Multicomponent, hydrogen-bonded cylindrical capsules

Article abstract of DOI:10.1021/jo901072m

(Figure Presented) Self-assembled, hydrogen-bonded capsules emerge from synthetic resorcinarene-derived cavitands and soluble glycolurils when appropriate guest molecules are present. The assembly consists of 2 cavitands, 4 glycolurils and guest(s), and t

Full text of DOI:10.1021/jo901072m

pubs.acs.org/joc
Multicomponent, Hydrogen-Bonded Cylindrical Capsules
Dariush Ajami 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
jrebek@scripps.edu
Received May 21, 2009
Self-assembled, hydrogen-bonded capsules emerge from synthetic resorcinarene-derived cavitands
and soluble glycolurils when appropriate guest molecules are present. The assembly consists of
2 cavitands, 4 glycolurils and guest(s), and the arrangement of glycolurils leads to a chiral structure.
3
˚
The capsule features a space of ∼620 A and accommodates narrow guests such as n-alkanes from C14
˚
to C19, or other molecules (e.g., capsaicin) and combinations of molecules of up to ∼22 A in length
(e.g., two p-methylstyrene molecules). Positions of encapsulated nuclei can be predicted from NMR
chemical shifts, with intense shielding of δΔ=-5 ppm near the resorcinarene ends and mild
deshielding of þ0.5 to 1 ppm near the glycolurils at the capsule’s center. Computational methods
using nucleus independent chemical shifts (NICS) were used to map the induced magnetic shielding/
deshielding for the inner space of the cavity. The asymmetric arrangement of the spacers creates a
chiral steric and magnetic environment in the capsule and the geminal hydrogen atoms of
encapsulated alkanes show diastereotopic proton signals. The two enantiomers interconvert
(racemize) through an achiral intermediate involving a slight rotation of the spacers and lengthening
of the cavity. Accordingly, longer, compressed alkanes accelerate the racemization by applying
pressure from the inside on the capsule’s ends. Guests that place hydrogen bond donors and acceptors
near the glycolurils in the middle (e.g., p-isopropylbenzyl alcohol) also accelerate the racemization by
facilitating the rotation of the glycolurils. Slow tumbling of guest on the NMR time scale inside the
capsule leads to social isomerism of para-disubstituted benzenes such as p-methylstyrene. Flexible
guests such as hexane tumble inside the cavity with an activation barrier of ΔGq =16.2 kcal/mol. The
middle of the extended capsule is narrow, but still accommodates phenyl groups such as those
presented by p-quaterphenyl and alkylated biphenylcarbonitriles. The aromatic units in these guests
report their positions by imparting magnetic anisotropy to the capsule components. Gases such as
propane, butane, isobutane, propylene, 2-methylpropene, and 1,3-butadiene even xenon are
coencapsulated with other guests and their motions inside are examined.
3
(420 A ),1-3 and molecules in this space enjoy a concentration
˚
Introduction
of ∼4 M. Like other reversibly formed capsules;whether
The hydrogen-bonded dimeric capsule 1.1 (Figure 1) was
introduced to surround and temporarily isolate guest molecules.
The capsule defines a nanosized space of ∼4.2ꢀ 10-25
L
(2) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Angew. Chem., Int. Ed.
1999, 38, 1136–1139.
€
(3) Korner, S. K.; Tucci, F. C.; Rudkevich, D. M.; Heinz, T.; Rebek, J.,
Jr. Chem.;Eur. J. 2000, 6, 187–195.
(1) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Nature. 1998, 394, 764–766.
6584 J. Org. Chem. 2009, 74, 6584–6591
Published on Web 08/05/2009
DOI: 10.1021/jo901072m
r
2009 American Chemical Society

Ajami and Rebek
JOCArticle
FIGURE 1. Top left: Chemical structure of the cavitand component and calculated structure of the capsule 1.1 with peripheral alkyl groups
removed. Top right: The shape of the space inside 1.1 and its cartoon representation. Bottom left: Incorporation of 4 glycoluril spacers 2 to give
the chiral extended 1.24.1. Peripheral alkyl and aryl groups have been removed; both enantiomers of the extended capsule are shown. Bottom
right: The shape of the space inside 1.24.1 and its cartoon representation.
hydrogen bonded4-11 or held together by metal/ligand
interactions,12,13 hydrophobic effects,14 or even covalent
bonds15;it can accommodate more than one small guest. But
unlike spherical capsules,16,17 its cylindrical shape channels their
contacts along predictable orientations, rather than the random
intermolecular encounters found in bulk solution. Combina-
tions of different encapsulated guests18 inside 1.1 have allowed
its use as a reaction chamber,19 chiral receptor,20 and a space
where single-molecule solvation can be observed.21 Attempts to
expand the capsule’s cavity by replacing the imide walls with
elongated panels proved insuperable; solubility problems were
consistently encountered, resulting in the inevitable collapse of
the large aromatic surfaces onto each other. An indirect
approach succeeded, involving the use of external spacer ele-
ments with the appropriate curvature, size, and hydrogen
bonding patterns to insert into the polar middle of the capsule.
