Acyclic cucurbituril featuring pendant cyclodextrins

Article abstract of DOI:10.1080/10610278.2021.1927033

Acyclic cucurbit[n]uril–β-cyclodextrin chimeric host H1 is presented. The goal of the study is to deepen the cavity of the receptor to allow β-CD complexation of moieties on the guest (especially fentanyl) that protrude from the cavity to enhance binding affinity and deliver new supramolecular antidotes for fentanyl intoxication. ¹H NMR spectroscopy was used to deduce the geometry of the complexes between H1 and H2 and the guest panel whereas isothermal titration calorimetry was used to determine the thermodynamic parameters of complexation. Hosts H1 and H2 retain the essential molecular recognition features of CB[n] receptors, but H1 binds slightly stronger towards the guest panel than H2. Compared to tetraanionic M1 and M2, dianionic H1 and H2 are less potent receptors which reflects the importance of electrostatic interactions in this series of hosts. The work highlights the challenges inherent in the optimisation of binding affinity of hosts as potential supramolecular antidotes.

Full text of DOI:10.1080/10610278.2021.1927033

Supramolecular Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gsch20
Acyclic cucurbituril featuring pendant
cyclodextrins
Ming Cheng & Lyle Isaacs
To cite this article: Ming Cheng & Lyle Isaacs (2021) Acyclic cucurbituril featuring pendant
cyclodextrins, Supramolecular Chemistry, 33:3, 53-62, DOI: 10.1080/10610278.2021.1927033
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SUPRAMOLECULAR CHEMISTRY
2021, VOL. 33, NO. 3, 53–62
https://doi.org/10.1080/10610278.2021.1927033
Acyclic cucurbituril featuring pendant cyclodextrins
Ming Cheng and Lyle Isaacs
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, United States
ABSTRACT
ARTICLE HISTORY
Received 2 March 2021
Accepted 1 May 2021
Acyclic cucurbit[n]uril–β-cyclodextrin chimeric host H1 is presented. The goal of the study is to
deepen the cavity of the receptor to allow β-CD complexation of moieties on the guest (especially
fentanyl) that protrude from the cavity to enhance binding affinity and deliver new supramolecular
antidotes for fentanyl intoxication. 1H NMR spectroscopy was used to deduce the geometry of the
complexes between H1 and H2 and the guest panel whereas isothermal titration calorimetry was
used to determine the thermodynamic parameters of complexation. Hosts H1 and H2 retain the
essential molecular recognition features of CB[n] receptors, but H1 binds slightly stronger towards
the guest panel than H2. Compared to tetraanionic M1 and M2, dianionic H1 and H2 are less
potent receptors which reflects the importance of electrostatic interactions in this series of hosts.
The work highlights the challenges inherent in the optimisation of binding affinity of hosts as
potential supramolecular antidotes.
KEYWORDS
Cucurbit[n]uril;
cyclodextrins; molecular
recognition; fentanyl;
supramolecular antidotes
Introduction
calixarenes, cyclophanes, cucurbiturils (CB[n]), resorcinar-
enes and related compounds, and most recently pillarar-
enes. [1b,1f,3] These covalent host systems have been
used for a variety of applications including the purification
of precious metals, the construction of molecular
machines, the preparation of (chiral) stationary phases,
as transmembrane ion channels, as household deodoris-
ing products, as supramolecular antidotes, and as critical
components of glucose sensors [4]. Most relevant to
human health has been the in vivo use of HP-β-CD and
CaptisolTM as solubilising excipients for hydrophobic inso-
luble pharmaceuticals [5] and Sugammadex as a reversal
agent for the neuromuscular blockers rocuronium and
vecuronium [6].
