Acyclic cucurbit[n]uril congeners are high affinity hosts

Article abstract of DOI:10.1021/jo100760g

(Figure Presented) We present the design, synthesis via methylene bridged glycoluril tetramer building blocks, and charaterization of acyclic cucurbit[n]uril congeners that function as hosts for a wide variety of ammonium ions in water. The X-ray crystallographic characterization of the free host and its complexes with p-xylylenediamine and spermine establish the flexibility of the methylene bridged backbone of the acyclic cucurbit[n]uril congeners that allow them to adapt to the structural features of the guest. We find that the acyclic cucurbit[n]uril congeners with their four contiguous methylene bridged glycoluril units and two aromatic o-xylylene walls bearing CO₂H substituents bind to ammonium ions in buffered water with values of K _a ranging from ～10⁵ M^-1 to greater than 10⁹ M^-1. Similar to the cucurbit[n]uril family of hosts, we find that increasing the concentration of metal cations in the buffer reduces the affinity of the acyclic cucurbit[n]uril congener toward guests by competitive binding at the ureidyl C - O portals. Although the acyclic cucurbit[n]uril congeners retain the ability to bind to ammonium ions with high affinity, they do so with lower selectivity than cucurbit[n]urils presumably do to the structural flexibility of the hosts. A methylene bridged glycoluril tetramer model compound that lacks the substituted o-xylylene walls is a much lower affinity host, which establishes the importance of these rings on the overall recognition behavior of the acyclic cucurbit[n]uril congeners. Overall, the results in this paper establish that acyclic cucurbit[n]uril receptors that contain four or more contiguous methylene bridged glycoluril units retain many of the excellent recognition properties of the cucurbit[n]uril family.

Full text of DOI:10.1021/jo100760g

pubs.acs.org/joc
Acyclic Cucurbit[n]uril Congeners Are High Affinity Hosts
Da Ma, Peter Y. Zavalij, and Lyle Isaacs*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742
lisaacs@umd.edu
Received April 19, 2010
We present the design, synthesis via methylene bridged glycoluril tetramer building blocks, and
charaterization of acyclic cucurbit[n]uril congeners that function as hosts for a wide variety of
ammonium ions in water. The X-ray crystallographic characterization of the free host and its
complexes with p-xylylenediamine and spermine establish the flexibility of the methylene bridged
backbone of the acyclic cucurbit[n]uril congeners that allow them to adapt to the structural features
of the guest. We find that the acyclic cucurbit[n]uril congeners;with their four contiguous methylene
bridged glycoluril units and two aromatic o-xylylene walls bearing CO2H substituents;bind to
ammonium ions in buffered water with values of Ka ranging from ∼105 M-1 to greater than 109 M-1
.
Similar to the cucurbit[n]uril family of hosts, we find that increasing the concentration of metal
cations in the buffer reduces the affinity of the acyclic cucurbit[n]uril congener toward guests by
competitive binding at the ureidyl CdO portals. Although the acyclic cucurbit[n]uril congeners retain
the ability to bind to ammonium ions with high affinity, they do so with lower selectivity than
cucurbit[n]urils presumably do to the structural flexibility of the hosts. A methylene bridged
glycoluril tetramer model compound that lacks the substituted o-xylylene walls is a much lower
affinity host, which establishes the importance of these rings on the overall recognition behavior of
the acyclic cucurbit[n]uril congeners. Overall, the results in this paper establish that acyclic cucurbit-
[n]uril receptors that contain four or more contiguous methylene bridged glycoluril units retain many
of the excellent recognition properties of the cucurbit[n]uril family.
Introduction
that constitute regions of high negative electrostatic potential.2,3
As a consequence of these structural features CB[n] compounds
bind to species that contain both hydrophobic chains and
cationic groups (Chart 1). In a series of elegant papers through-
out the 1980s Mock showed that CB[6] displays tight and highly
selective binding interactions toward alkaneammonium and
alkanediammonium ions in aqueous solution and used these
properties to catalyze a 3þ2 dipolar cycloaddition and construct
an early example of a molecular switch.4,5 Interest in the CB[n]
family of molecular containers surged after the isolation of the
larger CB[n] homologues that displayed even more interesting
recognition properties. For example, the exceptionally high
The cucurbit[n]uril (CB[n], n = 5, 6, 7, 8, 10) family of mole-
cular containers (Chart 1) are formed in a single step by the
condensation of glycoluril with formaldehyde under strongly
acidic conditions.1 The key structural features of CB[n] mole-
cular containers are the presence of a hydrophobic cavity
guarded by two symmetry equivalent ureidyl carbonyl portals
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66, 8094–8100. Freeman, W. A.; Mock, W. L.; Shih, N.-Y. J. Am. Chem. Soc.
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4786 J. Org. Chem. 2010, 75, 4786–4795
Published on Web 06/14/2010
DOI: 10.1021/jo100760g
r
2010 American Chemical Society

Ma et al.
JOCArticle
CHART 1. Structure of CB[n] Molecular Containers and the
CB[6] Hexanediammonium Ion Complex
characteristics of CB[6], CB[8], and CB[10] (<100 μM) in D2O.
A second, related issue is that the preparation of CB[n] deriva-
tives, especially those with enhanced solubility, is challenging,
particularly for the higher CB[n] homologues (n = 7, 8, 10).10
A final issue involves the dynamics of the formation and dis-
sociation of CB[n] complexes. Because of their narrow ureidyl
carbonyl portals, CB[n] compounds exhibit constrictive bind-
ing.11,12 In constrictive binding processes, large barriers to
dissociation and sometimes association translate into kinetics
of dissociation and association that are slow on the laboratory
time scale. Obviously, slow kinetics can be a limitation in many
applications.
3
Over the past decade we have been using mechanistic
insights to guide us toward synthetic approaches that alle-
viate some of these limitations. In one line of inquiry we have
used glycoluril surrogates to prepare CB[n] analogues with
built-in fluorescent walls.13,14 In a second line of inquiry we
have starved the CB[n] forming reaction of formaldehyde
and isolated acyclic glycoluril oligomers and a number of
macrocyclic CB[n]-type compounds lacking one or more
bridging CH2 groups (known as nor-seco-CB[n]).15-17 In a
third line of inquiry we have appended o-xylylene walls to
glycoluril dimers and related systems and delineated the
recognition properties (e.g., enantiomeric self-recognition,
heterochiral recognition, and self-sorting) of the resultant
acyclic CB[n] congeners.18-20 Recently, Sindelar has re-
ported the synthesis and recognition properties of a glyco-
luril trimer capped with o-xylylene rings.21 Throughout these
studies we have found that any structural change that
compromised the highly electrostatically negative ureidyl
carbonyl portals decreased the affinity of host toward guest.
