Synthesis and self-assembly processes of monofunctionalized Cucurbit[7]uril

Article abstract of DOI:10.1021/ja3058502

We present a building-block approach toward functionalized CB[7] derivatives by the condensation of methylene-bridged glycoluril hexamer 1 and glycoluril bis(cyclic ethers) 2 and 12. The CB[7] derivatives Me ₂CB[7] and CyCB[7] are highly soluble in water (264 mM and 181 mM, respectively). As a result of the high intrinsic solubility of Me ₂CB[7], it is able to solubilize the insoluble benzimidazole drug albendazole. The reaction of hexamer 1 with glycoluril derivative 12, which bears a primary alkyl chloride group, gives CB[7] derivative 18 in 16% isolated yield. Compound 18 reacts with NaN₃ to yield azide-substituted CB[7] 19 in 81% yield, which subsequently undergoes click reaction with propargylammonium chloride (21) to yield CB[7] derivative 20 in 95% yield, which bears a covalently attached triazolyl ammonium group along its equator. The results of NMR spectroscopy (¹H, variable-temperature, and DOSY) and electrospray mass spectrometry establish that 20 undergoes self-assembly to form a cyclic tetrameric assembly (20₄) in aqueous solution. CB[7] derivatives bearing reactive functional groups (e.g., N₃, Cl) are now available for incorporation into more complex functional systems.

Full text of DOI:10.1021/ja3058502

Article
pubs.acs.org/JACS
Synthesis and Self-Assembly Processes of Monofunctionalized
Cucurbit[7]uril
Brittany Vinciguerra,‡ Liping Cao,‡ Joe R. Cannon, Peter Y. Zavalij, Catherine Fenselau, and Lyle Isaacs*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
S
* Supporting Information
ABSTRACT: We present a building-block approach toward function-
alized CB[7] derivatives by the condensation of methylene-bridged
glycoluril hexamer 1 and glycoluril bis(cyclic ethers) 2 and 12. The
CB[7] derivatives Me2CB[7] and CyCB[7] are highly soluble in water
(264 mM and 181 mM, respectively). As a result of the high intrinsic
solubility of Me2CB[7], it is able to solubilize the insoluble
benzimidazole drug albendazole. The reaction of hexamer 1 with
glycoluril derivative 12, which bears a primary alkyl chloride group, gives
CB[7] derivative 18 in 16% isolated yield. Compound 18 reacts with
NaN3 to yield azide-substituted CB[7] 19 in 81% yield, which
subsequently undergoes click reaction with propargylammonium
chloride (21) to yield CB[7] derivative 20 in 95% yield, which bears a covalently attached triazolyl ammonium group along
its equator. The results of NMR spectroscopy (1H, variable-temperature, and DOSY) and electrospray mass spectrometry
establish that 20 undergoes self-assembly to form a cyclic tetrameric assembly (204) in aqueous solution. CB[7] derivatives
bearing reactive functional groups (e.g., N3, Cl) are now available for incorporation into more complex functional systems.
isolate (HO)1CB[6] and perform subsequent functionalization
reactions to deliver a self-complexing CB[6] derivative.20
INTRODUCTION
■
The cucurbit[n]uril (CB[n]; n = 5, 6, 7, 8, 10) family of
molecular containers1,2 is formed by the condensation reaction
of glycoluril and formaldehyde under strongly acidic con-
ditions.3−5 The defining structural features of the CB[n]
compounds (Chart 1) are their two symmetry-equivalent
ureidyl CO portals and their hydrophobic cavity, which
imparts the ability to bind to hydrophobic and cationic species
in water by a combination of ion−dipole interactions and the
hydrophobic effect.6 CB[n] compounds have emerged as a truly
privileged class of receptors for molecular recognition in water
as a result of their high affinity (Ka routinely 106−1012 M−1)
and their highly selective and stimuli-responsive binding
processes.6−8 Accordingly, CB[n] compounds have been used
in a wide range of applications, including drug delivery,9−11
molecular machines,12 supramolecular polymers,13 sensing
ensembles,14 and biomimetic systems.15 Despite the wide
range of applications that are enabled by CB[n] molecular
containers, there is an ongoing need for versatile synthetic
approaches toward functionalized CB[n] compounds that
retain their recognition properties and can be incorporated
into more complex functional systems. Until quite recently, the
only route to functionalized CB[n] compounds involved the
direct (per)hydroxylation of CB[n] introduced by Kim.16,17
