Steric and magnetic asymmetry distinguished by encapsulation

Article abstract of DOI:10.1021/ja049043w

Guests in an achiral cavity experience asymmetric magnetic environments induced by chiral centers outside the cavity. Copyright

Full text of DOI:10.1021/ja049043w

Published on Web 04/30/2004
Steric and Magnetic Asymmetry Distinguished by Encapsulation
Toru Amaya and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and the Department of Chemistry,
The Scripps Research Institute, MB-26, 10550 North Torrey Pines Road, La Jolla, California 92037
Received February 19, 2004; E-mail: jrebek@scripps.edu
Chiral objects in achiral containers create chiral spaces. For
meaningful (or measurable) consequences there is a requirement
of scale: A single glove in a room or a single molecule in a flask
is less likely to affect the behavior of the remaining space than a
glove in a small box or a molecule in a nanoscale chamber. We
recently provided an example of the latter by coencapsulation of
styrene oxide with isopropyl chloride1 (Figure 1). The guests are
held in the host capsule for ca. 0.5 s, and a chiral guest has ample
opportunity to provide an effective asymmetric environment for
its coencapsulated partner. Accordingly, the encapsulated halide
shows diastereotopic methyl groups in its NMR spectrum. The
present research was undertaken to determine if a chiral element
outside the capsule could influence the environment of the space
inside. That is, can the methyl groups of a guest be observed
diastereotopically only because of chirality outside of the capsule?
We are aware of the desymmetrization of a space using chiral
molecular capsules made of covalent bonds,2 hydrogen bonds,3 or
metal/ligand interactions.4 However, we are unaware of cases where
an achiral space is affected by remote chiral elements. Here we
show this effect.
The number of guests and their general positions in the capsule
were also varied: three isopropyl chlorides 4 are taken up by each
capsule; a single isopropyl chloride 4 is coencapsulated with
naphthalene 6 when both are present, and a single molecule each
of the longer biphenyl derivatives 5, 7, and 8 are encapsulated
(Figure 3). The capsules with three molecules of 4 show NMR
signals for the guests at the ends of the capsule and a separate signal
for the guest in the middle. The guests tumble freely but cannot
exchange their positions while within the capsule.7 The coencap-
sulation of 4 and 6 also features an isopropyl chloride at one end
of the capsule, but the large size of the naphthalene limits the
mobility of the smaller guest.8 The length of 5 allows some sliding
within the capsule, while this motion for the longer 7 and 8 is
limited. The methyl groups of the isopropyl esters are forced deep
into the ends of the capsule and are positioned close to whatever
The cylindrical capsule 1a5 (Figure 2) was chosen to explore
the effect. This capsule 1a forms reversibly in organic media when
suitable guests are present. The lifetime of the host capsule is ∼0.5
s, long enough to observe guests inside by conventional NMR
techniques under ambient conditions. We synthesized a series of
capsules 1b-f from the respective octols 2b-f, in which the number
of asymmetric centers and their distance from the capsule varies.
The shorter 1b has the array of asymmetric centers one CH2 group
closer to the ends of the capsule than 1c, while the longer 1d has
the array one CH2 group further away. These were prepared from
permethylated cholic acid following the procedure Kobuke6 de-
scribed for 2c. In addition, the asymmetric environment provided
by 1e resembles that of 1b but with fewer asymmetric centers.
Finally, in 1f only one asymmetric carbon is on each of the eight
pendant chains with a single CH2 spacer between capsule and the
chiral center.
Figure 1. Top: (left) a chiral object (hand) in an achiral container leaves
a chiral space; (right) the methyl groups of isopropyl chloride are
diastereotopic in the coencapsulation complex with styrene oxide. Bottom:
can a chiral center outside the capsule affect the behavior of the methyl
groups of isopropyl chloride?
Figure 2. Synthesis of the capsule 1a-f. A ball-and-stick representation
of the dimeric capsule and its cartoon representation are also shown.
9
6216
J. AM. CHEM. SOC. 2004, 126, 6216-6217