The covalent synthesis and non-covalent self-assembly of
molecular container compounds and studies of their
molecular recognition properties has occupied a central
space in the field of supramolecular chemistry for the past
several decades [1]. For example, the design principles for
the preparation of metal-organic cages and frameworks
by reversible metal•ligand interactions have been deli-
neated, their fundamental host•guest recognition proper-
ties studied, and a variety of applications have been
demonstrated (e.g. supramolecular nanoreactors, compo-
nents of sensing arrays, drug delivery vehicles, supramo-
lecular metallo drugs, and materials for separation and
sequestration) [2]. Within the realm of covalent molecular
containers, a variety of classes of compounds (Figure 1)
have been studied including cyclodextrins (CD),
Our research group has been most interested in the
synthesis and molecular recognition properties of the
CONTACT Lyle Isaacs
LIsaacs@umd.edu
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland, United States
© 2021 Informa UK Limited, trading as Taylor & Francis Group

54
M. CHENG AND L. ISAACS
Figure 1. Structures of cyclodextrins and (acyclic) cucurbit[n]urils.
CB[n] family of macrocycles (Figure 1) [7]. CB[n] are
composed of n glycoluril units connected by 2 n CH2-
groups which define a central hydrophobic cavity
flanked by two electrostatically negative ureidyl carbo-
nyl lined portals [8]. Accordingly, CB[n] hosts bind with
unusually high affinity and selectivity to hydrophobic
diammonium ions with Ka values up to 1017 M−1 in
water. [3e,9] CB[n]•guest complexes are, therefore,
highly responsive to electrochemical, photochemical,
and chemical (e.g. pH or competing guest) stimuli
[10]. Accordingly, macrocyclic CB[n] and their deriva-
tives have been used in a variety of applications includ-
ing as components of sensing arrays, molecular
machines, separations materials, supramolecular mate-
rials, non-covalent inducers of protein dimerisation, as
reversal agents, and for (targeted) drug delivery.
[4a,10a,11] More recently, we and others, [10d,12]
have explored the synthesis and molecular recognition
properties of acyclic CB[n]-type receptors (e.g. M1 and
M2, Figure 1). Acyclic CB[n]-type receptors are com-
posed of a central glycoluril oligomer, two aromatic
sidewalls, and alkoxy chains terminated by sulphonate
solubilising groups. Despite being acyclic, the polycyc-
lic backbone of M1, M2, and analogues preorganises
them into a C-shaped conformation that preserves the
essential recognition properties of macrocyclic CB[n]
but with more straightforward routes towards synthetic
modification [12e]. In a series of papers, we have
explored the influence of the glycoluril oligomer length
(monomer – pentamer), the aromatic sidewall (e.g. ben-
zene, naphthalene, anthracene, triptycene), the length
of the alkylene linking group, and the nature of the
ionic group (e.g. carboxylate, sulphonate, ammonium,
sulphate) on the molecular recognition properties of
acyclic CB[n]-type receptors [13]. By virtue of its high
aqueous solubility, acyclic CB[n]-type receptor M1 was
shown to be particularly effective as a solubilising exci-
pient for insoluble drugs for in vivo drug delivery
[13a,14]. Conversely, the high affinity displayed by
acyclic CB[n]-type receptors towards their guests
enables M1 and analogues to function as in vivo rever-
sal agents for the neuromuscular blockers rocuronium
and vecuronium which are commonly used by anaes-
thesiologists in the operating room as well as the
anaesthetics ketamine and etomidate [15]. Most
recently, the ability of M1 and M2 to function as
in vivo sequestration agents for fentanyl and metham-
phetamine by complexation of their phenethyl ammo-
nium ion moieties, respectively, have been
demonstrated [16]. In this paper, we explore the repla-
cement of the O(CH2)SO3Na groups of acyclic CB[n]-
type receptors with β-CD units to deepen the cavity of
the receptor and complement regions of guests that
protrude from the central acyclic CB[n] cavity as
a means to enhance binding affinity towards fentanyl
to create an improved supramolecular antidote.

SUPRAMOLECULAR CHEMISTRY
55
reaction we use an excess of W1 with respect to W2
to limit the quantity of M2 formed and enhance the
amount of the insoluble byproduct with two W1 walls
which allowed H2 to be isolated by recrystallisation
from H2O/acetone mixtures [19]. Host H2 features
a mirror plane passing through its equator but is
unsymmetrical from end-to-end due to the different
aromatic sidewalls and accordingly is Cs-symmetric.