Specifically, the notoriously insoluble glycolurils 2,22 bearing
peripheral, alkylated phenyl groups, were found to be compa-
tible with the imides of the cavitand 1. The concave face of the
glycoluril is congruent with the resorcinarene and the convex
face is coated with bulky groups that prevent stacking and
enhance solubility. Accordingly, NMR studies showed a new
extended capsule (1.24.1) was generated with these glycolurils
and 1 in deuterated mesitylene when, and only when, appro-
priate guests are present. Previously we have communicated the
composition and structure, its application as a spring-loaded
device,23 gas encapsulation,24 and social isomerization25 within.
In this article we provide experimental details on the properties
(4) Avram, L.; Cohen, Y. J. Am. Chem. Soc. 2004, 126, 11556–11563.
(5) Shivanyuk, A.; Rebek, J., Jr. Chem. Commun. 2001, 2424–2425.
(6) Kerckhoffs, J. M. C. A.; ten Cate, M. G. J.; Mateos-Timoneda, M. A.;
van Leeuwen, F. W. B.; Snellink-Ruel, B. 1; Spek, A. L.; Kooijman, H.;
Crego-Calama, M.; Reinhoudt, D. N. J. Am. Chem. Soc. 2005, 127, 12697–
12708.
(7) MacGillivary, L. R.; Atwood, J. L. Nature 1997, 389, 469–472.
€
(8) Gerkensmeier, T.; Iwanek, W.; Agena, C.; Frohlich, R.; Kotila, S.;
€
Nather, C.; Mattay, J. Eur. J. Org. Chem. 1999, 2257–2262.
(9) Kobayashi, K.; Ishii, K.; Sakamoto, S.; Shirasaka, T.; Yamaguchi, K.
J. Am. Chem. Soc. 2003, 125, 10615–10624.
ꢀ
(10) Gonzalez, J. J.; Ferdani, R.; Albertini, E.; Blasco, J. M.; Arduini, A.;
Pochini, A.; Prados, P.; de Mendoza, J. Chem.;Eur. J. 2000, 6, 73–80.
(11) Scarso, A.; Pellizzaro, L.; De Lucchi, O.; Linden, A.; Fabris, F.
Angew. Chem., Int. Ed. 2007, 46, 4972–4975.
(12) Yoshizawa, M.; Tamura, M.; Fujita, M. Science 2006, 312, 251–254.
(13) Ziegler, M.; Brumaghim, J. L.; Raymond, K. N. Angew. Chem., Int.
Ed. 2000, 39, 4119–4121.
(14) Kaanumalle, L. S.; Gibb, C. L. D.; Gibb, B. C.; Ramamurthy, V. J.
Am. Chem. Soc. 2005, 127, 3674–3675.
(15) Sherman, J. C. Tetrahedron. 1995, 51, 3395–3422.
(16) Shivanyuk, A.; Rebek, J., Jr. Chem. Commun. 2001, 2374–2375.
(17) Shivanyuk, A.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2001, 98,
7662–7665.
(18) Rebek, J., Jr. Angew. Chem., Int. Ed. 2005, 44, 2068–2078.
(19) Chen, J.; Rebek, J., Jr. Org. Lett. 2002, 4, 327–329.
(20) Scarso, A.; Shivanyuk, A.; Hayashida, O.; Rebek, J., Jr. J. Am.
Chem. Soc. 2003, 125, 6239–6243.
(21) Scarso, A.; Shivanyuk, A.; Rebek, J., Jr. J. Am. Chem. Soc. 2003,
125, 13981–13983.
(22) Sijbesma, R. P.; Kentgensf, A. P. M.; Lutz, E. T. G.; van der Maas, J.
H.; Nolte, R. J. M. J. Am. Chem. Soc. 1993, 115, 8999–9005.
(23) Ajami, D.; Rebek, J., Jr. J. Am. Chem. Soc. 2006, 128, 15038–15039.
(24) Ajami, D.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2008, 47, 6059–6061.
(25) Ajami, D.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A. 2007, 104,
16000–16003.
J. Org. Chem. Vol. 74, No. 17, 2009 6585

Ajami and Rebek
JOCArticle
FIGURE 2. Top: Models of encapsulated 7-tetradecene in both original capsule 1.1 and the expanded version 1.24.1 (peripheral groups
omitted for clarity). Bottom: The 1H NMR spectra (600 MHz, mesitylene-d12) of trans-7-tetradecene (5 mM) in 1.1 (1 mM) or 1.24.1 (1 mM).
The assignments are color coded.
of this extended capsule and the behavior of a range of organic
compounds inside its elongated cavity.