Kim and co-workers have used these functionalized CB[n]
compounds in a variety of applications, including nanocapsules
for drug delivery, membrane protein fishing, and hydrogels for
cellular engineering.10,18,19 Recently, Scherman and co-workers
tamed the (per)hydroxylation reaction, which allowed them to
Chart 1. Structure of CB[n], (HO)12CB[6], and Hexamer 1
Our group has been investigating the mechanism of CB[n]
formation21−24 as a route to prepare CB[n]-type receptors with
exciting structures and functions. For example, we have used
this mechanistic knowledge to prepare CB[n]-type receptors
that display homotropic allostery and chiral recognition, and are
useful in drug delivery applications.11,25 In 2011, we reported
the templated synthesis of methylene-bridged glycoluril
hexamer 1 and its transformation into monofunctionalized
Received: June 15, 2012
Published: July 16, 2012
© 2012 American Chemical Society
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CB[6] derivatives by macrocyclization reactions with sub-
stituted phthalaldehydes.24 Very recently, we reported the
synthesis of a clickable CB[6] derivative, its transformation into
a CB[6] derivative functionalized with an ammonium ion tail,
and its self-assembly into a cyclic [c2] daisy chain assembly.26
Despite the recent advances in the synthesis of monofunction-
alized CB[6] derivatives,20,24,26 there is still an unmet need for
versatile synthetic routes toward CB[7] derivatives,16,18,27 and
especially monofunctionalized CB[7] derivatives that are
amenable to further functionalization reactions. For example,
CB[7] is nicely soluble in water, whereas CB[6] and the CB[6]
derivatives prepared by us possess only modest solubility in the
absence of guest. In addition, the more spacious cavity of
CB[7] and its derivatives are able to bind to a wider variety of
chemically and biologically interesting guests. Finally, the Ka
values achieved with CB[7] are unsurpassed. In this paper we
present a building-block approach21,22,27−30 toward mono-
functionalized CB[7] derivatives and report on their self-
assembly behavior.
achieved by the addition of aqueous KI to an aqueous solution
of the crude reaction mixture, which results in precipitation of
most of the CB[6] byproduct, followed by final purification by
treatment with activated carbon to yield Me2CB[7] (380 mg)
in 31% yield. A similar reaction was performed between 1 and
2Cy, which delivered CyCB[7] in 18% yield. We find that
Me2CB[7] (≥264 mM) and CyCB[7] (≥181 mM) are
significantly more soluble in water than CB[7] itself (20−30
mM),1 which suggests that they might find utility in
applications where highly soluble compounds are needed
(e.g., supramolecular polymers or drug solubilization).32 When
we performed related reactions with 2Ph or 2CO Et, we did not
2
observe the formation of any CB[7] derivatives but rather
observed the formation of CB[6] by unimolecular cyclization of
1. From our previous work21,33 we know that 2Ph and 2CO Et are
2
less reactive than alkylated glycolurils 2Me and 2Cy, which makes
them less able to undergo bimolecular reaction with 1 to give
CB[7] derivatives. In contrast, however, a similar reaction
between 1 and 2MePh resulted in a mixture of CB[6] and
MePhCB[7] in a 61:30 ratio based on 1H NMR analysis of the
crude reaction mixture in the presence of 3. Pure MePhCB[7]
could only be obtained in a meager 3% yield after Dowex ion-
exchange chromatography.
X-ray Crystal Structure of Me2CB[7]. We were fortunate
to obtain single crystals of Me2CB[7] as its Me2CB[7]·3
complex and to solve its structure by X-ray crystallography.
Figure 1a shows a cross-eyed stereoview of the structure of one
RESULTS AND DISCUSSION
■
This section is organized as follows. First, we discuss the
preparation of CB[7] derivatives Me2CB[7], CyCB[7], and
MePhCB[7] by a building-block approach using glycoluril
hexamer 1 and glycoluril bis(cyclic ethers) 2. Then, we describe
their basic properties (e.g., X-ray crystallography, host−guest
binding, aqueous solubility, and drug solubilization). Next, we
synthesize monofunctionalized CB[7] derivatives that contain
reactive alkyl chloride and azide functional groups. Finally, we
describe the self-assembly of a CB[7] derivative to yield a cyclic
tetrameric assembly in water.