Results and discussion
This results and discussion section is organised as fol-
lows. First, we describe the design and synthesis of
acyclic cucurbituril–cyclodextrin chimeric host H1
along with receptor H2 as comparator. Next, we describe
the selection of the guests used in this study along with
qualitative investigations of their host•guest binding
1
processes by H NMR spectroscopy. Subsequently, we
1
Figure 2(a) shows the H NMR spectrum recorded for
perform direct isothermal titration calorimetry (ITC) titra-
tions to measure the thermodynamic parameters of
host•guest binding. Finally, we discuss the results and
offer some conclusions.
H2 in water. As expected based on Cs-symmetry, only 3
aromatic C-H resonances (Hg, Hh, Hi) are observed for
H2 at 8.08 (Hi), 7.47 (Hh), and 6.03 (Hg) ppm. The sur-
prisingly upfield shifted resonance for Hg can be
explained based on the conformation of H2 in water
which features edge-to-face π-π interactions between
the tip of the benzene and face of the naphthalene
sidewall which places Hg in the anisotropic shielding
region of the naphthalene ring. Only two resonances
(each integrating to 6 H) are observed for the four
different Me groups of H2 due to accidental overlap.
On the basis of Cs-symmetry, a total of 35 13C NMR
resonances would be expected for H2; experimentally,
we observe 33 resonances (2 resonances missing due to
overlap in the C=O and aromatic region). In the electro-
spray ionisation mass spectrum of H2 we observe an
ion at m/z = 1355 which can be assigned to the [H2 –
Na]− ion. Having firmly established the structure of H2
we moved on to its transformation into H1. Scheme 1
shows the click reaction between H2 and β-CD-N3
which was carried out in DMSO at 50 °C in the presence
of CuSO4 and sodium ascorbate as catalyst system.
Acyclic cucurbituril–cyclodextrin chimeric host H1 was
isolated in 27% yield after purification by silica gel
chromatography eluting with acetonitrile–water mix-
tures. Because the β-CD units of H1 are homochiral
and enantiomerically pure, the mirror plane present in
H2 is no longer present in H1. Therefore, H1 is C1-
symmetric and every proton and every carbon atom
in the structure of H1 (C142H198N22Na2O86S2;
MW = 3699) is chemically different. The 1H NMR
Design and synthesis of host H1
In a previous study we measured the binding of M1 and
M2 towards a panel of drugs of abuse and observed
tight binding (Ka ≈ 107 M−1) towards fentanyl in 20 mM
phosphate buffered water; [16a] follow up in vivo
experiments showed that M1 is capable of modulating
the physiological effects of fentanyl in Sprague Dawley
1
rats. [16b,17] H NMR investigations showed that M1
and M2 bound to the phenethyl ammonium ion bind-
ing epitope of fentanyl, whereas the pendant piperi-
dine and amido groups are outside the cavity.
Accordingly, as a means to improve binding affinity
towards fentanyl and perhaps improve its function as
an in vivo sequestration agent we decided to append β-
cyclodextrin rings on the arms of the acyclic CB[n]
receptor in the form of H1 (Scheme 1) to complement
the protruding functional groups of fentanyl. Molecular
modelling (Supporting Information, Figure S44) of
H1•fentanyl supports the molecular and supramolecu-
lar design elements. Synthetically, we allowed glycoluril
tetramer (Tet) to react with a mixture of W1 (2 equiv.)
and W2 (1 equiv.) in a 1:1 (v:v) mixture of CF3CO2H and
Ac2O as solvent at 70 °C to promote the envisioned
double electrophilic aromatic substitution reactions
[13c,18] which delivered H2 in 10% yield. In this
Scheme 1. Synthesis of H1 featuring an acyclic CB[n] core with pendant β-cyclodextrins.

56
M. CHENG AND L. ISAACS
1
Figure 2. H NMR spectra recorded for: a) H2 (400 MHz, D2O, RT), and b) H1 (400 MHz, DMSO-d6, RT).