Structure. The new capsule’s structure can be deduced
from NMR evidence. The 4 added glycolurils form hydrogen
bonds with each half of the original capsule and with each
other. In the model proposed in Figure 1, each glycoluril has
four hydrogen bonds with cavitands: two strong hydrogen
bonds between the imide NH of the cavitand (the best
hydrogen bond donor) and the ureido carbonyl of the
glycoluril (the best hydrogen bond acceptor). This results
in the 3 ppm downfield shift of the imide hydrogen to
13 ppm, as may be expected for an exceptionally strong
hydrogen bond. The other two hydrogen bonds between
spacer and cavitand are somewhat weak. These are between
the ureido NH of the glycoluril (a good donor) and the imide
carbonyl of the cavitand (the weakest acceptor). This signal
appears at about 7 ppm in the NMR spectra. Each spacer
unit also has four good hydrogen bonds with its adjacent
spacers that further stabilize the assembly. These signals
are located at ∼9 ppm and reflect the involvement of
good donors with good acceptors. The tilted (with respect
to the long axis of the assembly) arrangement of the spacer
elements in the middle of the capsule produces a chiral
structure, and the two enantiomers are shown in Figure 1.
This is a rare example of chiral assembly that arises from
only achiral subunits.27 Overall, 24 hydrogen bonds hold
the new assembly together; the spacer elements increase
Results and Discussion
Constitution. The cis fusion of the five-membered rings, the
rich array of hydrogen bonds and the octyloxyphenyl,
dodecylphenyl, or dibutylaniline on their convex faces pro-
vide glycolurils 2 with the appropriate curvature, adhesion,
and solubility to complement the corresponding features of
capsule 1.1. Mere addition of the glycoluril 2 to a deuterated
mesitylene solution of trans-7-tetradecene encapsulated in
1.1, under ambient conditions, results in the appearance of
the new signals within seconds in the NMR spectrum
(Figure 2).26 Integration of proton signals indicates that
4 molecules of glycoluril are present in the new assembly
and the changes in chemical shifts of the guest reveals it to be
in a larger space in the extended capsule. All of these capsules
feature aromatic walls with polarizable π surfaces that
impart an intense magnetic anisotropy to their cavities.
The resulting upfield shifts of the NMR signals of encapsu-
lated species are used to identify guests and monitor their
positions. Furthest upfield shifts correspond to nuclei closest
to the resorcinarene ends and to the capsule’s aromatic walls.
trans-7-Tetradecene is the longest alkene known to fit inside
˚
capsule 1.1, but even it is some 4 A longer, in a fully extended
˚
the length of the capsule by 7 A and its accessible volume
3
conformation, than the space on offer in the cavity. This
alkene compresses itself by adopting a coiled shape inside the
cavity through 8 gauche conformations. The coiled alkane is
shorter and thicker; the stabilization through attractive
C-H/π interactions with the cavity’s aromatic lining com-
pensates for the repulsive gauche interactions along the
chain. Longer alkenes such as pentadecene simply cannot
fit inside 1.1. Comparison of the signals of trans-7-tetrade-
cene in the two capsules shows that the hydrogen atoms on
C2/C13, C3/C12, and C4/C11 of this guest have moved away
from the walls and the ends of the new capsule: they are in an
extended rather than coiled conformation. In addition, the
doubling of the signals on C2/C13 and C4/C11 in the longer
capsule indicates that these hydrogen atoms experience an
asymmetric magnetic environment;they are diastereotopic.
˚
by ∼200 A .
The Inner Space. The increased dimensions of 1.24.1 allow
its encapsulation of n-alkanes from C14 to C19.27 The inner
space of 1.24.1 is distinctively anisotropic and is apparent in
the NMR spectra of encapsulated guests. The two resorci-
narene ends of this capsule induce a magnetic anisotropy and
intense shielding to the protons located in the inner space, as
they are positioned near the π faces of the aromatic panels.
The middle of the capsule has an opposite effect and
provides moderate deshielding to the guest protons in the
space defined by the 4 glycolurils. The nuclei in this area
are exposed to the edges of the aromatic units on the
convex surface of the glycolurils of the capsule. These
effects are consistent with earlier experiences with aromatic
(27) Rivera, J. M.; Craig, S. L.; Martın, T.; Rebek, J., Jr. Angew. Chem.,
Int. Ed. 2000, 39, 2130–2132.
(26) Ajami, D.; Rebek, J., Jr. J. Am. Chem. Soc. 2006, 128, 5314–5315.
6586 J. Org. Chem. Vol. 74, No. 17, 2009

Ajami and Rebek
JOCArticle
resorcinarene at the end of the capsule. Consequently, in
extended conformation C2 is closer to the aromatic walls
where the best CH-π interactions are possible. The next
carbon atom, C3, is located nearer the central axis and C4 is
again nearer the walls. In an extended conformation only
these last four carbon atoms are affected; C5 is in the region
of the electron-poor imide walls. The longer guests,
n-alkanes from C15 to C19, must undergo increasing com-
pression to fit within 1.24.1.26,27 As the alkane coils, the
number of methylene groups that fit into the aromatic zone
increases and gauche conformations force all protons
near the twisted walls. There they experience the chiral en-
vironment; for example, encapsulated n-nonadecane shows
six upfield shifted signals and all five sets of the geminal
hydrogens are diastereotopic.
FIGURE 3. Left: A top view of the cavitand part of 1.24.1
enantiomers minimized at B3LYP/3-21G. The walls of the capsule
are twisted and create an asymmetric magnetic environment. Right:
Calculated NICS values for the space inside using B3LYP/6-31G*.
