-D DOSY in 20% CD3OD in Na2HPO4/
NaH2PO4 (50 mM, pD 8.5) buffer – conditions under
which 1D chemical shifts show that pure monomer is
present. The Stokes-Einstein equation was used to
determine the monomer’s hydrodynamic radius as
8.51 Å (Table 1). This value is similar to the value
determined in the same CD3OD/buffer conditions for
Table 1. Diffusion coefficients obtained by 1-D DOSY and
corresponding hydrodynamic radii.
D (m2/s)
rH (Å)
7.3
8.51 0.03
11.31 0.04
11.3
PSC(a) (monomer control)
2(a) (monomer)
2(b) (dimer)
2.2 × 10−10
1.9 × 10−10
2.2 × 10−10
1.5 × 10−10
1(c) (dimer)
(a) 20% CD3OD in Na2HPO4/NaH2PO4 (50 mM, pD 8.5) buffer, [PSC] or
[2] = 1 mM.
(b) Na2HPO4/NaH2PO4 (50 mM, pD 8.5) buffer
(c)previously reported data (13), in D2O.

4
M. A. BEATTY ET AL.
Table 2. ITC-derived thermodynamic parameters for homodi-
merization of 1 and 2(a).
Kd (mM)
ΔG (kcal/mol)
ΔH (kcal/mol)
−TΔS (kcal/mol)
1(b)
2
1.0
0.57
−4.2
−4.5
−11
5.5
6.9
−10
(a) ITC dilution titrations in H2O containing Na2HPO4/NaH2PO4 (100 mM, pH
7.4.)
(b) Data taken from reference (13).
the control compound para-sulfonatocalix[4]arene
(PSC), which can’t undergo dimerization. In 100% aqu-
eous Na2HPO4/NaH2PO4 (50 mM, pD 8.5) solution the
hydrodynamic radius of the dimer was found to be
11.31 Å consistent with the value observed for its thor-
oughly characterized dimeric analog 1 (Table 1) (13).
ITC dilution titrations show that compound 2 forms
stronger dimers than 1, with different enthalpic and
entropic contributions. The Kd decreased from 1.0 mM
(1) to 0.54 mM (2) with the addition of a second
t-butylphenyl group (Table 2). In spite of the relatively
small structural change, the association of 1 was enthal-
pically favoured while 2 was entropically driven. NMR
data suggest dimers of similar structures, so we attri-
bute the differences mainly to the swap of a sulfonate
for a second t-butylphenyl group. Additional hydropho-
bic surface area must be de-solvated upon dimerization
of 2. The increase in entropic driving force follows the
classical view of the hydrophobic effect, which is appro-
priate considering that the new appended hydrophobic
group is not in a confined space and is largely exposed
to solvent in the free state.
Figure 2. (a) cartoon depiction of dimeric 2 dissociating to form
new host-guest complex which can be observed by the change
in chemical shift of the t-butyl singlet (blue circle) with (b)
various guests.
dissociated, the guest was encapsulated to form a
host-guest complex of the type that is well known for
sulfonated calix[4]arenes (21, 22). Similar observations
were made with other N-alkylated pyridinium guests
(Figure S4, S5 and Table 3). Complete NMR titrations
showing the evolving response upon addition of
selected guests are shown in the Supp. Info.
We were interested in testing 2 as a host with select
guests known to form strong inclusion complexes with
calix[4]arenes (Figure 2(a)). As this was not previously
tested with 1 and others in its series, we were inter-
ested seeing if hydrophobic cationic guests could per-
turb the dimer and form traditional 1:1 host-guest
complexes (Figure 2(b)).
Comparison of simple methylammonium ion guests
showed that more hydrophobic guests are more
1H NMR proved the formation of host-guest com-
plexes with concomitant dimer dissociation upon guest
addition. All resonances for these simple guest binding
studies were in fast exchange. Under these conditions,
the position of the chemical shift between the extremes
expected for free and bound states qualitatively indi-
cate the relative amounts of each state (Table 3). The
diagnostic position and shape of the t-butyl singlet was
used to track monomer-dimer equilibrium: a strong
hydrophobic guest like N-ethyl-4-methyl-pyridinium
caused the t-butyl singlet of 2 to sharpen and shift
downfield (blue diamonds, Δδ + 0.76 ppm) to the posi-
tion expected for monomeric 2 (Figure 3). The guest’s
CH3 triplet broadened and shifted upfield (red circle,
Δδ–0.25 ppm). This indicated that while the dimer
Table 3. Guest-induced chemical shift perturbation of reso-
nances for 2 away from the positions observed in the pure
2•2 homodimer.