Synthesis of Me2CB[7] and CyCB[7]. Given the ready
access to gram scale quantities of glycoluril hexamer 1 and
glycoluril bis (cyclic ethers) 2, we decided to investigate their
transformation into CB[7] derivatives (Scheme 1). After some
Scheme 1. Synthesis of Me2CB[7], CyCB[7], and
a
MePhCB[7]
Figure 1. Cross-eyed stereoviews of (a) the X-ray crystal structure of
Me2CB[7]·3 and (b) a portion of the crystal lattice showing the three-
dimensional packing motif. Color code: C, gray; H, white; N, blue; O,
red; H-bonds, red-yellow striped.
a
Conditions: (a) 9 M H2SO4, 110 °C, KI, 30 min.
experimentation, we performed the reaction between 1 and 2Me
with added KI in 9 M H2SO4 at 110 °C for 30 min.31 Analysis
of the crude reaction mixture using p-xylenediammonium ion
(3) as H NMR probe showed the presence of a 55:45 ratio
of CB[6] and Me2CB[7]. As expected, the major competing
reaction in this hexamer plus monomer building-block
approach to CB[7] derivatives is the unimolecular cyclization
of hexamer to give CB[6]. Purification of the mixture was
of the Me2CB[7]·3 complexes in the crystal. In contrast to
CB[6] derivatives, which display an ellipsoidal deformation
along their equator upon functionalization,24,29 the CB[7]
derivative Me2CB[7] appears structurally similar to CB[7]
itself.4 For example, the distance between the ureidyl CO O-
atoms of a single glycoluril unit averages 6.05 Å (range 5.87−
6.154 Å), which is comparable to that observed for CB[7] (6.05
Å; range 5.913−6.114 Å) itself. Similarly, the dimensions along
24
1
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the equator of Me2CB[7] are comparable to those of CB[7].
For example, the distance between the opposing methine C-
atoms on each fourth glycoluril on Me2CB[7] averages 11.398
Å (range 11.247−11.516 Å), whereas for CB[7] it averages
11.404 Å (range 11.173−11.591 Å). One structural parameter
that is rather different for CB[7] and Me2CB[7] is the average
distance between ureidyl CO O-atoms on every fourth
glycoluril at one portal. For Me2CB[7] the distances average
8.188 Å (range 7.197−9.026 Å; standard deviation = 0.644 Å),
whereas for CB[7] the distances average 8.139 Å (range 7.553−
8.718 Å, standard deviation = 0.364 Å). The glycolurils appear
to pivot such that one O-atom moves inward and one moves
outward, which results in the ureidyl CO portals undergoing
an ellipsoidal deformation. Overall, the molecular structures of
the cavity of CB[7] and Me2CB[7] are similar. Figure 1b shows
a cross-eyed stereoview of the basic packing of individual
complexes of Me2CB[7]·3 into a square array parallel to the xy-
plane within the crystal. The Me groups of two adjacent
Me2CB[7]·3 complexes orient themselves toward each other’s
ureidyl CO portals. The iodide counterions (not depicted)
are found at the corners of the square array and extend in
columns along the z-axis.
complexes. Given that the presence of the two Me groups
induces a change in the O···O distance in the substituted
glycoluril (vide supra), we thought that these protons might
exhibit different chemical shifts in the CB[7]·11 and Me2CB-
[7]·11 complexes. Experimentally, we find that Hn resonates at
8.95 ppm for CB[7]·11 and 8.96 ppm for Me2CB[7]·11
1
(Supporting Information). We used a H NMR competition
experiment (Supporting Information) to determine that the Ka
value for Me2CB[7]· 11 is 3.2 × 1012 M−1, relative to the
known Ka value for CB[7]·11 (1.98 × 1012 M−1).7 Accordingly,
it seems reasonable to expect that CB[7] derivatives like
Me2CB[7] will function well as CB[7] surrogates in more
complicated systems.
Molecular Recognition Properties of Me2CB[7] and
CyCB[7]. After establishing the basic structural features of
Me2CB[7], we decided to investigate its molecular recognition
properties. For this purpose, we used guests 3−11, shown in
Chart 2, which increase in size from hexanediamine 4 to
Chart 2. Structure of Guests Used in This Study
Figure 2. 1H NMR spectra (400 MHz, D2O, room temperature)
recorded for mixtures of (a) Me2CB[7] and 3 (2 equiv), (b)
Me2CB[7] and 4 (2 equiv), (c) Me2CB[7] and 7 (2 equiv), and (d)
Me2CB[7] and 10 (2 equiv). Resonances marked with * arise from
free guest.