Energetics. There are long-standing problems posed by
these reversible encapsulation complexes that can be traced
to the historical fact that we have never seen an empty
capsule. If there are no suitable guests to occupy the space,
the capsule simply does not assemble. Instead, some other
undefined aggregates are present that show broad, uninter-
pretable NMR spectra. The glycoluril itself in bulk mesity-
lene solution is also loosely organized in some hydrogen-
bonded arrays, again shown by a broad cluster of reso-
nances. Consequently, although it is possible to get relative
association constants through direct competition between
guests and derive thermodynamic parameters for guest ex-
change from these experiments, the absolute values are not
accessible: the resting state of the capsule alone is not known.
The energetic forces that drive the formation of the extended
assembly are not measured. The contributions that can
be identified must include the enthalpic benefits of a com-
plete set of hydrogen bonds to the components, including
those between the best donors (cavitand) and acceptors
(glycolurils). In the extended capsule the glycourils can have
the maximum number of hydrogen bonds with the minimum
number of partners. Another enthalpic benefit is the relaxa-
tion of the coiled guest to its extended conformation that
relieves gauche interactions. But during the unwinding of an
alkane guest, the C-H/π interactions within the aromatic
inner space must decrease and this desolvation of surfaces
creates a vacuum;clearly enthalpic liabilities. In the context
of proteins, this corresponds to ∼1.1 kcal/mol in free energy
for the creation of a cavity the size of a methylene group.32
The flexibility of the capsule’s hydrogen-bonded parts allows
some collapse around guests, so the empty space is not easily
estimated. From an entropic perspective, the first interpreta-
tion of the formation of this ordered, 6-component þ guest
assembly should be that it is extremely unfavorable. But on
reflection, any assembly (and even any molecular recogni-
tion event) liberates solvent molecules from the surfaces of
the solutes that become engaged. This is an entropic benefit,
but the number of such solvent molecules released in the
assembly process is difficult to even estimate, let alone
determine for organic solvents. (Again, there are figures
glycoluril-based capsules,28 and those involving asymmetric
elements outside capsules.29 The NMR spectrum of trans-7-
tetradecene (Figure 2) shows only 4 upfield shifted signals;
only 4 carbon atoms of this alkene can fit in the aromatic
envelope in an extended conformation. The methyl groups
are positioned at the tapered ends of the capsule where
the highest upfield shifts occur: Δδ is nearly -4.7 ppm!
In contrast, the vinyl hydrogen signals located near the
center of cavity are shifted downfield by 0.72 ppm.
Computational methods were applied to further explore
the induced magnetic shielding regions of the cavity. A map
of the induced magnetic shielding/deshielding for the inner
space was prepared by using nucleus independent chemical
shift (NICS)30 calculations at the B3LYP/6-31G* level
of density functional theory.31 These values are shown in
Figure 3 for coordinates along the central axis of 1.24.1 with
˚
spacing distances of 1 A. The calculated values are in good
agreement with the experimental results; the map can be used
to locate and monitor the position of a guest nucleus inside
the cavity.
The evidence of the capsule’s chirality is reflected in the
diastereotopic geminal hydrogen atoms of the encapsulated
guest, but how is the chirality in the middle of the capsule
transmitted to the aromatic subunits near the ends? The
answer lies in the hydrogen-bonding patterns of the spacers
with the imide walls. A carbonyl group of each imide wall is
left without a hydrogen bond donor. This asymmetric ar-
rangement causes a twist in the array of the imide walls that
changes the symmetry of the cavitands from C4v to C4, and
creates a chiral space, as shown in Figure 3. This twist is most
pronounced at the narrower middle of the extended capsule
to relieve the steric clashes of the unpaired carbonyl groups
with the adjacent imide panels.
Why do the geminal hydrogen signals of C2 and C4 in the
aliphatic guest show pronounced diastereotopic signals? The
methyl group of the alkane is positioned in the center of the
available for water, where the burial of hydrophobic, sol-
vent-accessible surface33 is ∼25 cal/mol for each A .) The
2
˚
€
(28) Lutzen, A.; Renslo, A. R.; Schalley, C. A.; O’Leary, B. M.; Rebek, J.,
Jr. J. Am. Chem. Soc. 1999, 121, 7455–7456.
guest molecules in mesitylene have the same C-H/π and
(29) Amaya, T.; Rebek, J., Jr. J. Am. Chem. Soc. 2004, 126, 6216–6217.
(30) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A.; Jiao, H.; Hommes, N.
J. R. v. H. J. Am. Chem. Soc. 1996, 118, 6317–6318.
(31) Frisher, M. J. et al. Gaussian 03; Guassian, Inc., Pittsburgh, PA,
2002; see the Supporting Information for the full reference).
(32) Kellis, J. T., Jr.; Nyberg, K.; Sali, D.; Fersht, A. R. Nature 1988, 333,
784–786.
(33) Raschke, T. M.; Tsai, J.; Levitt, M. Proc. Natl. Acad. Sci. U.S.A.
2001, 98, 5965–5969.
J. Org. Chem. Vol. 74, No. 17, 2009 6587

Ajami and Rebek
JOCArticle
FIGURE 5. Cartoon representation of the social isomers of (A)
p-cymene, (B) p-ethyltoluene, and (C) p-methylstyrene inside 1.24.1.