Δδ of resonances from 2 (ppm)(a)
Guest
t-butyl
ortho-aryl
7
8
9
10
11
12
13(b)
14
15
0.71
0.79
0.80
0.01
0.39
0.67
0.83
0.03
0.15
0.18
0.24
0.26
0.01
0.24
0.40
0.48
0.06
0.06
(a) All solutions are 1:1 mixtures of 2 and guest at 1 mM in Na2HPO4/
NaH2PO4 (50 mM, pD 8.5)-buffered D2O. See Supporting Information for
full titrations and spectra for selected guests.
(b) This ditopic guest was studied at a ratio of 0.5:1 guest:2 ([2] = 1 mM).

SUPRAMOLECULAR CHEMISTRY
5
Figure 5. NMR spectra show that more hydrophobic guests
disrupt 2•2 homodimer more effectively. Host and guests in
each sample are as shown; each is at 1 mM. The downfield
shift of 2 (blue diamonds) upon dimer disruption, and the
upfield shift (red dot) of guests upon host-guest complex for-
mation are apparent. N-methyl imidazole (13) disrupts dimer
formation but imidazole (14) does not. Buffer = Na2HPO4/
NaH2PO4 (50 mM, pD 8.5) in D2O.
Figure 3. NMR spectra demonstrate competition between 2•2
homodimerization and host-guest binding. (a) 1:1 (1 mM) host-
guest complex formed with N-ethyl-4-methyl-pyridinium (8)
indicated with an upfield shift of guest protons (red dot)
from its (b) unbound resonance and the downfield shift of 2
(blue diamond) (c) from its dimeric state. Buffer = Na2HPO4/
NaH2PO4 (50 mM, pD 8.5) in D2O.
imidazole, partially formed a complex, as supported
by the methyl singlet shifting Δδ– 0.37 ppm and the
t-butyl shifting Δδ + 0.2 ppm (Figure 5(a) and Table 3).
A bis-(trimethylammonium) guest, suxamethonium (9),
also induced dissociation of 2 by Δδ 0.83 and the guest
protons upfield shifted and broadened by Δδ–
1.44 ppm at 0.4 eq. (Figure S7 and Table 3).
effective at disrupting dimerization. The t-butyl singlet
of 2 travels from 0.4 ppm (Figure 4(c)) to 0.79 ppm (4b)
and to finally 1.06 ppm (4a) when treated with similar
concentrations of di-, tri- and tetramethylammonium,
respectively (blue diamonds). Similarly, the guest
methyl resonances show upfield shifts from their free
chemical shifts that are proportional to the expected
strength of guest binding: 2.39 ppm (dimethylammo-
nium), 1.88 ppm (trimethylammonium), and 1.49 ppm
(tetramethylammonium). Weaker guests like imidazole
did not perturb the dimer at all (Figure 5(c), S6 and
Table 3). Yet its methylated counterpart, N-CH3-
Lucigenin (LCG), a quinaldinium dye, showed unu-
sual host-guest behaviour with 2 and allowed fluores-
cence characterization of the complexes. LCG is
quenched upon binding sulfonated calixarenes (23). A
1:1 mixture of LCG and 2, each at 1 mM, yielded a
perfectly flat 1H NMR spectrum– all host and guest
resonances are in intermediate exchange, and the solu-
tion is clear and homogeneous, suggesting the forma-
tion of an undefined soluble aggregate (Figure 6(b)).
