Toward supramolecular polymers incorporating double cavity cucurbituril hosts

Article abstract of DOI:10.1016/j.tet.2009.02.055

We describe the synthesis of a series of guests (1-6) containing two adamantylammonium ions separated by xylylene spacing groups and their complexation properties toward double cavity cucurbituril host bis-ns-CB[10]. We observed the preferential formation of 1:1, 2:2, and oligomeric complexes rather than the desired n:n supramolecular polymers. Guest 7, which contains a longer biphenyl spacer successfully precludes the formation of the 1:1 complex but results in the formation of the 2:2 complex (bis-ns-CB[10]₂·7₂) rather than supramolecular polymer. Guest 8, which contains adamantylammonium, p-xylylene diammonium, and hexanediammonium ion binding regions is shown to reversibly form 2:2 and 1:2 complexes (bis-ns-CB[10]₂·8₂ and bis-ns-CB[10]·8₂) in response to changes in host:guest stoichiometry. Lastly, this equilibrium can be manipulated by the addition of exogenous CB[6], which selectively targets the hexanediammonium ion binding region of 8 and delivers the penta-molecular complex bis-ns-CB[10]·8₂·CB[6]₂.

Full text of DOI:10.1016/j.tet.2009.02.055

Tetrahedron 65 (2009) 7249–7258
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Toward supramolecular polymers incorporating double cavity
cucurbituril hosts
*
Regan Nally, Lyle Isaacs
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 January 2009
Received in revised form 31 January 2009
Accepted 23 February 2009
Available online 28 February 2009
We describe the synthesis of a series of guests (1–6) containing two adamantylammonium ions sepa-
rated by xylylene spacing groups and their complexation properties toward double cavity cucurbituril
host bis-ns-CB[10]. We observed the preferential formation of 1:1, 2:2, and oligomeric complexes rather
than the desired n:n supramolecular polymers. Guest 7, which contains a longer biphenyl spacer
successfully precludes the formation of the 1:1 complex but results in the formation of the 2:2 complex
(bis-ns-CB[10]2$72) rather than supramolecular polymer. Guest 8, which contains adamantylammonium,
p-xylylene diammonium, and hexanediammonium ion binding regions is shown to reversibly form 2:2
and 1:2 complexes (bis-ns-CB[10]2$82 and bis-ns-CB[10]$82) in response to changes in host:guest
stoichiometry. Lastly, this equilibrium can be manipulated by the addition of exogenous CB[6], which
selectively targets the hexanediammonium ion binding region of 8 and delivers the penta-molecular
complex bis-ns-CB[10]$82$CB[6]2.
Keywords:
Cucurbituril
Diffusion ordered spectroscopy
Supramolecular chemistry
Polymers
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
metal–ligand interactions.10 Most relevant to the work described in
this paper is the work of Harada who has investigated the use of
The synthetic and supramolecular chemistry of the cucurbit
[n]uril family (CB[n]) of macrocycles has undergone extensive
development since the pioneering work of Mock on CB[6] during
the 1980s.1,2 For example, the large values of Ka and high selectiv-
ities based on guest size, shape, and functional group preferences of
CB[6] have been shown to transfer to the larger homologues CB[7]
and CB[8].3 In turn these large values of Ka, the associated free
cyclodextrin molecular containers as building blocks for supra-
molecular polymers by hydrophobically driven host–guest com-
plexation in water.11 In supramolecular polymeric systems, the
degree of polymerization is controlled by the strength of the non-
covalent interactions between monomers with higher values of Ka
leading to longer polymers. As such, the use of members of the
CB[n] familydwith their exceedingly large values of Ka (up to
1015 Mꢁ1),3,12,13 din the preparation or modification of polymeric
and macromolecular species holds great promise. Accordingly,
several groups have decorated the main chain or side chains of
linear polymers14 or dendrimers15 with CB[n] binding groups and
were therefore able to modify the properties of the polymer by
addition of CB[n]. Kim’s group even used a CB[6] derivative as the
monomer to form covalent polymeric nanocapsules.16 Lastly, the
groups of Kim, Kaifer, and Scherman have used the ability of CB[8]
to form homo-ternary or hetero-ternary complexes4 to drive the
energy
(DDG), and the inherent stimuli responsiveness of
CB[n]$guest complexes (e.g., pH, photochemical, electrochemical,
chemical) have led to their use in the development of a variety of
molecular machines and biomimetic systems.4–6 Our research
group has been involved in studies of the mechanism of CB[n]
formation, which has resulted in the preparation of new CB[n] type
molecular containers (bis-ns-CB[10], (ꢀ)-bis-ns-CB[6], and ns-
CB[6]) with exciting properties (homotropic allosterism, chiral
recognition, and folding).7,8
The use of supramolecular chemistry as a means to create and
modify the properties of polymers has been the subject of active
investigation over the past decade.9 For example, a number of
groups have demonstrated the oligo- and polymerization of suit-
able dimeric systems based on reversible hydrogen bonding and
formation of self-assembly dendrimers and
a self-assembled
diblock copolymer.6,17
In 2006, we reported the isolation and recognition capacity of
bis-ns-CB[10].7 Bis-ns-CB[10] contains two cavities that are able to
bind to two guests simultaneously to form ternary complexes. In
this process, the binding of the first guest preorganizes the second
binding site for binding of the second guest, which is known as
allostery. Even more interesting was the ability of bis-ns-CB[10] to
distinguish between small and large guests within a mixture and
* Corresponding author. Tel.: þ1 301 405 1884; fax: þ1 301 314 9121.
E-mail address: lisaacs@umd.edu (L. Isaacs).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.055

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R. Nally, L. Isaacs / Tetrahedron 65 (2009) 7249–7258
possibility of preparing supramolecular polymers using the double
cavity host bis-ns-CB[10] in combination with suitable guests (e.g.,
1–8) containing two binding domains (e.g., bis-ns-CB[10]n$guestn).
Figure 1 depicts the desired n:n interaction between bis-ns-CB[10]
and divalent guests. Although this proposed supramolecular poly-
merization appears straightforward, in reality the situation is more
complex. For example, although linear supramolecular polymers
can be formed from solutions comprising n hosts and n guests, the
formation of discrete (cyclic) 1:1, 2:2, 3:3, or n:n aggregates can also
be readily envisioned.18 Compounding the situation is the reality
that smaller discrete assemblies are likely to be favored on entropic
grounds. Therefore, we decided to start simple and targeted guests
1–6 (Chart 1), which contain two adamantylammonium binding
domains linked together by o-, m-, and p-xylylene units for several
reasons. First, we envisioned that 1–6 would be straightforward to
synthesize by substitution reactions. Second, we hoped that the
different substitution patterns of 1–6 would result in the formation
of different discrete or polymeric assemblies. Lastly, we hoped that
the xylylene spacer between the adamantylammonium binding
domains would be rigid enough to prevent the formation of a 1:1
host:guest inclusion complex. Upon closer inspection post facto, we
realized that guests 1, 2, and 4–6 are more complex than we an-
ticipated and actually contain one xylenediamine and two ada-
mantylammonium binding domains (Fig. 2). In the discussion
below we abbreviate these domains as PXDA and Ad, respectively.
n
Figure 1. Hypothetical linear polymer comprising bis-ns-CB[10] and 1.
form ternary complexes with two identical guests. This latter pro-
cess is known as homotropic allostery. This ability is due to the
flexibility of the central CH2 bridges, which adjust their non-
bonded CH2/CH2 distance to accommodate the size of the guest.
