Refolding foldamers: Triazene-arylene oligomers that change shape with chemical stimuli

Article abstract of DOI:10.1021/ja073320s

We describe the preparation of five triazene-arylene oligomers (3, 4, 7, 8, and 11) and investigations of their folding properties in aqueous solution. These oligomers contain four 2-fold rotors and populate a conformational ensemble comprising at least 1

Full text of DOI:10.1021/ja073320s

Published on Web 08/16/2007
Refolding Foldamers: Triazene-Arylene Oligomers That
Change Shape with Chemical Stimuli
Simin Liu, Peter Y. Zavalij, Yiu-Fai Lam, and Lyle Isaacs*
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Maryland,
College Park, Maryland 20742
Received May 10, 2007; E-mail: lisaacs@umd.edu
Abstract: We describe the preparation of five triazene-arylene oligomers (3, 4, 7, 8, and 11) and
investigations of their folding properties in aqueous solution. These oligomers contain four 2-fold rotors
and populate a conformational ensemble comprising at least 10 states. Extensive 1D and 2D NMR studies
as well as X-ray crystallography establish that the presence of three members of the cucurbit[n]uril family
(CB[n]), CB[10], CB[7], and CB[8], results in the selective population of the (a,a,a,a)-, (a,s,s,a)-, and (a,a,a,s)-
conformers. As a result of the high affinity and highly selective binding properties of the CB[n] family, it is
possible to fold a single foldamer strand (3) into the CB[8]‚(a,a,a,s)-3 conformer by the addition of CB[8],
then unfold and refold it into the CB[7]‚(a,s,s,a)-3‚CB[7] conformer by addition of CB[7] and 3,5-
dimethylaminoadamantane (17), then unfold and refold it again into the CB[10]‚(a,a,a,a)-3 conformer by
addition of CB[10]‚CB[5] and aminoadamantane (18). The transformation of CB[8]‚(a,a,a,s)-3 into CB[7]‚
(a,s,s,a)-3‚CB[7] proceeds through the intermediacy of CB [8]‚(a,a,s,a)-3‚CB[7], which enhances the rate
of dissociation of strand 3 from CB[8].
Introduction
stood, the focus of research in the foldamer field has shifted
toward the development of systems that are functional and
The unique functions of nature’s oligomeric macromolecules,
proteins and nucleic acids, depend on the constitution (e.g.,
sequence) of these oligomers and more importantly upon their
precise three-dimensional folded conformations. Inspired by
these natural systems, chemists have begun to design and study
non-natural oligomers that fold into well-defined secondary,
tertiary, or even quaternary structures driven by H-bonds as well
as π-π and electrostatic interactions.1-3 Early examples of non-
natural folding oligomers, foldamers, include the aromatic
donor-acceptor stacks developed by Iverson,4,5 Moore’s phe-
nyleneethynylene oligomers,2,6 and the â-peptide system ex-
ploited by Seebach7 and Gellman.1,8 Of particular relevance to
the triazene-arylene oligomers described in this Article are the
folding preferences reported previously for oligo(amides), oligo-
(imides), oligo(ureas), and oligo(guanidines).9,10 As the folding
properties of non-natural oligomers have become better under-
conformationally switchable. For example, both the internal and
the external surfaces of foldamers have been used to recognize
the identity and chirality of suitable guests, to accelerate certain
reactions, and to influence the behavior of their natural
counterparts.11 Foldamers that can switch between two or
occasionally three different conformations in response to
environmental stimuli (e.g., pH, light, chemical stimuli, metal
ions, concentration, solvent) have been reported by a number
of groups.9,12
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J. AM. CHEM. SOC. 2007, 129, 11232-11241
10.1021/ja073320s CCC: $37.00 © 2007 American Chemical Society

Refolding Foldamers
A R T I C L E S
Scheme 1. Synthesis of Foldamers 3, 4, 7, 8, and 11a
a Conditions: (a) 13, THF, DIPEA, 0 °C, (b) 14, room temperature, (c) NH4OH, DMSO, 85 °C, (d) TFA, CH2Cl2, room temperature, (e) TFA, H2O,
reflux, (f) 15, room temperature, (g) 16, THF, DIPEA, 0 °C.
Although some proteins are capable of autonomously folding
into their native conformations, many require the presence of
chaperone proteins as molecular containers that promote folding
into the native state by preventing trapping in kinetically stable
misfolded or aggregated forms.13 In contrast, for the majority
of foldamers reported to date, the information that leads to well-
defined folding processes is either encoded in the 1° structure
of the oligomer itself or in combination with small molecule
guests with convex binding sites. We wondered whether it would
be possible to design foldamers with a large ensemble of nearly
isoenergetic conformational states that could be accessed in a
selective way by the presence of large synthetic molecular
containers possessing concave recognition surfaces. In this
manner, we thought it might be possible to switch between
several folded states in response to the structure of the molecular
container employed. Because molecular containers also respond
to the presence of guests in their environment, we thought that
it might be possible to change the shape of a given foldamer in
response to suitable chemical stimuli. Last year, Fujita showed
that concave bowl-shaped molecular containers are capable of
inducing the folding of natural peptides in water.14 A related
approach was implemented by the Yashima group who reported
an oligo(resorcinol) that forms a double helix in water but that
unfolds in the presence of a â-cyclodextrin (â-CD) molecular
container.15 The double helical form is repopulated when â-CD
is sequestered by the addition of suitable guest molecules. In
this Article, we report the folding behavior of five triazene-
arylene oligomers whose folding properties can be controlled
by the presence of cucurbit[n]uril (CB[n]) molecular contain-
ers16,17 and that also respond to the presence of competing
chemical stimuli.
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Results and Discussion
This section begins with a discussion of the rationale behind
the design of triazene-arylene oligomers 1-11 (Scheme 1), the
synthesis of water-soluble foldamers 3, 4, 7, 8, and 11, and the
enumeration of the conformational manifold open to 3. This is
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A R T I C L E S
Liu et al.
Chart 1. Chemical Structures of CB[n]
followed by the rationale for the selection of CB[n] molecular
containers for this study. Last, we describe how CB[n] molecular
containers can be used to control the conformations of foldamers
3, 4, 7, 8, and 11 and their response to suitable chemical stimuli.