The LCG emission is mostly quenched in a 1:1 solution
prepared at lower concentrations that are appropriate
for fluorescence measurements ([LCG] = [2] = 1 µM), as
≤ 10% of the intensity of free LCG emission is observed
in this sample. Upon changing the stoichiometry only
≥ 20% away from 1:1 ratio in either direction, reso-
nances for whichever species is in excess start to appear
alongside an otherwise flat NMR spectrum. This indi-
cates that the soluble aggregate, although not structu-
rally understood, is something that requires a 1:1 ratio
of 2 and LCG. When 2 is in excess the resonances for
homodimeric 2•2 are observed in the NMR spectrum
(Figure 6(a)). Fluorescence is completely quenched
under these conditions, showing that the LCG is fully
Figure 4. NMR spectra show that more hydrophobic guests
disrupt 2•2 homodimer more effectively. Each spectrum con-
tains a 1:1 (1 mM) mixture of 2 and guest. The downfield shift
of 2 (blue diamonds) upon dimer disruption, and the upfield
shift (red dot) of guests upon host-guest complex formation
engaged in an aggregate with
2 (Figure 6(a)).
Conversely, when LCG is in excess, the NMR resonances
for the uncomplexed dye are observed emerging from
the flat NMR spectrum that arises from the 2•LCG
+
+
are apparent. (a) N(CH3)4 (12); (b) HN(CH3)3 (11); (c) H2N
+
(CH3)2 (10); (d) no guest added. Buffer
= Na2HPO4/
NaH2PO4 (50 mM, pD 8.5) in D2O.

6
M. A. BEATTY ET AL.
1
Figure 6. Aggregation behaviour of LCG and 2 monitored by H NMR (left, [LCG] = 1 mM) and fluorescence spectroscopy (right,
[LCG] = 1 μM). (a) At LCG:2 ratio of 1:0.5 – free LCG resonances observed in the NMR, with significant fluorescence emission
observed to arise from free LCG. (b) At LCG:2 ratio of 1:1, no NMR resonances are observed which indicates a soluble aggregate
undergoing intermediate exchange with complete line broadening. Low fluorescence emission is observed, showing that most LCG
is bound to calixarene under these conditions. (c) At LCG:2 ratio of 1:2, homodimer 2•2 is observed by NMR and no free LCG
emission is seen by fluorescence spectroscopy. Buffer = Na2HPO4/NaH2PO4 (10 mM, pD 8.5) in D2O (for NMR) or H2O (for
fluorescence).
Scheme 1. The synthesis of the calix[4]arene clip, 2.
aggregate. Partial (30%) fluorescence intensity is
observed, as expected for a solution containing a
small amount of free LCG. Upon heating the solution
we observed at 80°C by NMR the appearance of reso-
nances of monomeric 2 and free LCG, as both the
soluble aggregate and the homodimer dissociate
(Figure S10). Data suggesting this sort of hetero-aggre-
gate behaviour were also observed for mixtures of 2
and Brooker’s merocyanine– another cationic pyridi-
nium dye (Figure S3 and S9).
structure (15, 17, 24–28). The synthesis of difunctiona-
lized 2 involves a Suzuki coupling that could be applied
to several other binding arms in order to introduce a
similarly diverse set of functions (29). This work opens
the door to a wide variety of clip-like hosts that com-
bine self-assembly and guest responsiveness in compe-
titive aqueous solutions.
Acknowledgement
In this report, we have synthesized a new calix[4]
arene clip, 2, characterized its homodimeric self-assem-
bly in buffered water, and studied the effects of com-
peting guests. Multiple research groups have used
trisulfonated calixarenes with a single upper-rim func-
tionalization to modulate guest binding, and/or to
impart many different functionalities to the host
We thank Chris Barr for assistance with DOSY NMR.
Disclosure statement
No potential conflict of interest was reported by the authors.

SUPRAMOLECULAR CHEMISTRY
7
Funding
(14) McGovern, R.E.; Snarr, B.D.; Lyons, J.A.; McFarlane, J.;
Whiting, A.L.; Paci, I.; Hof, F.; Crowley, P.B. Chem. Sci.
2015, 6, 442–449. DOI: 10.1039/C4SC02383H
(15) Gober, I.N.; Waters, M.L. J. Am. Chem. Soc. 2016, 138,
9452–9459. DOI: 10.1021/jacs.6b02836
This work was supported by the Natural Sciences and
Engineering Research Council of Canada [05832];
(16) Hof, F.;. Chem. Commun. 2016, 52, 10093–10108. DOI:
10.1039/C6CC04771H
(17) Beatty, M.A.; Borges-González, J.; Sinclair, N.J.; Pye, A.T.;
Hof, F. J. Am. Chem. Soc. 2018, 140, 3500–3504. DOI:
10.1021/jacs.7b13298
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