In this paper we continue the third line of inquiry by using
building blocks 1-4 to prepare hosts 5a and 5b that comprise
a methylene bridged glycoluril tetramer capped with two
substituted o-xylylene rings and control compound 6 that
binding constants (Ka up to 1015 M-1) displayed by CB[7]6,7 and
the ability of CB[8] and CB[10] to bind two guests simulta-
neously has resulted in a number of intriguing applications
including the preparation of molecular machines,8 chemical
sensors, stationary phases for chromatographic separations
and affinity capture, supramolecular polymers, supramolecular
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SCHEME 1. Synthesis of Acyclic CB[n] Congeners 5a and 5b and Tetramer 6a
aReagents and conditions: (a) MeSO3H, 50 °C, (b) hydroquinone, TFA, reflux, (c) BrCH2CO2Et, K2CO3, CH3CN, reflux then LiOH, MeOH/H2O,
70 °C then concd HCl, (d) (EtO2CCH2O)2C6H4, TFA, Ac2O, reflux then LiOH, MeOH/H2O, 70 °C then concd HCl, (e) 3,5-dimethylphenol, TFA,
reflux.
lacks the substituted o-xylylene walls and study their recog-
nition properties toward ammonium ions (7-32) in water.
hydrolyzed to yield 5a in moderate yield (32%). As a control
compound to study the influence of the substituted o-xylylene
walls we decided to prepare methylene bridged glycoluril tetra-
mer 6. Heating 3a with 3,5-dimethylphenol as a formaldehyde
scavenger14 in refluxing TFA delivered 6 in 45% yield.
Results and Discussion
This section is organized as follows. First, we describe the
design and synthesis of acyclic CB[n] congeners 5a and 5b.
Second, we discuss their conformational properties and
X-ray crystal structures, and verify the absence of self-
association of hosts 5a and 5b. Third, we use a combination
of direct and competitive UV/vis spectroscopy and 1H NMR
spectroscopy to study the strength and geometrical details of
the host-guest complexes of hosts 5a and 5b. Lastly, we
discuss the trends in the tabulated values of Ka that give
insights into the behavior of 5a and 5b.
Design and Synthesis of Acyclic CB[n] Congeners 5a and 5b.
Hosts 5a and 5b are composed of a central methylene brided
glycoluril tetramer that is capped by two o-xylylene rings. The
substituents (e.g., H and Ph or Me) on the central methylene
bridged glycoluril tetramer all point away from the cavity, which
preorganizes the oligomer into the C-shaped configuration re-
quired for binding. The bridging o-xylylene units are substituted
with OCH2CO2H groups, which were expected to enable the
synthetic route, enhance the solubility of 5a and 5b, and poten-
tially enhance the binding affinity toward ammonium ions due to
Conformational Properties of 5a and 5b. The chemical
structures of 5a and 5b greatly limit the conformational
degrees of freedom of the system. For example, the fused bicyclic
glycoluril ring system is conformationally locked. Similarly, the
eight-membered rings that connect the glycolurils together by
methylene bridges adopt the crown conformation that mini-
mizes 1,5-diaxial interactions between substitutents on the con-
vex face of the glycoluril rings.24 Finally, the seven-membered
rings (7-MR) that connect the terminal substituted o-xylylene
rings to the glycolurils have the potential to adopt two con-
formations (anti: o-xylylene ring oriented toward the cavity with
7-MR in chair conformation; syn: o-xylylene ring oriented away
from the cavity with 7-MR in boat conformation). On the basis
of previous studies by Nolte25 and our group20 we anticipated a
preference for the anti conformation (vide infra, Figure 1a). In
this manner, the 15 fused rings of 5a and 5b were designed to
prefer a single conformation that preorganizes these acyclic
hosts toward guest binding. Macrocyclization is not necessary.
X-ray Crystal Structures of Host 5b and Complexes 5b 20
3
and 5a 25. We were fortunate to obtain single crystals of 5b
3
additional electrostatic (e.g., carboxylate ammonium) interac-
3
in its uncomplexed form (Figure 1a). As expected based on
the precedent described above, 5b assumes a C-shaped
conformation that defines a hydrophobic cavity. There are
several interesting aspects of the structure of 5b that deserve
comment. First, although the 15 fused rings effectively limit
the conformation of the molecule to a C-shape, 5b is able to
undergo out-of-plane twisting. Figure 1a shows that the
substituted o-xylylene tips are skewed with respect to one
another with one residing above the mean plane of the
compound and the other below. This out-of-plane skewing
results in an overall helical shape of 5b and therefore 5b
tions. The synthesis of the acyclic CB[n] congeners follows a
building block approach (Scheme 1). First, glycoluril bis(cyclic
ethers) 1a or 1b22 are reacted with C-shaped dimer 2C16,23 in
MeSO3H at 50 °C to yield tetramer bis(cyclic ethers) 3a (35%)
and 3b (53%) in moderate yield. Compound 3a was reacted with
hydroquinone in refluxing TFA to install the HO-substituted
o-xylylene walls to yield 4. Compound 4 was then reacted with
ethyl bromoacetate to yield an intermediate ester that was directly
hydrolyzed to yield host 5b. For the synthesis of 5a we allowed
3a to react with (EtO2CCH2O)2C6H4 under acidic conditions
(TFA, Ac2O) to yield an intermediate ester that was directly
(24) Day, A. I.; Arnold, A. P.; Blanch, R. J. Molecules 2003, 8, 74–84. Ma,
D.; Gargulakova, Z.; Zavalij, P. Y.; Sindelar, V.; Isaacs, L. J. Org. Chem.
2010, 75, 2934-2941.