We envisioned that bis-ns-CB[10] with its ability to form tight
ternary complexes under positive homotropic allosteric control
would render bis-ns-CB[10] as an ideal component of supramo-
lecular polymers in combination with suitable guests containing
two binding epitopes. Figure 1 depicts the mode of polymerization
that might result from the combination of bis-ns-CB[10] and suit-
able guests. Given the fact that such supramolecular polymers
would be composed of two components we expected the behavior
of the system to be sensitively dependent on host:guest stoichio-
metry. In addition, we expected the system to be responsive to the
addition of exogenous host or guest by the formation of competi-
tive host$guest complexes. This paper reports our initial studies in
this research direction.
2.2. Synthesis of guests 1, 2, and 4–6
The synthesis of 1 and 2 was achieved by twofold SN2 reaction of
the corresponding bis-(bromomethyl)benzenes (12 and 13) with
adamantylamine (10) using Ag2O in THF (Scheme 1). The free-base
amines were then converted to the hydrochloride salts (1 and 2) by
treatment with anhydrous HCl. All attempts to synthesize ortho-
substituted 3 were unsuccessful due to competing intramolecular
five-membered ring formation. Accordingly, we decided to prepare
the tetramethylated series (4–6) of compounds to complete the
substitution pattern series. Compounds 4–6 were prepared by
reacting bis-(bromomethyl)benzenes (12–14) with N,N-dimethyl-
adamantylamine 11 in refluxing CH3CN.
2. Results and discussion
This section is subdivided into several parts. We start with
a discussion of the design of the guests (1–8, Chart 1) and their
synthesis. Next, we discuss the characterization of the supramo-
lecular species formed in the presence of bis-ns-CB[10] with a par-
ticular emphasis on absolute host:guest stoichiometry. Finally, we
discuss the application of stimuli in the form of additional CB[n]
hosts to control absolute binding stoichiometry in this system.
2.3. Characterization of bis-ns-CB[10] complexes with guests
2.1. Design of guests 1–6
1, 2, and 4–6
Chart 1 shows the structures of hosts CB[6], CB[7], and bis-ns-
CB[10] and guests 1–9 used in this study. We were attracted to the
After we had synthesized guests 1, 2, and 4–6 we decided to
investigate their use in the preparation of supramolecular
Ad
H2N
O
O
O
N
CB[6] (n = 1)
O
O
O
N
N N
Ad
H2
Ad
N
N
N
N
N
H2
N
N N
Ad NH2
N
H2N Ad
N
Ad
H2
N
N
N
N
N
1•2Cl
2•2Cl
5•2Br
N
N
N
N
N
N
N
N
6
O
O
O
O
n
O
3•2Cl
Ad
O
Ad
N
Ad
Ad
CB[7] (n = 2)
N
N
N
N
Ad
4•2Br
Ad
N
7
Ad NH2
O
O
O
N
O
O
Ad
HN
H
Bridging CH2
H
H
6•2Br
N
N
H2N Ad
N
N
N
N
N
N
N
N
O
O
O
O
O
7•2Cl
C2
C
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H3N
NH3
O
H2
O
O
O
9•2Cl
O
N
N
N
H
N
N
N
N
NH2
8 3 CF3CO2H
H
bis-ns-CB[10]
N
H
= Ad
O
O
O
O
O
Chart 1. Compounds used in this study.

R. Nally, L. Isaacs / Tetrahedron 65 (2009) 7249–7258
7251
PXDA
2 X
R2N
NR2
Ad
Ad
Figure 2. Depiction of the two different binding domains of the xylylene derived
guests (1, 2, and 4–6) along with their abbreviations used in this paper.
NR2
a) or b)
+
Ad
Ad
R2N
Br
Br
Br
Ad NR2
1•2Cl R = H (77%)
4•2Br R = CH3 (96%)
12
10 R = H
11 R = CH3
NR2
Ad
a) or b)
N
Br
N
+
R2
R2
2•2Cl R = H (43%)
5•2Br R = CH3 (35%)
10 R = H
11 R = CH3
13
N
Br
Br
Ad
N
Ad
N
b)
+
6•2Br
(47%)
14
Ad
NH2
Br
NH2
a)
+
Br
H2N
Ad
15
7•2Cl
Figure 3. 1H NMR spectra (400 MHz, D2O, rt) recorded for solutions of: (a) 1, (b) bis-ns-
CB[10]$1, (c) 2, (d) a mixture of 2 and bis-ns-CB[10]$2, (e) 4, (f) a mixture of 4 and bis-
ns-CB[10]$4, (g) 5, (h) a mixture of 5 and bis-ns-CB[10]$5, (i) 6, (j) bis-ns-CB[10]$6.
Scheme 1. Synthesis of guest compounds 1, 2, and 4–7. Conditions: (a) Ag2O, THF; (b)
CH3CN, reflux.
polymers. Figure 3 shows the 1H NMR spectra recorded for guests 1,
2, and 4–6 alone and in the presence of bis-ns-CB[10]. The 1H NMR
spectra for the complexes between p-xylylene diamine derivatives
1 and 4 and bis-ns-CB[10] (Fig. 3b and f) are sharp and dispersed,
which is indicative of a single, well-defined geometry. In contrast,
the spectra obtained for the bis-ns-CB[10] complexes of m-xylylene
diamine derivatives 2 and 5 (Fig. 3d and h) and o-xylylene diamine
derivative 6 are broader and less well defined, which suggested the
possibility of oligomeric or polymeric assemblies. Comparison of
the 1H NMR spectra for para-substituted 1 before (Fig. 3a) and after
the addition of bis-ns-CB[10] (Fig. 3b) reveals that the protons
corresponding to the Ad binding domain are shifted upfield
whereas those of the PXDA binding domain are shifted downfield.