Stability of Me2CB[7]. Experiments performed by Day and
co-workers established that CB[5], CB[6], and CB[7] are quite
stable under the hot acidic conditions (conc HCl, 100 °C, 24 h)
used in their formation.5 Accordingly, we wondered whether
the Me substituents on the convex face of Me2CB[7] might
stabilize cationic intermediates accessible under acidic con-
ditions and thereby accelerate decomposition reactions of
Me2CB[7]. Figure 3 shows a plot of the mole fraction of
Me2CB[7] versus time for a solution of Me2CB[7] heated at
adamantane derivatives 9−11. Guests 3−11 are well known to
form complexes with unsubstituted CB[7] with binding
constants up to 4.2 × 1012 M−1 for CB[7]·9.7 Figure 2 shows
1
the H NMR spectra recorded for Me2CB[7]·3, Me2CB[7]· 4,
Me2CB[7]·7, and Me2CB[7]·10. The guest resonances
1
observed in H NMR spectra are nearly identical in chemical
shift to those measured for the corresponding CB[7]
complexes (Supporting Information), which indicates that the
magnetic environments inside the cavities of CB[7] and
Me2CB[7] are quite similar. The resonances observed in the
1H NMR spectra that correspond to the H-atoms of C2v-
symmetric Me2CB[7] reflect its lower symmetry. For example,
three doublets of relative integral 2, and one doublet of relative
integral 1, are observed for the upfield-shifted H-atoms of the
diastereotopic CH2 groups of the Me2CB[7]·3 complex (Figure
2a). The main reason for synthesizing CB[7] derivatives is to
be able to incorporate them into more complex systems while
maintaining their recognition properties. Therefore, we viewed
it as critical to verify that the high binding constants observed
for CB[7] are maintained for CB[7] derivatives like Me2CB[7].
For this purpose, we used the complexes CB[7]·11 and
Me2CB[7]·11, because the H-atoms adjacent to the pyridinium
N-atom are located at the ureidyl CO portal in the
Figure 3. Plot of the mole fraction of Me2CB[7] upon heating at 110
°C in 9 M H2SO4 as a function of time.
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110 °C in 9 M H2SO4. Over the course of 6 days, Me2CB[7]
albendazole? We believe that the introduction of the Me groups
on the convex face of uncomplexed Me2CB[7] dramatically
increases its solubility relative to that of CB[7] because they
prevent the CH···O interactions between the methine C−H
groups on the convex face of one container with the ureidyl
CO portals of another container in the solid state, which has
been implicated as a controlling factor in the solubility trends of
CB[n] compounds.37 Within the Me2CB[7]·albendazole and
CB[7]·albendazole complexes, the drug fills the cavity and
protrudes through the ureidyl CO portals. Accordingly, the
Me groups cannot enhance the solubility of Me2CB-
[7]·albendazole in the same way as they do Me2CB[7]. On
the contrary, the presence of the hydrophobic Me groups
decreases the solubility of Me2CB[7]·albendazole relative to
that of CB[7]·albendazole. A similar trend was noted for the
solubilization of camptothecin by CB[7] and Me2CB[7]
(Supporting Information). These results suggest that a major
consideration in the design of CB[n] derivatives for use as
solubilizing excipients is the incorporation of groups designed
to enhance the solubility of both the container and its
container·drug complexes.
1
completely decomposes. The H NMR spectrum of the crude
reaction mixture using 3 as probe after 6 days shows the
presence of macrocycles with CB[6]-sized cavities (∼24% of
the crude mixture). Electrospray mass spectrometry of the
crude reaction mixture allows us to identify the presence of
comparable amounts of CB[6] and Me2CB[6]. Given that few
applications require such highly acidic and high-temperature
conditions, we believe that dialkylated CB[7] derivatives will be
sufficiently stable in most situations.
Drug Solubilization Using Me2CB[7]. One of the
emerging areas for application of CB[n] molecular containers
involves their use as solubilizing excipients for insoluble
pharmaceutical agents.11,34 Given the high solubility of
Me2CB[7] in water, we decided to test its ability to solubilize
albendazole and camptothecin, which have previously been
solubilized by unsubstituted CB[7].35 Figure 4 shows the phase
Synthesis of Glycoluril Derivative 12. The preparation of
glycoluril derivative 1230 bearing a primary alkyl chloride is
shown in Scheme 2. First, we reacted butanedione 13 with
a
Scheme 2. Synthesis of Glycoluril Derivative 12
Figure 4. Phase solubility diagram constructed (D2O, DCl, pH 2.0,
room temperature) for the solubilization of albendazole in the
○
●
presence of CB[7] ( ) or Me2CB[7] ( ).