(25) Sijbesma, R. P.; Kentgens, A. P. M.; Lutz, E. T. G.; van der Maas,
J. H.; Nolte, R. J. M. J. Am. Chem. Soc. 1993, 115, 8999–9005. Sijbesma,
R. P.; Wijmenga, S. S.; Nolte, R. J. M. J. Am. Chem. Soc. 1992, 114, 9807–13.
(22) Jansen, K.; Wego, A.; Buschmann, H.-J.; Schollmeyer, E.; Dopp, D.
Des. Monomers Polym. 2003, 6, 43–55. Niele, F. G. M.; Nolte, R. J. M. J. Am.
Chem. Soc. 1988, 110, 172–7.
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M.; Xiao, H.; Day, A. I. Chin. Sci. Bull. 2004, 49, 1111–1116.
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FIGURE 1. Cross-eyed stereoviews of the X-ray crystal structures of (a) 5b, (b) 5b 20, and (c) 5a 25. Color code: C, gray; H, white; N, blue; O,
red; H-bonds, red-yellow striped.
3
3
assumes a chiral conformation in the crystal. Within the
crystal of 5b there are equal amounts of the two enantio-
meric forms of 5b. Second, the OCH2CO2H groups on the
o-xylylene rings are oriented roughly parallel to the cavity.
In the neutral form of 5b present in the crystal, the CO2H
groups form intramolecular H-bonds back to the ureidyl
CdO portal of 5b as expected on the basis of its highly
negative electrostatic potential. Third, although the chemical
structure of 5b contains six units (e.g., four glycolurils and
two o-xylylene rings) the cavity of 5b appears to be larger
than that of CB[6]. To quantify this effect we consider the
distance between the quaternary (PhC) carbon atoms on
opposite sides of 5b and CB[n]. The relevant distances for 5b
and is held in place by two ureidyl CdO HN H-bonds and
3 3 3
one carboxylic acid CdO HN H-bond. Host 5b under-
3 3 3
goes a structural change that decreases the size of the host
cavity in the 5b 20 complex. This structural change is
reflected in the decreased distance between the opposing
3
˚
quaternary PhC carbon atoms (11.44 and 11.85 A). In
addition, one of the terminal o-xylylene rings of 5b engages
in an offset π-π stacking interaction (mean plane separa-
˚
˚
tion = 3.45 A; centroid-centroid distance = 3.74 A) with
the aromatic ring of guest 20. Figure 1c shows a stereoview of
the X-ray crystal structure of 5a 25. Spermine 25 is bound
3
within the caviþty of 5a by virtue of four H-bonds between the
central -NH2 groups of 25 and the ureidyl CdO groups
and the carboxylic acid groupþs of 25. In addition, each of the
terminal -H2Nþ(CH2)3NH3 groups folds back and form
additional H-bonds to the CdO portal of 5a. In total the
˚
are 11.91 and 12.60 A. Comparable values for CB[5] are 8.48
˚
and 7.60 A, for CB[6] are 10.05 and 10.05 A, for CB[7] are
˚
˚
˚
10.74 and 11.37 A, and for CB[8] are 11.47 and 12.54 A. By
this measure, the curvature of the methylene bridged glyco-
luril tetramer subunit of 5b is most similar to that of CB[8].
However, the 7-MR adopt a chairlike conformation that
projects the connected substituted o-xylylene rings into the
cavity of 5b at a sharper angle than is observed for CB-
[6]-CB[8]. In this manner it appears that 5b contains struc-
tural regions that resembles CB[8] and other regions that are
similar to smaller CB[n].
5a 25 complex benefits from six H-bonds. One of the inter-
3
esting structural features of the 5a 25 complex is the pro-
3
nounced out-of-plane skewing of the terminal o-xylylene
rings. This geometrical feature places the CH2 groups of
the central butylene linker within the shielding region of the
adjacent aromatic ring, which is reflected in the large upfield
shifts observed for Hm and Hn in the 1H NMR spectrum of
the 5a 25 complex (vide infra). Overall, hosts 5a and 5b
3
Figure 1b shows a stereoview of the X-ray crystal structure
of 5b 20. In this structure, 20 is bound within the cavity of 5b
exhibit a substantial ability to respond to the structural
characteristics of the guest.
3
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CHART 2. Chemical Structures of Guests Used in This Study
1
Hosts 5a, 5b, and 6 Do Not Undergo Self-Association. In
our previous studies of methylene bridged glycoluril oligo-
mers bearing terminal o-xylylene walls self-association has
been an important and in some cases dominant mode of
interaction.19 Therefore, before proceeding to study the
host-guest recognition properties of 5a, 5b, and 6 we wanted
to rule out the possibility of self-association in water. For this
purpose we performed 1H NMR dilution experiments
(Supporting Information) and do not observe any changes
in chemical shift over the 60 μM to 1.52 mM range of
concentration. These results indicate that 5a, 5b, and 6 do
not undergo self-association, which allows us to study their
host-guest recognition properties free of these effects.
Binding Studies between Hosts 5a, 5b, and 6 and Guests
7-32. This section describes the noncovalent interaction
between the hosts and guests 7-32 (Chart 2) by several
different methods.
Figure 2d-f shows the H NMR recorded for 5a, spermine
25, and an equimolar mixture of 5a and 25. In this case the
pattern of upfield shift of the resonances for guest 25 suggests
that the central diaminobutane linker of 25 is bound within
the central cavity of 5a with the N(CH2)3NH3þ arms extend-
ing past the ureidyl CdO portals of 5a. This interpretation is
supported by the X-ray crystal structure of the 5a 25 shown in
3
Figure 1c and discussed below.
Direct UV/Vis Titrations. Because the values of Ka for the
1
interaction between 5a and 20 were inaccessible by H NMR
titrations we decided to resort to competitive UV/vis binding
assays. We used competitive UV/vis binding assays rather than
the competitive H NMR binding method used by us previ-
1
ously6 because most of the complexes of 5a display fast exchange
kinetics on the chemical shift time scale. We found that dye 7
(rhodamine 6G) binds to 5a and undergoes changes in its UV/vis
spectrum. Figure 3a shows the UV/vis spectra recorded when a
fixed concentration of 7 (9.23 μM) was titrated with 5a (0-
49 μM). The UV/vis spectra show large changes at 520 and
550 nm and the presence of an isosbestic point at 533 nm that
allowed us to conclude that 5a and 7 undergo clean formation of
1H NMR Investigations of the Binding Interactions. Initially,
we used 1H NMR to study the interaction between 5b and 20.
