Pseudo-capsule assemblies characterized by 19F NMR techniques

Full text of DOI:10.1021/ja809224p

Published on Web 01/29/2009
Pseudo-Capsule Assemblies Characterized by 19F NMR Techniques
Agustí Lledo´, Per Restorp, and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and Department of Chemistry, The Scripps Research Institute, 10550
North Torrey Pines Road, La Jolla, California 92037
Received November 25, 2008; E-mail: jrebek@scripps.edu
Molecular recognition events in nature rely on combinations of
weak intermolecular interactions comprising hydrogen bonds,1
ionic,2 and hydrophobic effects.3 These forces and other polar
attractions appear in synthetic receptors as well, but the weakest
interactionssdispersion forcessseldom appear alone. We have now
used them along with CH-π interactions to stabilize a new
multicomponent assembly between cavitand host 1 (Figure 1) and
ditopic guests 2 and 3a-c. The clustered spectroscopic signals
arising from these weak attractions required the use of 19F NMR
techniques to differentiate the species present in solution, and we
describe these applications here.
as a singlet at δ -138.87 ppm in mesitylene-d12, and upon mixing
with 1, three additional sets of resonances appear; they are shifted
upfield by the shielded environment provided by the π systems of
1 (Scheme 1). The two doublets of doublets (J ) 22.0, 11.5 Hz) at
-139.30 ppm and -140.45 ppm result from desymmetrization of
the A4 spin system in 3a into an AA′XX′ system and were assigned
to a 1:1 complex A (Scheme 1). These resonances collapse again
into a X4 spin system (signals at -140.88 and -140.91 ppm) when
the incorporation of a second host molecule renders the assembly
symmetric and both sides of the aromatic linker experience the same
shielding effect from the neighboring amide groups. The 2:1
complex (B) actually exists as an equal mixture of two cyclodias-
tereomers arising from a clockwise/clockwise or a clockwise/
anticlockwise arrangement of the secondary amide groups at the
rim of 18 which interconvert slowly on the NMR time scale.9 As
expected, when the 1 to 3a ratio in the mixture is gradually
increased the formation of B is favored.
Scheme 1. Formation of Assemblies A and B and Evolution of the
19F NMR Spectrum (300 K)a
Figure 1. Host and guest structures.
Host 1 is a resorcinarene derived structure, stabilized in a vase
conformation by a seam of intramolecular hydrogen bonds provided
by the amide groups on the rim.4 Adamantane derivatives are among
the best guests for its hydrophobic cavity due to favorable CH-π
interactions and the appropriate filling of the space inside 1.5
Accordingly, we expected that a guest containing two adamantyl
groups connected by a suitably rigid linear linker would be an ideal
ditopic ligand to bring two host molecules together. This could give
rise to a new capsule-like assembly without any stabilizing contacts
between the two cavitands.
Guests 26 and 3a-c were prepared by Sonogashira coupling
reactions between the corresponding alkynes and 1,4-diiodobenzene
derivatives. Although the binding of 2 within 1 could be observed
a 1 to 3a ratios are 0.16:1 (a), 1:1 (b), and 3:1 (c), respectively ([3a] )
5-6 mM).
1
readily by H NMR in mesitylene-d12 (a noncompeting solvent),
an accurate characterization of the system’s stoichiometries was
not possible: the two hydrophobic anchors experience almost
identical upfield shifts7 in either a 1:1 or a 2:1 complex, and the
noncovalent interactions with the guest lacked diagnostic NH or
CH NMR signals. The aromatic protons on the guest linker do
experience upfield shifts on complexation, but they overlap with
other aromatic signals from the host.
In contrast, fluorinated guest 3a allowed resolution of the multiple
species that appear in solution as the 19F NMR spectrum is devoid
of any interference by the cavitands’ signals. The free guest appears
The system could be further characterized by implementing
various NMR techniques in the 19F dimension. The 19F DOSY
experiment10 shows decreasing diffusion coefficients for the free
guest (D ) 859 µm2 s-1), complex A (D ) 509 µm2 s-1), and
complex B (D ) 412 µm2 s-1) according to the increase in size of
each molecular species in this series (Figure 2a). The 19F ROESY11
(318 K) spectrum clearly shows the stepwise formation of A and
B from 1 and 3a (Figure 2b). Off-diagonal peaks arising from
9
2440 J. AM. CHEM. SOC. 2009, 131, 2440–2441
10.1021/ja809224p CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Intrinsic Binding Constantsa with Host 1
chemical exchange can be observed between the free guest signal
and the resonances assigned to A which in turn correlate to the far
upfield signals assigned to B. The latter also have a correlation
with the free guest peak which probably accounts for a dissociative
process of B into 1 and 3a. The slow interconversion between the
three species on the NMR time scale allows the extraction of
association constants from the spectra by simple integration. The
b
)
b
guest
K1i (M-1
K2i (M-1
)
3a
3b
3c
565
120
-
(5
(2
220
24
-
(5
(2
c
c
a K1 ) 2K1 , K2
)
1/2K2 , see ref 12. b In mesitylene-d12, [1] ) 5-6
i
i
mM. c Binding not observed.
12
i
intrinsic binding constant for the first equilibrium process (K1 )
i
was found to be larger than that for the second one (K2 ) but the
same order of magnitude. This suggests only modest steric clashes
exist between the ethyl groups on the two cavitand rims. Kinetic
data can also be extracted from 19F EXSY13 experiments, and the
18.1 kcal/mol barriers obtained this way for the dissociation of both
The case of 3a establishes that a guest can be more or less
completely surrounded in an assembly lacking direct attractions
between host subunits. This type of self-assembly would find
applications in template synthesis when reaction conditions are
incompatible with, for example, hydrogen bonds. In addition, the
present study showcases the advantages of 19F NMR spectroscopy
in the characterization of complex supramolecular systems. The
19F nucleus has a much broader range of chemical shift than the
proton yet offers the same applications of NMR techniques in the
19F dimension.
1
A and B compare well to the values previously calculated by H
EXSY5 and coalescence experiments.4a
Acknowledgment. We are grateful to the Skaggs Institute and
NIH (GM 27953) for support. We thank Dr. Laura Pasternack for
NMR assistance and Dr. Richard J. Hooley for helpful discussions.
A.L. thanks Fundacio´n Ramo´n Areces (Spain) for a postdoctoral
fellowship. P.R. is a Swedish Knut and Alice Wallenberg Post-
doctoral Fellow.
Supporting Information Available: Synthesis and characterization
data for guests 2 and 3a-c, additional information for the 19F NMR
experiments including fitting curves for DOSY calculations. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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(9) The two resonances show coalescence upon heating to 325 K which is
within the range of the energy barrier previously reported for such processes
(ref 8). See Supporting Information.
Figure 2. (a) 19F DOSY spectrum displaying different diffusion coefficients
(D) for 3a, A, and B. (b) 19F ROESY spectrum (318 K) showing chemical
exchange between these species.
(10) For an application of this experiment to discrete, well-defined assemblies,
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attractions in the formation of B. The cyclohexyls of 3b have the
size and shape to fit deeply in the space but are not as attractive as
the adamantyl groups for 1.14 As a result, the binding event is less
effective in overcoming the entropic (and perhaps steric) penalties
of bringing the three components together. Linear aliphatic residues
such as the n-hexyl groups in 3c can only properly fill the cavity
if they coil into a higher energy conformation.15 Consequently, no
binding was observed with the n-alkanes.
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two ways to dissociate. See: Rebek, J., Jr.; Costello, T.; Marshall, L.;
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(15) Trembleau, L.; Rebek, J., Jr Science 2003, 301, 1219–1220.
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