Multiple Guests. The size of 1.1 has given rise to several
phenomena including coencapsulation,19 a situation that
arises when one molecule of a potential guest does not fill
enough space but two molecules cannot fit. The capsule then
selects combinations of two different molecules that together
fill the right amount of space. The increased dimensions
of extended capsule 1.24.1 now allow two long molecules
(or several short ones) to be observed inside. Take, for
example, p-cymene. Two molecules are inside but the spec-
trum shows two arrangements in the space;a symmetrical
one and one with two different ends (Figure 4 trace a, and
Figure 5). These are social isomers.35 They arise from
restricted motion in the confined space and give rise to
supramolecular diastereomers. The guests are too thick to
slip past each other and too long to tumble rapidly (on the
NMR time scale) inside the cavity, thus separate sets of
signals appear in the NMR spectrum for each arrangement.
Long molecules (e.g., p-disubstituted benzene derivatives)
generally show this behavior and the orientation of one guest
depends on the presence and nature of the other. Three
different arrangements are possible for guests with two
different substituents such as p-cymene or p-ethyltoluene
(Figure 5). For the former, only two are formed, the isomer
with 2 isopropyl groups in the narrower center of the
assembly is missing. In the case of the p-ethyltoluene, the
most favored isomer places the methyl of the tolyl group in
the tapering ends of the capsule where it can achieve close
C-H/π interactions with the aromatic surface of the resor-
cinarene. Although the unsymmetrical isomer is statistically
favored, it represents only 4% of the total isomers and must
be the highest energy form of three arrangements. The
energetic differences between the social isomers reflect not
only the better “fit’’ in the space but also the interactions
between the coencapsulated molecules. Surprisingly,
p-methylstyrene behaves much differently than p-ethylto-
luene although they are closely related. All three social
isomers of p-methylstyrene in 1.24.1 coexist in the capsules
in their statistically predicted populations: the unsymmetri-
cal isomer (which was very underrepresented in the case of
p-ethyltoluene) is now 50% of the population!
FIGURE 4. Top: Model of encapsulated capsaicin in the proposed
(achiral) intermediate structure of the capsule (peripheral groups
1
omitted for clarity). Bottom: The upfield region of the H NMR
spectra (600 MHz, mesitylene-d12) of 1.24.1 (1 mM) with (a) p-
cymene (5 mM), (b) 4-isopropylbenzyl alcohol (5 mM), and (c)
capsaicin (5 mM).
van der Waals interactions available, inside or outside the
capsule, but the potential guest must organize a large number
of the solvent molecules around itself to experience the same
level of attraction it can achieve with the walls of the capsule.
In other words, the capsule acts as an organized solvent
offering 16 fixed aromatic rings and the entropic penalty for
its organization has already been paid through the synthesis
of cavitand 1.
Dynamics . Previously, we showed that coiled alkanes
apply pressure on the inside of capsule 1.24.1, and facilitate
racemization;the interconversion of enantiomeric cap-
sules.34 We proposed formation of an achiral and slightly
longer intermediate in the racemization process. This inter-
mediate likely forms by the concerted ∼30° rotation of all
glycolurils in one direction, in a process that creates new
hydrogen bonds as the old ones are broken. For longer
alkanes such as n-C18 and n-C19 this process was slow at
room temperature and we could measure the rate of inter-
conversion and the racemization activation energy at the
coalescence temperature by heating. The racemization rates
increased with increased length of the guests: the longer,
more compressed guests applied more pressure to the interior
of the assembly and forced it toward the racemization
transition structure. Surprisingly, some guests are capable
of accelerating the racemization of the chiral capsule,
in a manner unrelated to “pressure”. In the extreme cases
the racemization is so fast that the encapsulated guest
experiences an average achiral environment at room tem-
perature. Both capsaicin (Figure 4c) and p-isopropylbenzyl
alcohol (as a dimer) show broadened NMR signals for
their terminal isopropyl groups (Figure 4b). These guests
present hydrogen bond donor and acceptor groups to the
middle of the assembly that apparently catalyze the rota-
tion of the glycolurils and accelerate racemization of their
complexes.
What governs this behavior? There is some tumbling
inside the cavity of 1.24.1: 2D ROESY spectroscopy shows
exchange cross peaks and the three social isomers can
interconvert at room temperature, but this tumbling is slow
(35) Shivanyuk, A.; Rebek, J., Jr. J. Am. Chem. Soc. 2002, 124, 12074–
(34) Ajami, D.; Rebek, J., Jr. Nature, Chem. 2009, 1, 87–90.
6588 J. Org. Chem. Vol. 74, No. 17, 2009
12075.