10.1021/ja049043w CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Figure 4. Upfield region of the 1H NMR spectra (600 MHz, 300 K) of
encapsulation complexes of 1a-f (1 mM) in mesitylene-d12 (0.6 mL) and
the guest 7 (1.5 µL).
Figure 3. Guests and inclusion complexes.
In summary, we detected the effect of chiral elements outside
the capsule through the desymmetrization study where there is no
direct contact between the guest and asymmetric centers.9 For the
present, the search for the origins of biological homochirality could
be expanded to include influences such as those shown here that
are more remote than previously thought possible.
Table 1. ∆δ between Diastereotopic Methyl Groups of
Encapsulated Speciesa
complex
9
10
11
12
13
PCb
53%
45%
47%
50%
50%
∆δ between diastreotopic methyl groups [Hz]
host
1b
1c
1d
1e
1f
0
0
0
<2
0
5.9
0
0
7.3
0
16.1
0
0
19.1
6.6
13.2
4.4
0
14.7
5.9
13.8c
0c
Acknowledgment. We are grateful to the Skaggs Foundation
and the National Institutes of Health (GM 50174) for financial
support. We thank Professors K. Wu¨thrich and J. Williamson for
advice. T.A. is a Skaggs Postdoctoral Fellow.
16.1c
8.0c
a
Capsule: 1 mM, guest: excess, mesitylene-d12: 0.6 mL, 300 K, 600
Supporting Information Available: Synthetic details and spec-
troscopic data for all of new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
b
MHz. PC was calculated on the basis of the volumes which were
minimized with the program Hyperchem 7.0, Hypercube Inc., 2002, at
semiempirical PM3 level and calculated with WebLab Viewer Pro 4.0 by
c
Molecular Simulation, Inc. 13C NMR (Apt) experiment (150 MHz).
References
(1) Scarso, A.; Shivanyuk, A.; Hayashida, O.; Rebek, J., Jr. J. Am. Chem.
Soc. 2003, 125, 6239-6243.
anisotropy is on offer from the asymmetric centers just outside.
The deuterated derivative 7 simplifies (and amplifies) the signals
(2) (a) Canceill, J.; Lacombe, L.; Collet, A. J. Am. Chem. Soc. 1985, 107,
6993-6996. (b) Yoon, J.; Cram, D. J. J. Am. Chem. Soc. 1997, 119,
11796-11806. (c) Judice, J. K.; Cram, D. J. J. Am. Chem. Soc. 1991,
113, 2790-2791.
1
of the methyl groups in its H NMR spectra, whereas the labeled
8 offered the advantages of 13C NMR spectroscopy. The results of
the spectroscopy are summarized in the Table 1.
(3) (a) Castellano, R. K.; Kim, B. H.; Rebek, J., Jr. J. Am. Chem. Soc. 1997,
119, 12671-12672. (b) Tokunaga, Y.; Rebek, J., Jr. J. Am Chem. Soc.
1998, 120, 66-69. (c) Nuckolls, C.; Hof, F.; Martin, T.; Rebek, J., Jr. J.
Am. Chem. Soc. 1999, 121, 10281-10285. (d) Castellano, R. K.; Nuckolls,
C.; Rebek, J., Jr. J. Am. Chem. Soc. 1999, 121, 11156-11163. (e) Rivera,
J. M.; Martin, T.; Rebek, J., Jr. J. Am. Chem. Soc. 2001, 123, 5213-
5220.
(4) (a) Hiraoka, S.; Fujita, M. J. Am. Chem. Soc. 1999, 121, 10239-10240.
(b) Ikeda, A.; Udzu, H.; Zhong, Z.; Shinkai, S.; Sakamoto, S.; Yamaguchi,
K. J. Am. Chem. Soc. 2001, 123, 3872-3877. (c) Ayabe, M.; Yamashita,
K.; Sada, K.; Shinkai, S.; Ikeda, A.; Sakamoto, S.; Yamaguchi, K. J. Org.
Chem. 2003, 68, 1059-1066.
(5) Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Nature 1998, 394, 764-766.
(6) Yoshino, N.; Satake, A.; Kobuke, Y. Angew. Chem., Int. Ed. 2001, 40,
457-459.
None of the guests in capsule 1d showed any evidence of the
anisotropy of its exterior asymmetric centers. Nor did any capsules
containing only 4. Yet the influence of the chiral centers outside
capsules 1b, c, e, and f was clearly present inside and experienced
by other guests. Specifically, Figure 4 shows the 1H NMR signals
for the methyl groups of 7 in all of the capsules. A singlet appears
only in the achiral 1a and the capsule with the most distance
between asymmetric centers and the cavity 1d. The other cases
show diastereotopic methyl groups. The distance between external
asymmetric centers and the cavity is a factor as is the mobility of
the guests within since neither the longest spacer of capsule 1d
nor the freely tumbling guest 4 showed any evidence of desym-
metrization. Unexpectedly, the sheer number of asymmetric centers
is insufficient (there are 88 in 1b-d but only 8 in 1f).
(7) Shivanyuk, A.; Rebek, J., Jr. Angew. Chem., Int. Ed. 2003, 42, 684-686.
(8) Shivanyuk, A.; Rebek, J., Jr. Chem. Commun. 2002, 2326-2327.
(9) It is conceivable that the asymmetric centers somehow affect the shape
of the capsule. The many negative results (zeroes in the table) argue against
this possibility.
JA049043W
9
J. AM. CHEM. SOC. VOL. 126, NO. 20, 2004 6217