Selective stabilization of self-assembled hydrogen-bonded molecular capsules through π-π Interactions

Article abstract of DOI:10.1021/ja211410x

Subtle noncovalent forces such as π-π interactions play an import role in the folding of biological macromolecules such as DNA and proteins. We describe here a system where such interactions on the outside of a molecular capsule trigger a selective change of its structure as a self-assembled receptor.

Full text of DOI:10.1021/ja211410x

Communication
pubs.acs.org/JACS
Selective Stabilization of Self-Assembled Hydrogen-Bonded
Molecular Capsules Through π−π Interactions
Konrad Tiefenbacher 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, United States
S
* Supporting Information
ABSTRACT: Subtle noncovalent forces such as π−π
interactions play an import role in the folding of biological
macromolecules such as DNA and proteins. We describe
here a system where such interactions on the outside of a
molecular capsule trigger a selective change of its structure
as a self-assembled receptor.
oncovalent interactions of aromatic rings play an
important role in biological systems: They stabilize the
Figure 1. (a) Molecular model of dimeric capsule 1.1, its approximate
N
accessible cavity length and structure of cavitand unit 1. (b) Structure
of propanediurea spacer unit 2. (c) Molecular model of extended
capsule I consisting of two cavitand units 1 and four PD spacer units 2,
which are arranged in a “twisted-belt” fashion. (d) Molecular model of
an isomeric capsule II again with two cavitands and four spacer units;
In this case two PD units are oriented in a twisted fashion, while the
remaining two PD units (marked by orange arrows) are bound
horizontally with respect to the cavitand. (Peripheral alkyl groups have
been deleted for easier viewing.).
structure of biomolecules such as DNA and proteins and also
play a crucial role in protein−ligand binding.1 Although indivi-
dual π−π interactions are weak, they are typically numerous in
protein interiors and contribute in sum to protein folding and
thermal stability. We sought to engineer such stabilizing aro-
matic π−π interactions into hydrogen-bonded molecular
capsules and report here that a number of these weak inter-
actions impart selectively on the self-assembly process.
A multitude of capsules have been devised over the last two
decades, held together mainly either via covalent bonds,2
hydrogen bonds,3 metals, and ligands,4 or simple hydrophobic
effects.5 Inside these capsules a molecule’s behavior is quite
different than it is in bulk solvent; interactions are amplified,6
reactive intermediates are stabilized,4b,f,g,7 reactions are acce-
lerated8 and even catalyzed,4c,9 unusual reaction pathways are
facilitated,10 and new types of stereochemistry emerge.11
Hydrogen-bonded capsules have been extended with spacer
modules,12 and we recently reported the extension of the
dimeric host capsule 1.1 (Figure 1a) with propanediurea (PD)
units 2 (Figure 1b) through self-assembly in the presence
of suitable n-alkane guests.13 The shorter n-alkane guests
(n-tetradecane to n-hexadecane) induced the formation of the
isomeric assemblies I and II. Assembly I (Figure 1c) features a
chiral arrangement of four PD units in a “twisted belt” orien-
tation; assembly II (Figure 1d) features a plane of symmetry as
two of the PD units are in a “horizontal” orientation (Figure 1d).
At equilibrium, mixtures of I and II are formed for these
guests, with ratios ranging from 2:1 to 1:5 for n-tetradecane and
n-hexadecane, respectively (Table 1). The preference follows
considerations of length (I is slightly shorter than II). Accord-
ingly, assembly I favors the shorter guests, n-tetradecane and
n-pentadecane, while host II favors the longer n-hexadecane
and n-heptadecane. Size also bears on the corresponding
packing coefficients (PCs) and the extent to which the longer
guests must assume gauche conformations to fit inside. These
assemblies prefer a PC of slightly above 50%,14 but the existence
Table 1. Distribution of Assemblies I and II formed with
Guests n-Tetradecane to n-Heptadecane and Corresponding
Packing Coefficients (PC)
formation of I
(%)
formation of II
(%)
guest
PC in I
PC in II
n-tetradecane
n-pentadecane
n-hexadecane
n-heptadecane
67
67
17
−
50
53
55
56
33
33
47
50
53
53
83
100
of mixtures indicates that assemblies I and II are very close in
free energy. This thermodynamic balance suggested the system
could be a measure of π−π interactions, as even small con-
tributions from these subtle attractive forces could tip the balance
for formation of one assembly over the other. This turned out
to be the case.
We engineered additional stabilization into the self-
assembling systems I/II through π−π interactions on the
outside of the assembly. Specifically, aromatic panels were insta-
lled on the propanediurea units that could fold onto the outer
surface of the capsule. Direct connection of phenyl groups to
the propanediurea framework (PD 3) results in rigid aromatic
units directed away from assembly I (1.34.1, Figure 2a), but
connection through the flexible benzyl groups permits the
Received: December 6, 2011
Published: January 20, 2012
© 2012 American Chemical Society
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Figure 2. (a) Molecular models of assemblies I incorporating phenyl-
PD 3 (cyan) units; (b) Model of assemblies I incorporating benzyl-PD
4 (red); (c) Model of assemblies II incorporating benzyl-PD 4
(marked red if oriented in a “twisted” fashion or marked orange if
bound “horizontally” to the cavitand). The benzylic side chains of the
PD 4 units bound in a “twisted” fashion (marked red) can fold back
onto the surface of the capsule and give rise to potentially stabilizing
π−π interactions with the assembly’s hydrogen-bonding array.
(Peripheral alkyl groups have been deleted for easier viewing.)
Figure 4. Comparison of the 1H NMR spectra of assemblies
containing either spacer unit 5 or unit 2, formed in the presence of