solubility diagrams constructed for albendazole with either
Me2CB[7] or CB[7]. To construct the phase solubility
diagrams,36 we stirred a solution of a known concentration of
host with an excess of insoluble drug overnight, filtered the
solution to remove excess insoluble drug, and measured the
concentration of soluble drug by 1H NMR using CH3SO3− as a
nonbinding internal standard of known concentration. The
phase solubility diagrams for albendazole and Me2CB[7] or
CB[7] are quite similar at low concentrations of container (up
to 10 mM). This result can be explained by the fact that the
linear region of phase solubility diagrams for 1:1 host:guest
complexes obeys eq 1, where Ka is the host·guest binding
a
Conditions: (a) Et2O, TiCl4; (b) LDA, THF, Cl(CH2)3I, 69%; (c)
HCl, urea, 35%; (d) HCl, formalin, 68%.
isopropylamine 14 in Et2O with TiCl4 to deliver the known
diimine 15.38 Next, we deprotonated 15 with LDA in THF,
followed by alkylation with 3-iodo-1-chloropropane to give 16
in 69% yield after hydrolytic workup.39 Compound 16 was
transformed into glycoluril 17 by reaction with urea in HCl at
room temperature in 35% yield. Finally, treatment of 17 with
formalin in HCl gave 12 in 68% yield.
slope
s0(1 − slope)
Ka =
(1)
constant (M−1) and s0 is the intrinsic solubility of guest (drug).
Given that s0 for albendazole is the same regardless of which
host is used and that the Ka values for the CB[7]·albendazole
and Me2CB[7]·albendazole are expected to be very similar,
then the initial slopes should also be very similar, according to
eq 1. Somewhat surprisingly, at higher concentrations of
Me2CB[7] (e.g., 25−50 mM), the concentration of albendazole
in solution reaches a plateau of 5.8 mM, which is lower than
that achieved with 15 mM CB[7] (8.1 mM). The plateau in the
phase solubility diagram for Me2CB[7]·albendazole indicates
that the complex possesses only moderate solubility in water
(∼5.8 mM). Why does Me2CB[7]which is far more water-
soluble CB[7]perform less well in the solubilization of
Synthesis of Monofunctionalized CB[7] Derivatives
18−20. With access to gram-scale quantities of 12, we decided
to synthesize monofunctionalized CB[7] derivative 18 (Scheme
3). The reaction between 1 and 12 was conducted in 9 M
H2SO4 at 110 °C in the presence of KI, as developed for the
synthesis of Me2CB[7], CyCB[7], and MePhCB[7] described
1
above. The H NMR spectrum of the crude reaction mixture
obtained using 3 as probe allowed us to estimate that 18
comprised 66% of the crude material. Purification by Dowex
ion-exchange chromatography allowed us to isolate 210 mg of
18 in pure form in 16% yield. Clearly, the purification process is
far from ideal, and we are working to improve the process. We
found that 18 can be transformed into monofunctionalized
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of discrete cyclic assemblies would predominate.41 Figure 5b
shows the H NMR spectrum recorded for a 3.3 mM solution
a
Scheme 3. Synthesis of CB[7] Derivatives 18−20
1
of 20 in D2O at room temperature. A single, relatively sharp
triazole C−H resonance is observed at 6.45 ppm, which
suggests the formation of a well-defined assembly. On the other
hand, the upfield region of the spectrum between 2.70 and 1.00
ppm, corresponding to the (CH2)4 linker between the CB[7]
moiety and the triazole binding unit, is broadened, and the
presence of several groups of resonances suggests the presence
1
of several different assemblies. Figure 5c shows the H NMR
spectrum recorded at 80 °C, which shows that these different
groups of resonances coalesce and sharpen into four distinct
resonances corresponding to each of the four CH2 groups of
the linking chain. The fact that the resonances for Ht and Hs are
still strongly upfield shifted in the 1H NMR spectrum recorded
at 80 °C (spectrum b versus c, Figure 5) suggests that the
assembly 20n persists at high temperature. To gain insight into
the degree of oligomerization (n) of the self-assembled species
(20n) formed in D2O, we performed diffusion-ordered
spectroscopy (DOSY)42 for the monomeric complex 20·3
and for the self-assembled species 20n, as shown in Figure 6.
The diffusion coefficients measured using four different
resonances for 20·3 and 20n averaged (2.646
0.026) ×
10−10 and (1.638 0.045) × 10−10 m2 s−1, respectively (Figure
6). The ratio of diffusion constants for 20·3 and 20n is 1.616.
The Stokes−Einstein equation (eq 2) shows the relationship
a
Conditions: (a) 9 M H2SO4, KI, 110 °C, 16%; (b) NaN3, 80 °C,
’s catalyst, H2O, 50 °C, 95%.