Figure 2a-c shows the 1H NMR spectra recorded for 5b, 20,
and for an equimolar mixtureof5b and 20. The protons onthe
aromatic ring of 20 undergo a substantial upfield shift in the
presence of 5b suggesting that 20 is bound within the cavity of
5b, which is corroborated by the X-ray crystal structure of
the 5a 7 complex. Figure 3b shows a plot of UV/vis absorbance
3
at 520 nm versus the concentration of 5a that can be fitted to a
1:1 binding model to determine the stability of the 5a 7 complex
3
5b 20 (Figure 1b). When 5b and 20 are mixed at a 1:2
(Ka = (2.1 ( 0.1) ꢀ 105 M-1). With this value of Ka in hand it is
possible to measure Ka values for weaker binding guests by
competitive indicator displacement assays.27
3
stoichiometry we observe resonances for free 20 and com-
plexed 20, which establishes that the dynamics of exchange
are slow on the chemical shift time scale. Attempts to perform
1H NMR titration experiments to determine values of Ka were
unsuccessful because they exceeded those that can be deter-
mined accurately (Ka < 105 M-1) by this technique.26
UV/vis Indicator Displacement Assays. In indicator dis-
placement assays, a complex is formed between a host and an
indicator that undergoes a UV/vis change upon complexa-
tion. Upon addition of a competitive binding guest, the
(26) Connors, K. A. Binding Constants; John Wiley & Sons: New York,
1987.
(27) Wiskur, S. L.; Ait-Haddou, H.; Lavigne, J. J.; Anslyn, E. V. Acc.
Chem. Res. 2001, 34, 963–972. Anslyn, E. V. J. Org. Chem. 2007, 72, 687–699.
4790 J. Org. Chem. Vol. 75, No. 14, 2010

Ma et al.
JOCArticle
FIGURE 3. (a) UV/vis spectra obtained during the titration of a
fixed concentration of 7 (9.23 μM) with 5a (0-49 μM); (b) plot of
absorbance versus [7] used to determine the value of Ka by nonlinear
least-squares fitting; and (c) Job plot ([5a] þ [7] = 7.65 μM) of mole
fraction of 5a versus ΔA ꢀ χ.
FIGURE 2. 1H NMR spectra recorded for (a) 5b, (b) 20, and (c) an
equimolar mixture of 5b and 20 (400 MHz, room temperature, 25
mM sodium phosphate buffered D2O, pH 7.4) and (d) 5b, (e) 25, and
(f) an equimolar mixture of 5b and 25 (600 MHz, room temperature,
25 mM sodium phosphate buffered D2O, pH 7.4).
values of the binding constants for a subset of these guests
toward CB[6]5,28 and CB[7].6,29
Trends in the Values of Ka between Host 5a and Guests. The
values of Ka given in Table 1 derived from the work of
Mock,5 Isaacs,6 and Inoue28 allow us to make comparisons
between various guests that shed light on the overall binding
properties of 5a compared to CB[n].
indicator is released resulting in a UV/vis spectral change. On
the basis of a knowledge of the concentrations employed and
the value of Ka for either the host indicator complex or the host
3
3
Influence of Chain Length. One of the best studied phe-
nomena in the binding properties of the CB[n] family is the
influence of guest length on the binding affinity of alkane-
diammonium ions. For the relatively rigid host CB[6] a
maximum binding affinity is seen for pentanediammonium
and hexanediammonium ions 10 and 11 with greatly reduced
affinity toward longer and shorter diammonium ions.5,28
Figure 4 shows a plot of binding affinity of 5a and CB[6]
toward diammonium ions 9-17 as a function of chain length
in the competitive medium 1:1 H2O:HCO2H determined
by Mock5 and in the less competitive medium 50 mM NaCl
determined by Inoue.28 Several trends in these data are
worth noting. First, host 5a binds more tightly to the longer
guest interaction it is possible to calculate the unknown Ka.
We used this strategy (Supporting Information) with dyes
(indicators) 7 and 8 to determine the values of Ka for the
complexes between host 5a and guests 9-30 (Table 1). We first
used the competition between UV/vis inactive guest butylam-
monium ion 26 and rhodamine G (7) to determine the stabi-
lity of the 5a 26 complex (Ka=(1.4 ( 0.1)ꢀ105 M-1). Subse-
3
quently we performed an indicator displacement assay between
5a, UV/vis active acridine dye 8, and 26 that allowed us to deter-
mine the value of Ka for the 5a 8 complex (Ka=(7.2 ( 0.4) ꢀ
3
108 M-1). We then measured the values of Ka for the remaining
complexes of 5a by indicator displacement assays using the
5a 8 complex (Table 1). The data from the UV/vis competition
3
assays and their analysis to extract the Ka values are given in the
Supporting Information. Table 1 also presents the literature
(29) Values of Ka for some of the other guests are available from the
literature, but were measured with different buffers or pH values. To avoid
additional complications due to these effects we have restricted our discus-
sion to values of Ka from the systematic works of Mock, Inoue, and our
group.
(28) Rekharsky, M. V.; Ko, Y.-H.; Selvapalam, N.; Kim, K.; Inoue, Y.
Supramol. Chem. 2007, 19, 39–46.
J. Org. Chem. Vol. 75, No. 14, 2010 4791

Ma et al.
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TABLE 1. Binding Constants (Ka) for the Interaction of Hosts 5a,
CB[6], and CB[7] with Various Guests
Ka (M-1
)
guests
host 5a
(2.1 ( 0.1) ꢀ 105
(1.4 ( 0.1) ꢀ 106 1.5 ꢀ 105 a
(2.8 ( 0.3) ꢀ 107 2.4 ꢀ 106 a
(1.6 ( 0.1) ꢀ 108 2.8 ꢀ 106 a
CB[6]
CB[7]b
7
8
9
(7.2 ( 0.4) ꢀ 108
(2.0 ( 0.2) ꢀ 107 c
(1.5 ( 0.1) ꢀ 108 c
(4.5 ( 0.8) ꢀ 108 b
(2.9 ( 0.2) ꢀ 108 c
(1.7 ( 0.2) ꢀ 107 c
10
11
(9.0 ( 1.4) ꢀ 107
12
13
(1.4 ( 0.1) ꢀ 108 4.3 ꢀ 104 a
(3.6 ( 0.4) ꢀ 108 9.1 ꢀ 103 a
FIGURE 4. Plot of log (Ka) versus chain length for the interaction
between alkanediammonium ions (9-17) and hosts 5a (b), CB[6] in
1:1 H2O:HCO2H (9), and CB[6] in 50 mM NaCl ([).