the guests n-tetradecane to n-heptadecane. The labels I or II refer to
aromatic panels to fold back on the outer surface of capsule I
(1.44.1) and offer stabilizing π−π interactions to the assembly’s
hydrogen-bonding array (Figure 2b). The molecular models
indicated that the distance of the benzylic side chains to the
hydrogen-bonding array is approximately 3.5 Å, a value that is
in good agreement with literature distances for π−π inter-
actions of hydrogen-bonded arrays to aromatics.1a,b In the case
of 1.44.1, eight benzene rings (two on each of the four PD
units) could form such interactions. However, the same com-
ponents assembled as capsule II (1. 4′2.42.1) lose half of these
interactions, since the “horizontally” bound PD units (high-
lighted in orange in Figure 2c) present the benzylic func-
tions in a way that prevents stacking on the capsular surface.
Encapsulation studies with these systems were performed in
mesitylene-d12, which, due to its size and inconvenient shape,
does not compete for the capsules with the intended guest
molecules. This solvent required that a soluble (lipophilic)
derivative of PD 4 be synthesized. Earlier experiments with
related glycoluril spacer units12a suggested the attachment of
remote dibutylamino groups onto the aromatic side chains
(PD 5, Figure 3) and PD 5 was synthesized in nine steps and 7%
Figure 5. Comparison of the 1H NMR spectra of assemblies
containing either PD spacer unit 6, 2, or 7. These PD-units lack the
ability to stack to the outside of the capsule and all form assembly II in
the presence of n-heptadecane as guest.
As described above, use of 2 gave mixtures of arrays I and II for
guests n-C14H30 to n-C16H34 and II exclusively with n-C17H36.
A further test of the role π−π stacking plays was provided by
propanediurea derivative 6 (Figure 3) (synthesized in four
steps, 47% overall yield; see SI). This also features benzylic side
chains, but the two bulky tert-butyl groups on each benzene
prevent efficient stacking onto the capsules surface. In the
experiment, PD 6 behaves in the same manner as the original
Figure 3. Structures of the investigated propanediurea spacers.
overall yield (see SI for details). Its assembling properties with
cavitand 1 in the presence of n-alkanes were compared with
those of dioctyl-PD 2. Using 5, the shorter guests (n-C14H30 to
n-C17H36) were exclusively encapsulated in assembly I (Figure 4).
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Figure 6. Overview of the self-assembled molecular capsules formed with PD 5 (top part) in the presence of an n-alkane guest, ranging from
n-tetradecane to n-tricosane. For comparison the reported results13 with PD 2 are displayed in the lower part. (Peripheral alkyl and aryl groups have
been deleted for easier viewing.)
dioctyl-PD 2; it gives assembly II exclusively with n-C17H36
(Figure 5: top). Additionally, a shortened relative of PD 5, namely
PD 7, was synthesized (six steps, 8% overall yield; see SI). It
lacks the flexibility of the benzylic side chains (cf. PD 3 in
Figure 2a) so the phenyl groups of 7 cannot fold onto the
capsule. Using 7 with these guests, we saw a behavior similar to
that seen with 2 and 6 (Figure 5: bottom), further corro-
borating the role π−π stacking plays in the case of PD 5. The
stacking interactions between the aromatic side chains in 5 and
the hydrogen-bonding array are also revealed in the NMR
spectra (see SI-Figure 7).
Additional consequences of the folded aromatics of spacer 5
(as compared to 2) appeared when longer guests were
encapsulated. With n-C18H38 and n-C19H40 a banana-shaped
assembly III dominated (Figure 6) with results comparable to
those with the original spacer 2; however, starting with n-C19H40
a cylindrical, doubly extended assembly12a V was formed. Even
longer guests (n-C22H46 and n-C23H48) were cleanly encap-
sulated as expected in the S-shaped assembly IV. How can
these observations be rationalized? There are two main factors
influencing these self-assemblies beyond guest size. (1) First,
there is an intrinsic tendency for PD units to assemble in the
fashion displayed by assemblies II, III, and IV, where the
assemblies feature two “horizontal” and two “twisted” propane-
diurea units.13 With the dioctyl-PD 2, this preferred arrange-
ment is abandoned only for the shortest guests, which enjoy a
more favorable packing coefficient in the smaller host I. (2)
Second, there are contributions from π−π interactions
(described in this communication) which favor assemblies
I and V (with eight stacking interactions) over assemblies II, III,
and IV (with four stacking interactions) (Figure 6).
The folding results in exclusive formation of host I for the
shorter n-alkanes and the appearance of new host V for longer
guests. These assemblies, which present their spacer units in a
“twisted” fashion can most efficiently stack onto the hydrogen-
bonding array of the capsule (as modeled in Figure 2b).
In conclusion, a propanediurea spacer unit was developed
that features aromatic surfaces that interact with the hydrogen-
bonding seams of a capsule on its outer surface. The intra-
complex π−π interactions increase the selectivity of the self-
assembling process. While elegant devices can assess subtle
forces in intramolecular settings,15 this represents an example
where a recognition event outside of the capsule triggers a change
of its structure as a self-assembled receptor.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
jrebek@scripps.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Skaggs Institute and NSF
CHE-1037590. We are grateful to the Austrian Science Fund
■
(FWF): J2995-N19 for an Erwin Schrodinger Scholarship to
̈
K.T.
What do the properties of spacer 5 teach us about self-
assembly? Folding, when it can be arranged, minimizes un-
occupied space (e.g., unsolvated surfaces), the characteristic
of vacuums. Folding liberates solvent and increases over-
all intermolecular interactions that stabilize assemblies.
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