1
spectrum recorded for H1 in water is broadened, but
the spectrum recorded in DMSO-d6 (Figure 2(b)) is suf-
ficiently sharp to analyse essential features. For exam-
ple, two singlets are observed at 8.24 and 8.21 ppm
which are assigned to the two different triazolyl pro-
tons (Hn and Hn*) along with two resonances for Hi/Hi*
and Hh/Hh* centred at 8.01 and 7.44 ppm. Protons Hg
and Hg* appear as a pair of coupled doublets at 6.88
and 6.84 ppm as expected. The downfield shift of the
Hg and Hg* resonances in DMSO-d6 (Figure 2(b)) relative
to that observed for Hg (6.03, Figure 2(a)) of H1 in D2O is
due to differences in cavity solvation where DMSO acts
as a guest that changes the orientation of the tips of the
aromatic sidewalls. Finally, four methyl resonances are
observed (j, k, l, m) at 1.76, 1.74, 1.70, 1.63 ppm as
expected which reflects the absence of left-to-right
symmetry. The electrospray ionisation mass spectrum
shows an ion at m/z = 1826 which can be ascribed to
the [H1 – 2Na]2- ion. Having established the structures
of H1 and H2 we moved on to an examination of their
host•guest recognition properties.
properties by H NMR spectroscopy. We selected guests
G1 – G8 and fentanyl as the members of our guest panel
(Figure 3). Guests G1 – G4 were selected because they
are commonly investigated with macrocyclic and acyclic
CB[n]-type receptors, [9a,20] and differ in the width/
length of the hydrophobic moiety between the cationic
N-atoms. Compounds G5 – G8 are derivatives of G3
which contain a common central hexanediammonium
ion moiety which constitutes an excellent binding
domain for acyclic CB[n] hosts and two pendant (CH2)n
Ph groups (n = 1, 2, 3, 4) that are intended to protrude
from the acyclic CB[n] cavity and allow complexation by
the pendant β-cyclodextrin rings of H1. Compounds
G5 – G7 are known in the literature [21] but the syn-
thetic routes and characterisation data were not
reported for G6 and G7, whereas G8 is unknown.
Compounds G5 – G8 were prepared by the alkylation
of N,N,N’,N’-tetramethyl hexanediamine with the appro-
priate alkyl halide in hot DMF to give G5 – G8 in 50–56%
yield. Finally, we selected fentanyl as a member of the
guest panel because it represents a biologically relevant
target that can benefit from the presence of the pendant
β-CD cavities of H1.
Qualitative Investigation of the Host Guest proper-
ties of H1 and H2. After completing the synthesis and
charaterization of the H1 and H2 hosts, we decided to
qualitatively investigate their host•guest recognition
To qualitatively assess the host-guest recognition
properties of H1 and H2 towards the guest panel,
Figure 3. Chemical structures of guests G1 – G8 and fentanyl that we investigated in this study.

SUPRAMOLECULAR CHEMISTRY
57
1
we initially collected H NMR spectra of H1 or H2 in
on the chemical shift timescale. Slow kinetics of
guest exchange are generally observed for tighter
host•guest complexes which encouraged us to mea-
sure the thermodynamics of host•guest complexa-
tion by isothermal titration calorimetry as described
below. Related 1H NMR spectra were acquired for
the remainder of the H1•guest and H2•guest com-
plexes (Supporting Information). In these complexes,
we generally observe upfield shifting of the reso-
nances corresponding to the central hydrophobic
domain of guests G1 – G8 as they bind inside the
anisotropic shielding region of the acyclic CB[n] cav-
ity. Precipitation is observed when preparing mix-
the presence of 1 equiv. and 2 equiv. of guests G1 –
G8. Figure 4 shows the H NMR spectra recorded for
1
mixtures of host H1 and guest G2. The 1H NMR
spectrum of H1 in D2O is heavily broadened and
spin-spin splitting cannot be observed; nonetheless
some assignments can be made based on chemical
shift and intensity. Interestingly, at a 1:1 H1:G2 ratio