(1.08 ( 0.06) ꢀ 106 c
14
15
(2.2 ( 0.2) ꢀ 108 4.8 ꢀ 102 a
(2.0 ( 0.2) ꢀ 108 1.0 ꢀ 102 a
(1.67 ( 0.06) ꢀ 104 c
16
17
18
19
20
21
22
23
24
(7.2 ( 0.7) ꢀ 107
(3.2 ( 0.3) ꢀ 107
(4.3 ( 0.4) ꢀ 107
(7.1 ( 0.8) ꢀ 105
(6.8 ( 0.9) ꢀ 108
(4.0 ( 0.4) ꢀ 108
(3.5 ( 0.4) ꢀ 106
(4.8 ( 0.5) ꢀ 105
(2.6 ( 0.4) ꢀ 107 1.4 ꢀ 106 a
(4.5 ( 0.4) ꢀ 108 1.3 ꢀ 107 a
(1.4 ( 0.1) ꢀ 105 1.0 ꢀ 105 a
(1.4 ( 0.1) ꢀ 106 2.2 ꢀ 103 a
show significant upfield shifts for all of the CH2 groups
indicating that they are within the hydrophobic cavity of 5a
rather than outside the cavity or near the CdO portals.
Binding Capacity of 5a. On the basis of the analysis of the
X-ray structure of 5a (Figure 1) and the ability of 5a to bind
the longer diammonium ions tightly (e.g., decanediammo-
nium ion 15) we anticipated that host 5a would be able to
complex larger guests that typically only bind to the more
spacious hosts CB[7] and CB[8]. For this purpose, we studied
the binding affinity of 5a toward guests 18-23 that display a
range of guest sizes. For example, CB[6] binds to the smaller
guests 19 and 20, CB[7] can accommodate slightly larger
guests 18, 21, and 22, and CB[8] is able to bind tightly even to
dimethyl adamantaneammonium ion 23.6 In contrast, host
5a forms complexes with all six size probe guests 18-23
albeit with differences in affinity. For example, host 5a binds
(2.3 ( 0.4) ꢀ 107
(2.1 ( 0.3) ꢀ 106
(1.8 ( 0.3) ꢀ 109
(1.3 ( 0.2) ꢀ 107
(4.2 ( 1.0) ꢀ 1011
(2.5 ( 0.4) ꢀ 104
(4.1 ( 0.3) ꢀ 108 c
(3.3 ( 0.4) ꢀ 109 c
(3.1 ( 0.2) ꢀ 106 c
(1.67 ( 0.08) ꢀ 105 c
25
26
27
28
29
30
31
32
(3.6 ( 0.5) ꢀ 109
(2.0 ( 0.2) ꢀ 109
(9.8 ( 0.9) ꢀ 107 9.1 ꢀ 103 a
(3.1 ( 0.4) ꢀ 108 1.7 ꢀ 106 a
(1.4 ( 0.2) ꢀ 108
relatively weakly to the smallest (19, Ka = 7.1 ꢀ 105 M-1
)
and largest (23, Ka = 4.8 ꢀ 105 M-1) guests in this series. The
intermediate sized guests 18, 20, and 21 are all bound more
tightly by 5a. These higher levels of affinity may be due to a
better size match between the cavity of host 5a and guests 18,
20, and 21, the possibility of π-π interactions between guests
20 or 21 and the substituted o-xylylene walls of host 5a, or a
combination of these factors. The 1H NMR spectra recorded
for the 5a 18, 5a 21, and 5a 22 complexes (Supporting
aMeasured in H2O/85% HCO2H (1:1).5 bMeasured in 50 mM NaOAc
buffer, pH 4.74.6 cMeasured in 50 mM NaCl.28
alkanediammonium ions (12-15) than CB[6] does. These
higher binding constants may reflect (1) that the larger
hydrophobic cavity of 5a (relative to CB[6]) provides a larger
hydrophobic driving force toward complexation and/or (2)
-
the energetic contributions of the interaction between the CO2
3
3
3
arms of host 5a and the diammonium guest (vide infra).
Second, host 5a appears to be less sensitive to changes in
length than CB[6]; host 5a is less selective than CB[6] and
binds 11-15 with high affinity (Ka > 108 M-1). We believe
this lower selectivity is due to the structural flexibility of host
5a relative to CB[6]. For example, when host 5a adopts a
skewed (helical) conformation the distance between its ur-
eidyl CdO portals also change. It is well-known that the
ureidyl CdO portals of CB[n] provide a significant portion of
the driving force for the binding of ammonium ions by ion-
dipole/H-bonding interactions. Because host 5a is acyclic it
may increase its cavity size by flexing its pairs of CH2 bridges.
This process allows 5a to accommodate longer guests per-
haps by folding the hydrophobic chain of the guest inside the
host.17,30 Indeed the 1H NMR spectra of the complexes
between 5a and 13, 15, and 17 (Supporting Information)
Information) show upfield shifts for all of the guest protons
indicating that the guests reside inside the anisotropic shield-
ing region defined by the aromatic rings and glycoluril
tetramer sububits of 5a. In combination these results suggest
that the effective cavity volume of 5a is similar to or slightly
3
3
˚
larger than that of CB[7] (V = 272 A ). It is worth noting
that the affinity of 5a toward several of these size probe
guests (18, 21, and 23) exceeds the Ka values measured
toward CB[7] (Table 1). In contrast, the affinity of CB[7]
toward its best guests (20 and 22) is greater than that
measured toward 5a. These results reinforce our belief that
the flexibility of 5a makes it a more general purpose high
affinity but modest selectivity host in water.
Effect of the Number of Ammonium Groups. In his pioneer-
ing work Mock demonstrated that the addition of ammo-
nium groups to guests for CB[6] generally resulted in a
10-1000-fold increase in binding affinity.5,28 This effect is
also seen for other CB[n]. For example, spermine 25 (Ka =
1.3 ꢀ 107 M-1) binds ca. 10-fold stronger to CB[6] than
(30) Ko, Y. H.; Kim, H.; Kim, Y.; Kim, K. Angew. Chem., Int. Ed. 2008,
47, 4106–4109.