Design and Synthesis of Triazene-Arylene Oligomers
1-11. To date, foldamer design has relied heavily on the
introduction of intramolecular conformational biases (e.g.,
H-bonds and π-π interactions) that shunt the conformational
manifold toward a particular folded structure. We thought it
would be interesting to design a system that exhibited a complex
ensemble of nearly isoenergetic states from which individual
folded conformations could be selected by interaction with
molecular containers. For this purpose, we designed foldamers
3, 4, 7, 8, and 11 (Scheme 1), which contain two amino-
substituted triazene rings linked by arylene units. It is well
known that amino-substituents on triazene rings may adopt two
conformations, unlike peptide bonds, of nearly equal energy.18,19
Compounds 3, 4, 7, 8, and 11 with four such amino-triazene
substituents were expected to exhibit a complex manifold of
conformations with different shapes and H-bonding patterns.
selectivity (up to 106) based on subtle structural changes in their
guests.22-24 The well-defined recognition properties of individual
CB[n] have been exploited in many applications including
molecular shuttles, chemical sensors, drug delivery, supramo-
lecular dye lasers, and supramolecular macromolecules.25 Kim’s
group have used CB[8]-based folding processes to develop a
variety of molecular machines including a molecular loop-lock.26
Urbach has recently shown that CB[8] can be used for peptide
recognition and dimerization in water.27,28 We recently reported
that the CB[n] family, which display high selectivity toward a
common guest, collectively constitute a prime platform for the
construction of the stimuli responsive systems.23 For these
reasons, we selected several members of the CB[n] family as
the molecular containers to control the folding of the triazene-
arylene oligomers (3, 4, 7, 8, and 11) described below.
We synthesized triazene-arylene oligomers 1-11 from cya-
nuric chloride (12) and building blocks 13-16 using well-
established chemistry.18,19 For example, 12 can be reacted with
1 equiv of 13 in the presence of diisopropylethylamine (DIPEA)
followed by 0.5 equiv of 14 to yield 1 in 63% yield. Compound
1 can be transformed into 2 (87%) by heating with ammonium
hydroxide in DMSO at 85 °C. Compound 2 can be deprotected
by treatment with trifluoroacetic acid (TFA) to yield 4 (100%)
as its trifluoroacetate salt. Compound 1 can also be transformed
into 3 by heating at reflux in aqueous TFA (91%). Although
we depict 3 as a single triazene-NH tautomer, it likely exists
in aqueous solution as an equilibrating mixture of tautomers.
Compounds 5-11 are prepared in an entirely analogous manner
in very good yields. Compound pairs 3 and 4, and 7 and 8 differ
only in the nature of the third substituent (e.g., NH2 or dO) on
the two symmetry equivalent triazene rings. In this Article, we
investigate the folding behavior of water-soluble compounds 3
and 4, 7 and 8, and 11 in the presence of CB[7], CB[8], and
CB[10].
Enumeration of the Conformational Manifold for 3. In
our design of 3, we sought to introduce a tractable level of
conformational complexity that might be controlled by com-
plexation with CB[7], CB[8], and CB[10]. It is well known that
compounds containing triazene C-N bonds (Scheme 2, green
arrows) may exist as two rotamers with intermediate exchange
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541. Day, A.; Arnold, A. P.; Blanch, R. J.; Snushall, B. J. Org. Chem.
2001, 66, 8094-8100. Day, A. I.; Blanch, R. J.; Arnold, A. P.; Lorenzo,
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(17) Lee, J. W.; Samal, S.; Selvapalam, N.; Kim, H.-J.; Kim, K. Acc. Chem.
Res. 2003, 36, 621-630.
(18) Steffensen, M. B.; Simanek, E. E. Org. Lett. 2003, 5, 2359-2361. Simanek,
E. E.; Mammen, M.; Gordon, D. M.; Chin, D.; Mathias, J. P.; Seto, C. T.;
Whitesides, G. M. Tetrahedron 1995, 51, 607-619.
(19) Zhang, W.; Simanek, E. E. Org. Lett. 2000, 2, 843-845.
9
11234 J. AM. CHEM. SOC. VOL. 129, NO. 36, 2007

Refolding Foldamers
A R T I C L E S
Scheme 2. Ten Distinct Conformations Are Available to 3 by Rotation around Triazene C-N Bonds
kinetics on the chemical shift time-scale.18,19 For compounds
like 3 that contain four such triazene C-N bonds, there are 24
(16) possible conformations of which 10 are unique (Scheme
2). To distinguish between these 10 conformations, we consider
the orientation of the aryl-N group relative to the triazene Cd
O group and denote the two rotamers as either anti (a) or syn
(s). In enumerating the 10 possible conformations of 3, we
consider each such aryl-N group sequentially to produce a
unique identifier (e.g., a,a,a,a-3). In analogy to 3, there are 10
possible conformations for compounds 4, 7, 8, and 11. In
addition to these 10 rotamers involving the triazene C-N bonds,
there are several Ar-N and Ar-C single bonds (Scheme 2,
red arrows) that may exist in numerous possible conformations,
which adds further complexity to the conformational manifold
exhibited by 3.
In Their Complexes with CB[10], Compounds 3, 4, 7, 8,
11 Exclusively Populate the a,a,a,a-Conformer. Initially, we
targeted the population of the a,a,a,a-conformer of the triazene-
arylene oligomers because we hypothesized that this conforma-
tion might benefit from enhanced π-π interactions driven by
the hydrophobic effect in water. On the basis of our previous
experience with the CB[n] family of molecular containers,16,17
we selected CB[10],21 with its spacious 870 Å3 cavity, for this
purpose. Experimentally, we found that CB[10] forms stable
well-defined complexes with all five oligomers in D2O. Figure
1
1 shows the H NMR spectra recorded for CB[10]‚4, CB[10]‚
8, and CB[10]‚11. All three complexes exhibit a common
spectral fingerprint: (1) a single set of upfield shifted resonances
for the terminal and central arylene units of 4, 8, and 11, (2) a
single set of resonances for the CB[10] macrocycle, and (3) a
pair of doublets for the terminal CH2-group that are diaste-
reotopic in the CB[10]‚4 and CB[10]‚8 complexes. In combina-
tion, these three spectral features uniquely identify the com-
plexes as the CB[10]‚a,a,a,a-4, CB[10]‚a,a,a,a-8, and CB[10]‚
a,a,a,a-11 conformers. For example, observation (1) eliminates
the six unsymmetrical conformers (a,a,a,s-; a,a,s,a-; a,s,a,s-;
a,a,s,s-; s,a,s,s-; a,s,s,s-) that would exhibit additional sets of
resonances. Of the remaining four conformations (a,a,a,a-;
s,a,a,s-; a,s,s,a-; and s,s,s,s-), only the a,a,a,a-conformer that
positions all of the protons inside the shielding region of the
cavity of CB[10] is consistent with the pattern of observed
Compounds 3, 4, 7, 8, and 11 Do Not Exhibit a Preferred
Conformation in Water. Before attempting to control the
conformation of compounds 3, 4, 7, 8, and 11 through the
application of CB[n] molecular containers, we sought to
determine the innate conformational preferences of the oligomers
1
themselves. Accordingly, we recorded the H NMR spectra
separately for all five water-soluble oligomers at room temper-
ature (Supporting Information). The spectra are broad and
featureless, which indicates that none of the oligomers adopts
a dominant well-defined conformation in D2O in the absence
of CB[n] hosts.
9
J. AM. CHEM. SOC. VOL. 129, NO. 36, 2007 11235

A R T I C L E S
Liu et al.
Figure 1. 1H NMR spectra (400 MHz, D2O, room temperature) recorded
for: (a) CB[10]‚4, (b) CB[10]‚8, and (c) CB[10]‚11.