81%; (c) 21, Pericas
̀
D = kBT/6πηrs
(2)
CB[7] derivative 19, which contains a reactive azide functional
group, in 81% yield by simply heating with NaN3 in H2O at 80
°C for 2 days. Azide 19 reacts with propargyl ammonium
between the diffusion coefficient (D) and the hydrodynamic
radius (rs) in a medium of viscosity η, where kB is Boltzmann’s
constant and T is temperature.42 If we assume that 20·3 and
20n are roughly spherical, then the ratio of the measured
diffusion coefficients can be converted into a ratio of molecular
weights, which gives the oligomerization number. For trimeric,
tetrameric, and pentameric assemblies, theory predicts the
ratios D(20·3)/D(20n) = 1.442 (n = 3), 1.587 (n = 4), and
1.709 (n = 5). In this manner, the measured ratio of diffusion
coefficients of 1.616 strongly suggests the formation of the
cyclic tetrameric assembly 204.
To provide additional evidence for the formation of the
cyclic tetrameric assembly 204, we performed electrospray
ionization mass spectrometry of 100 μM solutions in H2O and
100 000 resolution on an LTQ-Orbitrap instrument (Thermo-
Fisher, San Jose, CA). Figure 7a shows the mass spectrum
obtained, which incidates a 4+ ion at m/z = 1329.97, a 5+ ion at
m/z = 1068.68, and a 6+ ion at m/z = 894.31. The 4+ ion
chloride (21) in the presence of Pericas
̀
’s catalyst40 in H2O at
1
50 °C to give 20 in 95% yield. The H NMR spectrum of the
purified sample of 20 in the presence of 3which is a strong
binder for CB[7]-sized cavities7 and thereby disrupts any
potential self-assembly processes of 20is shown in Figure 5a.
Self-Assembly of 20 To Yield Cyclic Tetramer 204. We
anticipated that 20, which contains both a CB[7]-sized cavity
and a covalently attached triazolyl ammonium ionwhich is a
good guest for CB[7]-sized cavitieswould undergo self-
assembly processes in water. A priori it was hard to predict
whether supramolecular polymerization processes or formation
4+
corresponds to the 204 assembly. Figure 7b shows the
expansion of the region of the 204 ion, and Figure 7c shows
4+
the theoretical ion distribution for molecular formula
C
200H228N128O56. The excellent match between panels b and
c in Figure 7 provides strong evidence for the description of
this structure as the cyclic tetramer 2044+. Other ions of
significant intensity in Figure 7a were observed at m/z =
1068.68, which corresponds to [204·Na]5+, and m/z = 894.31,
which corresponds corresponds to [204·Na2]6+. To gain further
4+
insight into this system, we isolated ion 204 and performed
collision-induced dissociation experiments (Figure 7d). We
observed the cleavage of covalent bonds rather than the
expected dissociation of non-covalent aggregate 204 into
smaller non-covalent aggregate ions (e.g., monomers, dimers,
or trimers). Overall, the electrospray mass spectrometric
4+
Figure 5. 1H NMR spectra (400 MHz, D2O) recorded for mixtures of
(a) 20 and 3 (1.4 equiv), (b) 20 (3.3 mM) at 20 °C, and (c) 20 (3.3
mM) at 80 °C. Resonances marked with * arise from free 3.
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Scheme 4. Self-Assembly of CB[7] Derivative 20 To Give the
Cyclic Tetramer 204 as a Mixture of Diastereomers
Figure 6. DOSY spectra recorded (600 MHz, D2O, room temper-
ature) for (a) 20·3 and (b) cyclic tetramer 204.
rotation of the CB[7] group and re-complexation of the
triazolyl ammonium through the opposite ureidyl CO portal
of the CB[7] moiety. In this way, averaging of the signals
observed in the high-temperature 1H NMR spectrum shown in
Figure 5c is readily understandable.
CONCLUSION
■
In summary, we have shown that CB[7] derivatives are
accessible by a building-block approach that involves the
condensation of glycoluril hexamer 1 with glycoluril bis(cyclic
ethers) 2Me, 2Cy, 2MePh, and 12. Just like CB[7] itself, the high
water solubility of Me2CB[7] and its outstanding host·guest
recognition properties make it well suited as a solubilization
agent for poorly soluble pharmaceutical agents. Compound 18,
which bears a reactive primary alkyl chloride group, is the first
monofunctionalized CB[7] derivative to be reported. Com-
pound 18 undergoes further functionalization reactions to yield
19 and subsequently 20 by click chemistry. We find that 20
undergoes a self-assembly process in water to yield cyclic
tetramer 14 as established by NMR (VT and DOSY) and mass
spectrometric measurements.