4792 J. Org. Chem. Vol. 75, No. 14, 2010

Ma et al.
JOCArticle
spermidine 24 (Ka=1.4 ꢀ 106 M-1), that in turn binds ca.
10-fold stronger to CB[6] than butanediammonium ion
(9, Ka =1.5 ꢀ 105 M-1) does. The values of Ka contained
in Table 1 allow us to ascertain whether similar trends hold
for 5a. For example, butylammonium ion (26, Ka = 1.4 ꢀ
105 M-1) binds 10-fold weaker to 5a than butanediammo-
nium ion (9, Ka=1.4 ꢀ 106 M-1) does. Similarly, hexylam-
monium ion (27, Ka = 1.4 ꢀ 106 M-1) binds ca. 100-fold
weaker to 5a than hexanediammonium ion (11, Ka=1.6 ꢀ
108 M-1). Related trends (17-185-fold increase in Ka per
ammonium group) can be seen when comparing the binding
of butanediammonium ion (9, Ka=1.4 ꢀ 105 M-1) with that
of triammonium ion spermidine 24 (Ka=2.6 ꢀ 107 M-1) and
tetraammonium ion spermine 25 (Ka = 4.5 ꢀ 108 M-1).
Acyclic CB[n] congener 5a displays similar gains in Ka as a
result of additional ammonium groups as CB[6] does.
Effect of the Degree of Alkylation of the Ammonium Ion.
The affinity of CB[6] toward alkanediammonium ions is dra-
matically affected by the degree of alkylation of the N-atoms.
For example, CB[6] binds tightly to hexanediammonium ion 11
(Ka = 2.8 ꢀ 106 M-1) and N,N0-dimethylhexanediammonium
ion 31 (Ka = 1.7 ꢀ 106 M-1) but binds only weakly to N,N,N0,
N0-tetramethylhexanediammonium ion 30 (Ka = 9.1 ꢀ 103
M-1). This effect can be explained based on the geometry of the
FIGURE 5. Plot of log Ka versus the concentration of sodium
phosphate buffer (H2O, pH 7.4) for the formation of the 5b 7
complex.
3
of Naþ for the CdO portals of 5b. This analysis indicates
that the ureidyl CdO portals of host 5b retain this essential
feature of the CB[n] family that supports our description of
5a and 5b as acyclic CB[n] congeners.
Contribution of the Substituted o-Xylylene Walls to the
Binding. On the basis of the excellent binding affinity of 5a
toward the aromatic guests 8, 20, 21, 28, and 29 and the X-ray
structure of 5b 20 (Figure 1b) we suspected that π-π interac-
3
tions between the substituted o-xylylene walls of 5a and the
aromatic rings of the guest might be an important driving force
in the recognition behavior of host 5a. Accordingly, we prepared
compound 6that lacks the substituted o-xylylene walls of 5a. We
measured the value of Ka for the interaction between 6 and
hexanediammonium ion (11, Ka=(5.6 ( 0.4) ꢀ 103 M-1) or p-
xylenediammonium ion (20, Ka=(1.5 ( 0.1) ꢀ 104 M-1) by
direct 1H NMR titrations (Supporting Information). These Ka
values are substantially smaller than the corresponding values
CB[6] 11 complex (Chart 1) that possesses two N-H OdC
3 3 3
3
H-bonds per portal. Accordingly, each ammonium ion can have
two C-subsitutents and 2 H-atoms and still assume this ideal
geometry; addition of a third C-subsitutent (e.g., 30) results in
severe steric interactions between host and guest. The affinity of
5a toward 11 (Ka = 1.8 ꢀ 108 M-1), 31 (Ka = 3.1 ꢀ 108 M-1),
30 (Ka =9.8ꢀ 107 M-1), and32 (Ka =1.4ꢀ 108 M-1) does not
follow a similar trend. The comparable affinities of 5a toward
11, 31, 30, and 32 suggest that the flexibility of 5a allows it to
for the interaction of 5a with 11 (Ka = (1.6 ( 0.1) ꢀ 108 M-1
)
compensate for the loss of N-H OdC H-bonds by adjusting
and 20 (Ka = (6.8 ( 0.9) ꢀ 108 M-1). This indicates that the
substituted o-xylylene walls of 5a do contribute substantially to
the overall binding behavior of 5a. The fact that reduction in
affinity for aliphatic 11 ((2.8 ꢀ 104)-fold) is comparable to that
of aromatic 20 ((4.5ꢀ 104)-fold) suggests that the aromatic walls
do not engage in strong specific π-π interactions but instead
probably enhance binding by defining a structured environment
that releases water upon binding. To ascertain the potential
contributions of carboxylate-ammonium ion electrostatic in-
teractions on the recognition behavior of 5a we compared its
binding toward 28 and 29. Both 28 and 29 are derivatives of
p-xylylenediamine; 29 contains two CH2CH2CH3 arms whereas
28 contains two CH2CH2NH3þ arms. We specifically chose thþe
two carbon linkers to prevent backfolding of the CH2CH2NH3
arms to the ureidyl CdO portals of 5a and potentially promote
carboxylate-ammonium ion electrostatic interactions in the
3 3 3
the size of the cavity to best accommodate the geometrical
requirements of the interaction between the ammonium ion and
1
the ureidyl CdO portal. The H NMR spectra recorded for
5a 11, 5a 30, 5a 31, and 5a 32 show remarkably similar
3
3
3
3
patterns of upfield shifts of the central CH2 groups and very
little change in chemical shift for the NMe groups (Supporting
Information). This suggests that all four complexes (5a 11,
3
5a 30, 5a 31, and 5a 32) possess a similar overall geometry
3
3
3
with the hexylene chain fully bound inside the cavity of 5a.