Figure 3. 1H NMR spectra (400 MHz, D2O, room temperature) recorded
for: (a) CB[8]‚(a,a,a,s)-3 and (b) CB[8]‚(a,a,a,s)-7.
resonances are observed for CB[7]‚3‚CB[7], CB[7]‚4‚CB[7],
CB[7]‚7‚CB[7], and CB[7]‚8‚CB[7], which indicates a single
well-defined conformation in D2O. To determine the folded
conformation of these CB[7]‚guest‚CB[7] complexes, we invoke
symmetry considerations and chemical shift anisotropy argu-
ments. For example, symmetry considerations rule out the six
unsymmetrical conformers (a,a,a,s-; a,a,s,a-; a,s,a,s-; a,a,s,s-;
s,a,s,s-; a,s,s,s-) that would display additional resonances. Unlike
the CB[10] complexes whose guest resonances move uniformly
upfield upon binding, the CB[7]‚4‚CB[7] and CB[7]‚7‚CB[7]
complexes exhibit resonance(s) (4, Hd; 7, Hd-Hf) that move
significantly downfield.30 On the basis of the well-established
deshielding nature of the region just outside the ureidyl CdO
portal of CB[n], we conclude that these protons are in the
immediate vicinity of the portals.16,22 This conclusion has been
further confirmed by an observed ROESY interaction between
Hd and Hx in the CB[7]‚4‚CB[7] complex. Of the remaining
four conformations, only the a,s,s,a-conformer satisfies this
distance constraint. Hence, we formulate the complex between
CB[7] and 3, 4, 7, and 8 as CB[7]‚a,s,s,a-guest‚CB[7]. Quite
interestingly, but perhaps not surprisingly, CB[7] does not
stabilize a distinct conformation of 11 because the terminal 1,5-
diaminonaphthalene groups do not bind efficiently inside the
cavity of CB[7].
In Their Complexes with CB[8], Compounds 3 and 7
Exclusively Populate the a,a,a,s-Conformer. Given the ex-
tremely well-defined folding preferences of the triazene-arylene
oligomers in the presence of CB[10] and CB[7], we decided to
investigate the influence of CB[8] on the conformational
ensemble populated by 3 and 7. We anticipated that CB[8], with
its more spacious cavity (479 Å3), would be able to bind to
substantial portions but not all of 3 or 7. Figure 3 shows the 1H
NMR spectra recorded for CB[8]‚3 and CB[8]‚7. Unlike the
cases described above with CB[10] or CB[7], two sets of
resonances are observed upon complexation with CB[8]. For
Figure 2. 1H NMR spectra (400 MHz, D2O, room temperature) recorded
for: (a) CB[7]‚4‚CB[7] and (b) CB[7]‚7‚CB[7]. x ) trace HCO2H impurity.
upfield shifting. This conclusion is supported by the X-ray
crystal structures of CB[10]‚3, CB[10]‚4, and CB[10]‚7 (vide
infra). The detailed spectral assignment is based on the COSY
and selective 1D ROESY experiments performed on the
complexes (Supporting Information). Although the NMR ex-
periments allow us to conclude that the a,a,a,a-conformer is
dominant inside CB[10], it does not provide us with information
regarding the CR-NR-NR′-CR′ and Câ-Nâ-Cγ-Nγ dihedral
angles (Scheme 2, red arrows), which are needed to fully define
the three-dimensional structure of the CB[10]‚a,a,a,a-4 (or 8 or
11) complex.
In Their Complexes with CB[7], Compounds 3, 4, 7, 8,
11 Exclusively Populate the a,s,s,a-Conformer. Given the very
encouraging results with the CB[10] complexes described above,
we wondered whether it would be possible to selectively
stabilize any of the other nine members of the conformational
ensemble open to 3, 4, 7, 8, and 11. For this purpose, we selected
CB[7], which is a smaller member of the CB[n] family. CB[7]
has an estimated cavity volume of 262 Å3, similar to â-cyclo-
dextrin, and easily binds to alkyl- and arylammonium ions
including guests as large as adamantane. We envisioned that
CB[7] would only be able to bind to the terminal regions of
guests 3, 4, 7, 8, and 11 and might therefore stabilize different
conformations than CB[10]. Figure 2 shows the 1H NMR spectra
recorded for mixtures of CB[7] (2 equiv) and 4 or 7.29 Similar
to the CB[10] complexes described above, a single set of sharp
(29) We also examined the influence of 1 equiv of CB[7] on the folding
properties of 3, 4, 7, and 8. At this stoichiometry, a mixture of free guest,
1:1 complex, and 1:2 complex was observed, which made further analysis
impractical.
(30) This downfield shifted resonance has been identified by a combination of
COSY and selective 1D ROESY spectroscopy (Supporting Information).
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11236 J. AM. CHEM. SOC. VOL. 129, NO. 36, 2007

Refolding Foldamers
A R T I C L E S
+
example, (1) the terminal -CH2NH3 groups within CB[8]‚3
appear as two broadened resonances at 4.3 and 3.7 ppm, (2)
the terminal phenylene rings display two pairs of doublets at
7.8 and 7.7 ppm as well as 6.6 and 6.4 ppm, and (3) a broadened
resonance is displayed for the central arylene protons at 6.3
ppm. As described above, the observation of two sets of
resonances eliminates the possibility of the four symmetric
conformations, leaving only the six unsymmetric conformations
(a,a,a,s-; a,a,s,a-; a,s,a,s-; a,a,s,s-; s,a,s,s-; a,s,s,s-) under con-
sideration. The substantial upfield shifts observed for two of
the three aromatic rings strongly suggest that the central arylene
ring and one terminal arylene ring are inside the cavity of
CB[8], which is only possible if the first two N-triazene bonds
populate the a,a-conformer, which leaves only three possible
conformations (a,a,a,s-; a,a,s,a-; and a,a,s,s-). The downfield
chemical shifts observed for Hf in CB[8]‚3 suggested that Hf
was just outside the ureidyl CdO portal of CB[8] within the
complex. This conclusion was further substantiated by the
observation of a ROESY cross-peak between Hf and Hx in the
CB[8]‚3 complex. This distance constraint is only satisfied
1
within the CB[8]‚(a,a,a,s)-3 complex. Figure 3b shows the H
1
NMR spectrum of CB[8]‚7. Two interesting aspects of the H
NMR of CB[8]‚(a,a,a,s)-7 are the observation of: (1) a widely
separated pair of doublets (Ha and Ha′) for the upfield shifted
diastereotopic CH2-group, and (2) four resonances for the bound
terminal arylene rings (Hb, Hc, Hd, and He). Both observations
indicate a well-defined conformational preference with restricted
rotation around the terminal arylene ring relative to the central
1,5-diaminonaphthalene residue. Similar to the case of CB[8]‚
3 described above, a combination of symmetry considerations
and chemical shift analysis allows us to determine that the
complex between CB[8] and 7 has the CB[8]‚(a,a,a,s)-7 folded
conformation.