It is well known that the cavity region of CB[n] compounds con-
stitutes an NMR shielding region whereas the regions just outside
the C]O lined portals are deshielding.2 Accordingly, within the bis-
ns-CB[10]$1 complex, both Ad binding domains are inside the
cavities of bis-ns-CB[10] whereas the PXDA group is outside the
portal. Similar observations were made for the complex between
p-substituted 4 and bis-ns-CB[10]. In contrast, the 1H NMR spectra
recorded for the complexes between bis-ns-CB[10] and 2, 5, and 6
show two classes of resonances for the PXDA (unshifted and
downfield shifted) and Ad groups (unshifted and upfield shifted),
which suggested that some of the Ad and PXDA domains are un-
bound and remote from the cavities of bis-ns-CB[10]. The in-
tegration of the resonances present in the 1H NMR spectra of each
of the bis-ns-CB[10] complexes with 1, 2, and 4–6 suggests that host
and guest are present in equimolar amounts.19 This observed rel-
ative stoichiometry is consistent with 1:1, 2:2, or the desired n:n
complexes (Fig. 4).
2.4. Determination of absolute host:guest stoichiometry by
diffusion ordered spectroscopy
In order to determine the absolute stoichiometry of complexes
between bis-ns-CB[10] and guests 1, 2, and 4–6 we performed
diffusion ordered NMR spectroscopy (DOSY).20 DOSY spectroscopy

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R. Nally, L. Isaacs / Tetrahedron 65 (2009) 7249–7258
was performed on samples prepared from equimolar amounts of
host and guest for compounds 1, 2, and 4–6 with bis-ns-CB[10]. The
bis-ns-CB[10]$92 complexdwhich does not undergo exchange
processes with assemblies formed from bis-ns-CB[10] and guests 1,
2, and 4–6dwas used as an internal standard of known molecular
size.7 The diffusion coefficients for these complexes were de-
termined in the standard manner by fitting a plot of field strength
versus intensity using Eq. 1. In Eq. 1, I and I0 are signal intensities, D
n
is the diffusion coefficient measured in m2 sꢁ1
netic ratio measured in sꢁ1 Tꢁ1, g is the gradient strength measured
in G cmꢁ1
is the length of the gradient measured in milliseconds,
and
is the diffusion time measured in milliseconds.20,21 Table 1
, g is the gyromag-
,
d
D
Figure 4. Potential equilibrium between bis-ns-CB[10]$1, bis-ns-CB[10]2$12, and bis-
ns-CB[10]n$1n complexes.
summarizes the results of the DOSY measurements. The diffusion
coefficients measured for the complex between bis-ns-CB[10] and
p-xylylene diamine derivative 1 were nearly identical to that
measured for bis-ns-CB[10]$92, which indicates this complex is best
formulated as the 1:1 complex (bis-ns-CB[10]$1). Figure 5a shows
an MMFF minimized model of the bis-ns-CB[10]$1 complex. In
contrast, the diffusion coefficient measured for the complex be-
tween p-substituted quaternary ammonium guest 4 is only 61% of
that of bis-ns-CB[10]$92. For perfect spheres, theory predicts that
increasing the molecular weight n-fold should lead to a decreased
diffusion coefficient by a factor of nꢁ1/3; dimers (trimers) are
therefore expected to have diffusion coefficients 79% (69%) those of
the corresponding monomers. For the rod-like oligomers expected
for assemblies based on bis-ns-CB[10] we have previously shown
that dimers should have diffusion coefficients roughly 67–72%
those of monomers.22 We, therefore, formulate the complex be-
tween bis-ns-CB[10] and 4 as bis-ns-CB[10]2$42. Examination of an
MMFF model of bis-ns-CB[10]2$42 (Fig. 5b) illustrates the 2:2
allows a determination of the diffusion coefficients (Ds) of a given
species in solution. From this knowledge of the values of Ds it is
possible to infer the size of the species and therefore the absolute
stoichiometry of the supramolecular complexes. Diffusion NMR
Table 1
Diffusion coefficients (10ꢁ10 m2 ꢁ1) measured for the complexes between bis-ns-
s
CB[10] and guests 1–8 (D2O, 400 MHz, 25 ꢂC) and the corresponding dimensionless
ratio of diffusion coefficients relative to internal standard bis-ns-CB[10]$92
Guest
Ds complex
Ds bis-ns-CB[10]$92
Ratio (Ds/Ds(bis-ns-CB[10]$9$9))
1
2
4
5
6
7
2.47
1.10
1.40
1.04
1.08
1.61
1.22
2.45
2.24
2.27
2.18
2.31
2.42
1.54
1.01
0.49
0.61
0.48
0.47
0.67
0.79
8 (10 ꢂC)
Figure 5. Stereoviews of the MMFF minimized geometries of: (a) bis-ns-CB[10]$1 and (b) bis-ns-CB[10]2$42. Color code: C, gray; H, white; N, blue; O, red; H-bonds, red-yellow
stripped.

R. Nally, L. Isaacs / Tetrahedron 65 (2009) 7249–7258
7253
stoichiometry.23 For the complexes between 2, 5, 6, and bis-ns-
CB[10] the diffusion coefficients are significantly smaller and clus-
tered in the range 0.47–0.49. This clearly suggests an absolute
stoichiometry greater than 2:2. Unfortunately, in the absence of
well-defined 1H NMR spectra, X-ray crystallographic results, or
electrospray mass spectrometric data assignment of an absolute
stoichiometry to these aggregates is speculative.24 Disappointed by
these results, we decided to investigate some of the structural
variables that might circumvent 1:1 or 2:2 complex formation and
promote the formation of higher order linear oligomers or
polymers.
g
2g2d2
ð
D
d
ꢁ =3Þ
I ¼ I0eꢁD
(1)
2.5. Increased linker length between Ad binding domains
First, we decided to investigate the influence of the length of the
linker between the Ad binding domains. For this purpose we tar-
geted compound 7, which connects two Ad binding domains with
a biphenyl linker. We surmised that the length and rigidity of the
biphenyl linking group would preclude the formation of a 1:1
complex and promote the formation of n:n oligomeric or polymeric
structures. The synthesis of 7 was achieved by treatment of 15 with
adamantylamine in the presence of Ag2O in THF (Scheme 1).
Figure 7. Plot of signal intensity versus gradient strength and the best fit of the data to
Eq. 1. Symbols: o, bis-ns-CB[10]2$72; ,, bis-ns-CB[10]$92.
a preference for 2:2 complex formation (e.g., cyclization) rather than
oligomerization. This result highlights one of the main challenges in the
formation of supramolecular polymers from pairs of monomers con-
taining two binding groups.