(Figure 4(c)) the spectrum sharpens dramatically
indicating a well defined H1•G2 complex. Upon for-
mation of the H1•G2 complex, host resonances Hg
and Hg* shift downfield as the edge-to-face π-π
interactions between the benzene and naphthalene
sidewalls are disrupted upon host•guest complexa-
tion [19]. Conversely, the four different host Me
groups (j, k, l, m) become well resolved upon forma-
tion of the H1•G2 complex. Interestingly, upon for-
mation of the H1•G2 complex, guest protons Hc shift
upfield to 6.18 ppm and appear as a pair of coupled
doublets which is due to the fact that the top and
the bottom of H1 are different. The upfield shifting
is consistent with the binding of the p-phenylene
unit of G2 inside the anisotropic shielding region
of H1. Similarly, two upfield shifted NMe3 reso-
nances (a’ and a”) are observed upon formation of
H1•G2. When an excess of guest G2 is present
(Figure 4(d)), separate sharp resonances are
observed for H1•G2 and uncomplexed G2 which
indicates that the guest exchange process is slow
tures of H1 with G5
–
G8 at 2.5 mM
concentrations; sufficient concentrations of H1•G5 –
1
H1•G8 remain in solution and H NMR spectra were
obtained (Supporting Information). This result could
mean that the pendant aryl rings do not bind inside
the intended β-CD cavity and instead cause inter-
molecular aggregation. However, we also observed
precipitation when preparing host•guest complexes
of H2 with G5 – G8 which instead suggests that the
complexation of dianionic hosts H1 or H2 with dica-
tionic guests G5 – G8 results in the overall neutral
zwitterionic complexes which might be expected
to display lower aqueous solubility. Slow to inter-
mediate kinetics of guest exchange on the
chemical shift timescale are typically observed for
H1 and H2.
1
Figure 4. H NMR spectra recorded (400 MHz, D2O, RT) for: a) H1 (2.5 mM), b) G2 (2.5 mM), c) a mixture of H1 (2.5 mM) and G2
(2.5 mM), and d) a mixture of H1 (2.5 mM) and G2 (5.0 mM).

58
M. CHENG AND L. ISAACS
to a single set of sites binding model with Ka
= (5.30 0.23) × 106 M−1 and △H = −10.8 0.04 kcal
mol−1. Related direct ITC titrations were performed for
the remainder of the host•guest complexes of H1 and
H2 with guests G1 – G8 and fentanyl and the values of
Ka and △H are presented in Table 1. Table 1 also pre-
sents the thermodynamic parameters for the complexes
between hosts M1 and M2 with guests G1 – G3 and
fentanyl drawn from the literature. [13d,16a,20b,23] The
Ka values for H1 and H2 fall in the relatively narrow
range of 1.72 × 105 M−1 – 1.78 × 107 M−1. Interestingly,
H1 is generally (8 out of 9 cases) a more potent than H2
towards a specific guest ranging from a low of 0.78-fold
(for G6) to a high of 40-fold (for G4). Clearly the presence
of the pendant β-CD rings increase the binding affinity
of H1 relative to H2. However, the reasons for this
increase remain unclear because one would expect
higher Ka values only for guests G5 – G8 and fentanyl
which contain pendant aryl rings that protrude from the
acyclic CB[n] cavity but not for guests G1 – G4 which
does not agree with the experimental results. The poten-
tial influence of the inclusion of the hydrophilic sulpho-
nate groups of H1 in the hydrophobic cavities of the
adjacent β-CD units on binding thermodynamics is con-
sidered unlikely. As expected based on precedent from
macrocyclic and acyclic CB[n]-type receptors, the com-
plexation enthalpies (△H) are uniformly negative values
which reflect the fact that the uncomplexed receptors
encapsulate H2O molecules that do not have a full com-
plement of H-bonds which leads to enthalpic gains upon
host•guest complexation [24]. The △H values for the
complexes of H1 with a specific guest are uniformly
larger negative values than the corresponding complex