X-ray Crystal Structures of CB[10]‚3, CB[10]‚4, CB[10]‚
7, and CB[7]‚7‚CB[7]. Through a detailed analysis of their 1H
NMR and ROESY spectra, it was possible to assign the a,a,a,a-,
a,s,s,a-, and a,a,a,s-conformers to the various triazene-arylene
oligomers in the presence of CB[10], CB[7], and CB[8],
respectively. It was not possible, however, to glean any
information about the relative orientations (e.g., dihedral angles)
of the various aromatic rings within the complex. A priori, one
might postulate that maximization of favorable π-π interactions
between the various aromatic rings might drive the formation
of a compact conformation in which as little hydrophobic surface
area is exposed as possible. Conversely, in accord with the
observations of Urbach on CB[8]‚peptide complexes,27 one
might postulate that maximization of favorable N-H‚‚‚OdC
H-bonds and NH3+‚‚‚OdC ion-dipole interactions would guide
the folding process to its lowest energy conformer. Given the
known very large binding constants for CB[n]‚guest complexes
Figure 4. Cross-eyed stereoviews of the X-ray crystal structures of: (a)
CB[10]‚a,a,a,a-3, (b) CB[10]‚a,a,a,a-4, (c) CB[10]‚a,a,a,a-7, and (d) CB-
[7]‚a,s,s,a-7‚CB[7]. Color code: C, gray; H, aqua; N, blue; O, red; H-bonds,
red-yellow striped.
multiple favorable N-H‚‚‚OdC H-bonds and NH3+‚‚‚OdC
ion-dipole interactions. In contrast, a brief inspection of Figure
4a and b shows the arylene rings of 3 (4) do not benefit from
any intramolecular π-π interactions within CB[10]. The
absence of such interactions is reflected in the observed CR-
NR-NR′-CR′ (82° and 77°) dihedral angles, which splay the
terminal arylene rings outward from the central arylene ring.
Similarly, Figure 4c shows the structure of CB[10]‚(a,a,a,a)-7,
with its central 1,5-diaminonaphthalene ring, benefits from
multiple N-H‚‚‚OdC H-bonds and NH3+‚‚‚OdC ion-dipole
interactions but no intramolecular π-π interactions. In this case,
the larger 1,5-diaminonaphthalene spacer of 7 results in a smaller
CR-NR-NR′-CR′ (59°) dihedral angle to accommodate the
H-bonds and ion-dipole interactions. Although CB[10]‚(a,a,a,a)-
7 displays Câ-Nâ-Cγ-Nγ dihedral angles of 104° and 123°
(up to 1012 M-1 23,24
and the fact that H-bonds or ion-dipole
)
interactions individually enhance affinity by 101-103 M-1, it
was unclear to us which factor would dominate experimentally.
Fortunately, we were able to obtain X-ray crystal structures
of CB[10]‚(a,a,a,a)-3, CB[10]‚(a,a,a,a)-4, CB[10]‚(a,a,a,a)-7, and
CB[7]‚(a,s,s,a)-7‚CB[7], which allows us to shed some light on
these issues (Figure 4). Figure 4a and b shows the X-ray crystal
structures of CB[10]‚(a,a,a,a)-3 and CB[10]‚(a,a,a,a)-4, which
are very closely related structurally. In both cases, foldamers 3
and 4 adopt conformations within CB[10] that benefit from
9
J. AM. CHEM. SOC. VOL. 129, NO. 36, 2007 11237

A R T I C L E S
Liu et al.
Scheme 3. Schematic Illustration of the Change of Conformation
of 3 (Purple Strand) in Response to Chemical Stimuli
in the crystal, we do not expect this dihedral angle to display
pronounced conformational preferences in water because several
ureidyl carbonyl groups on the portals of CB[10] are available
to satisfy the need for cation-dipole interactions.
Why do the constraints of H-bonds and ion-dipole interac-
tions dominate the conformations of CB[n]‚triazene-arylene
oligomer complexes when the hydrophobic driving force for
CB[n] complexes is known to be dominant? There appear to
be several important factors. A major consideration is the sheer
number of H-bond donating NH groups (four) and NH3+ groups
(two) that need to be satisfied. Although individually weak,
collectively these interactions are strong. A more subtle factor,
but one that is presumably quite important, is differential
aqueous solvation of free guest versus complexed guest. When
free guest is transferred to the cavity of CB[10], it must shed a
substantial portion of its solvating H2O molecules regardless
of the conformation assumed inside CB[10]. Once inside, where
the guest experiences the low polarizability of the CB[n]
cavity,31 the guest is willing to trade the intramolecular π-π
interactions between the arylene rings for the interaction with
the π-systems of the 20 ureidyl (N-CdO-N) groups that define
the walls of CB[10] and the possibility to maximize the H-bonds
and ion-dipole interactions. The message is clear and strikingly
similar to those derived from studies of protein folding; although
desolvation may provide the main thermodynamic driving force
for folding, it is the more directional H-bonds and electrostatic
interactions that dictate their precise three-dimensional folded
structure.
Figure 5. 1H NMR spectra recorded (400 MHz, D2O, room temperature)
by sequential addition for: (a) CB[8]‚(a,a,a,s)-3, (b) CB[8]‚3‚CB[7], (c)
CB[8]‚17 (control spectrum), (d) CB[8]‚17 and CB[7]‚(a,s,s,a)-3‚CB[7],
(e) CB[7]‚18 (control spectrum), (f) CB[10]‚(a,a,a,a)-3 and CB[5] (control
spectrum), and (g) CB[10]‚(a,a,a,a)-3, CB[8]‚17, CB[7]‚18, and CB[5].
7 where intracavity folding is important, the CB[7]‚(a,s,s,a)-7‚
CB[7] conformation can be rationalized on the basis of the
maximization of NH‚‚‚O H-bonds elucidated by Urbach.27
Oligomer 3 Changes Shape in Response to Chemical
Stimuli. Previously, we and others have shown that individual
members of the CB[n] family (e.g., CB[6], CB[7], or CB[8])
display remarkable affinity toward their guests with high
selectivities based on small structural changes.22-24 We also
showed that the various CB[n] (e.g., CB[6] vs CB[7] vs CB-
[8]) showed large differences in Ka (equivalent to ∆∆G driving
force) toward a common guest and argued that these properties
made the CB[n] family particularly well suited as a component
of biomimetic self-sorting systems.23 Given the separate ability
of CB[10], CB[8], and CB[7] to control the folding of a non-
natural oligomers, a biomimetic event, we wondered whether
it would be possible to fold and refold a single triazene-arylene
oligomer strand (e.g., 3) in response to specific chemical stimuli
(e.g., hosts and guests).