2.6. Characterization of the complex between
bis-ns-CB[10] and guest 7
2.7. Design of heterovalent guest 8
The 1H NMR spectrum of a sample containing equimolar amounts of
bis-ns-CB[10] and 7 shows a single set of resonances, which is consis-
tent with a single well-defined host$guest complex (Fig. 6). The bis-ns-
CB[10]:7 ratio was determined to be 1:1 based on integration of the 1H
NMR spectrum. The protons of the Ad domain in Figure 6b are shifted
upfield relative tothe adamantyl protons of uncomplexed 7in Figure 6a,
which suggests that the Ad domain of 7 is bound inside the bis-ns-
CB[10] cavity. Also of interest were the resonances for the biphenyl
group, which split into one upfield and one downfield shifted set of
resonances in the complex. To differentiate between the multitude of
possible n:n complexes formed, we performed diffusion NMR experi-
ments. Figure 7 shows a plot of intensity versus field strength for an
equimolar mixture of (bis-ns-CB[10]$7)n and bis-ns-CB[10]$92 as an
internal monomeric standard. Fitting these curves to the theoretical
equation (Eq. 1) allowed us to extract diffusion coefficients for (bis-
Although we were disappointed that guest 7 with a rigid linker
did not result in supramolecular polymers when combined with
bis-ns-CB[10] we hypothesized that the presence of two identical
Ad binding domains was to blame. Given that bis-ns-CB[10] ex-
hibits homotropic allosterism we wondered what would happen if
we synthesized 8, which contains Ad and hexanediammonium
(HDA) binding domains connected by a p-xylylene linker (Fig. 8).
Would bis-ns-CB[10] choose to form the 1:1 complex bis-ns-
(a)
H
N
Ad
PXDA
8 • 3CF3CO2H
ns-CB[10]$7)n
(Ds¼1.61ꢃ10ꢁ10 m2 sꢁ1
)
and
bis-ns-CB[10]$92
NH2
(Ds¼2.42ꢃ10ꢁ10 m2 sꢁ1) as an internal standard. The ratio of the values
of Ds for (bis-ns-CB[10]$7)n and bis-ns-CB[10]$92 is 0.67. This diffusion
constant ratio falls in the lower end of the range expected (0.67–0.72)
for rod-shaped dimers.22,25 On the basis of the DOSY measurements we
formulate the complex as bis-ns-CB[10]2$72. In contrast to the 1:1
complex observed between bis-ns-CB[10] and guest 1, which contained
a short p-xylylene linking group, guest 7 did form a higher order
complex but with a 2:2 absolute stoichiometry. Although the longer
biphenyl linker present in 7 did preclude 1:1 complex formation as
designed, we believe that the rigidity of the linking group resulted in
N
H
HDA
(b)
n
Figure 8. (a) Depiction of the three binding domains of 8 along with their abbrevia-
tions used in this paper. (b) Theoretical equilibrium between a linear polymer com-
prising bis-ns-CB[10] and 8 and bis-ns-CB[10]2$82.
Figure 6. 1H NMR spectra (400 MHz, D2O, rt) recorded for solutions of: (a) 7, (b) bis-ns-
CB[10]2$72.

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R. Nally, L. Isaacs / Tetrahedron 65 (2009) 7249–7258
CB[10]$8 in which the two cavities are filled by different sized
binding groups (e.g., Ad and HDA) and violate homotropic allo-
stery? Would bis-ns-CB[10] choose to form the 2:2 complex bis-ns-
CB[10]2$82 (Fig. 8)? We hypothesized that homotropic allostery
might destabilize the cyclic aggregate bis-ns-CB[10]2$82 that con-
tains two molecules of bis-ns-CB[10] of different non-bonded
CH2/CH2 distance (e.g., steric mismatch). When both of those
hypotheses are true we might expect the formation of a supramo-
lecular polymer bis-ns-CB[10]n$8n.
2.8. Synthesis of heterovalent guest 8
The synthesis of 8 was achieved in three steps, starting with
commercially available nitrile 16 as depicted in Scheme 2. Con-
version of nitrile 16 to aldehyde 17 was carried out according to the
literature procedure.26 Benzyl bromide 17 was alkylated with 10 to
afford compound 18 in 47% yield. Subsequent reaction of 18 with N-
(tert-butoxycarbonyl)-1,6-hexanediamine (19) afforded the corre-
sponding diamine, which was deprotected to yield 8 (75%) as
a water-soluble trifluoroacetate salt.
Figure 9. 1H NMR spectra (400 MHz, D2O, rt) recorded for: (a) 8, and mixtures of bis-
ns-CB[10] and 8 at different relative stoichiometries (b) 1:1, (c) 2:1, and (d) 1:2.
Ad
HN
domain is inside the cavity of bis-ns-CB[10], we refer to the situa-
tion as PXDAin. The spectroscopic fingerprint for a PXDAin situation
is a shielding of the resonances for the PXDA domain. Figure 9b
shows spectroscopic fingerprints for PXDAout, Adin, and HDAin
binding modes. Accordingly, we formulate the geometry of the bis-
ns-CB[10]2$82 complex as shown in Scheme 3. We depict the bis-ns-
CB[10]2$82 assembly, which displays homotropic allostery but we
believe the alternate diastereomer where each molecule of bis-ns-
CB[10] contains one HDA and one Ad binding domain is also
formed.
Br
Br
a)
b)
47%
80%
CN
16
CHO
18
CHO
17
H
N
Given the ability of bis-ns-CB[10] to display homotropic allos-
terism we wondered whether changing the relative stoichiometry
of bis-ns-CB[10] to guest 8 would result in changes in the molec-
ularity of the resulting complex or changes in the location of the
host along guest 8 (e.g., PXDAin binding mode). Figure 9c shows the
1H NMR spectrum obtained from a 2:1 mixture of bis-ns-CB[10] and
8. This spectrum is nearly identical to that shown in Figure 9b,
which indicates that an excess of host bis-ns-CB[10] is not sufficient
to change the absolute molecularity of the assembly.29 In contrast,
Figure 9d shows the 1H NMR obtained from a 1:2 mixture of bis-ns-
CB[10] and 8. At a 1:2 relative stoichiometry, the 1H NMR spectrum
shows a reduction in the intensity of the resonances corresponding
to HDAin and Adin geometries and the appearance of a new set of
resonances corresponding to a PXDAin geometry. Scheme 3 depicts
three possible diastereomers of the bis-ns-CB[10]$82 complex un-
der homotropic allosteric control. The diastereomers with two
PXDAin, Adin, and HDAin binding modes are referred to as 8a, 8b,
and 8c, respectively. Because the cavity of bis-ns-CB[10] contains
two distinct ureidyl C]O portals (e.g., top and center) there are
three possible diastereomers (e.g., top–top, top–center, and center–
center) for 8a, 8b, and 8c.30 The dominant formation of a 1:2
host:guest stoichiometry complex was further supported by the
observation of a peak at m/z¼794 in the ESI-MS, which corresponds
to the [bis-ns-CB[10]$82]3þ ion. We confirmed a spacing of 0.33 m/z
units, which supports our formulation of a 3þ ion. We also observed
an ion of substantial intensity for the 4þ state. The driving force for
this stoichiometry induced change from bis-ns-CB[10]2$82 to bis-
ns-CB[10]$82 is interesting and informative. Bis-ns-CB[10] contains
two cavities each of which contribute significant binding free en-
ergy upon complexation. In contrast, guest 8 contains three binding
sites (Ad, PXDA, and HDA). Because the Ad, PXDA, and HDA binding
regions are connected by common NHþ2 groups, it is not possible for
two adjacent binding regions (e.g., Ad and PXDA or PXDA and HDA)
to be bound simultaneously. In contrast, the more widely spaced Ad
c)
18
8 • 3CF3CO2H
75%
NH2
N
H
Scheme 2. Synthesis of 8. Reaction conditions: (a) (i) DIBAL, toluene, 0 ꢂC, 1 h. (ii) 10%
HCl, 1 h, rt. (b) 10, Ag2O, THF. (c) (i) N-(tert-butoxycarbonyl)-1,6-hexanediamine (19),
toluene, reflux, 20 h. (ii) NaBH4, MeOH, reflux (30 min), then stir at rt (15 h). (iii) TFA/
CH2Cl2 (1:1), rt, 8 h.