Effect of the Concentration of Buffer Used. It is well-known
from CB[n] supramolecular chemistry that the presence of
metal cations in solution reduces their apparent binding
affinity toward guests due to competitive binding at the
electrostatically negative ureidyl CdO lined portals.12,20,31
We hypothesized that the ureidyl CdO portals of acyclic
CB[n] congeners 5a and 5b that are shaped by four contig-
uous glycoluril units should also bind to metal cations and
thereby reduce their affinity toward guests. Accordingly, we
measured the affinity of rhodamine 6G (7) toward 5b by
direct UV/vis titration in sodium phosphate buffer (pH 7.4)
at different concentrations. Figure 5 shows a plot of Ka
versus phosphate concentration. As the concentration of
sodium phosphate is increased the log Ka value undergoes
a steady decrease as expected based on competitive binding
5a 28 complex. Experimentally, we find that the binding con-
3
stants measured for 5a 28 and 5a 29 are quite similar, which
3
3
suggests that carboxylate-ammonium ion electrostatic interac-
tions do not play a large role in the recognition behavior of 5a.
Conclusions
In summary, we have presented the synthesis of acyclic
CB[n] congeners 5a and 5b that contain four contiguous
methylene bridged glycoluril units. Despite the acyclic nature
of 5a and 5b the 15 fused rings effectively preorganize 5a and
5b into a C-shape required for binding. By a combination of
direct UV/vis titrations along with indicator displacement
(31) Buschmann, H. J.; Cleve, E.; Schollmeyer, E. Inorg. Chim. Acta 1992,
193, 93–97. Jeon, Y.-M.; Kim, J.; Whang, D.; Kim, K. J. Am. Chem. Soc.
1996, 118, 9790–9791. Ong, W.; Kaifer, A. E. J. Org. Chem. 2004, 69, 1383–
1385.
J. Org. Chem. Vol. 75, No. 14, 2010 4793

Ma et al.
JOCArticle
assays we determined the values of Ka for the interaction
of 5a with a variety of guest compounds (7-32). We find
that 5a acts as a high affinity host;just like CB[n];with
binding constants in the 105-109 M-1 range. The cavity
volume of host 5a is comparable to that of CB[7]. Unlike
CB[n], 5a displays only moderate levels of selectivity based
on guest length and the degree of alkylation of the N-atoms
of the ammonium ion guests. We attribute this lower selec-
tivity to the conformational changes of the host that occur
4H), 5.48 (d, J = 8.6 Hz, 2H), 5.34 (d, J = 8.6 Hz, 2H), 5.12 (d,
J = 10.9 Hz, 4H), 4.79 (d, J = 10.9 Hz, 4H), 4.18 (d, J = 15.2
Hz, 4H), 4.14 (d, J = 14.6 Hz, 2H), 1.76 (s, 6H), 1.59 (s, 6H). 13
C
NMR (100 MHz, TFA, DMSO-d6 as internal reference): δ
157.0, 156.6, 78.5, 74.5, 71.2, 71.0, 70.6, 52.3, 48.1, 15.5, 14.4.
MS (ESI): m/z 781 ([M þ H]þ).
Compound 3b: A mixture of 2C (0.920 g, 3.00 mmol) and 1b
(2.61 g, 6.90 mmol) in MeSO3H (10 mL) was stirred at room
temperature for 20 min. Then the mixture was stirred and heated
at 50 °C for 4 h. The reaction mixture was poured into MeOH
(500 mL). After filtration, the crude solid was dried in high
vacuum. The crude solid was recrystallized from TFA (25 mL)
and water (25 mL) to yield 3b as a white solid (1.700 g, 1.65
mmol, 53%). Mp >350 °C. TLC (MeCN/H2O, 4:1) Rf 0.47. IR
upon formation of the host guest complexes. Similar to
3
CB[n], the binding affinity of 5a toward its guests increases
by a factor of 10-1000 as the number of ammonium ions
in the guests is increased (e.g., 9 vs 24 vs 25) whereas the
affinity is reduced as the concentration of metal cations in the
buffer increases due to competitive binding at the ureidyl
CdO portals.
1
(cm-1): 3450 w, 1722 s, 1445 m, 1362 m, 1314 m, 1198 s. H
NMR (400 MHz, DMSO-d6): δ 7.13-6.94 (m, 20H), 5.82 (d,
J = 15.2 Hz, 4H), 5.68 (d, J = 14.8 Hz, 2H), 5.38 (d, J = 10.4
Hz, 4H), 5.20 (d, J = 9.2 Hz, 2H), 5.03 (d, J = 9.2 Hz, 2H), 4.32
(d, J = 10.4 Hz, 4H), 4.08 (d, J = 14.8 Hz, 2H), 4.05 (d, J = 15.2
Hz, 4H). 13C NMR (100 MHz, TFA, DMSO-d6 as internal
reference): δ 159.6, 157.5, 130.7, 130.3, 129.6, 128.9, 128.3,
128.2, 127.4, 87.8, 81.9, 72.3, 72.0, 71.6, 53.2, 50.6. MS (ESI):
m/z 1029 ([M þ H]þ).
To date, three major issues for the use of CB[n] compounds
in practical applications have been the following: (1) their
generally poor solubility in aqueous solution, (2) challenges
for their selective functionalization, and (3) the relatively
slow uptake and release rates of guests due to the constrictive
binding nature of the CB[n] cavity. The acyclic CB[n] con-
geners presented in this paper were prepared by convergent
building block routes and feature terminal o-xylylene rings
that are readily functionalized and endowed with carboxylic
acid groups that increase solubility in aqueous solution. By
virtue of its fused ring acyclic structure 5a is both preorga-
nized for ammonium ion binding and capable of fast uptake
and release of its guests. Macrocyclization is not necessary to
achieve high affinity interactions between acyclic CB[n]
congeners and ammonium ion guests. The availability of
acyclic CB[n] congeners that can be readily functionalized
while maintaining the outstanding recognition properties of
the CB[n] family promises their future use in a variety of
applications including chemical sensing, controlled release
or sequestration, and as a component of molecular ma-
chines.