For this purpose, we prepared a solution containing 3 (Scheme
3 and Figure 5). As discussed above, 3 accesses a manifold of
10 possible conformations in the absence of CB[n] molecular
containers. Upon addition of CB[8], 3 folds into the (a,a,a,s)-3
conformation within the CB[8]‚3 complex. It is possible to
unfold and then refold 3 by the addition of 2 equiv of CB[7]
and 1 equiv of 3,5-dimethylaminoadamantane (17) to yield a
well-defined state comprising CB[7]‚(a,s,s,a)-3‚CB[7] and CB-
[8]‚17. The fidelity of the refolding process depends critically
upon the addition of 17; when 17 is omitted, a mixture of the
Figure 4d shows the X-ray crystal structure of CB[7]‚7‚CB-
[7]. As expected on the basis of the NMR studies, 7 exclusively
populates the (a,s,s,a)-7 conformer in the crystal. Once again,
the folding process appears to be controlled by the presence of
multiple NH‚‚‚OdC H-bonds and ion-dipole interactions.
Interestingly, it is the ring NH group rather than the exocyclic
NH group of the triazene that forms the H-bonds to the ureidyl
CdO of CB[7]. In contrast to the structure of CB[10]‚(a,a,a,a)-
(31) Marquez, C.; Nau, W. M. Angew. Chem., Int. Ed. 2001, 40, 4387-4390.
9
11238 J. AM. CHEM. SOC. VOL. 129, NO. 36, 2007

Refolding Foldamers
A R T I C L E S
Figure 6. Plot of the release of guest 3 from the CB[8]‚3 complex as a
function of time after addition of 17, CB[7], or a mixture of 17 and CB[7].
b ) [CB[7]‚3‚CB[7]; 9 ) [CB[7]‚3‚CB[7]; [ ) CB[8]‚17.
CB[7]‚(a,s,s,a)-3‚CB[7] and CB[8]‚(a,a,a,s)-3 is obtained. The
addition of 17 provides a potent driving force for the equilib-
rium because 17 binds 107-fold23 more tightly to CB[8] than to
CB[7]. Next, it is possible to transform 3 into the (a,a,a,a)-3
conformation by the addition of 2 equiv of 1-aminoadamantane
(18) and 1 equiv of CB[10]‚CB[5]. In this remarkable process,
the 2 equiv of 18 with their high affinity for CB[7] (Ka ) 4.2
Figure 7. Representations of the proposed geometries of the CB[8]‚(a,a,a,s)-
3 and CB[8]‚(a,a,s,a)-3‚CB[7] complexes.
conformer units, we formulate this complex as CB[8]‚(a,a,s,a)-
3‚CB[7]. The rate of dissociation of 3 from CB[8]‚(a,a,a,s)-3 is
enhanced by formation of termolecular complex CB[8]‚(a,a,s,a)-
3‚CB[7] in which the terminal arylene unit is pulled away from
CB[8] by complexation with CB[7]. Figure 7 shows schematic
representations of CB[8]‚(a,a,a,s)-3 and CB[8]‚(a,a,s,a)-3‚CB-
[7] that illustrate the conformational change. In this manner, it
is possible to access a fourth member of the 10-member
conformational ensemble open to 3.
× 1012 M-1 23
)
release 3 to free solution where it displaces
CB[5] from the CB[10]‚CB[5] complex under formation of
CB[10]‚(a,a,a,a)-3. CB[5] remains in its free state because its
cavity (82 Å3) is too small to act as a molecular container. In
theory, but not yet in practice, it should be possible to release
free unfolded 3 into solution by the application of a guest that
binds to CB[10] even more tightly than 3. By the selection of
components that provide sufficient driving force (∆∆G), it is
possible to fold, unfold, and refold 3 into three distinct
conformations under thermodynamic control.
Conclusions
We have described the synthesis of five water-soluble oligo-
(triazene-arylenes) containing two triazene and three aromatic
rings (3, 4, 7, 8, and 11). These oligomers possess four 2-fold
rotors and populate a conformational ensemble consisting of at
least 10 distinct states of similar energy. We find that the
presence of specific CB[n] molecular containers is capable of
stabilizing a single member of this conformational ensemble.
For example, CB[7] results in the population of the CB[7]‚
(a,s,s,a)-3‚CB[7] conformer, CB[8] yields the unsymmetrical
CB[8]‚(a,a,a,s)-3 complex, and the more spacious cavity of CB-
[10] stabilizes the most compact CB[10]‚(a,a,a,a)-3 conformer.
Although the hydrophobic effect provides a potent driving force
for inclusion of 3 in the various CB[n] molecular containers, it
is the directionality inherent in the NH‚‚‚O H-bonds and the
need to satisfy cation-dipole interactions that dictate the specific
member of the conformational ensemble that is expressed. Most
interestingly, we found that foldamer 3 can be passed from CB-
[8] to CB[7] to CB[10] wherein the (a,a,a,s)-3, (a,s,s,a)-3, and
(a,a,a,a)-3 conformers are expressed in sequence in response to
chemical stimuli (17 and 18). In this process, we observed that
CB[7] is capable of catalyzing the dissociation of 3 from the
CB[8]‚(a,a,a,s)-3 complex by transient stabilization of the CB-
[8]‚(a,a,s,a)-3‚CB[7] complex.
CB[7] Enhances the Rate of Dissociation of the CB[8]‚3
Complex. Given the slow rates observed for the unimolecular
dissociation of some CB[n] complexes,32 we were surprised that
the transformation of CB[8]‚(a,a,a,s)-3 into CB[8]‚17 and CB-
[7]‚(a,s,s,a)-3‚CB[7] by the addition of 17 and CB[7] occurred
so readily upon brief heating at 60 °C. We, therefore, decided
to monitor the process by the addition of CB[7] and 17 alone
1
and in combination by H NMR at room temperature (Figure
6). For example, when we added 17 to CB[8]‚(a,a,a,s)-3 (Figure
6, + 17 only), we observed no change after 120 h (5 days).
Conversely, when only CB[7] is added to CB[8]‚(a,a,a,s)-3
(Figure 6, + CB[7] only), an equilibrium mixture is established
over the same time period. When both 17 and CB[7] are added,
the system has largely transformed (∼87%) to the thermody-
namic state comprising CB[7]‚(a,s,s,a)-3‚CB[7] and CB[8]‚17
in 120 h. The addition of CB[7] either alone or in combination
with 17 substantially enhances the rate of release of 3 from
CB[8]‚(a,a,a,s)-3! We can speculate as to the cause of the
dramatic rate enhancement. When 1 equiv of CB[7] is added
to CB[8]‚(a,a,a,s)-3, a new species is formed within minutes
(Figure 5b). On the basis of the upfield shifts observed for both
the terminal arylene protons Hf (7.8 to 6.9) and Hg (7.7 to 6.7),
we conclude that the “free” arm of CB[8]‚(a,a,a,s)-3 has become
complexed to yield a new complex CB[8]‚3‚CB[7]. On the basis
In addition to the system-specific observations described
above, the study enables a series of more broadly applicable
conclusions. First, the work represents a new direction in the
foldamer field wherein intramolecular conformational biases are
abandoned and replaced with a shallow conformation potential
energy surface and a complex ensemble of conformations.33 The
ability to select a given member of that conformational ensem-
ble in response to the presence of molecular containers (e.g.,
1
of the analysis of the anisotropic effects observed in the H
NMR spectrum and the above-described propensity of CB[8]
to stabilize a,a-conformer units and CB[7] to stabilize s,a-
(32) Marquez, C.; Nau, W. M. Angew. Chem., Int. Ed. 2001, 40, 3155-3160.