2.9. Characterization of the complex between
bis-ns-CB[10] and guest 8
We first prepared the complex between equimolar amounts of
bis-ns-CB[10] and 8. The 1H NMR spectra of uncomplexed guest 8
and its complex are shown in Figure 9a,b. The 1H NMR spectrum of
the complex (Fig. 9b) is composed of a significant number of rela-
tively sharp resonances, which suggested that the system is not
polymeric. Integration of the 1H NMR spectrum of the assembly
confirmed that equal numbers of molecules of bis-ns-CB[10] and 8
were incorporated. The diffusion coefficient for the complex was
79% that of the monomeric standard bis-ns-CB[10]$92 (Table 1),
which suggests that complex is best formulated as bis-ns-
CB[10]2$82.27 Fortunately, we also observed a peak at m/z¼1339 in
the ESI-MS, which corresponds to [bis-ns-CB[10]2$82]3þ, which
confirms the assignment of 2:2 stoichiometry.28
It was possible to tease some information from the chemical
shifts of the resonances for distinct regions of guest 8 within the
bis-ns-CB[10]2$82 complex. For example, when either the Ad or the
HDA portion of guest 8 is bound within the interior of bis-ns-CB[10]
the adjacent PXDA domain is positioned directly outside the host
cavity. We refer to this situation as PXDAout. The spectroscopic
fingerprint for a PXDAout situation is a slight deshielding of the
resonances for the PXDA domain. Conversely, when a PXDA binding

R. Nally, L. Isaacs / Tetrahedron 65 (2009) 7249–7258
7255
Three of the nine diastereomers possible
under homotropic allosteric control
6
7
7
6
bis-ns-CB[10]
6
bis-ns-CB[10]2•82
6
8a
8c
8b
bis-ns-CB[10]•82•CB[6]2 CB[6]•8•CB[7]
Scheme 3. Depiction of the equilibrium structures obtained upon treatment of bis-ns-CB[10]2$82 with 8 then CB[6] then CB[7].
and HDA binding domains may be complexed simultaneously.
2.11. Stimuli–responsive switching behavior
Consequently, at a 1:1 bis-ns-CB[10]:8 stoichiometry guest 8 is
forced to use both the Ad and the HDA binding domains in order for
both cavities of bis-ns-CB[10] to be filled. When the bis-ns-CB[10]:8
stoichiometry is raised to 1:2 there is enough guest present so that
the Ad, PXDA, and HDA binding domains compete for inclusion
inside each cavity of bis-ns-CB[10] based on their individual bind-
ing affinities.31
In the previous sections, we showed that a change in bis-ns-
CB[10]:8 stoichiometry resulted in a reversible change in the
molecularity of the host$guest complex. We rationalized this
behavior in terms of the binding constants of various binding
domains of the guest toward bis-ns-CB[10]. Given the very high
binding affinity and high selectivity exhibited by various members
of the CB[n] family toward ammonium ion guests (e.g., Ka
(CB[6]$hexanediammonium)¼4.5ꢃ108 Mꢁ1 and Ka (CB[7]$adam
antylammonium)¼4.2ꢃ1012 Mꢁ1) we wondered whether CB[6]
and CB[7] could be used to selectively complex the HDA and Ad
binding domains of 8 and thereby serve as an exogenous chemical
stimulus to control the molecularity of the interaction of bis-ns-
CB[10] with 8 and potentially reduce the number of diastereomers
observed.
2.10. Reversibility of host:guest molecularity
Understanding that the molecularity of the bis-ns-CB[10]$82
complex is responsive to host:guest stoichiometry, we wanted to
demonstrate the reversibility of the switching process shown in
Scheme 3 in a stimuli–responsive manner. Figure 10a shows the 1H
NMR spectrum of an initial sample containing bis-ns-CB[10]$82.
Figure 10b shows the 1H NMR spectrum recorded after the sample
of Figure 10a was saturated with solid bis-ns-CB[10]. The spectrum
shown in Figure 10bdwhich shows only peaks for a PXDAout
binding modedindicates the transformation from bis-ns-CB[10]$82
molecularity to bis-ns-CB[10]2$82. Figure 10c shows the 1H NMR
spectrum recorded after the sample of Figure 10b was treated with
2 equiv of 8. The 1H NMR spectrum shows return of the equilibrium
to favor the bis-ns-CB[10]$82 complex in the presence of excess
guest. We find this reversible change in molecularity intriguing
because it results, in principle, in a change in the overall length of
the aggregate, which could be very useful in the construction of
molecular muscles.32
Figure 11b shows the 1H NMR spectrum measured after the
addition of 2 equiv of CB[6] to a solution containing the mixture of
diastereomers of bis-ns-CB[10]$82, which is shown in Figure 11a.
The addition of CB[6] results in the selective complexation of the
HDA binding domain by CB[6] because of its high Ka value, which
sterically precludes binding at the PXDA binding domain of 8 and
leaves only the Ad binding domain open for complexation with bis-
ns-CB[10]. There are three possible diastereomers of the penta-
molecular complex bis-ns-CB[10]$82$CB[6]2, which are shown in
Figure 12. The 1H NMR spectrum of the major diastereomer of bis-
ns-CB[10]$82$CB[6]2 shows a pair of doublets for the PXDA binding
Figure 10. Aromatic region of the 1H NMR spectra (400 MHz, D2O, rt) of a sample
undergoing alternate successive additions of bis-ns-CB[10] and 8: (a) a 1:2 ratio of bis-
ns-CB[10] to 8, (b) after addition of excess bis-ns-CB[10], and (c) after addition of
excess 8.