We believe that the implications of this research go well
beyond the system-specific details described above. For
example, unfunctionalized CB[7] has been the most widely
applied CB[n] compound because of its good solubility in
water and its exceptional binding affinity and selectivity toward
its guests in water. This paper provides two water-soluble
monofunctionalized CB[7] derivatives that are amenable to
further functionalization reactions by SN2 and click chemistry,
which promises to allow the homogeneous covalent attachment
of CB[7] to solid phasesmacromolecules like proteins and
polymersand incorporation into other complex and func-
tional (bio)molecular systems. When that occurs, the continued
impact of the CB[n] family of molecular containers on the
chemical sciences will be significant.
Figure 7. Electrospray ionization mass spectra recorded for (a) a
solution of 14 (100 μM, H2O), (b) expansion of the 14 ion region,
and (c) theoretical distribution obtained for the molecular formula
C200H228N128O564+. (d) Mass spectrum obtained upon collision-
induced dissociation.
4+
investigations strongly support that 20 self-assembles to give a
4+
highly stable cyclic tetrameric aggregate 204
.
Enumeration of the Different Diastereomers of 204.
Although compound 1 is achiral due to the presence of a mirror
plane that runs through the equator of the molecule,
complexation events that desymmetrize the cavity result in
the formation of complexes that are enantiomers, and the two
CO portals can be described as enantiotopic. Accordingly,
when four molecules of 1 self-assemble to form 14, there are
several diastereomers that can form (Scheme 4). For example,
all four Me groups can be pointing up (u,u,u,u-14), three up and
one down (u,u,u,d-14), and two different combinations of two
up and two down (u,u,d,d-14 and u,d,u,d-14).43 The various
diastereomers are able to interconvert with one another by a
sequence of dissociation of one of the CB[7]·triazolyl
ammonium complexes to give a linear tetramer, followed by
13138
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Journal of the American Chemical Society
Article
14H), 5.60−5.40 (m, 12H), 4.48 (t, J = 6.3, 2H), 4.32 (s, 2H), 4.35−
4.20 (m, 10H), 4.20 (s, unbound 3), 4.15 (d, J = 15.4, 4H), 3.89 (s,
4H), 2.40−2.30 (m, 2H), 2.10−2.00 (m, 2H), 1.79 (s, 3H), 1.15−1.05
(m, 2H). 13C NMR (125 MHz, D2O, dioxane as internal reference, >1
equiv of 3): 156.7, 156.7, 156.5, 156.5, 156.5, 156.1, 133.7, 133.6,
129.6, 128.0, 125.4, 80.4, 78.7, 71.7, 71.6, 71.5, 71.4, 71.3, 71.2, 71.2,
71.1, 53.2, 53.1, 52.6, 52.6, 52.3, 49.9, 49.2, 48.8, 42.7, 42.4, 34.0, 28.8,
27.4, 19.1, 14.7 (only 36 of the 42 resonances expected were
EXPERIMENTAL SECTION
■
Compound 18. A mixture of 1 (1.00 g, 1.03 mmol) and KI (0.230
g, 1.35 mmol) was dissolved in 9 M aqueous H2SO4 (5 mL) and then
treated with 12 (0.510 g, 1.55 mmol). The flask was then sealed with a
rubber septum and heated at 110 °C for 30 min. The reaction solution
was poured into MeOH (40 mL), which resulted in a gray precipitate.
The mixture was centrifuged at 7200 rpm for 5 min. The supernatant
was decanted, and the precipitate was washed with MeOH (40 mL ×
3) and centrifuged at 7200 rpm for 5 min. The precipitate was dried
under high vacuum to give a crude, gray powder (1.46 g). The crude
solid was dissolved in 88% formic acid/0.4 M HCl (1:1, v:v, 10 mL).
The solution containing the crude solid was loaded onto a column (3
cm diameter × 20 cm long) containing Dowex 50WX2 ion-exchange
resin pretreated with 88% formic acid/0.4 M HCl (1:1, v:v). The
column was eluted with 88% formic acid/0.4 M HCl (1:1, v:v, 400
mL), and then 88% formic acid/0.6 M HCl (1:1, v:v, 400 mL), and
then 88% formic acid/0.8 M HCl (1:1, v:v, 400 mL). The fraction
observed). HR-MS: m/z 733.2910 ([20·3]2+
C50H56N32O14·C8H14N22+, 733.2905).