of H2. One can also perform a comparison between the
complexation abilities of H1 and H2 with the previously
studied M1 and M2. [13d,20b,23] Of course, H1 and H2
possess one phenyl wall and one naphthalene wall
whereas M1 possesses two phenyl walls and M2 pos-
sesses two naphthalene walls. As such, the comparisons
should be made with caution. Table 1 shows that M1
and M2 bind slightly more weakly (≈ 0.6-fold) than H1
towards cyclohexanediammonium ion G1 which is not
surprising given that G1 is never a tight binder to acyclic
CB[n] because the 4 C-atom spacing between N-atoms is
not optimal to complement the distance between urei-
dyl carbonyl portals of the host. For guests G2 and G3,
however, host H1 is inferior to hosts M1 and M2 (G2: M1
10-fold and M2 142-fold; G3: M1 29-fold and M2 151-
fold). This is not surprising given that M1 and M2 are
two of our tightest binding hosts (13a,15a,16) and that
H1 and H2 are dianionic hosts whereas M1 and M2 are
tetraanionic hosts. The electrostatic component of the
binding of macrocyclic and acyclic CB[n]-type receptors
Determination of the thermodynamic parameters
for host•guest complexes by isothermal titration
microcalorimetry
After having demonstrated binding of guests G1 – G8
into the cavity of H1 and H2 by analysis of the com-
plexation induced changes in chemical shift, we decided
to measure the thermodynamic parameters for forma-
tion of the complexes. Host•guest complexes of macro-
cyclic and acyclic CB[n] are often too strong to measure
by 1H NMR or even UV/Vis titrations, so we turned to ITC
which can be conducted at low µM concentrations and
deliver Ka values up to ≈ 107 M−1 reliably by direct ITC
titrations. Figure 5(a) shows the thermogram recorded
during the titration of a solution of H1 (50 µM) in the ITC
cell with a solution of fentanyl (500 µM) in the ITC injec-
tion syringe. In this experiment we used [H1] = 50 µM so
as to lower the c-value (c = Ka × [Host]) into the range
required for reliable measurements [22]. Figure 5(b)
shows the a plot of △H versus the H1:fentanyl molar
ratio with was fitted with the PEAQ ITC analysis software
Figure 5. a) Thermogram obtained during the titration of
a solution of H1 (50 µM) in the cell with a solution of fentanyl
(500 µM) in the syringe at 298 K in 20 mM sodium phosphate
buffered water at pH 7.4. b) Plot of △H (kcal mol−1) versus host:
guest molar ratio which was fitted to a single set of sites model
to extract Ka = (5.30 0.23) × 106 M−1 and △H = −10.8 0.04
kcal mol−1.

SUPRAMOLECULAR CHEMISTRY
59
Table 1. Thermodynamic parameters (Ka (M−1); △H (kcal mol−1)) measured for the host•guest complexes by isothermal titration
calorimetry. Conditions: 20 mM sodium phosphate buffered water, pH 7.40, 298 K.
Host H1
Host H2
Host M1 (16a,23)
Host M2 (13d,16a,20b)
Ka △H
Guest
Ka
△H
Ka
△H
Ka △H
G1
G2
G3
G4
G5
G6
G7
G8
(3.02 0.30) × 106 −7.25 0.070 (5.26 0.36) × 105 −4.35 0.059 (1.95 0.09) × 106 −5.70 0.027 (1.77 0.09) × 106 −5.54 0.03
(1.78 0.18) × 107 −9.74 0.073 (9.20 0.54) × 106 −7.88 0.035 (1.78 0.07) × 108 −11.4 0.022 (2.53 0.12) × 109 −14.3 0.04
(3.02 0.30) × 106 −7.71 0.050 (1.46 0.07) × 106 −5.74 0.036 (8.93 0.33) × 107 −9.35 0.021 (4.59 0.09) × 108 −10.6 0.15
(6.99 0.42) × 106 −7.06 0.034 (1.72 0.28) × 105 −3.80 0.031
(4.15 0.25) × 106 −20.00 0.260 (1.67 0.29) × 105 −6.87 0.340
(2.36 0.25) × 105 −9.30 0.270 (3.01 0.52) × 105 −5.62 0.240
(2.84 0.38) × 106 −8.90 0.120 (3.14 0.25) × 105 −3.88 0.077
(3.84 0.82) × 106 −10.10 0.200 (2.92 0.18) × 106 −4.21 0.027
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Fent- (5.30 0.23) × 106 −10.80 0.040 (6.81 0.28) × 105 −5.16 0.038 1.1 0.04 × 107 −20.9 0.06 (7.6 0.5) × 106 −20.2 0.07
anyl
n.d. = not determined
is known to make a significant contribution towards the
overall binding free energy of the host•guest complexes.