Figure 11. 1H NMR spectra (400 MHz, D2O, rt) recorded for solutions of: (a) bis-ns-
CB[10]$82, (b) after addition of 2 equiv CB[6] to obtain CB[6]2$82$bis-ns-CB[10], and (c)
after addition of 2 equiv CB[7] to obtain CB[7]$8$CB[6] and solid bis-ns-CB[10]. (d)
Control spectrum for a mixture of CB[6]$8 and excess 8.

7256
R. Nally, L. Isaacs / Tetrahedron 65 (2009) 7249–7258
mixture by selective complexation of the HDA and Ad binding domains
6
of 8, respectively.
6
In conclusion, this work highlights some of the challenges that
need to be overcome in the formation of supramolecular polymers
from divalent hosts and divalent guests, namely the preferential
formation of lower molecularity (cyclic) complexes (e.g., 1:1, 2:2),
which are favored from an entropic viewpoint in the absence of
enthalpic penalties for formation of 1:1 and 2:2 complex formation.
In ongoing work we are targeting the preparation of trivalent guests
that contain a central CB[7] binding region and terminal ada-
mantylammonium binding groups that will prevent 1:1 and 2:2
complex formation by steric interaction between CB[7] groups. An
aspect of the work with potentially broad impact is the recognition
of the special behavior of guests (e.g., 8) that contain multiple
overlapping binding regions. In such systems, binding at one domain
sterically prevents binding at an adjacent domain. The addition of
CB[n] molecular containers that selectively complex a given portion
of guest 8 (e.g., CB[6] and CB[7]) can control the reversible extension
and contraction of this system, which is of potential use in the for-
mation of stimuli–responsive molecular machines (e.g., molecular
muscles). Lastly, we would like to highlight the successful formation
of the penta-molecular complex bis-ns-CB[10]$82$CB[6]2, which is
enabled by the extremely high affinity of CB[n] hosts for their am-
6
6
a
c
b
6
6
Figure 12. Three different diastereomers of the bis-ns-CB[10]$82$CB[6]2 complex.
domain in the PXDAout region along with a single set of resonances
for the Ad and HDA binding domains in the Adin and HDAin regions.
The observation of a pair of doublets in the PXDAout region is
consistent with the top–top and center–center diastereomers, but
is inconsistent with the top–center diastereomer based on sym-
metry considerations.33 Most interesting to us is the observation
that bis-ns-CB[10]$82$CB[6]2 is on average longer than the pre-
cursor mixture of diastereomers of bis-ns-CB[10]$82. The free en-
ergy associated with the complexation of the HDA binding region of
8 by CB[6] performs work and stretches the CB[10]$82 complex. The
reversible control of the extension and contraction of such supra-
molecular (polymeric) systems would be very interesting in the
creation of molecular machines.
To control the subsequent contraction of the bis-ns-
CB[10]$82$CB[6]2 complex we decided to take advantage of the
remarkably high binding affinity of CB[7] toward ada-
mantylammonium ions. Figure 11c shows the 1H NMR spectrum
recorded for a solution containing bis-ns-CB[10]$82$CB[6]2 that was
treated with 2 equiv of CB[7]. The resonances for the PXDA and Ad
domains exhibit new patterns but remain in the PXDAout and Adin
regions indicative of the formation of CB[7]$8$CB[6]. Free bis-ns-
CB[10] precipitates. In this process, the binding free energy of CB[7]
toward the Ad domain of 8 and the precipitation of bis-ns-CB[10]
provide the driving force for the reduction in the overall di-
mensions of the supramolecular complex.
monium ion targets (Ka up to 1015
M
ꢁ1) in water.12 The formation of
high molecularity complexes where multiple different components
occupy a predetermined location on the basis of simple binding
affinities34 in water suggests methods for the construction of even
higher molecularity functional systems.
4. Experimental section
4.1. General
Starting materials were purchased from commercial suppliers
and used without further purification. Compound 17 was prepared
according to a literature procedure.26 THF and toluene were distilled
from sodium benzophenone ketyl before use. TLC analysis was
performed using precoated plates from EMD Chemicals Inc. Column
chromatography was performed using silica gel (230–400 mesh,
0.040–0.063 mm) from Sorbent Technologies using eluents in the
indicated v/v ratio. Melting points were measured on a Meltemp
apparatus in open capillary tubes and are uncorrected. IR spectra
were recorded on a JASCO FT/IR-4100 spectrophotometer and are
reported in cmꢁ1. NMR spectra were measured on Bruker AM-400,
DRX-400, and DRX-500 instruments operating at 400 MHz or
500 MHz for 1H and 100 MHz or 125 MHz for 13C. The chemical shift
for 1,4-dioxane in the 13C NMR spectra was referenced at 67.19 ppm.
Mass spectrometry was performed using a VG Autospec instrument
by fast atom bombardment (FAB) using the indicated matrix or
a JEOL AccuTOF instrument by electrospray ionization (ESI) using
solutions of the complexes in 50:50 MeOH/H2O (v/v).
3. Conclusions
In summary, we have studied the complexation between double
cavity host bis-ns-CB[10] and divalent guests 1–8 with the goal of
forming stimuli–responsive supramolecular polymeric systems of n:n
absolute stoichiometry. In practice, we found that guests 1, 2, and 4–6,
which contain two adamantylammonium ion binding domains
separated by p-, m-, and o-xylylene groups preferentially form 1:1
(bis-ns-CB[10]$1), 2:2 (bis-ns-CB[10]2$42), and short potentially cyclic
oligomeric complexes (with 2, 5, and 6). We found that a longer spacer
between the adamantyl binding groups (e.g., biphenyl spacer in 7)
successfully prevents 1:1 complex formation but promotes 2:2 complex
formation (bis-ns-CB[10]2$72) at the expense of supramolecular poly-
mers. Finally, we investigated the interaction between bis-ns-CB[10]
and guest 8, which contains Ad, PXDA, and HDA binding domains with
a particular emphasis on bis-ns-CB[10]:8 stoichiometry. At 1:1 bis-ns-
CB[10]:8 stoichiometry the Ad and HDA binding domains are com-
plexed to satisfy the ability of bis-ns-CB[10] to complex two binding
groups simultaneously. At 1:2 stoichiometry all three binding domains
become complexed during formation of a mixture of diastereomers of
bis-ns-CB[10]$82. Lastly, we showed that the addition of CB[6] and CB[7]
molecular containers substantially simplifies the composition of this
4.2. Compound 1
To a solution of 12 (117 mg, 0.442 mmol) in anhyd THF (10 mL) was
added Ag2O (205 mg, 0.884 mmol). After 5 min, 10 (200 mg,
1.32 mmol) was added and the reaction mixture was sonicated for 8 h.