Ajami and Rebek
JOCArticle
FIGURE 6. Cartoon representation of the bimolecular encapsu-
lation of guests as a single social isomer inside 1.24.1.
on the NMR time scale, and separate sets of signals appear in
the spectrum for each arrangement. Similar observations
have been reported for p-methylstyrene in a water-soluble
capsule, although that capsule is much wider than 1.24.1.36
(The exchange and NOE cross-peaks are not defined in this
publication.) For p-methylstyrene to tumble inside 1.24.1
some large breathing motions of the capsule walls must take
place. The social isomers could, in principle, interconvert
also by disassembly/reassembly of the encapsulation com-
plex but this is unlikely to be the case: the chance that the
same guest molecule is released and again re-encapsulated is
spectacularly improbable. The time scale of the assembly/
dissipation of this capsule must await kinetic studies using
fluorescence at nanomolar concentrations.37-39
Two molecules of monosubstituted phenyls such as ethyl-,
propyl-, and butylbenzene are also accommodated inside
1.24.1. Their NMR spectra are consistent with the existence
of only one social isomer, the one with the phenyl groups
located at the aromatic ends of the capsule and the alkyl
groups positioned in the (more polar) middle. Apparently,
two thin, flexible alkyl chains can better fit the narrower
middle region of the capsule than two stacked, rigid phenyl
groups (Figure 6). London dispersion forces are presumably
the only attraction between these guests. Other functiona-
lized guests such as 1-chloro-3-phenylpropane, 1-chloro-4-
phenylbutane, or 4-phenyl-1-butyne behave similarly and
only assemble as one social isomer with the phenyl groups at
the ends and substituted groups toward the middle. This
tendency provides an opportunity to perform reactions in-
side this confined space,40 and we are pursuing this line of
research.
FIGURE 7. Top: The upfield region of the 1H NMR spectra (600
MHz, mesitylene-d12) of 1.24.1 (1 mM) with (a) n-pentane (5 mM),
(b) n-hexane (5 mM), and (c) n-heptane (5 mM). Bottom: 2D
ROESY spectrum of n-hexane in 1.24.1, the exchange cross peaks
have been circled.
Smaller Guests. Three pentane molecules fit inside the
capsule 1.24.1 and they tumble freely but do not exchange
positions while inside the cavity. Accordingly, a single
average (broadened) proton signal is observed for the guests
in the cavitands (Figure 7a), but signals due to the central
pentane are obscured by signals from the cavitands’ alkyl
groups. Two heptane molecules, however, do not tumble
rapidly inside the cavity at room temperature (on the NMR
time scale). The spectrum features sharp signals for the
heptanes (Figure 7c) and no cross-peaks are observed in
the 2D ROESY spectra. The behavior of n-hexane is some-
where in between. Four broadened, upfield shifted signals
are observed for its methyl and methylene protons
(Figure 7b) and 2D ROESY spectroscopy shows that the
proton signals are in slow exchange at room temperature.
The activation barrier for the hexane tumbling inside was
calculated as 16.2 kcal/mol, using magnetization exchange
rate constants. The mechanism of this tumbling is revealed
by NOE cross peaks of the alkane with fixed protons of the
capsule. The methyl group of hexane outside the cavitand
exchanges with the methyl group inside. Both methyl and
methylene signals of guest hexane show NOE cross peaks
with the imide hydrogens of the capsule but only the methyls
have NOE cross peaks with aromatic signals at the ends of
the capsule (see the SI). The two different N-H signals of the
glycoluril also exchange slowly in the complex of pentane
and hexane with 1.24.1 at room temperature. The third
molecule of these guests probably facilitates the racemiza-
tion process as the intermediate is longer. Cyclic alkanes such
as cyclopentane and cyclohexane also fit and tumble freely
inside the cavity (see the SI).
Although the extended capsule models as having a narrow
middle, it does accommodate phenyl groups: p-quaterphenyl
and substituted biphenyls are taken in. The rigid p-quater-
phenyl is poorly soluble in mesitytlene but 1.24.1 absorbs it
very effectively to form a stable complex. The pattern of
magnetic anisotropy in this host-guest system is dramatic;
while the hydrogen atoms at the two ends of the guest (the
CH’s at the para positions of the terminal benzene rings) shift
upfield 3.6 ppm, the hydrogen atoms of the central aromatics
experience a downfield shift of around 1.5 ppm (see the SI).
(36) Parthasarathy, A.; Kaanumalle, L. S.; Ramamurthy, V. Org. Lett.
2007, 9, 5059–5062.
(37) Castellano, R. K.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. J. Am.
Chem. Soc. 2000, 122, 7876–7822.
(38) Barrett, E. S.; Dale, T. J.; Rebek, J., Jr. J. Am. Chem. Soc. 2007, 129,
3818–3819.
(39) Barrett, E. S.; Dale, T. J.; Rebek, J., Jr. J. Am. Chem. Soc. 2007, 129,
8818–8824.
(40) Chen, J.; Rebek, J., Jr. Org. Lett. 2002, 4, 327–329.
Nematic liquid crystal components such as alkylated
biphenylcarbonitriles were also examined in the confined
J. Org. Chem. Vol. 74, No. 17, 2009 6589

Ajami and Rebek
JOCArticle
FIGURE 8. Top: Model of encapsulated 4-heptylbiphenyl carbo-
nitrile inside 1.24.1 (peripheral groups omitted for clarity). Bottom:
The 1H NMR spectra (600 MHz, mesitylene-d12) of 1.24.1 (1 mM)
with (a) 4-octylbiphenyl (5 mM), (b) 4-heptylbiphenyl (5 mM),
(c) 4-hexylbiphenyl (5 mM), and (d) 4-pentylbiphenyl (5 mM).