Experimental Details
Compounds Tet, W1, W2, M1, M2 and β-CD-N3 were
prepared according to literature procedures [14,25].
NMR spectra were measured on 400 MHz, 500 MHz,
and 600 MHz spectrometers (400, 500, 600 MHz for
1H NMR; 100, 126 MHz for 13C NMR) at room temperature
in the stated deuterated solvents unless otherwise sta-
ted. Low resolution mass spectrometry was performed
using a JEOL AccuTOF electrospray instrument.
Conclusions
In summary, we have reported the design and synthesis
of acyclic CB[n]-type receptor H1 which contains two
pendant β-cyclodextrin rings via click reaction of β-
CD-N3 with H2 as a potential route to deepen the cavity
of the host and complement pendant groups on the
guest (especially fentanyl) that protrude from the cavity
of the acyclic CB[n] receptors. The molecular recogni-
tion properties of H1 and H2 towards a panel of dia-
mmonium ion guests (G1 – G8) and fentanyl were
Host H2
Compound Tet (1.00 g, 1.28 mmol) was first dissolved in
a mixture of CF3CO2H and Ac2O (v:v = 1:1, 30 mL) and
heated at 70 °C for 5 min. Compounds W1 (0.47 g,
2.56 mmol) and W2 (0.57 g, 1.28 mmol) were added and
the reaction mixture was stirred and heated at 70 °C for
another 12 h. The reaction mixture was poured into acet-
one (40 mL) to give a yellow precipitate. The precipitate
was collected by centrifugation and then dried under
high vacuum overnight. The crude solid was recrystallised
from water (15 mL) and acetone (30 mL) to yield H2 as
a white solid (0.18 g, 0.13 mmol, 10%). M.p. > 310 °C. IR
(ATR, cm−1): 1722s, 1457s, 1223s, 1179s, 1081 m, 795 m.
ESI-MS: m/z 1355.59, calcd. for [H2-Na]−: 1355.36. 1H NMR
(400 MHz, D2O): δ 8.09 (ABq, 2H), 7.47 (ABq, 2H), 6.03 (s,
2H), 5.64 (d, J = 15.7 Hz, 2H), 5.62 (d, J = 15.3 Hz, 2H), 5.56
(d, J = 16.4 Hz, 2H), 5.47 (d, J = 9.0 Hz, 1H), 5.42 (d,
J = 15.5 Hz, 2H), 5.39 (d, J = 9.0 Hz, 1H), 5.35 (d,
J = 9.0 Hz, 1H), 4.99 (d, J = 16.1 Hz, 2H), 4.51 (d, J = 16.4,
2H), 4.45–4.35 (m, 2H), 4.30 (s, 2H), 4.28 (d, J = 16.0, 2H),
4.20 (d, J = 15.8, 2H), 4.20–4.10 (m, 2H), 4.14 (d, J = 15.4,
2H), 4.01 (d, J = 16.0, 2H), 3.31 (m, 4 H), 2.45 (m, 4 H), 2.39
(s, 2H), 1.89 (s, 6 H), 1.63 (s, 6 H). 13C NMR (150 MHz,
DMSO-d6) δ 155.4, 154.3, 154.1, 149.4, 148.3, 128.3,
127.9, 126.6, 122.8, 114.6, 79.9, 77.8, 77.6, 76.4, 76.3, 74.3,
70.5, 67.1, 67.0, 57.6, 52.7, 48.7, 48.5, 48.0, 36.0, 34.4, 30.7,
30.7, 26.5, 25.2, 25.1, 16.9, 16.0, 15.9, 15.7.