The silver salts were removed by filtration and the filtrate was con-
centrated by rotary evaporation. The residue was chromatographed
(SiO2, CHCl3/MeOH 40:1þ2% NH4OH) giving 1 as a white solid. The free
base was dissolved in CHCl3 (25 mL) and HCl gas was bubbled through
the solution to deliver 1$(HCl)2 (162 mg, 0.339 mmol) in 77% yield.
Mp>300 ꢂC (dec). TLC (CHCl3/MeOH 20:1þ1% NH4OH) Rf 0.25. IR
(cmꢁ1): 3415m, 2913s, 2852m, 1616w, 1454m, 1080m, 836m. 1H NMR
(400 MHz, D2O): 7.52 (s, 4H), 4.25 (s, 4H), 2.24 (br s, 6H), 2.00 (br s,12H),
1.78 (d, J¼12.6, 6H), 1.70 (d, J¼12.2, 6H). 13C NMR (100 MHz, D2O, 1,4-

R. Nally, L. Isaacs / Tetrahedron 65 (2009) 7249–7258
7257
dioxane as reference): 133.3, 131.0, 59.0, 43.5, 38.6, 35.5, 29.5. MS (FAB,
glycerol): m/z 405 (100, [MþH]þ). HRMS (FAB, glycerol): m/z 405.3269
([MþH]þ, C28H41N2, calcd 405.3270).
31.2. MS (FAB, glycerol): m/z 541 (100, [MꢁBr]þ). HRMS (FAB,
glycerol): m/z 541.3184 ([MꢁBr]þ, C32H50N2Br, calcd 541.3157).
4.7. Compound 7
4.3. Compound 2
To a solution of 15 (225 mg, 0.662 mmol) in anhyd THF
(12 mL) was added Ag2O (307 mg, 1.33 mmol). After 5 min, 10
(300 mg, 1.99 mmol) was added and the reaction mixture was
sonicated for 8 h. The silver salts were removed by filtration and
the filtrate was concentrated by rotary evaporation. The residue
was chromatographed (SiO2, CHCl3/MeOH 35:1þ1% NH4OH) giv-
ing 7 as a white solid. The free base was dissolved in CHCl3
(25 mL) and HCl gas was bubbled through the solution to deliver
7$(HCl)2 (153 mg, 0.318 mmol) in 48% yield. Mp>330 ꢂC (dec).
TLC (CHCl3/MeOH 30:1þ1% NH4OH) Rf 0.10. IR (cmꢁ1): 2918s,
2851w, 2757w, 1456m, 1309m, 1099m, 794s. 1H NMR (400 MHz,
D2O): 7.68 (d, J¼7.8, 4H), 7.47 (d, J¼7.8, 4H), 4.17 (s, 4H), 2.14
(br s, 6H), 1.92 (br s, 12H), 1.69 (d, J¼12.5, 6H), 1.60 (d, J¼12.5,
6H). 13C NMR (100 MHz, D2O, 1,4-dioxane as reference): 141.3,
131.8, 131.0, 128.3, 58.9, 43.7, 38.7, 35.5, 29.6. MS (FAB, 3-NBA):
m/z 481 (100, [MþH]þ). HRMS (FAB, 3-NBA): m/z 481.3583
([MþH]þ, C34H45N2, calcd 481.3583).
To a solution of 13 (175 mg, 0.662 mmol) in anhyd THF (12 mL)
was added Ag2O (307 mg, 1.32 mmol). After 5 min, 10 was added
(300 mg, 1.987 mmol) and the reaction mixture was sonicated for
8 h. The silver salts were removed by filtration and the filtrate was
concentrated by rotary evaporation. The residue was chromato-
graphed (SiO2, CHCl3/MeOH 35:1þ1% NH4OH) giving 2 as a white
solid. The free base was dissolved in CHCl3 (25 mL) and HCl gas was
bubbled through the solution to deliver 2$(HCl)2 (136 mg,
0.284 mmol) in 43% yield. Mp>300 ꢂC (dec). TLC (CHCl3/MeOH
30:1þ1% NH4OH) Rf 0.20. IR (cmꢁ1): 3419w, 2906s, 2761s, 1571m,
1452m,1366m,1078s, 803m, 699s. 1H NMR (400 MHz, D2O): 7.67 (s,
1H), 7.60–7.45 (m, 3H), 4.25 (s, 4H), 2.24 (br s, 6H), 2.00 (br s, 12H),
1.78 (d, J¼12.6, 6H), 1.70 (d, J¼12.4, 6H). 13C NMR (125 MHz, D2O,
1,4-dioxane as reference): 132.6, 130.9, 130.7, 130.2, 58.5, 43.1, 38.1,
35.0, 29.0. MS (FAB, glycerol): m/z 405 (100, [MþH]þ). HRMS (FAB,
glycerol): m/z 405.3285 ([MþH]þ, C28H41N2, calcd 405.3270).
4.4. Compound 4
4.8. Compound 8
A
solution of 12 (100 mg, 0.379 mmol) and 11 (204 mg,
A
10 mL flask containing
a
solution of 17 (103 mg,
1.14 mmol) in CH3CN (5 mL) was heated to reflux for 12 h and then
cooled to rt. The resulting precipitate was filtered and washed with
CH3CN (3 mL). The white solid was dried under high vacuum to af-
ford 4 (110 mg, 0.177 mmol) in 96% yield. Mp 273–277 ꢂC. IR (cmꢁ1):
2914s, 2854m, 1475m, 1387m, 1306m, 1034m, 854s, 748m. 1H NMR
(400 MHz, D2O): 7.55 (s, 4H), 4.37 (s, 4H), 2.68 (s, 12H), 2.26 (br s,
6H), 2.12 (br s,12H),1.65 (d, J¼12.4, 6H),1.59 (d, J¼12.4, 6H).13C NMR
(125 MHz, D2O, 1,4-dioxane as reference): 134.8, 131.1, 76.9, 60.6,
43.7, 35.4, 31.2 (only seven of the eight expected resonances were
observed). MS (FAB, glycerol): m/z 541 (100, [MꢁBr]þ). HRMS (FAB,
glycerol): m/z 541.3160 ([MꢁBr]þ C32H50N2Br, calcd 541.3157).
0.382 mmol) and 19 (99 mg, 0.458 mmol) in anhyd PhCH3 (6 mL)
was fitted with a Dean–Stark trap and reflux condenser. The
reaction mixture was refluxed for 16 h and then cooled to rt. The
solvent was removed by rotary evaporation and the residue dried
at high vacuum. The residue was dissolved in MeOH (5 mL) and
cooled to 0 ꢂC. A solution of NaBH4 (87 mg, 2.292 mmol) in
MeOH (1 mL) was added dropwise and then the mixture was
heated at reflux for 30 min before stirring at rt for 15 h. The
solvent was concentrated by rotary evaporation and the residue
dissolved in EtOAc (25 mL) and washed with brine (2ꢃ25 mL).