Marquez, C.; Hudgins, R. R.; Nau, W. M. J. Am. Chem. Soc. 2004, 126,
5808-5816.
(33) Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.; Wietor, J.-L.; Sanders, J.
K. M. Chem. ReV. 2006, 106, 3652-3711.
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A R T I C L E S
Liu et al.
(only 12 of the 13 expected resonances were observed). MS (ES): m/z
737.3 (100, [M + H]+, C36H45N14O4, calcd 737.3748).
CB[n]) makes the behavior of the system environmentally
sensitive. Second, the ability to forcibly unfold and then refold
the oligomer in response to chemical stimuli (e.g., 17 or 18)
provides a vivid illustration of the great potential of CB[n]
molecular containers, with their high affinities, high selectivities,
and therefore large ∆∆G driving forces, in the construction of
complex self-sorting biomimetic systems.23,34 A third goal that
remains is the release of kinetically stable folded forms of these
oligomers, just like natural chaperone proteins13 do, from the
molecular containers in which they fold. We believe this third
goal may be accomplished upon progression to longer oligomers
and those with backbone-backbone intramolecular contacts that
are expected to exhibit higher kinetic barriers for the folded-
unfolded transition.5 Alternatively, it might be possible to
employ covalent capture techniques35 to stabilize and release
such folded oligomers. When fully developed, the ability to fold,
release, and recycle folded non-natural oligomers is expected
to impact diverse areas of science including the development
of supramolecular catalysts, synthetic multicomponent molecular
machines, and enable the interfacing of supramolecular and
biomolecular systems.
Compound 3. Compound 1 (170 mg, 0.220 mmol) was dissolved
in a mixture of TFA (1.0 mL) and H2O (1.0 mL) and heated at reflux
for 10 h. The reaction mixture was cooled to room temperature, and
precipitate was collected by filtration and dried on the frit for 3 d
yielding 3 (150 mg, 0.200 mmol, 91%) as a white solid. Mp: > 300
°C. IR (KBr, cm-1): 3037m, 2890m, 1740s, 1688s, 1595s, 1500s,
1365m, 1195s, 1146m, 841m, 724m. 1H NMR (500 MHz, DMSO, 70
°C): 10.50 (br s, 4H), 8.19 (br s, 6H), 7.67 (d, J ) 8.4 Hz, 4H), 7.59
(s, 4H), 7.18 (d, J ) 8.4 Hz, 4H), 4.01 (s, 4H). 13C NMR (125 MHz,
2
DMSO, 70 °C): 158.9 (q, JCF ) 34 Hz), 158.0, 152.5, 137.4, 133.6,
129.6, 129.0, 122.5, 121.4, 116.1 (q, 1JCF ) 292 Hz), 41.8 (only 11 of
the 12 expected resonances were observed). MS (ES): m/z 539.2 (100,
[M + H - 2TFA]+, C26H27N12O2, calcd 539.2380).
Compound 4. Compound 2 (120 mg, 0.160 mmol) was dissolved
in a mixture of CH2Cl2 (1.2 mL) and TFA (1.2 mL) and stirred at room
temperature for 2 h. The solvent was removed to give compound 4
(125 mg, 0.160 mmol, 100%) as a white salt. Mp: 106-109 °C. IR
(KBr, cm-1): 3122m, 2924m, 1682s, 1631s, 1508s, 1427s, 1204s,
1
1138s, 840m, 724m. H NMR (500 MHz, DMSO, 70 °C): 9.50 (s,
2H), 9.44 (s, 2H), 8.19 (br s, 6H), 7.78 (d, J ) 8.4 Hz, 4H), 7.64 (s,
4H), 7.37 (d, J ) 8.4 Hz, 4H), 7.20-6.80 (br, 4H), 3.99 (s, 4H). 13C
2
NMR (125 MHz, DMSO, 70 °C): 163.1, 161.9, 161.6, 158.3 (q, JCF
1
Experimental Section
) 34 Hz), 139.3, 134.0, 128.8, 127.6, 121.3, 120.4, 116.2 (q, JCF
)
292 Hz), 41.8. MS (ES): m/z 537.2 (25, [M + H - 2TFA]+, C26H29N14,
calcd 537.2700).
General experimental details have been reported previously.23
Compounds 1319 and 1636 were prepared by the literature procedures.
Compound 5. Cyanuric chloride (735 mg, 3.96 mmol) was dissolved
in anhydrous THF (15.0 mL) at 0 °C, and 4-(N-t-butoxycarbonylami-
nomethyl)aniline (900 mg, 4.05 mmol) and N,N-diisopropylethylamine
(1.65 mL, 10.0 mmol) in THF (10.0 mL) were added to the solution.
The mixture was stirred at 0 °C for 30 min, and then for another 1 h
at room tempearture. After that, 1,5-diaminonaphthalene (290 mg, 1.83
mmol) was added, and the reaction mixture was stirred at room
temperature for 72 h. The precipitate was collected by filtration and
washed with THF (8.0 mL) and then cold water (25.0 mL). Compound
5 was obtained as a white solid after drying under high vacuum (870
mg, 1.05 mmol, 58%). Mp: > 300 °C. IR (KBr, cm-1): 3282m, 2977m,
2928w, 1696m, 1573s, 1511s, 1392s, 1244m, 1167m, 994m, 803m.
1H NMR (500 MHz, DMSO, 70 °C): 10.10 (s, 2H), 9.85 (s, 2H), 7.97
(d, J ) 8.4 Hz, 2H), 7.66 (d, J ) 7.1 Hz, 2H), 7.57 (t, J ) 7.9 Hz,
2H), 7.50-7.35 (br m, 4H), 7.20-6.90 (br m, 6H), 4.02 (s, 4H), 1.38
(s, 18H). 13C NMR (125 MHz, DMSO, 70 °C): 168.2, 165.7, 163.5,
155.3, 136.8, 134.6, 133.5, 129.9, 126.7, 125.2, 124.0, 121.3, 120.0,
77.4, 42.9, 27.9. MS (ES): m/z 825.4 (100, [M + H]+, C40H43Cl2N12O4,
calcd 825.2907).
Compound 6. Compound 5 (250 mg, 0.300 mmol) and ammonium
hydroxide (2.00 g, 13.0 mmol) in DMSO (8.0 mL) were sealed in a 20
mL pressure tube, and the mixture was heated at 85 °C for 12 h. The
reaction mixture was cooled to room temperature and poured into H2O
(40 mL). The precipitate was collected by centrifugation and dried under
high vacuum. Flash chromatography (SiO2, CHCl3/CH3OH/NH4OH 9:1:
0.05) gave compound 6 (195 mg, 0.24 mmol, 82%) as a white solid.