,
calcd for
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthetic procedures; characterization data and H and 13C
1
1
NMR spectra for all new compounds; H NMR spectra for
host−guest complexes; details of the X-ray structure of
1
Me2CB[7]·3; H NMR spectra used for Krel calculation; ES-
1
purity was assessed by H NMR using 3 as a probe. The appropriate
MS data for the decomposition reaction of Me2CB[7]; and
MMFF-minimzed models of 204. This material is available free
of charge via Internet at http://pubs.acs.org.
fractions were combined, solvent was removed by rotary evaporation,
and the precipitate was dried under high vacuum. The yellow solid was
then washed with MeOH (40 mL) and centrifuged at 7200 rpm for 5
min. The supernatant was decanted, and the precipitate was dried
under high vacuum to give 18 as a white powder (0.21 g, 0.16 mmol,
16%). Mp: >300 °C. IR (KBr, cm−1): 3001w, 2917w, 1729s, 1479s,
AUTHOR INFORMATION
Corresponding Author
LIsaacs@umd.edu
■
1
1423m, 1376m, 1321s, 1290m, 1235s, 1193s, 968m, 828m, 807s. H
NMR (500 MHz, D2O, >1 equiv of 3): 7.51 (s, unbound 3), 6.62 (s,
4H), 5.80−5.65 (m, 14H), 5.60−5.40 (m, 12H), 4.40−4.20 (m, 10H),
4.21 (s, unbound 3), 4.16 (d, J = 15.4, 4H), 3.92 (s, 4H), 3.64 (t, J =
6.3, 2H), 2.40−2.30 (m, 2H), 1.90 (s, 3H), 1.95−185 (m, 2H), 1.40−
1.30 (m, 2H). 13C NMR (125 MHz, D2O, dioxane as internal
reference, >1 equiv of 3): 156.8, 156.7, 156.5, 156.5, 156.5, 156.2,
133.7, 133.6, 129.6, 128.0, 80.5, 78.8, 71.7, 71.6, 71.5, 71.4, 71.3, 71.2,
71.2, 71.1, 70.3, 53.2, 53.1, 52.6, 52.6, 52.3, 49.3, 48.9, 44.8, 42.7, 42.4,
31.2, 27.4, 19.6, 14.7 (only 35 of the 39 resonances expected were
Author Contributions
‡B.V. and L.C. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Derick Lucas for initial experiments directed
toward the preparation of Me2CB[7]. We thank the National
Science Foundation (CHE-1110911 to L.I.) and the National
Institutes of Health (GM021248 to C.F.) for financial support.
observed). HR-MS: m/z 702.2476 ([18·3]2+
, calcd for
C47H51ClN28O14·C8H14N22+, 702.2493).
Compound 19. A mixture of 18 (100 mg, 0.079 mmol) and NaN3
(39 mg, 0.60 mmol) was dissolved in H2O (2 mL). The mixture was
heated at 80 °C for 2 days. The reaction solution was poured into
MeOH (3 mL), which resulted in a gray precipitate. The mixture was
centrifuged at 7200 rpm for 5 min. The supernatant was decanted, and
the precipitate was washed with MeOH (5 mL × 3) and centrifuged at
7200 rpm for 5 min. The precipitate was dried under high vacuum to
give 19 as a white powder (81 mg, 0.064 mmol, 81%). Mp: >300 °C.
IR (KBr, cm−1): 3442m, 3001w, 2923w, 2099w, 2034m, 1729s, 1476s,
This paper is dedicated to Prof. Franco̧ is Diederich on the
occasion of his 60th birthday.
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1420m, 1378m, 1322m, 1236s, 1192m, 971m. H NMR (400 MHz,
D2O, >1 equiv of 3): 7.47 (s, unbound 3), 6.62 (s, 4H), 5.80−5.60 (m,
14H), 5.60−5.40 (m, 12H), 4.35 (d, J = 16.0, 2H), 4.29 (d, J = 15.6,
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80.4, 78.8, 71.7, 71.6, 71.6, 71.5, 71.4, 71.3, 71.2, 71.2, 71.0, 70.3, 53.1,
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̀
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centrifuged at 7200 rpm for 5 min. The supernatant was decanted, and
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7200 rpm for 5 min. The precipitate was dried under high vacuum to
give 20 as a white powder (50 mg, 0.037 mmol, 95%). Mp: >300 °C.
IR (KBr, cm−1): 3442m, 2994w, 2916w, 1729s, 1473s, 1422m, 1378m,
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