The organic layer was dried over MgSO4, filtered, and concen-
trated by rotary evaporation. The resulting residue was taken up
in a mixture of TFA (3 mL) and CH2Cl2 (3 mL) and stirred at rt
overnight. Upon removal of the solvent under reduced pressure
and high vacuum, 8 (135 mg, 287 mmol) was obtained in 75%
yield. Mp 175–178 ꢂC. IR (cmꢁ1): 2921w, 2855w, 1655s, 1459w,
1174s, 1129s, 830m, 798m, 720s. 1H NMR (400 MHz, D2O): 7.39
(s, 4H), 4.12 (s, 4H), 2.94 (t, J¼7.9, 2H), 2.85 (t, J¼7.4, 2H), 2.10 (br
s, 3H), 1.87 (br s, 6H), 1.70–1.50 (m, 10H), 1.27 (br m, 4H). 13C
NMR (100 MHz, CDCl3): 133.7, 132.7, 131.2, 59.2, 51.2, 47.9, 43.7,
40.1, 38.8, 35.7, 29.7, 27.3, 26.0, 25.9. MS (FAB, 3-NBA): m/z 370
(100, [MþH]þ). HRMS (FAB, 3-NBA): m/z 370.3218 ([MþH]þ,
C24H40N3, calcd 370.3222).
4.5. Compound 5
A
solution of 13 (100 mg, 0.379 mmol) and 11 (204 mg,
1.14 mmol) in CH3CN (5 mL) was heated to reflux for 12 h and then
cooled to rt. The resulting precipitate was filtered and washed with
CH3CN (3 mL). The white solid was dried under high vacuum to
afford 5 (83 mg, 0.134 mmol) in 35% yield. Mp 206–210 ꢂC. IR
(cmꢁ1): 2907s, 2851m, 1470s, 1378m, 1305m, 1035s, 817s, 756s. 1H
NMR (400 MHz, D2O): 7.65–7.50 (m, 4H), 4.38 (s, 4H), 2.69 (s, 12H),
2.27 (br s, 6H), 2.13 (br s, 12H), 1.66 (d, J¼12.6, 6H), 1.60 (d, J¼12.6,
6H). 13C NMR (125 MHz, D2O, 1,4-dioxane as reference): 139.0,
136.3, 130.5, 129.8, 76.9, 60.8, 43.6, 35.4, 35.4, 31.3. MS (FAB, glyc-
erol): m/z 541 (100, [MꢁBr]þ). HRMS (FAB, glycerol): m/z 541.3168
([MꢁBr]þ, C32H50N2Br, calcd 541.3157).
4.9. Compound 18
4.6. Compound 6
To a solution of 17 (209 mg, 1.05 mmol) in anhyd THF (10 mL)
was added Ag2O (236 mg, 1.05 mmol). After 5 min, 10 (159 mg,
1.05 mmol) was added and the reaction mixture was sonicated for
8 h. The silver salts were removed by filtration and the filtrate was
concentrated by rotary evaporation. The residue was chromato-
graphed (SiO2, CHCl3/MeOH 20:1þ1% NH4OH) giving pure 18
(103 mg, 0.382 mmol) as a white solid in 47% yield. Mp 75–78 ꢂC. IR
(cmꢁ1): 2899m, 2845m, 1686s, 1606m, 1578m, 1141m, 1096m, 820s,
776s. 1H NMR (400 MHz, CDCl3): 9.95 (s, 1H), 7.79 (d, J¼8.0, 2H),
7.49 (d, J¼8.0, 2H), 3.82 (s, 2H), 2.07 (br s, 3H), 1.60–1.20 (m, 12H).
13C NMR (100 MHz, CDCl3): 192.1, 149.3, 135.1, 129.9, 128.7, 51.0,
44.9, 42.9, 36.7, 29.6. MS (FAB, 3-NBA): m/z 270 (100, [MþH]þ).
A
solution of 14 (100 mg, 0.379 mmol) and 11 (204 mg,
1.14 mmol) in CH3CN (5 mL) was heated to reflux for 12 h and then
cooled to rt. The resulting precipitate was filtered and washed with
CH3CN (3 mL). The white solid was dried under high vacuum to
afford 6 (110 mg, 0.177 mmol) in 47% yield. Mp 155–158 ꢂC. IR
(cmꢁ1): 3477m, 3380, 3044w, 2915s, 2880s, 2853m, 1478s, 1372m,
1303m, 1033s, 827m, 752s. 1H NMR (400 MHz, D2O): 7.70–7.60 (m,
4H), 4.44 (s, 4H), 2.63 (s, 12H), 2.30 (br s, 6H), 2.17 (br s, 12H), 1.68
(d, J¼12.6, 6H), 1.61 (d, J¼12.6, 6H). 13C NMR (100 MHz, D2O, 1,4-
dioxane as reference): 136.5, 132.0, 130.0, 78.1, 57.0, 43.4, 35.3, 35.1,

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R. Nally, L. Isaacs / Tetrahedron 65 (2009) 7249–7258
HRMS (FAB, 3-NBA): m/z 270.1861 ([MþH]þ, C18H24NO, calcd
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270.1858).
Acknowledgements
We thank the National Science Foundation (CHE-0615049 to L.I.)
and the Department of Education (P200A060238-07, GAANN fel-
lowship to R.N.) for financial support.
Supplementary data
16. Kim, D.; Kim, E.; Kim, J.; Park, K. M.; Baek, K.; Jung, M.; Ko, Y. H.; Sung, W.; Kim,
H. S.; Suh, J. H.; Park, C. G.; Na, O. S.; Lee, D.-k.; Lee, K. E.; Han, S. S.; Kim, K.
Angew. Chem., Int. Ed. 2007, 46, 3471–3474.
17. Kim, S.-Y.; Ko, Y. H.; Lee, J. W.; Sakamoto, S.; Yamaguchi, K.; Kim, K. Chem. Asian
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Supplementary data includes 1H and 13C NMR spectra for new
compounds, DOSY results for selected complexes, and electrospray
mass spectra. Supplementary data associated with this article can
be found in the online version, at doi:10.1016/j.tet.2009.02.055.
18. de Greef, T. F. A.; Ercolani, G.; Ligthart, G. B. W. L.; Meijer, E. W.; Sijbesma, R. P.
J. Am. Chem. Soc. 2008, 130, 13755–13764.
19. The solutions for 1H NMR were prepared by stirring an excess of solid bis-ns-
CB[10] with a solution of known concentration of guest. Integration of the
resonances for host and guest allowed a determination of the relative stoi-
chiometry (n:n).
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