TLC (CHCl3/CH3OH/NH4OH 9:1:0.05): Rf 0.25. Mp: 165-169 °C.
IR (KBr, cm-1): 3396m, 3336m, 2977w, 2932w, 1696s, 1600s, 1570s,
1500s, 1411s, 1366m, 1166m, 811m. 1H NMR (500 MHz, DMSO, 70
°C): 8.76 (s, 2H), 8.68 (s, 2H), 7.90 (d, J ) 8.4 Hz, 2H), 7.66 (d, J )
7.1 Hz, 2H), 7.60 (d, J ) 8.3 Hz, 4H), 7.49 (t, J ) 7.9 Hz, 2H), 7.04
(d, J ) 8.3 Hz, 4H), 7.10-6.90 (br, 2H), 6.23 (s, 4H), 4.03 (d, J ) 6.0
Hz, 4H), 1.39 (s, 18H). 13C NMR (125 MHz, DMSO, 70 °C): 166.9,
166.1, 164.4, 155.4, 138.7, 134.9, 132.8, 130.2, 126.6, 124.8, 123.3,
120.2, 119.4, 77.4, 43.0, 28.0. MS (ES): m/z 787.3 (40, [M + H]+,
C40H47N14O4, calcd 787.3905).
Compound 1. Cyanuric chloride (460 mg, 2.49 mmol) was dissolved
in anhydrous THF (5.0 mL) at 0 °C, and 4-(N-t-butoxycarbonylami-
nomethyl)aniline (550 mg, 2.48 mmol) and N,N-diisopropylethylamine
(1.00 mL, 6.05 mmol) in THF (5.0 mL) were added to the solution.
The mixture was stirred at 0 °C for 30 min, and then for another 1 h
at room temperature. After that, p-phenylenediamine (130 mg, 1.20
mmol) was added, and the reaction mixture was stirred at room
temperature for 48 h. The precipitate was collected by filtration and
washed with THF (5 mL) and cold water (20 mL). Compound 1 was
obtained as a white solid after drying under high vacuum (590 mg,
0.760 mmol, 63%). Mp: > 300 °C. IR (KBr, cm-1): 3281m, 2978m,
2932w, 1689s, 1579s, 1511s, 1417s, 1394s, 1244s, 1169m, 990s, 803m.
1H NMR (500 MHz, DMSO, 70 °C): 9.94 (s, 4H), 7.65-7.55 (m,
8H), 7.18 (d, J ) 7.7 Hz, 4H), 7.10-6.90 (br, 2H), 4.08 (d, J ) 5.6
Hz, 4H), 1.38 (s, 18H). 13C NMR (125 MHz, DMSO, 70 °C): 168.0,
163.6, 155.4, 136.7, 135.1, 133.8, 126.9, 121.2, 120.6, 77.4, 42.9, 27.9
(only 12 of the 13 expected resonances were observed). MS (ES): m/z
775.3 (15, [M + H]+, C36H41Cl2N12O4, calcd 775.2751).
Compound 2. Compound 1 (200 mg, 0.260 mmol) and ammonium
hydroxide (1.80 g, 12.0 mmol) in DMSO (8.0 mL) were sealed in a 20
mL pressure tube, and the mixture was heated at 85 °C for 12 h. The
reaction mixture was cooled to room temperature and poured into H2O
(40 mL). The precipitate was collected by centrifugation and dried under
high vacuum. Flash chromatography (SiO2, CHCl3/CH3OH/NH4OH 9:1:
0.05) gave compound 2 (165 mg, 0.220 mmol, 87%) as a white solid.
TLC (CHCl3/CH3OH/NH4OH 9:1:0.05): Rf 0.25. Mp: 163-166 °C.
IR (KBr, cm-1): 3396m, 2976w, 2928w, 1696s, 1603s, 1558s, 1500s,
1
1415s, 1366m, 1247m, 1166m, 810m. H NMR (500 MHz, DMSO,
70 °C): 8.71 (s, 2H), 8.66 (s, 2H), 7.68 (d, J ) 8.3 Hz, 4H), 7.61 (s,
4H), 7.12 (d, J ) 8.3 Hz, 4H), 7.10-6.90 (br, 2H), 4.07 (d, J ) 6.1
Hz, 4H), 1.40 (s, 18H). 13C NMR (125 MHz, DMSO, 70 °C): 166.7,
164.3, 155.4, 138.7, 134.3, 133.0, 126.7, 120.2, 119.7, 77.4, 43.0, 28.0
(34) Wu, A.; Isaacs, L. J. Am. Chem. Soc. 2003, 125, 4831-4835. Mukho-
padhyay, P.; Wu, A.; Isaacs, L. J. Org. Chem. 2004, 69, 6157-6164.
Mukhopadhyay, P.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc. 2006, 128,
14093-14102.
(35) Hartgerink, J. D. Curr. Opin. Chem. Biol. 2004, 8, 604-609.
(36) Liu, Y.-S.; Zhao, C.; Bergbreiter, D. E.; Romo, D. J. Org. Chem. 1998,
63, 3471-3473.
Compound 7. Compound 5 (250 mg, 0.300 mmol) was dissolved
in TFA (1.2 mL) and stirred for 1 h at room temperature. After H2O
(5.0 mL) was added, the solution was heated at reflux for 10 h. The
9
11240 J. AM. CHEM. SOC. VOL. 129, NO. 36, 2007

Refolding Foldamers
A R T I C L E S
reaction mixture was cooled to room temperature, and the precipitate
was collected by filtration and dried on the frit for 3 d yielding 7 (185
mg, 0.230 mmol, 76%) as a white solid. Mp: > 300 °C. IR (KBr,
cm-1): 3440m, 3037m, 2885m, 1757s, 1684s, 1628s, 1600s, 1509m,
1204s, 1142m, 840m, 724m. 1H NMR (500 MHz, DMSO, 70 °C):
10.80-10.20 (br, 2H), 9.20-8.40 (br, 2H), 8.12 (s, 6H), 8.05 (d, J )
8.4 Hz, 2H), 7.75 (d, J ) 7.1 Hz, 2H), 7.65 (t, J ) 7.9 Hz, 2H), 7.42
(br, 4H), 7.21 (br, 4H), 3.92 (s, 4H). 13C NMR (125 MHz, DMSO, 70
°C): 159.2 (q, 2JCF ) 34 Hz), 157.3, 151.6, 137.3, 132.3, 129.7, 129.2,
128.8, 125.7, 124.5, 121.7, 120.8, 116.1 (q, 1JCF ) 292 Hz), 41.6 (only
14 of the 15 expected resonances were observed). MS (ES): m/z 589.2
(100, [M + H - 2TFA]+, C30H29N12O2, calcd 589.2536).