Assignments are color coded.
FIGURE 9. The upfield region of the 1H NMR spectra (600 MHz,
mesitylene-d12) of 1.24.1 (1 mM) with propane gas coencapsulated
with (a) n-dodecane (5 mM), (b) n-undecane (5 mM), (c) n-decane
(5 mM), and (d) n-nonane (5 mM) . The peaks of propane have been
marked with red stars.
space and they revealed additional information about the
structure of the assembly. The phenyl rings of the guest can
impart magnetic anisotropy to the capsule’s protons and
cause them to shift upfield as well. The 4-pentylbiphenylcar-
bonitrile fills about of 42% of the space and is fully extended
inside the cavity. It has a slight translational movement
(Figure 8d) that results in an average upfield shift of the
spacers’ NH proton signals. Through elongating the alkyl
group;hexyl, heptyl, and octyl;of the biphenyl carboni-
trile, the biphenyl core is forced toward one end of the
capsule. As a result, the different NHs of the glycolurils are
exposed to different degrees of magnetic shielding and they
show separate signals. The phenyl group of the guest can also
shield the spacer’s protons by as much as 0.25 ppm. The
groups on the convex face of the glycoluril (outside) are also
affected by the magnetic environment provided by nearby
phenyl groups on the inside (Figure 8).
Both 1.1 and 1.24.1 are capable of encapsulating gases and
we have reported25 that 3 molecules of cyclopropane occupy
39% of the inner space of 1.1 and 4 fill 36% of the extended
capsule’s cavity. 2D ROESY41,42 spectroscopy confirmed
that encapsulated cyclopropanes move past each other at
measurable rates (on the NMR time scale) as they exchange
their positions while within the capsule. This phenomenon
has not been observed for liquid or solid guests in these
cylindrical capsules. Although 1.1 has a higher packing
coefficient with cyclopropane, it shows a slightly lower
activation barrier for the exchanging of positions (17.5
kcal/mol) than extended capsule 1.24.1 (18.5 kcal/mol).
This probably reflects the constricted middle region of the
extended capsule 1.24.1.
between 36% and 40%. A symmetrical capsule is observed
for encapsulated cyclopropane, n-butane, isobutane, and
1,3-butadiene, but the other gases mentioned also show
asymmetric capsules that are likely due to the coencapsula-
tion of atmospheric gases such as nitrogen or oxygen.
Coencapsulation of a gas molecule with other guests is
well-known: those gases that alone are not a good fit for
1.24.1 such as methane, ethane, xenon, or carbon dioxide can
be captured and studied by using a matching coguest.43 The
NMR spectrum of coencapsulated propane and nonane in
1.24.1 is shown in Figure 9. The propane occupies almost
one-third of the inner space and it tumbles freely; the
propane’s protons experience similar magnetic environment
and they no longer show coupling, resulting in a broad NMR
signal (Figure 9c,d). The 2D ROESY spectrum showed that
the two guests do not slip past each other and nonane does
not tumble inside the cavity (see the SI). Elongation of the
coguest puts pressure on the propane and pushes it further
into the tapered end of the capsule. Replacing nonane with
dodecane increases the packing coefficient of propane from
30% to 60% and well-resolved signals can be observed for
methyl and methylene of the gas (Figure 9a). One methyl
group of the dodecane is at the tapered end while the other
methyl reaches into the opposite cavitand (near the propane)
where it experiences magnetic shielding and appears at
0.2 ppm.
Simple ideal gas calculations give a pressure of 387 atm for
propane encapsulated with dodecane and 196 atm for coen-
capsulation with nonane. Does this compression convert the
gaseous propane to liquid or solid propane? The calculated
pressures are hardly valid since these gases are far from ideal.
The gases are neither point masses nor are their collisions
with the walls elastic. Rather, there exist CH/π interactions
between the gases and the aromatic panels of the capsules
A wide variety of other gases such as propane, butane,
isobutane, propylene, 2-methylpropene, and 1,3-butadiene
also fit inside the extended capsule with packing coefficients
(41) Perrin, C. L.; Dwyer, T. J. Chem. Rev. 1990, 90, 935.
(42) Zolnai, Z.; Juranic, N.; Vikic-Topic, D.; Macura, S. J. Chem. Inf.
Comput. Sci. 2000, 40, 611–621.
(43) Shivanyuk, A.; Scarso, A.; Rebek, J., Jr. Chem. Commun. 2003, 11,
1230–1231.