Compound 5a: To a mixture of 3a (6.56 g, 8.36 mmol) and 4
(17.9 g, 66.9 mmol) in TFA (40 mL) was added Ac2O (6.30 mL,
66.9 mmol). The mixture was heated at reflux for 2 h. The
solvent was removed by rotary evaporation. The solid was
washed twice with diethyl ether (2 ꢀ 200 mL). Filtration and
drying on high vacuum gave a white solid. This white solid was
mixed with LiOH (1.70 g, 70.8 mmol) and dissolved in MeOH
and water (1:1, v/v, 400 mL). The mixture was heated at 80 °C
for 15 h. The solvent was removed by rotary evaporation. The
crude solid was dissolved in water (60 mL) and treated with
concd HCl (14 mL). The solid was obtained by filtration, dried
on high vacuum, and then recrystallized with TFA (40 mL) and
water (120 mL) to yield 5a as a white solid (3.2 g, 2.65 mmol,
32%). Mp >310 °C dec. IR (ATR, cm-1): 1707 s, 1477 m,
1313 m, 1200 m, 964 m, 785 s. 1H NMR (400 MHz, DMSO-d6): δ
6.74 (s, 4H), 5.56 (d, J = 14.8 Hz, 2H), 5.46 (d, J = 14.8 Hz, 4H),
5.35 (d, J = 9.6 Hz, 2H), 5.25 (d, J = 15.6 Hz, 4H), 5.24 (d, J =
9.6 Hz, 2H), 4.65 (m, 8H), 4.13 (d, J = 15.6 Hz, 4H), 4.03 (d, J =
14.8 Hz, 4H), 4.03 (d, J = 14.8 Hz, 2H), 1.65 (s, 6H), 1.63 (s, 6H).
13C NMR (100 MHz, TFA, DMSO-d6 as internal reference): δ
175.7, 157.0, 156.6, 149.5, 127.4, 113.7, 79.9, 78.3, 72.0, 71.4,
65.8, 53.2, 48.4, 35.0, 15.1, 14.3. HR-MS (ESI): calcd for
C70H61N16O20 1197.3622, found 1197.3548.
Experimental Section
General Experimental. Starting materials were purchased
from commercial suppliers and were used without further
purification. Compounds 1a, 1b, 2C, 28, and 29 were prepared
according to literature procedures.16,22,32 Melting points were
measured in open capillary tubes and are uncorrected. TLC
analysis was performed with use of precoated plastic plates. IR
spectra were recorded on a FT-IR spectrometer (reported in
cm-1). NMR spectra were measured on spectrometers operat-
ing at 400 MHz for 1H and 100 MHz for 13C. Mass spectrometry
was performed with the electrospray ionization (ESI) technique.
Compound 3a: To a mixture of 2C (7.42 g, 24.0 mmol) in
anhydrous MeSO3H (55 mL) was added 1a (24.46 g, 96.2 mmol).
The mixture was stirred and heated at 50 °C for 3 h. The reaction
mixture was poured into water (700 mL). After filtration, the
crude solid was dried in high vacuum. The crude solid was
recrystallized from TFA (15 mL) and water (45 mL) to yield 3a
as a white solid (6.60 g, 8.45 mmol, 35%). Mp >227 °C dec. IR
(ATR, cm-1): 1714 s, 1456 m, 1314 m, 1223 s, 1177 s, 1079 m,
960 m, 920 m, 857 m, 799 s, 757 m, 668 m. 1H NMR (400 MHz,
DMSO-d6): δ 5.65 (d, J = 14.6 Hz, 2H), 5.50 (d, J = 15.2 Hz,
Compound 5b: A mixture of 4b (2.90 g, 2.39 mmol), ethyl
bromoacetate(3.20 g, 19.1 mmol), and anhydrousK2CO3 (6.62 g,
48.0 mmol) in MeCN (300 mL) was heated at reflux for 10 h.
Solvent was removed under reduced pressure. Crude product
was extracted with acetone (3 ꢀ 70 mL). After the solvent was
removed with rotary evaporation, the crude product was
washed with ethyl acetate (15 mL) to yield a white solid. And
then this white solid was mixed with LiOH (0.400 g, 16.7 mmol)
and dissolved in MeOH and water mixture (1:1, v/v, 120 mL).
The mixture was heated at 80 °C for 15 h. Solvent was removed
with rotovapory evaporation. The crude solid was treated with
water (60 mL) and concd HCl (1.6 mL, 19.2 mmol) and then
filtered to yield 5b as a white solid (1.7 g, 1.2 mmol, 50%).
Mp >248 °C dec. IR (ATR, cm-1): δ 1713 s, 1462 s, 1380 m,
1315 m, 1224 s, 1196 s, 1094 m, 971 s, 863 m, 801 m, 696 m. 1H
NMR (400 MHz, D2O): δ 7.02-6.81 (m, 20H), 6.57 (s, 4H), 5.71
(d, J = 16.0 Hz, 4H), 5.58 (d, J = 15.2 Hz, 2H), 5.21 (d, J = 8.8
Hz, 2H), 5.09 (d, J = 15.2 Hz, 4H), 4.93 (d, J = 8.8 Hz, 2H), 4.31
(d, J = 15.6 Hz, 4H), 4.28 (d, J = 15.2 Hz, 4H), 4.18 (d, J = 15.6
Hz, 4H), 4.10 (d, J = 16.0 Hz, 4H), 3.99 (d, J = 15.2 Hz, 2H).
13C NMR (100 MHz, TFA, 1,4-dioxane as internal reference): δ
173.7, 157.5, 155.0, 148.0, 128.3, 128.04, 127.3, 127.1, 126.3,
(32) Haeg, M. E.; Whitlock, B. J.; Whitlock, H. W. J. Am. Chem. Soc.
1989, 111, 692–696. Couri, M. R. C.; Vieira de Almeida, M.; Fontes, A. P. S.;
Chaves, J. D. A. S.; Cesar, E. T.; Alves, R. J.; Pereira-Maia, E. C.; Garnier-
Suillerot, A. Eur. J. Inorg. Chem. 2006, 1868–1874.
4794 J. Org. Chem. Vol. 75, No. 14, 2010

Ma et al.
JOCArticle
126.1, 125.4, 125.3, 112.4, 86.3, 85.3, 70.6, 69.6, 64.2, 52.2, 48.5,
35.3. HR-MS (ESI): calcd for C70H61N16O20 1445.4248, found
1445.4252.
Supporting Information Available: Synthetic procedures
and characterization data for 4b and 6, direct and competitive
1
binding titrations for determination of Ka values, H and 13C
NMR spectra for all new compounds, 1H NMR spectra of
selected host-guest complexes of 5a, and crystallographic
information files for 5b, 5b 20, and 5a 25 (CIF). This material
Acknowledgment. L.I. thanks the National Science
Foundation (CHE-0615049 and CHE-0914745) for financial
support.
3
3
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 14, 2010 4795