Compound 10. A solution of compound 9 (200 mg, 0.240 mmol)
and ammonium hydroxide (1.8 g, 12 mmol) in DMSO (8 mL) was
sealed in a 20 mL pressure tube. The mixture was heated at 85 °C for
12 h. The reaction mixture was cooled to room temperature and poured
into H2O (40 mL). The precipitate was collected by centrifugation and
dried under high vacuum. Flash chromatography (SiO2, CHCl3/CH3-
OH/NH4OH 9:1:0.05) gave compound 10 (130 mg, 0.160 mmol, 65%)
as a pale-yellow solid. TLC (CHCl3/CH3OH/NH4OH 9:1:0.05): Rf 0.23.
Mp: 171-173 °C. IR (KBr, cm-1): 3394m, 3324m, 3227m, 2977w,
2932w, 1707m, 1600s, 1545s, 1495s, 1407s, 1367m, 1243m, 1161m,
1
1024m, 811m, 785m. H NMR (500 MHz, DMSO, 70 °C): 8.97 (s,
2H), 8.68 (s, 2H), 8.51 (s, 2H), 7.89 (d, J ) 8.4 Hz, 2H), 7.85 (d, J )
8.4 Hz, 2H), 7.63 (d, J ) 7.2 Hz, 2H), 7.53 (d, J ) 7.2 Hz, 2H), 7.50
(t, J ) 7.2 Hz, 2H), 7.50-7.35 (m, 2H), 7.40 (s, 4H), 6.19 (s, 4H),
1.51 (s, 18H). 13C NMR (125 MHz, DMSO, 70 °C): 166.9, 166.1,
164.3, 153.9, 135.1, 134.1, 133.9, 130.3, 129.0, 124.8, 124.7, 123.3,
121.3, 120.2, 119.8, 78.6, 27.9 (only 17 of the 18 expected resonances
were observed). MS (ES): m/z 809.3 (100, [M + H]+, C42H45N14O4,
calcd 809.3748).
Compound 8. Compound 6 (90 mg, 0.11 mmol) was dissolved in
a mixture of CH2Cl2 (1.0 mL) and TFA (1.0 mL) and stirred at room
temperature for 2 h. The solvent was removed to give compound 8
(95 mg, 0.11 mmol, 100%) as a white salt. Mp: 233-236 °C. IR (KBr,
cm-1): 3374m, 3125m, 2920m, 1685s, 1631s, 1608s, 1513s, 1429s,
1380m, 1198s, 1143s, 840m, 798m, 724m. 1H NMR (500 MHz, DMSO,
70 °C): 9.55 (s, 2H), 9.41(s, 2H), 8.12 (s, 6H), 7.97 (d, J ) 8.4 Hz,
2H), 7.75-7.65 (m, 6H), 7.57 (t, J ) 7.9 Hz, 2H), 7.26 (d, J ) 8.3
Hz, 4H), 7.20-6.80 (br, 4H), 3.95 (s, 4H). 13C NMR (125 MHz,
Compound 11. Compound 10 (100 mg, 0.120 mmol) was dissolved
in a mixture of CH2Cl2 (1.0 mL) and TFA (1.0 mL) and stirred at room
temperature for 2 h. The solvent was removed to give compound 11
(105 mg, 0.120 mmol, 100%) as a pale-yellow salt. Mp: 208-
211 °C. IR (KBr, cm-1): 3359m, 3171m, 3107m, 2917m, 1682s, 1616s,
2
DMSO, 70 °C): 163.3, 162.2, 158.1 (q, JCF ) 34 Hz), 139.3,
1
133.8, 130.2, 128.7, 127.3, 125.2, 124.0, 120.9, 120.0, 116.2 (q, JCF
) 292 Hz), 41.8 (only 14 of the 15 expected resonances were observed).
MS (ES): m/z 587.2 (20, [M + H - 2TFA]+, C30H31N14, calcd
587.2856).
1
1565s, 1507s, 1415s, 1356m, 1204s, 1137s, 841m, 785m, 724m. H
NMR (500 MHz, DMSO, 70 °C): 10.15-10.00 (br s, 2H), 9.90 (s,
2H), 8.06 (d, J ) 8.4 Hz, 2H), 7.90-7.20 (br, 10H), 7.58 (d, J ) 7.2
Hz, 2H), 7.50-7.40 (m, 4H), 7.35-7.25 (m, 6H), 6.88 (d, J ) 7.2 Hz,
2H). 13C NMR (125 MHz, DMSO, 70 °C): 159.6, 158.8, 158.2 (q,
2JCF ) 34 Hz), 142.7, 133.6, 131.8, 130.3, 126.9, 124.2, 123.9, 123.2,
Compound 9. After cyanuric chloride (228 mg, 1.24 mmol) was
dissolved in anhydrous THF (15.0 mL) at 0 °C, mono-BOC-protected
1,5-diaminonaphthalene (320 mg, 1.24 mmol) and N,N-diisopropyl-
ethylamine (0.55 mL, 3.30 mmol) were added to the solution. The
mixture was stirred at 0 °C for 30 min, and then for another 1 h at
room temperature. After that, p-phenylenediamine (62 mg, 0.56 mmol)
was added, and the reaction mixture was stirred at room temperature
for 72 h. The precipitate was collected by filtration and washed with
THF (5 mL) and then cold water (20 mL). Compound 9 was obtained
as a white solid after dried under high vacuum (254 mg, 0.300 mmol,
53%). Mp: 290 °C (dec). IR (KBr, cm-1): 3395m, 3282m, 2978w,
2928w, 1699m, 1560s, 1497s, 1409s, 1368m, 1239m, 1159m, 988m,
1
121.7, 121.3, 115.8 (q, JCF ) 292 Hz), 111.6, 109.6 (only 16 of the
17 expected resonances were observed). MS (ES): m/z 609.2 (100,
[M + H - 2TFA]+, C32H29N14, calcd 609.2700).
Acknowledgment. We thank the National Science Foundation
(CHE-0615049) for financial support of this work.
Supporting Information Available: Selected NMR spectra
1
for CB[n]‚foldamer complexes, H and 13C NMR spectra for
1
782m. H NMR (500 MHz, DMSO, 70 °C): 10.10-9.90 (br s, 2H),
all new compounds, and details of the X-ray structures of
CB[10]‚3, CB[10]‚4, CB[10]‚7, and CB[7]‚7‚CB[7] (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
9.75-9.60 (br s, 2H), 9.01 (s, 2H), 7.99 (d, J ) 8.4 Hz, 2H), 7.81 (d,
J ) 8.4 Hz, 2H), 7.70-7.40 (m, 8H), 7.35-7.15 (br. s, 4H), 1.51 (s,
18H). 13C NMR (125 MHz, DMSO, 70 °C): 168.2, 165.7, 163.4, 153.8,
134.2, 133.5, 133.4, 129.9, 128.9, 125.3, 124.7, 123.8, 121.4, 121.2,
120.4, 119.8, 78.7, 27.9. MS (ES): m/z 847.3 (45, [M + H]+, C42H41-
Cl2N12O4, calcd 847.2751).
JA073320S
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J. AM. CHEM. SOC. VOL. 129, NO. 36, 2007 11241