6590 J. Org. Chem. Vol. 74, No. 17, 2009

Ajami and Rebek
JOCArticle
Experimental Section
1
General Considerations. H, 2D NOESY, and 2D ROESY
NMR spectra were recorded on a 600 MHz spectrometer with a
5-mm QNP probe. Proton (1H) chemical shifts are reported in
parts per million (δ) with respect to tetramethylsilane (TMS,
δ = 0), and referenced internally with respect to the protio
solvent impurity. All calculations were performed with Gauss-
ian 03. Geometries of stationary points were fully optimized
by using the B3LYP method and 3-21G basis set on a LINUX
cluster. NICS calculations were executed with the B3LYP
method and 6-31G* basis set. Cylindrical capsule subunit 1
and precursors were synthesized according to the literature
procedure.44
Synthesis of Bis[(dibutylamino)phenyl]glycouril 2c. 4,40-Bis-
(dibuthylamino)benzil (4.6 g, 10 mmol), urea (1.3 g, 22 mmol),
toluene (50 mL), and trifluoroacetic acid (2 mL) were combined
in a flask equipped with a Dean-Stark trap. After overnight
reflux, the mixture was cooled to room temperature. The
mixture was filtered and the filter cake was washed with
dichloromethane (50 mL) and methanol (50 mL) and air-dried.
The residue was purified by column chromatography on silica
gel, eluting with 50% ethyl acetate in hexane, to afford glycouril
2 (3.8 g, 6.9 mmol, 69%) as a white solid. 1H NMR (600 MHz,
acetone) δ 7.00 (d, J = 8.1 Hz, 4H), 6.47 (d, J = 8.4 Hz, 4H),,
3.24 (t, J = 7.4 Hz, 8H), 1.5 (p, J = 7.8 Hz, 8H), 1.35 (h, J = 7.6
Hz, 8H), 0.94 (t, J = 7.4 Hz, 12H). 13C NMR (151 MHz,
DMSO-d6) δ 160.7, 147.1, 127.9, 124.3, 110.3, 81.8, 49.7, 28.8,
19.7, 13.8. HRMS (MALDI-FTMS: MHþ) calcd for
C32H49N6O2þ 549.3911, found 549.3906.
Procedure for 2D NOESY and 2D ROESY Experiments. The
2D NOESY spectra of the assembly were recorded at 300 K at
600 MHz with the phase-sensitive NOESY pulse sequence. Each
of the 512 F1 increments was the accumulation of 32 scans. Two-
dimensional ROESY spectra were also taken to determine
whether the cross-peaks observed derived from NOE enhance-
ments or chemical exchange, and were recorded at 300 K at
600 MHz with the phase-sensitive ROESY pulse. Before Fourier
transformation, the FIDs were multiplied by a 90° sine square
function in both the F2 and the F1 domain. 1K ꢀ 1K real data
points were used, with a resolution of 1 Hz/point. For EXSY,
two NOESY spectra were taken sequentially, one with 300 ms
mixing time and then with 0 ms mixing time. The rate constant
k was calculated by using the EXSYCALC program (Mestrelab
Research, Santiago de Compostela)41 and is the sum of the two
dependent magnetization-transfer rate constants obtained from
the calculations, an approximation due to the system being in
equilibrium.
FIGURE 10. The upfield region of the 2D ROESY spectrum of
n-dodecane coencapsulated with Xenon in 1.24.1 at 340 K. The
exchange cross peaks are circled. The broadened methyl peak of the
singly encapsulated dodecane intermediate is marked with
a star.
and these favorable attractions lower the potential energy
and thereby permit the “high pressures”.
Xenon is also coencapsulted with n-alkanes from nonane
through dodecane. Despite the spherical shape of xenon, it
does not slip past the alkane inside the cavity at ambient
tempertaure, as revealed by 2D spectroscopy. But at higher
temperatures (340 K) encapsulated deodecane begins to
exchange its position with xenon in the cavity and the two
ends of the capsule exchange as well. Two different mechan-
isms could be in play for this observation: either dodecane
and xenon slip past each other or xenon leaves the capsule
and the returning xenon enters the opposite end (half of the
time). The 2D ROESY spectrum (Figure 10) confirmed the
existence of an intermediate in which dodecane is encapsu-
lated alone! The peaks for the encapsuated alkane are very
broad for this intermediate because the alkane can translate
freely between two ends.
Conclusions
A range of guests;solids, liquids, and gases;can provide
the appropriate size, shape, and chemical surfaces to be
recognized by the extended capsule 1.24.1. The inner space
3
˚
of the capsule has a capacity of around 600 A , and there are
few directional interactions between the host and the guest;
instead London dispersion forces and C-H/π interactions
dominate. The inner cavity with its polarizable π surface
provides attraction to molecules bearing a thin layer of
positive charge such as the C-H bonds of n-alkanes. Flexible
guests show a variety of motions;coiling, sliding, tumbling,
and even exchanging positions inside. The capsules provide a
means to study single or multiple copies of a molecule
isolated from the bulk solution. The reversible encapsulation
complexes operate at equilibrium, under ambient conditions,
and in the liquid phase. As modern tools of physical organic
chemistry, they reveal the otherwise invisible behavior of
molecules in small spaces.
Acknowledgment. We are grateful to the Skaggs Institute
for financial support. We thank Drs. Laura Pasternack and
Dee-Hua Huang for NMR assistance.
Supporting Information Available: 1H NMR and 2D NOE-
SY/ROESY spectra discussed but not present in the text,
and also general procedures for samples preparation. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(44) Ajami, D.; Iwasawa, T.; Rebek, J., Jr. Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 8934–8936.
J. Org. Chem. Vol. 74, No. 17, 2009 6591