1
investigated by means of H NMR spectroscopy and
isothermal titration calorimetry. We find that H1 and
H2 retain the essential molecular recognition features
of macrocyclic and acyclic CB[n]-type receptors (e.g. the
ability to bind to diammonium ions in water with single
digit µM to 100 nM dissociation constants). Acyclic
CB[n]-cyclodextrin chimeric host H1 binds slightly
stronger towards the guest panel than H2 but the
origin of the tighter binding cannot be ascribed to the
occupation of the β-CD cavities by the pendant func-
tional groups on the guest. Dianionic hosts H1 and H2
are less potent receptors than tetraanionic hosts M1
and M2 which reflects the importance of electrostatic
(ion-ion and ion-dipole) interactions on the strength of
acyclic CB[n]•guest complexes. In conclusion, we find
that the incorporation of β-CD rings into H1 slightly
enhances guest binding relative to propargylated H2.
However, the removal of the two anionic sulphonate
groups that synthetically enabled β-CD attachment by
click reaction more than offset the expected gains in
binding affinity relative to M1 and M2. The work high-
lights the challenges inherent in the optimisation of
binding affinity of hosts as potential supramolecular
antidotes.[4a,4j]

60
M. CHENG AND L. ISAACS
Host H1
spaces.” Acc. Chem. Res. 2009, 42, 1660-1668; e)
Yoshizawa, M.; Klosterman, J. K.; Fujita, M., “Functional
molecular flasks: New properties and reactions within
discrete, self-assembled hosts.” Angew. Chem. Int. Ed.
2009, 48, 3418-3438; f) Jordan, J. H.; Gibb, B. C.,
“Molecular containers assembled through the hydro-
phobic effect.” Chem. Soc. Rev. 2015, 44, 547-585.
Compound H2 (0.020 g, 0.015 mmol) and β-CD-N3
(0.036 g, 0.032 mmol) were dissolved in DMSO (3 mL)
and stirred for 5 min. Subsequently, CuSO4•5H2O (9.0 mg,
0.036 mmol) and sodium ascorbate (0.014 g, 0.072 mmol)
were added to the solution and the reaction mixture was
stirred and heated at 50 °C for 24 h. The reaction mixture
was poured into acetone (20 mL) to give a yellow pre-
cipitate which was isolated by filtration and then dried
under high vacuum. The crude solid was purified by
column chromatography (SiO2, CH3CN/H2O, 2:3) to give
H1 (15.0 mg, 27%) as a white solid. M.p. > 310 °C. IR
(ATR, cm−1): 3358 m, 1727 m, 1658 m, 1462 m, 1026s,
797 w. ESI-MS: m/z 1826, calcd. for [H1-2Na]2–1826.
1H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 8.20 (s, 1H),
8.01 (m, 2H), 7.44 (m, 2H), 6.88 (d, J = 7.7 Hz, 1H), 6.84 (d,
J= 6.7 Hz, 1H), 5.90–5.10 (m, 43 H), 5.00–4.75 (br m, 17 H),
4.75–3.90 (m, 30 H), 3.90–3.40 (m, 40 H), 3.05–2.80 (m,
6 H), 2.30–2.10 (br, 4 H), 1.76 (s, 3 H), 1.74 (s, 3 H), 1.70 (s,
3 H), 1.63 (s, 3 H). 13C NMR (150 MHz, DMSO-d6): δ 156.1,
155.0, 154.8, 154.7, 150.7, 150.4, 148.8, 148.6, 143.4, 143.3,
128.7, 128.7, 128.3, 128.0, 127.2 (br), 126.9, 126.4, 123.2
(br), 114.8 (br), 102.7, 102.5 (br), 102.1, 101.9, 83.6, 82.4,
82.1, 81.9, 81.6, 78.1, 77.9, 76.9, 76.8, 74.5 (br), 73.5 (br),
72.9, 72.7, 72.5, 70.9, 70.6, 70.1, 66.8, 63.7, 63.4, 60.4 (br),
59.8, 53.0 (br), 50.5, 48.9, 48.4, 40.9, 36.4 (br), 34.9 (br),
31.1, 26.8, 17.5, 16.5, 16.1.
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Disclosure statement
L.I. is an inventor on patents held by the University of Maryland
on the biomedical application of acyclic cucurbiturils.
Funding
We thank the National Institutes of Health (GM132345) for
financial support
ORCID
Lyle Isaacs
http://orcid.org/0000-0002-4079-332X
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